Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: September, 2019
Sep 30, 2019

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 I'm Greg Hundley, associate editor at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off?

Dr Carolyn Lam:                I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes?

                                                Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL.

Dr Greg Hundley:             So Carolyn, what did they find in this interesting study?

Dr Carolyn Lam:                Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes.

Dr Greg Hundley:             Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines.

                                                Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines.

Dr Carolyn Lam:                Wow. So what did they find, Greg?

Dr Greg Hundley:             Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention.

                                                So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR.

Dr Carolyn Lam:                Wow, Greg. So what are the take home messages? That was a lot of numbers.

Dr Greg Hundley:             Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly.

Dr Carolyn Lam:                Great, Greg. So what are the clinical implications?

Dr Greg Hundley:             Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis.

Dr Carolyn Lam:                Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter.

                                                And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease.

Dr Greg Hundley:             So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work?

Dr Carolyn Lam:                Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five.

Dr Greg Hundley:             Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue?

Dr Carolyn Lam:                I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it.

                                                And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject.

Dr Greg Hundley:             Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal.

Dr Carolyn Lam:                Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it?

Dr Greg Hundley:             Absolutely. So how about onto our feature discussion?

Dr Carolyn Lam:                You bet, Greg.

Dr Greg Hundley:             Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population?

Dr William Gray:               The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well.

                                                The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design.

Dr Greg Hundley:             So Bill, tell us now about the results.

Dr William Gray:               It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone.

                                                Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out.

                                                When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects.

Dr Greg Hundley:             Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease?

Dr Joshua Beckman:        I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December.

                                                On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices.

                                                And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal.

                                                It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray.

                                                This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices.

Dr William Gray:               Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups.

                                                So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true.

                                                I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there.

                                                And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly.

Dr Joshua Beckman:        So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field.

Dr Greg Hundley:             We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Sep 23, 2019

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

Dr Carolyn Lam:                Greg, what do you think is the association between preeclampsia and hypertensive diseases of pregnancy and cardiovascular disease and future? Well, we're going to find out in a large U.K. pregnancy cohort of linked electronic health records, the CALIBER Study, but that's a feature discussion that's coming right up.

                                                I think we need to start by discussing this week's hot issue. For the first paper, we know that the incidents of acute cardiovascular complications are highly dependent on the time of day. Greg, have you ever wondered what mechanisms drive the rhythmicity of ischemic vascular events?

Dr Gregory Hundley:       You know what, Carolyn, I had a dream about that and I think that somehow maybe it might be something to do with leukocytes.

Dr Carolyn Lam:                Good guess, Greg. Well, Dr Christoph Scheiermann and his colleagues from University of Geneva looked at this and they examined the role of rhythmic leukocyte adhesions and what those play in different vascular beds. They did this by evaluating leukocyte recruitment in vivo with real time, multichannel fluorescence intravital microscopy of a TNF alpha induced acute inflammation Murine model.

                                                Now, they also used ablation of sympathetic nerves or adrenergic receptors to assess their relevance for these rhythmic leukocyte adhesions. Basically what they found was that leukocytes adhere to arteries and veins following a circadian rhythm in mice, with adhesion peaking in the arteries in the morning and in the veins at night.

                                                These peaks in leukocyte adhesion at different times in the two vascular beds were associated with increased vascular inflammation and shortened times to local basal occlusive events occurring out of phase between the arteries and the veins. The differences in cell adhesion molecules and leukocyte adhesions were ablated when disrupting the sympathetic nerves, thus demonstrating their critical role in this process and the importance of beta2-adrenergic receptor signaling. Neat, huh?

Dr Gregory Hundley:       Really neat. It's interesting how that ties together sympathetic nerve activity and leukocyte adhesion.

Dr Carolyn Lam:                You got a paper?

Dr Gregory Hundley:       I've got a paper to discuss and it's from Dr John Cooke at the Houston Methodist Research Institute. It's involving nuclear S-nitrosylation and how that defines an optimal zone for inducing pluripotency, the ability to generate induced pluripotent stem cells or I.P.S.C's from somatic cells as it enhanced the field of regenerative medicine.

