Circulation December 10, 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 Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And this is Dr Greg Hundley from VCU health, the Poly Heart Center in Richmond, Virginia. Well, Carolyn, this week's feature analyzed a pool cohort of all patients in partner one and partner two, both the trials and registries. Patients had severe aortic stenosis and were treated with TAVR or SAVR and then were analyzed with respect to the development of prosthetic valve endocarditis. But more to come on that later.

Dr Carolyn Lam: Let me start by telling you about my picks from this week's journal. So the first one is a really interesting natural experiment. First, do you think that a short term visit to a location with severe air pollution increases the risk of cardiovascular disease?

Dr Greg Hundley: Well, Carolyn, I would say yes.

Dr Carolyn Lam: Greg, you're too smart. But let me tell you what these investigators did. So their co-corresponding authors, Dr Araujo from David Geffen School of Medicine and UCLA, Dr Zhu from UCLA Fielding School of Public Health, and Dr Qiu from College of Environmental Sciences and Engineering in Peking University. These co-corresponding authors and their colleagues did a natural experiment by collecting urine and blood samples from 26 healthy adult residents of Los Angeles before, during, and after they spent 10 weeks in Beijing during the summer of 2014 and 2015.

Dr Greg Hundley: I am really excited to hear this. Carolyn, what did they find?

Dr Carolyn Lam: So traveling from less polluted Los Angeles to more polluted Beijing induced pro oxidative and pro inflammatory effects, which reversed after returning to Los Angeles. This is also the first human study associating exposures to polycyclic aromatic hydrocarbons with changes in paraoxonase 1, enzymatic activity, and circulating levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids. Cool, huh?

Dr Greg Hundley: Absolutely. Carolyn, you did an awesome job. Very nice. Well, my article comes from the world of basic science and it's from Dr Philip Shaul at the University of Texas Southwestern medical Center. So Carolyn, in recent studies of obesity induced insulin resistance in mice with corroborating findings in human type 2 diabetics, this group, Shaul’s group, previously made the surprising discovery that the insulin resistance is driven by an altered post-translational modification in IgG that leads to enhanced activation of FCYR2B in endothelial cells. And as a result, there is an attenuation of insulin transcytosis across endothelial cells and delivery to skeletal muscle myocytes where up to 80% of glucose disposal usually occurs.

Dr Carolyn Lam: Oh. Interesting, Greg. So what did the authors find in the study and how did these findings equate with obesity and hypertension?

Dr Greg Hundley: Well, they found that hyposialyation of the Fc glycan on IgG is identified as a key contributing factor in obesity induced hypertension. And therefore low levels of IgG Fc glycan sialylation may identify individuals at greater risk of developing hypertension. In addition, the degree of sialylation of IgG may predict the relative response of an individual to any hypertensive therapy.

Dr Carolyn Lam: Nice. So my next paper is from Dr Al-Lamee from Imperial College, London, and colleagues who studied the ability of a pre-randomization stress echocardiographic score to predict the placebo-controlled efficacy of PCI within the ORBITA trial. Now as a reminder, the primary results of the ORBITA trial showed us smaller than expected effect size of PCI in comparison with placebo in single vessel stable coronary artery disease on the primary end point of change in treadmill exercise time.

Now in the current study, 183 patients underwent dobutamine stress echo cardiography before randomization, and they found that the degree of ischemia assessed by dobutamine stress echo cardiography predicted the placebo-controlled efficacy of PCI on patient reported angina frequency.

Dr Greg Hundley: Hmm. Very interesting. So help me out again, Carolyn. What's the clinical importance of this?

Dr Carolyn Lam: Ah, so this study really provides the first placebo-controlled evidence of an association between stress echo cardiography, ischemia, and the magnitude of placebo-controlled benefit attributable to PCI. And the greater the downstream stress echo cardiography abnormality caused by the stenosis, the greater the reduction in symptoms from PCI. That's the take home.

