Circulation March 5, 2019 Issue

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

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

Dr Carolyn Lam:                Have you heard of long non-coding RNAs? Well, they are definitely the hot topic and our feature paper today discusses the first demonstration of the importance of a linked RNA in atherosclerotic lesions not just in mice but also in humans. You have to listen on, it's coming up right after our copy chat.

                                                Greg, what are your picks upon the journal this week?

Dr Greg Hundley:             The first paper I wanted to discuss comes from France, and it's basically looking at ambulance density and outcomes after out of hospital cardiac arrest from Florence Dumas from Hôpital Cochin in Paris, France. This manuscript addresses the geographic disparities and survivorship of out of hospital cardiac arrest and the relevance of the patients characteristics versus whether ambulances are equipped with those trained in basic or advanced cardiac life support. So, what they did they had nineteen neighborhoods in Paris, and the number of BLS trained versus ALS ambulances was collected, and the authors assessed that respective associations of socio-economic characteristics of the patient population and the ambulance resources of these neighborhoods and compared those with successful return of spontaneous circulation or risk as the primary end point and then survival of out of hospital discharge as the second end-point.

                                                So, they had 80754 non-traumatic out of hospital cardiac arrests across the Paris area. 42% at ROSK 9% head survival at discharge, and after accounting for the patient's socio-economic status, greater than one and a half advanced cardiac life support ambulances per neighborhood and greater than 4 basic cardiac support basic life support units per neighborhood were associated with ROSK, but only the 1.5 ALS units per neighborhood were associated with survival.

Dr Carolyn Lam:                Oh, interesting Greg. So does this we need more advanced life support units?

Dr Greg Hundley:             So, Paul Dorian from St. Micheal's Hospital in Toronto, Canada wrote an excellent editorial, and one point he made related to these ALS units is that it was really a very small 1.3 adjusted odd ratio for survival to hospital discharge, and it's important to note that although the increase in survival was associated with more ALS units, there were many other variables that were likely important and not recorded in this study. For example, including the time to collapse, to calling for EMS, the time from the call to the deployment of that ALS unit to the scene, the time from collapse to the defibrillation, the total "no flow time" sort of in quotation, which is the total duration of collapse until CPR is started and so I think one of the points in this observational study is there could've been many differences that would've associated with the findings, interesting findings how about one of the papers that you liked?

Dr Carolyn Lam:                So, the paper that I selected here is a first time that a targeted anti-inflammatory therapy has been shown to reduce hospitalization for heart failure and at-risk patients. So, you know that some clinical inflammation associates with an increased risk of heart failure and associates with the worst prognosis in patients with heart failure, and yet, so far, treatments specifically directed at reducing inflammation in patients with heart failure have not been shown to improve clinical outcomes. That's why today's paper is so special and it's from Dr Everett and colleagues from Brigham and Women's Hospital Harvard Medical School in Boston, and basically, the authors looked at CANTOS and tested the hypothesis that the interleukin -1β inhibitor can canakinumab would prevent heart failure hospitalizations and the composite of heart failure hospitalizations on heart failure related mortality in the CANTOS trial.

                                                Now, remember the CANTOS trial randomized more than 10 000 patients with a prior myocardial infarction and with high sensitivity C-reactive proteins at least two or greater, and they were randomized to canakinumab 50, 150, and 300 mg or placebos. Now, before randomization, these participated were asked if they had a history of heart failure and 22% said yes so the current paper actually looks at this stratification of patients who said they had heart failure, and during a meeting follow-up of 3.7 years, 385 patients had a new heart failure hospitalization event. Now, here's the key: the authors found a dose dependent reduction in the risk of hospitalization for heart failure as well as the composite of hospitalization for heart failure or heart failure related mortality among those allocated to Canakinumab.

Dr Greg Hundley:             So, how does this differ from prior attempts targeting inflammation and heart failure? I mean is this ready for prime time thing?