                                                It has facilitated studies of development in differentiation, promoted insights into pathobiology, and generated a novel platform for drug discovery and testing. In fact, work in this area has been sufficient to induce nuclear reprogramming to pluripotency and galvanized our whole scientific community. Recently in 2012, this work was recognized by the Nobel Prize for physiology or medicine.

Dr Carolyn Lam:                Wow. What did this week's paper show in this area?

Dr Gregory Hundley:       Well, Carolyn, in this study, the team identified an optimal zone. They call it the Goldilocks zone of innate immune activation for nuclear reprogramming to pluripotency. The authors believe that this Goldilocks zone for nuclear reprogramming may have broad relevance for epigenetic control, for regenerative processes, and for the pathobiology of cancer and even other diseases.

                                                Consequently, the results from this study may help to develop methods that identify whether a patient or tissue is in an optimal zone of inflammatory signaling to improve surgical and medical therapies. In addition, they may provide a method to detect early inflammatory signaling and DNA accessibility and thereby reverse these processes to guide cancer prevention.

Dr Carolyn Lam:                Oh wow, Greg. It sounds like a real landmark paper. Everyone, you've got to pick that one up. As with this next paper, it is the first randomized trial comparing internal cardioversion by commanded shock and external cardioversion in patients with ICD's who present in atrial arrhythmias.

                                                Dr Lüker and colleagues from University Hospital Cologne randomized 230 consecutive patients with ICD's undergoing elective cardioversion for atrial arrhythmias at 13 centers and they randomized them to either internal or external cardioversion. The primary safety endpoint was a composite of lead or device malfunction and conversion of the atrial arrhythmia to sinus rhythm was the primary efficacy endpoint. Myocardial damage was studied by measuring troponin release in both groups.

Dr Gregory Hundley:       I really like where this study's going. What did they find?

Dr Carolyn Lam:                They found that external cardioversion was superior for the restoration of sinus rhythm, with shock efficacy of 93% in the external cardioversion group compared to 65% in the internal cardioversion group. There were three cases of preexisting silent lead malfunction that were unmasked by the internal shock resulting in lead failure. Troponin release did not differ between the groups.

                                                In summary, these findings suggest that external cardioversion may be considered as the first line approach to electrical cardioversion in patients with ICD's and atrial fibrillation. Because silent lead malfunction may be present in some ICD patients, internal cardioversion may be considered in select patients to detect it and with no difference in adverse events associated with internal or external shocks. That's a good sign but needs to be evaluated in larger randomized trials.

Dr Gregory Hundley:       Oh, very nice, Carolyn. Well, my next paper is entitled the Androgenic Effects on Ventricular Repolarization and it's a translational study from the International Pharmacovigilance Database to iPSC-cardiomyocytes. The corresponding author is Dr Joe-Elie Salem from Vanderbilt University Medical Center.

                                                Male hypogonadism arising from a range of ideologies, including androgen deprivation therapies and other things, has been reported as a risk factor for acquired long QT syndrome, as well as torsade de pointes. The authors searched the International Pharmacovigilance Database, VigiBase, for men and they had 6,560,000 plus individual case safety reports presenting with long QT syndrome, torsade de pointes, or sudden death associated with androgen deprivation therapies.

                                                In cardiomyocytes derived from induced pluripotent STEM cells from men, they also studied the electrophysiological effects of androgen deprivation and dihydro testosterone.

Dr Carolyn Lam:                That's super interesting. What did they find, Greg?

Dr Gregory Hundley:       It's one of these combinations of a clinical study as well as basic science. Of the 10 androgen deprivation therapies examined, seven had disproportional association reporting odds ratios of one four to four seven with long QT syndrome, torsade de pointes, and sudden death. The minimum medium times to sudden death were from 0.25, a quarter of a day, to 92 days respectively. The androgen receptor antagonist, enzalutamide was associated with more deaths than any other androgen deprivation therapy used for prostate cancer.