Dr Greg Hundley: Oh wow. Very interesting. You know, especially we perform so many stress echo cardiograms. What a great relationship to unfold and present. Well, Carolyn, I'm going to walk through several other important publications in this issue of the journal. The first is from Dr Peter Eckman from the Minneapolis Heart Institute, and he provides an In-Depth review of veno-arterial extra corporal membrane oxygenation, or VA-ECMO, for cardiogenic shock and it's beautifully written for the busy clinician. Robert Platt, PhD, and colleagues discuss in an On My Mind piece the fact that those with adverse cardiovascular sequelae during pregnancy may require development of new cardiovascular risk prediction models. The hypertension or the diabetes that occurs during pregnancy, perhaps we need to incorporate that into our prediction models.

Next. Our own associate editor Torbjørn Omland provides results in a research letter from the peace trial relating the relationship between smoking and high sensitivity troponin T levels. Dr Allen Sniderman from McGill University Health Center writes a letter to Welsh and Associates regarding their study of the UK bio bank database and measures of HDLC. A paper we discussed just a few weeks ago. Dr Derek Chew from the DCRI and Durham North Carolina has another EKG challenge for us. And Dr Tracy Hampton provides an updated news report regarding cardiovascular disease from several recently published articles in the world of basic science. And then finally Dr Thomas Krieg from the University of Cambridge has a nice piece regarding clinical implications of targeting succinate metabolism in ischemia reperfusion injury.

Well, Carolyn, what a great slate, but I can't wait to get to that feature discussion related to prosthetic valve endocarditis.

Dr Carolyn Lam: Me too. Let's go.

Our feature discussion today is really the first paper that describes adjudicated evaluation of prosthetic valve endocarditis in patients with transcatheter and surgical aortic valve replacement. Very unique and valuable data from the partner's trial. I'm so pleased to have with us the corresponding author, Dr Wael Jaber from Cleveland Clinic as well as our associate editor, Dr Manos Brilakis from UT Southwestern. So Wael, very unique question. Could you please tell us how you went about doing this? And I suppose in this setting, the first question on everyone's mind is how did you make this diagnosis of prosthetic valve endocarditis?

Dr Wael Jaber: Actually we saw this as an opportunity that probably we should never miss. I think this is one of the rarer instances where we can objectively not only look at SAVR data but also TAVR data. And over the past maybe seven years, eight years, we started getting here as a referral center patients with TAVR endocarditis for surgery. And we never thought we'd start seeing these weird organisms, different bugs. Of course this is a population that's frail or elderly, but we never had any idea if they behave similarly to SAVR or differently than SAVR in our previous experience with SAVR endocarditis.

So we planned this actually about maybe five years ago, but we didn't have the data because you know the partner trials were undergoing another evolution by going to lower and lower risk population. So we pose this question about a year and a half ago to CRS by asking them, can you provide us with the data on all the endocarditis in partner.

The idea was not only to answer one question but to answer multiple questions. So the first question was in the modern era, what happens in SAVR? All the SAVR endocarditis information we have so far as you will know has been from mainly single center studies or even when we learn about it from multiple centers sites, usually IN European studies, the Swedish registry, the Danish registry, and these are usually limited by the fact that there are a multicenter. The adjudication is at the site what endocarditis happened. So that was the first question. Then the second issue for us was, does TAVR, because of the unusual access to the heart and the fact that we dilate the valve, post dilate the valve, their paravalvular AI, they could be micro-fractures of the refis. This is provide a different opportunity for these bugs to form on the valve, and do they behave differently?

And the third question was, is there any difference between SAVR and TAVR incidence of endocarditis? And bugs. And the final question was what happens to patients when they develop endocarditis in the current decade. Do they do well? Especially for septic endocarditis or do they succumb to their illness? And also this is how we came up with a strategy to answer all these questions.

Dr Carolyn Lam: Very nice. So Wael, could you just expand a little bit more about how the diagnosis or adjudication of prosthetic valve endocarditis was done? And then tell us please, what did you find?

Dr Wael Jaber: All the partner patients, the records were sent to a central place. So the ECHOS first were educated at central places. We were one of those centers. Other places were Columbia University, MedStar and Quebec, the group in Quebec. So all the ECHOS were adjudicated centrally. So that's first, as far as from the echo side of calling it endocarditis or not.