Dr Carolyn Lam:                So, we have to bear a few things in mind here you know. CANTOS was different from a previously published randomized controlled trials, which were basically neutral and that was like of infliximab and etanercept so the drug in CANTOS targets interleukin-1 beta whereas the prior ones targeted the TNF-alpha, and also very importantly, CANTOS did not specifically enroll patients with an established heart failure only. CANTOS patients had to have a history of myocardial infarction and there was no data on their ejection fraction or natriuretic peptides at the time of randomization nor at the time of heart failure hospitalization. So, by the way, we don't know whether there's a differentially effect on hep pef versus hep-ref. So, again difference from the heart failure focused trial previously that used an anti-inflammatory agents.

                                                The other thing: although there was a dose dependent reduction in the risk of hospitalization for heart failure no single dose of Canakinumab compared to the placebo had a statistically significant reduction in the risk of heart failure hospitalization. Only the trend was statistically significant so all in all, this was a pre-specified aim of CANTOS to look at heart failure, the data presented here should really be considered hypothesis generally, but really quite promising. And what about you Greg? What's your other paper?

Dr Greg Hundley:             We're going to switch gears a little bit and shift over to the Jackson heart study. The large longitudinal cohort from Jackson, Mississippi that's recruited to follow for cardiovascular events, and it's an area of the United States where we have some of the highest cardiovascular disease event rates really across the nation so this study focuses on sleep apnea and is the Jackson's heart sleep study. It's a sub-study of this larger Jackson's heart study that involves 913 patients, and the investigators were looking at the association between sleep apnea and blood pressure control among those of a Black race. So, Dayna Johnson of Emerald University is the first author on the paper. What's nice about this sub-study, this sleep sub-study is that there are objective measures using an in-home type III sleep apnea study. They had clinical blood pressure measurements and then anthropometry as opposed to questionnaire derived data that may have been performed in the larger cohort.

                                                And the study determined these associations between moderate or severe obstructed sleep apnea with controlled, uncontrolled and resistant hypertension. So the analytic sample of the individuals with hypertension was 664, and they had an average age of about 64 years. They were predominately women 69%, obese 58%, College-educated at 51%. Among the sample, about a quarter had obstructive sleep apnea, which was untreated and unrecognized in 94% of the participants. That's an interesting point, just right there.

                                                Overall, 48% of the participants had uncontrolled hypertension and 14% had resistant hypertension. So, multiple medications, often four and still unable to control the blood pressure. So the findings participants with moderate or severe obstructive sleep apnea had 2 times higher odds' ratio of resistant hypertension.

Dr Carolyn Lam:                Whoa Greg, that's a huge risk and very important finding. I mean if sleep apnea could be modifiable risk factor perhaps for very important issue among African Americans resistant hypertension. What do you think about clinical implication?

Dr Greg Hundley:             One of the things to be considering now is what are we going to do about that cause as you know CPAP is really the preferred treatment for resistant hypertension, but it's efficacy hasn't been really that well studied in African Americans and CPAP tolerance is low so this study highlights for us potentially new mechanisms for resistant hypertension, but we still got to be thinking about what would be our next therapeutic intervention for this particular patient population. And what about your next study?

Dr Carolyn Lam:                The next study is about Impella support for acute myocardial infarction complicated by cardiogenic shock. Now, we use it all the time, but did you know that to date, there is no large randomized study actually comparing the use of Impella to other contemporary cardiac support devices and medical treatment in stem related cardiogenic shock. So, Dirk Westermann and colleagues from University Heart Center in Hamburg tried to address this knowledge gap by using a multi-national database of patients with acute myocardial infarction complicated by cardiogenic shock and treated with the Impella device and compared in a matched fashion their outcomes to patients from the IABP Shock II trial, which you would recall is a randomized trial which demonstrated similar outcomes between IABP and medical treatment in myocardial infarction in cardiogenic shock.