                                                In the basic science experiment, in induced pluripotent STEM cells acute and chronic enzalutamide at 25 micromolar, a. Significantly prolonged action potential durations, b. Generated after depolarizations and activity, c. Inhibited delayed rectifier potassium currents, and d. Chronically enhanced late sodium currents.

                                                Interestingly, dihydrotestosterone at 30 nanomolar reversed the enzalutamide electrophysiologic effects on these induced pluripotent STEM cells.

Dr Carolyn Lam:                Again, really interesting approach from this Pharmacovigilance Database as well as bench work and clinical work, but what do we do with this information?

Dr Gregory Hundley:       Couple of key points, Carolyn. One, men receiving androgen deprivation therapy are at increased risk for drug induced QT prolongation and torsade de pointes. Two, in men developing acquired long QT syndrome or torsade de pointes, a diagnostic workup might include evaluation of testosterone blood levels, androgen deprivation therapy intake, and evaluation for endocrine conditions associated with hypogonadism. Three, in men treated with androgen deprivation therapy for example, for prostate cancer, other risk factors for torsade de pointes should be sought and corrected to avoid any accumulation of risk. And finally number four, in men treated with androgen deprivation therapy, the role of electrocardiographic monitoring to detect QT prolongation really requires an additional study.

Dr Carolyn Lam:                Cool, Greg. What else in the journal did you find cool?

Dr Gregory Hundley:       Yeah, this is great, Carolyn. We're going to start now with sort of a new format where we go through all the other wonderful information. We're just going to trade back and forth.

                                                The first one I'm going to tell you about is a letter from James Tisdale who is from the College of Pharmacy at Purdue University, and he demonstrates in a small randomized controlled trial that transdermal testosterone attenuates drug induced QT lengthening in older men. Really kind of links back to that study I just told you about.

Dr Carolyn Lam:                Nice. Well, I want to highlight an on my mind paper and it's entitled, Chronic Severe Aortic Regurgitation, Should we Lower Operating Thresholds? This is from Dr Desai at Cleveland Clinic and he considers newer EchoMRI methods to assess the severity of aortic regurgitation and determine suitability for valve intervention. It's a large study and just a really nice read of a short on my mind paper.

Dr Gregory Hundley:       Excellent. Well, you know we also highlight excellent reviews in circulation and the one I'm going to discuss briefly is from Schuyler Jones from Duke and he revisits the role of primary aspirin for primary prevention of cardiovascular disease.

                                                He talks about the indications, that there are really few indications for aspirin in those with diabetes mellitus, community dwelling elderly individuals, and patients without diabetes who are at intermediate risk for atherosclerotic events. Also, he discusses the role of aspirin and reviews very nicely the role of aspirin in primary prevention including the optimal drug formulations, different dosing schedules, weight-based dose selection, and the interplay between sex and treatment response. It's a great review.

Dr Carolyn Lam:                Ah, and then from a nice in-depth review we also have a perspective, a nice short read. This one is from Dr Simari from Kansas who discusses diversity in clinical trials and you know, his title is actually a question, when will clinical trials finally reflect diversity? Really lovely paper. He points out that to increase the diversity of enrollment, we need to consider expanding the diversity of investigators. So, a nice piece there, too. Thanks, Greg. That was a super chat. Shall we go on to our feature discussion now?

Dr Gregory Hundley:       Absolutely. Welcome everyone to discussion of our featured article focusing on hypertensive disorders in pregnancy, and then the subsequent long-term outcomes related to that. For our author discussion, we have Fergus McCarthy from Ireland and the Irish Center for Fetal and Neonatal Translational Research at Cork. Then, we also have our associate editor, Sharon Reimold.

                                                Fergus, could you tell us a little bit about what was your thinking behind starting this study? What type of questions were you trying to answer? And then after that, tell us a little bit about the study design.