On the clinical side, again, all the records and the forms were sent to a central adjudication committee, CDC group. We served at the Cleveland Clinic as the CDC for most of these trials and actually even for the current trials. So they were sent and they were adjudicated according to the Duke criteria. Which is, you know, the most, probably, reliable way still today to adjudicate these.

And then there was the CDC and the echo core labs were separate. So the people who have information from the CDC did not have access to what's going on in the core lab and vice versa. So these were independently adjudicated as far as echocardiographic evidence and clinical evidence. And then they were fed into it. So by the end, when you hold it on a Duke criteria endocarditis, the echo was fed after the fact, not before. So this is in general how it happened. So all the events were educated centrally, not at the site. And the ECHOS, the same thing, were adjudicated centrally.

Dr Carolyn Lam: Fantastic. And I would love to hear the results.

Dr Wael Jaber: The first question was, what's the incidence of endocarditis? And we decided because of the way these trials were done, to report the incidents as you would see in the results section, to report the incidents of endocarditis per 1000 person year because of the imbalances in follow up and the competing risk for death from other reasons. So we found in general that the incidents of endocarditis was 5.2 endocarditis events per 1000 patients per year in the TAVR side and 4.1 in the SAVR side with a non statistically significant difference. More importantly, we found out that once you develop endocarditis, unfortunately most of these patients succumb to the illness and are dead after the diagnosis. So the risk of dying after developing endocarditis is 4.4 times higher than patients who did not have endocarditis in the trials. In all the trials.

Now there's some caveats here. First, these are trials with different patient populations, as you well know. Starting with partner with the inoperable patients moving on to the most modern S3 trial, which was on the lowest kind of side of population. So we have totally different population groups. Some of them had prolonged hospitalizations before and after, so this should be taken with a little bit of caution.

However, if you look at some of the individual trial data, we found that incidents of endocarditis at least have a trend towards a reduction of incidence of endocarditis over time going from partner, the initial experience with partner, all the way to the modern era.

Dr Carolyn Lam: That is so great. Manos, you know, as an interventional cardiologist yourself, could you tell us how important these results are? Does it affect your practice?

Dr Emmanouil Brilakis: Thanks again, Carolyn. I would like to congratulate Wael for a phenomenal paper. I think it's a very timely study and addresses one of the common concerns there is about whether TAVR does predispose people to more risk for endocarditis. Although again, the opposite grade was kind of low at 0.5% a year. I think this may be a little more than people are commonly seeing in the setting of TAVR, and I think the paper is a good reminder that this is something we should always be mindful and watching. Although typically we'll discuss with the patient about the risk of stroke or access complications, but the risk of infection may not be as well emphasized. And based on this one question I would have is about what can we do if there is something that could potentially lower that risk? I understand the limitations of retrospective study, but are there any recommendations that you have based on the study? Should give more aggressive antimicrobial therapy? Any other biotic prophylaxis or anything else that can be done to reduce the risk of endocarditis in those patients?

Dr Wael Jaber: Actually this is the question we raised. Unfortunately we did not. So the guidelines did not catch up with what we know. So if you look right now, like I was reviewing this paper that came up last month from the Swedish Registry for Endocarditis, it came out in Europe in the European Heart Journal, and one of the questions they raised is how to address, in the editorial, how to address the risk of endocarditis and prophylaxis in this population. There are no standards for that. This is one aspect of it. We need first an update of the guidelines of how to address this issue.

The second question is we do not have any idea, unfortunately, about duration of antibiotics. How the antibiotics prophylaxis were given before the procedure, like as we do right now commonly in surgery, and after the procedure in these patients. We do not know that. Like right now, at least at our center, if you go in for aortic or mitral valve surgery or any valve surgery, you have to have a dental clearance before you start, before you go to surgery. I don't know if this was rigorously applied in the setting of TAVR, and I think it would be a good idea to apply it to make sure that there are no dental, phosphide or potential infections and things like that. So I think it's a multi-front battle to get these patients to the lowest risk possible. I don't think there's one single silver bullet here.