                                                So, they looked at 237 matched-pairs so remember this was pairs from this registry of acute myocardial infarction with shock and using an Impella matched with IABP shock patients and what they found was that there was no significant difference in 30-day all-cause mortality. Instead, severe or life-threatening bleeding and peripheral vascular complications occurred significantly more often in the Impella group when they limited the analysis to the IABP treated group as controlled versus Impella that was still the same results.

Dr Greg Hundley:             So, Carolyn, there are trying to match patient population from two different studies and they may have confounders in there that we can't account for so why we not able to produce large randomized trials of Impella devices in studies of patients with acute myocardial infarction?

Dr Carolyn Lam:                The rate of acute myocardial infarction complicated by cardiogenic shock has really declined in the past decade. Furthermore, clinical signs of shock really appear in half to three quarter of cases several hours after hospital admission so making randomization before primary PCI of the AMI really very difficult. And finally, many interventional cardiologists believe that there's equipoise that has already been reached on the use of these cardiac assistive devices in patients with cardiogenic shock and this was from registry data, and so if interventionists believe this then they also believe its unethical to randomize these patients in trials. Still, I think that current study to date really causes us to pause and to acknowledge that we really need to evaluate this better and prospective randomize trials of Impella treatment are warranted.

                                                Let's now go to our featured discussion, shall we?

                                                For our featured paper discussion today, we are talking about a basic science paper, and we have none other than the best of the best Dr Charles Lowenstein, our associate editor from University of Rochester Medical Center joining us as well as the first author of a really fantastic paper on long non-coding RNA in a specific type involved in arthrosclerosis and plaque formation. This first author is Sebastian Creamer from Goethe University in Frankfurt.

                                                Charlie, could you start us off by telling us what is a long non-coding RNA? We've heard a lot about this in recent times. What's the big deal about them?

Dr Charlie Lowenstein:  So in the last decade, scientists have learned that your genome, your DNA inside you, every cell codes about 20,000 genes and those 20000 genes encode proteins, but there are another 20000 genes that encode RNA only, RNA that never turns into protein that leaves RNA are an amazing diversity of different kinds of RNA really short micro RNA, longer RNA that defends the host from viruses and long non-coding RNA that have a huge variety of effects regulating genes, turning genes on and off in proliferation and cell growth and inflammation so long non-coding RNAs are increasingly appreciated as an important part of the genome.

Dr Carolyn Lam:                What a perfect set up with that. Sebastian, could you tell us about your study please?

Dr Sebastian Creamer:   Our laboratory was interested in non-coding RNAs for some time and previously, we've found that this specific non-coding RNA MALAT1 regulates endothelial cell functions and because we were interested in analyzing this particular RNA in the disease setting it shows at a risk growth so it's because also we saw that when it's regulated by flow and end of previous cells and so we cross MALAT1 deficient mice to Apoe mice and set them on a high fat diet and analyzed and subtracted in both groups. And while we only saw a modest increase in plaque size in MALAT1 deficient mice, we could appreciate a higher amount of inflammatory cells in plaque of aortic roots in those mice, which let us hypothesize that inflammatory responses was appreciated and is a very important contributor to arthrosclerosis in MALAT1 deficient mice. And to test this, we decided to transplant MALAT1 deficient bone marrow in Apoe knockout mice with MALAT1 and interestingly, we saw that now plaques were significantly larger than compared to mice who received controlled MALAT1 white cell bone marrow, and also inflammatory cells were more prominent in those mice.

Dr Greg Hundley:             Sebastian, this is Greg Hundley. You also did some experiments in human subjects. Could you tell us a little bit about those too?

Dr Sebastian Creamer:   So, because we saw this interesting phenotype, we were very much interested if this also translates into the human setting. Luckily, we got a really nice collaboration receding in Stockholm access to high impact material from patients with arthrosclerosis and what we could see here that MALAT1 expression was down regulated in patients with arthrosclerosis and it also correlated with disease progression. Moreover, in another collaboration, we consolidated those findings with experiments, which showed that human cells have less MALAT1 compared to normal vasculature.