Dr Fergus McCarthy:       I'm an obstetrician by trade and we have this funny paradox where a lot of us know that pregnancy is not just about the nine-month periods that a woman is pregnant and then ultimately delivers, that what happens in pregnancy can influence long-term maternal health. But despite this, we have this paradox whereby a woman becomes pregnant, the pregnancy may be complicated by hyper pressure in pregnancy, the woman delivers her baby, goes home and often doesn't see a healthcare practitioner for possibly another 10, 20 years.

                                                Even though we know if a pregnancy is affected by high blood pressure, we don't really do a huge amount about it and we deal with this funny situation. We know that high blood pressure in pregnancy affects two to 8% of pregnancies, depending on the population studied. What we wanted to do was examine specifically the impact of hypertension or high blood pressure in pregnancy on long-term maternal health.

                                                But importantly, what we also wanted to try and determine was is there any factor that may be modifiable that may be ultimately able to improve or reduce the long-term morbidity associated with having hyper pressure in pregnancy? So, if you have high blood pressure in pregnancy, is that it or is there anything that we maybe could make women aware of that may ultimately improve their long-term health?

                                                Also as I said, despite research documented in the association between preeclampsia, which is high blood pressure in pregnancy and major cardiovascular disorders later in life, but we felt also that there was a lot of limitations with the evidence that's there.

                                                Firstly, a lot of the evidence is focused on more composite endpoints and secondly, over the past several decades, the pattern of initial presentation of cardiovascular disease has changed significantly. And thirdly, a lot of the studies that are out there have been unable to adjust for post-pregnancy factors such as hypertension. We wanted to see whether that was a significant factor. But that's the thought process behind why we undertook this study.

                                                Then we had a great opportunity with the collaboration with the Fire Institute in London and University College London, whereby we were able to use a database which is called CALIBER. What CALIBER stands for is cardiovascular research using linked bespoke studies and electronic health records, bit of a mouthful. But what CALIBER is, is basically it's a combination of the GP database in the U.K., which is called the Clinical Practice Research Database, hospital episodes, statistics, and the Office for National Statistics cause specific mortality records. What that does is basically it combines a lot of pregnancy data with long-term really well phenotyped cardiovascular disease.

                                                In particular, what CALIBER is very strong for is they have phenotypes, 12 cardiovascular phenotypes, in an extremely strong robust way. So, we were able therefore to examine the impact of pregnancy using the GP database, using the CPRD with these 12 cardiovascular phenotypes as our outcomes.

Dr Gregory Hundley:       Tell us a little bit about your study population and what were some of the results of your study?

Dr Fergus McCarthy:       What we did was we used electronic health records from a period of 1997 to 2016 and we looked at a U.K. population core of about 1.3 million women. The mean age of delivery of these women was about 28 years of age and they had about just under 2 million, 1.9 million completed pregnancies.

                                                Over the 20-year study period, we were able to observe just over 18,000 cardiovascular disorders, 65% of which had occurred in women under the age of 40. Again, this was quite surprising because using cardiovascular disease, you think a much older group, and when we looked at the pregnancies that were affected by hypertension in pregnancy, we were able to see that compared to women without hypertension in pregnancy, women who had one or more pregnancies affected by preeclampsia had increased hazard ratio for stroke, atherosclerotic events, heart failure, atrial fibrillation, cardiovascular death, and for chronic hypertension.

                                                What was particularly interesting was that the differences in the cumulative incidence curves that we were able to see. According to preeclampsia, we were able to see these differences within one year of the first index pregnancy. So again, this was quite fascinating from our point of view because I think prior to this study, maybe we thought that it was happening a bit earlier than we thought in women's lives, but actually, to see something so soon occur after pregnancy was quite interesting.