Dr Emmanouil Brilakis: So thanks again, Wael for addressing this. I agree that there's a lot of information to be gained understanding the intricacies of endocarditis prophylaxis. And building on this, let's say another patient develops endocarditis as you've shown in your 170 patients in the study. It was fascinating that staph aureus was actually less common than it was for surgical valves, which has been shown in other studies as well. So you think this affects the choice of the biotic prophylaxis? And then also if the patient develops endocarditis, I understand many people who are not candidates for surgery, but from the ones who did actually undergo surgery, what are the outcomes encouraging?

Dr Wael Jaber: This is a fascinating question actually. This is one of the reasons we had... There was a delay for us in getting the paper out from when we presented it as an abstract at TCT a year and a half ago, is we didn't know. We wanted to answer that question. The second part of the question is how many patients went to surgery? And unfortunately, very few patients. So less than a handful of patients end up going to surgery. And we do not know why. So this is the dilemma here. Is why the rate of referral to surgery for redo surgery was very low.

Was it because these patients were the sickest of the sick? Maybe it is because we waited too long and we did not treat them the same way. We should have treated prosthetic valve endocarditis, which is surgery to be offered as soon as possible because there's no really antibiotic cure for that. So we do not have the answer for that because these very few patients went to surgery and actually I think of those who went to surgery, even the mortality there even was similar to people who did not go to surgery. But we cannot speculate on that because the very few patients.

As far as the bug involved, I think this could be a reflection of the antibiotics given at the time of the procedure, so probably we're covering that very well. But if you notice from the paper, most of the infections happen more than 30 days after the procedure. Whether this is something that was acquired because these patients are more likely to end up in the hospital again for other reasons, whether these patients had endocarditis because they have more instrumentation down the road... Remember this is a population in general above the age of 65 which would require colonoscopies, frequent urinary tract issues, and other procedures.

So we know that we're covering very well, at least I can speculate, we're covering very well for the first 30 days because very few patients had endocarditis right after the procedure, but we're not covering probably after the 30 days. And that remains to be studied. And the worrisome thing is to try to treat these patients with prophylactic antibiotics for a long time and then end up with bug resistance and things like that. Now the CDC issued a big warning about this yesterday. I am not comfortable to speculate from this small number of patients on how to treat for prophylaxis, but I'm comfortable to say probably patients should be sent to surgery as soon as possible after developing endocarditis, especially prosthetic valve endocarditis because the outcomes are dismal.

Dr Emmanouil Brilakis: And do you think... Let's say patient is not a candidate for surgery and gets endocarditis, and I presume they get into prolonged therapy. There were some patients like this that did okay, right? So there is some hope even for those patients.

Dr Wael Jaber: I feel like I'm the cup half full here because if you look at the mortality curves here, we're talking about north of 95% death in this population. So the people who survive this must be very few people survive. So probably about seven patients who survive. So the mortality was 96% at six months versus 46%. So there are very few people who survived that event. Maybe I should go back now and figure out what was the quality of life after survival. So I don't think the picture we have right now is very rosy as far as the way we're managing endocarditis.

Dr Carolyn Lam: Manos, I'm going to give you the final parting words from this very interesting discussion. I mean what do you think are the take home messages and future directions from here?

Dr Emmanouil Brilakis: I agree that this is a phenomenal landmark study and my key takeaways are the same ones that Dr Jaber presented before. But the main thing is, on the consent process, who can tell the patients there is about 0.5% per year. So it's not zero, but it's very high either. The second thing is that this choice between TAVR versus SAVR, that should not have to do with the risk of infection because as it was shown very convincingly, it was very similar to the two groups. And number three that everything possible should be done to prevent this because if you do get infection, the outcomes are not very good.

Dr Carolyn Lam: Thank you so much Manos, Wael. Thank you so much audience for joining us today. You've been listening to Circulation on the Run. Tune in again next week.

This program is copyright American Heart Association 2019.