Dr Carolyn Lam:                It all sounds so sensible and logical and so on but let me just frame this for our audience. This is actually the first time that it's been demonstrated. The importance of long non-coding RNA in arthrosclerosis. Charlie, could you tell us a little bit about how significant these findings are?

Dr Charlie Lowenstein:  Sure. So, I'm really interested in the final figure in this paper because there are lots of interesting human data, showing that MALAT1 expressed more in normal than atherosclerotic arteries and also that MALAT1 expression is correlated with fewer major adverse cardiac events so the whole story is a very nice story saying that the expression of this anti-inflammatory link RNA not only has an effect in mice but it can be extended into the human field of arthrosclerosis and inflammation. It's particularly important because there's a lot of attention in the last decade that inflammation drives atherosclerosis, and in light of CANTO trial showing that anti-inflammatory therapy can actually decrease atherosclerosis and decrease cardiovascular events in humans. This is important cause it shows another pathway, which regulates inflammation. Not only in mice, but also in humans, and in the human atherosclerotic setting.

Dr Carolyn Lam:                Amazing. Sebastian, what are the next steps? How far are we away from clinical applications here? What are the next steps to get it in the clinic?

Dr Sebastian Creamer:   So, the very difficult thing is that MALAT1 is down-regulated in atherosclerosis and also therapeutic approaches is very difficult in such a complicated disease like atherosclerosis to actually increase the expression of such a long non-coding RNA. What we are currently working on is to decipher more than the clinical malade-1 is actually influencing atherosclerosis so we have lots of hints or some evidence that adhesion of inflammatory substances altered and the bone marrow activity, which is very important in atherosclerosis and also in other cardiovascular diseases like myocardial infarction is altered so we think that malade-1 might actually influence the resolution of inflammation and when it's lacking, inflammation can be resolved. So, we are now putting somewhat mechanistic studies and finally, we hope that we can find another downstream target like micron AB, we talked about in our paper, which we can directly target in the future.

Dr Charlie Lowenstein:  So, I agree with Sebastian. I think MALAT1 is going to turn out as one of those major link RNAs that controls inflammation possibly controlling the way in which the bone marrow reacts to systemic inflammation and produces cells and then have those cells home in on various inflammatory targets so I think this is an important observation that's going to have not only implications for atherosclerosis but also for other inflammatory diseases.

Dr Carolyn Lam:                Excellent. If you don't mind, I would love to switch tracks a little bit. We find it that very special and we can discuss basic papers with people who can explain it so well because we understand that there's so much work that goes in to these papers and so on. Charlie, could you take behind the scenes a little bit with the editors and tell us what is it that circulation looks for in basic science papers that makes us published?

Dr Charlie Lowenstein:  We get a lot of really good basic science papers, and it's a challenge for the associate editors, and the editors to figure out what's right for circulation and let me use this manuscript as a great example because this is a terrific paper. So, this paper is divided into four sections, and these sections are what we look for in any basic science paper that's going to reach an audience of clinicians who are interested in pathways and therapeutics so this paper has a section on mice. There's a gene in mice that's important then the paper delves into cells what's happening with cells and then a little bit of mechanisms and genes and proteins and then this paper takes the observation back into humans and shows that there's some human and clinical relevance so this is not only a great paper, but it is a classic example of what the associate editors are looking for in a basic science paper that's targeted towards clinicians.

Dr Charlie Lowenstein:  There's some in vivo work with mice, there's some mechanistic work then they take it back to the humans. Plus, of course like anything that comes into circulation, it's going to be novel, interesting and has some important relevance to human cardiovascular disease. This paper that we're discussing is a great example of a paper that we love to publish in a circulation and it's a real tribute to Dr Dimmeler and her team and to Sebastian that they put this paper together and submitted it to us.

Dr Carolyn Lam:                Thank you audience for joining Greg and I today. You've been listening to circulation on the run. Don't forget to tune in again next week.