                                                The other thing that, and one of our motivations to do this was to say, okay, well is there anything we can do about it? Is there anything that might be modifiable here? What we were able to do within our study was we were able to examine, is this just because women are leaving hospitals with high blood pressure and this high blood pressure is not being treated? What we were able to do was we were able to adjust into our models this concept of having postpartum hypertension. If we were able to adjust for the mediating effect of post-pregnancy hypertension, we observed a 35% reduction in the point estimates of the hazards ratio for any cardiovascular disease event.

                                                One of the things I think that this study shows is that it is critically important that women have appropriate medical follow-up after their pregnancy. It's a very difficult period. People have young babies, they may be going home to more children at home, and often the neglected person in this situation is the mother. What we're saying is that actually even if we could focus on that one factor which is post-pregnancy adequate control of hypertension, we may be able to reduce the hazards ratio of developing a cardiovascular disease by approximately 35% is what the study is suggesting.

Dr Gregory Hundley:       Really interesting results, Fergus. Sharon, I wanted to turn to you a little bit. How do the results of this study change for us the way we might practice in terms of managing this patient population?

Dr Sharon Reimold:         This study, I think, is very interesting because of the large population and the significant number of unfortunately adverse outcomes and the ability to compare those with and without preeclampsia and hypertension. I think that we end up with two or three different issues or ways that we think about dealing with them.

                                                First of all, just as Fergus alluded to is we need to make sure that we take hypertension seriously in pregnancy and since it's a small, but significant number of women leave the hospital and will remain hypertensive, we need to assure that they are getting care. The other thing that I think is important in this group, but you would never be able to capture in the current study is my approach is also to think about, well, what other risk factors does this woman have other than just high blood pressure? Is she at risk to be a diabetic? Does she smoke? Is she getting enough exercise? What other things can we do to modify their long-term risks?

                                                This points out a method to identify those patients pretty easily. Are they hypertensive early post-pregnancy, and then it's up to the medical community to really develop strong guidelines and training that emphasizes using prevention in the outpatient setting.

                                                The two things I found very interesting about this work, first of all, the rapid separation of these curves. I know that they had some very young women that gave birth and then some obviously women of what I guess would be termed advanced maternal age. But we do think of a woman who has a child at 30 maybe being at higher risk when she's 50 or 60, but the risk is much earlier, and patients are really not aware of this.

                                                Then, the ultimate thing is how do we identify these women early in their pregnancy or before they're pregnant, so we can help avoid these complications altogether? I guess the take home message is if somebody has hypertension or they're going home hypertensive, they need early follow-up and we need to be aggressive about their treatment.

Dr Gregory Hundley:       Both of you have emphasized the point that this paper makes of early identification of hypertension. In the paper, it talks about hypertensive disorders of pregnancy. I think many of us understand about preeclampsia or eclampsia and relatively high blood pressures, HELLP syndrome, et cetera. Are there other issues that we need, like what blood pressure ranges are we thinking about?

                                                If I'm picking up a chart of a woman in their early forties, late thirties what should I be looking back for retrospectively in terms of blood pressure levels? Do I follow the new guidelines and I'm looking for blood pressures above 120 systolic? Can either of you give us some guidance on what to look for, how I would set up a program, what the timing would be, when I need women to come back? Just practical things like that.

Dr Sharon Reimold:         I believe that is still in the obstetric world that the older guidelines are really what are used and whether those shift over time to lower thresholds for the diagnosis of hypertension is not clear, but usually it's 140 over 90. You want to try to get the patient history and differentiate between those people that perhaps were hypertensive prior to their pregnancy, people who had isolated short-term hypertension during their pregnancy, and those people who then left pregnancy remaining hypertensive. But I'll ask Fergus since he deals with this a lot more than I do with the pregnancies, what they use as the cutoff in the U.K.

Dr Fergus McCarthy:       In general, we had the CHIPS Study, which was published several years ago. That advocated, certainly during pregnancy, that a tighter control of blood pressure was associated with an improved pregnancy and improved maternal outcome. That type of control generally aimed for a systolic blood pressure of under 135. In general, when we are managing our patients, that's usually what we're aiming for, to keep the systolic blood pressure under 135.

                                                I think the other thing that is becoming apparent from a lot of the work that's been done is that it's maybe not just about the pre-eclamptic woman, which is generally the woman with hypertension and proteinuria that gestation and hypertension, which often is nonproteinuric by definition, is also playing a significant part.

                                                Certainly, when you look at populations where I previously worked in the U.K. and London, women with chronic hypertension, pregnancy is becoming a huge issue, both with increasing obesity and certain ethnic groups, and with advanced maternal age women coming into pregnancy with chronic hypertension is really becoming a major issue for us, as well, and is associated with a much worse pregnancy outcome. But to answer the question, that's usually where we're aiming for and we're trying to, where possible, run as tight a control of blood pressure as possible.

Dr Gregory Hundley:       Thank you very much, and we look forward to talking and discussing with you with Carolyn next week.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.


Sep 16, 2019


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

Dr. Carolyn Lam: Greg, you know I'm vegetarian and any paper on plant-based diet will always interest me, and of course, we have one as a featured paper this week, very interestingly talking about changes in plant-based diet quality, meaning that there could be good plant-based diets and not so good plant-based diets. I mean we all know that potato chips, for example, are still plant-based. But, anyways, so this feature paper discusses the changes in these plant-based diet quality and association with total and cost-specific mortality. Neat, huh?

Dr. Greg Hundley: Yeah. I can't wait to hear about that one. I know that's a favorite topic of yours. How about if we have a sip of coffee and jump into our other articles?

Dr. Carolyn Lam: Sure. I'm sipping away, and have already picked my first paper. This talks about mutations in plakophilin 2, which are the most common cause of gene-positive familial arrhythmogenic right ventricular cardiomyopathy.

Dr. Greg Hundley: No quizzes for me on plakophilin 2, please.

Dr. Carolyn Lam: All right, well, let me tell you all about it. Plakophilin 2 is classically defined as a protein of the desmosome, which is an intracellular adhesion structure. Studies though have suggested that plakophilin 2 also translates information at the initiation. Recent studies have also shown that plakophilin 2 translates information initiated at the site of cell to cell contact into intracellular signals that maintain structural and electrical homeostasis. Now, the important thing is that mutations in plakophilin 2 associated with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy or ARVC. However, the molecular and cellular mechanisms responsible for arrhythmias in ARVC remain unclear.

Dr. Carolyn Lam: In today's paper, Doctors Delmar and Cerrone from New York University School of Medicine and their colleagues studied the role of cardiomyocyte plakophilin-2 expression in cardiac function. To do that, they utilized a cardiomyocyte-specific, tamoxifen-activated, plakophilin-2 knockout murine line. They found that loss of plakophilin-2 expression caused, as an early event and predominantly in the right ventricle, a non-transcriptional and likely arrhythmogenic, connexin-43-dependent disruption of calcium homeostasis.

Dr. Carolyn Lam: The phenotype included accumulation of calcium in three intracellular compartments, the junctional sarcoplasmic reticulum, the cytoplasm, and the mitochondria. Right ventricular myocytes also showed increased eagerness of ryanodine-receptor-2 channels to release calcium from the sarcoplasmic reticulum. Intrinsic ryanodine-receptor-2 properties were also modified further contributing to the pro-arrhythmogenic state. In summary, the authors postulated that disruption of calcium homeostasis in the right ventricle is a major arrhythmia trigger in patients with ARVC. The data identified both the ryanodine-receptor-2 channel and the connexin-43 hemichannel as targets for antiarrhythmic therapy in this population.

Dr. Greg Hundley: Very interesting that ARVC is such a worrisome concern, and gathering this mechanistic information is just so helpful.

Dr. Carolyn Lam: Exactly.

Dr. Greg Hundley: I have a basic science paper, but it was actually interesting because of the conduct was in many, many human subjects. It emanates from the large Million Veteran Program. There are a whole list of coauthors that are recognized as equal contributors, but Scott Damrauer actually serves as the corresponding author from the VA Medical Center. What it's addressing, about 13% of African American individuals carry two copies of the APOL1 risk alleles, G1 or G2, that are associated with a one and a half to two and a half fold increase in the risk of chronic kidney disease.

Dr. Greg Hundley: There've been conflicting reports as to whether an association exists between these APOL1 risk alleles and cardiovascular disease independent of the effects of the APOL1 on kidney disease. Here, the investigators thought to test the association of these G1 and G2 alleles with coronary artery disease, peripheral arterial disease, and stroke among African American individuals in the Million Veterans Program.

Dr. Carolyn Lam: Seems like a great study population and designed to look at this. What did they find?

Dr. Greg Hundley: Among 30,903 African American Million Veterans Program participants, 3,941 or about 13% carried the two APOL1 risk allele, high-risk genotype. Individuals with normal kidney function at baseline with the two risk alleles had a slightly higher risk of developing coronary artery disease compared to those with no risk alleles. Similarly, modest associations were identified with incident stroke and peripheral arterial disease. However, when modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease while no significant association with the cardiovascular disease endpoints could be detected. In conclusion, what the authors are indicating is that the APOL1 risk variants display a modest association with cardiovascular disease, and this association is likely mediated by the already previously known association of APOL1 with chronic kidney disease.

Dr. Carolyn Lam: Interesting.

Dr. Carolyn Lam: My next paper also has to do with chronic kidney disease and this time looking at metformin use and clinical outcomes in patients with diabetes with or without heart failure or kidney dysfunction. We know that metformin is the first-line therapy for type 2 diabetes, although its effects on the cardiovascular system are actually, not fully proven. In this next paper, the authors examine metformin use in the SAVOR-TIMI 53 Trial.

Dr. Greg Hundley: Tell us a little bit about that SAVOR-TIMI 53 Trial. How is that organized?

Dr. Carolyn Lam: Just as a reminder, the SAVOR-TIMI 53 trial was a multinational, randomized, controlled cardiovascular outcomes trial that compared the dipeptidyl peptidase-4 or DPP4 inhibitor, Saxagliptin, with placebo, enrolling almost 16,500 patients with type 2 diabetes and cardiovascular disease or elevated cardiovascular risk.

Dr. Carolyn Lam: Now, in the current paper led by Dr. Bergmark from TIMI study group in Brigham and Women's Hospital and Harvard Medical School, the authors performed the post hoc analysis and looked at patients in SAVOR-TIMI 53 with baseline biomarker samples of whom there were more than 12,000 patients and classified these patients as ever versus never taking metformin during the trial period. The associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting, Cox modeling.

Dr. Carolyn Lam: They found that among patients with type 2 diabetes and high cardiovascular risk in the SAVOR-TIMI 53 trial, metformin use was associated with lower rates of all-cause mortality including after adjustment for clinical variables and biomarkers, however not lower rates of the composite endpoint of cardiovascular death, MI or stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.

Dr. Greg Hundley: Excellent.

Dr. Greg Hundley: I'm going to transition to another clinical trial and this one is looking at ezetimibe in elderly patients and looking at efficacy for preventing cardiovascular-related events. The paper comes from Yasuyoshi Ouchi from Toranomon Hospital in Japan. Evidence regarding the primary prevention of coronary artery disease events by LDL-C/lipid-lowering therapy in order individuals that are above the age of 75 years, is somewhat incomplete. This trial tested whether LDL-C lowering with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. They implemented a multicenter, prospective, randomized but open-label, blinded, endpoint, however, evaluation design conducted among 363 medical institutions in Japan.

Dr. Greg Hundley: In the study, there're 3,796 patients that are aged greater than 75 years with elevated LDLC without a history of coronary artery disease that already were receiving dietary counseling. They're randomly assigned one-to-one to receive as ezetimibe 10 milligrams once daily versus usual care with their randomization stratified in a block design on age, sex, and baseline LDL-C. The primary outcome is the composite of sudden cardiac death, myocardial infarction, coronary revascularization, and stroke.

Dr. Carolyn Lam: Ooh, so tell us the results.

Dr. Greg Hundley: There were several patients that had to be excluded, so what ended up happening, there's 1,716 and then 1,695 that are included in each of the two respective arms for the primary analysis. What they found is that as ezetimibe reduced the incidents of the primary outcome. Then, regarding some secondary outcomes, the incidents of composite cardiovascular events and coronary revascularization were lower in the ezetimibe group than in the control group. But, there was no difference in the incidents of stroke, all-cause mortality, or adverse events in the two different groups.

Dr. Carolyn Lam: Can you sum it up for us, Greg? What should we take home regarding ezetimibe and what further do we need to do?

Dr. Greg Hundley: Good point, Carolyn. I think what we can take away from this study is that LDL-C lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals greater than 75 years of age with an elevated LDL-C. However, remember, it was open label, so I think a placebo, controlled, randomized clinical trial will be required to validate the data that were obtained in this study. I think another study is probably going to be needed.

Dr. Carolyn Lam: Thanks, Greg. Well, let's move on to our feature discussion, shall we?

Dr. Carolyn Lam: Today's feature paper is of personal interest to me and I'm sure of widespread interest to everybody. Why? It's on plant-based diet. We've heard a lot about it. I'm vegetarian and very, very loudly self-confessed, but does the quality of a plant-based diet actually matter? Such an important question.

Dr. Carolyn Lam: I'm so pleased to have the authors of this very remarkable paper, Dr. Megu Baden as well as Dr. Shilpa Bhupathiraju, both from the Harvard T.H. Chan School of Public Health; and our associate editor, Dr. Mercedes Carnethon from Northwestern University Feinberg School of Medicine. Welcome, ladies. What a nice chat we're going to have on this very personal topic to me as well.

Dr. Carolyn Lam: First of all, maybe, could I ask, Shilpa, do we need another study on plant-based diet? Could you tell us the rationale for what you did this time?

Dr. Shilpa Bhupathiraju: Like you said, when we talk about plant-based diets and what people usually think is, well, it's vegetarian or not. But, I think there's much more to a vegetarian diet. It's the quality that matters. Previous studies really then differentiate the quality of a vegetarian diet.

To this extent, we developed plant-based diet indices, which actually capture the quality of a plant-based diet, so we have an overall plant-based diet index which captures the amount of plant-based foods; a healthy plant-based diet index, which captures the quantity of healthy plant-based foods; and again, the unhealthy plant-based diet index, which captures the quantity of unhealthy, plant-based foods.

Dr. Carolyn Lam: Thanks. Meg, if you don't mind, I know everybody is asking this as they're listening. Could you give us some examples of what an unhealthy plant-based diet index would consist of compared to healthy? Then, perhaps, tell us a little bit about your study and what you found.

Dr. Megu Baden: First of all, let me explain again. In this study, we use three versions of plant-based diet indices that can assess the quality of plant foods in general population. The first index is an overall plant-based diet index, PDI for short. A second one is a healthful plant-based diet index, HPDI. The third one is an unhealthful plant-based diet index, UPDI. In order to create these indices, we divide all food groups into three larger categories. One is the healthy plant foods, which contains whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; less healthy plant foods such as fruits juice, refined grains, potatoes, sugar-sweetened beverages, and sweets or desserts; and animal foods, which is animal food, dairy, eggs, fish, meat, miscellaneous animals-based food.

Dr. Megu Baden: We investigated the association between preceding trailblazing changes in these indices and subsequent total and cause basic mortality in two large US cohorts. We found that compared with participants whose diet remained stable, the hazard ratio for total mortality, among those risks, the greatest increase in PDI was 0.95; for the greatest increase in HPDI, the healthful versions of the PDI was 0.90; and the greatest increasing in unhealthful PDI was 1.12. In contrast, the hazard ratio among participants with the greatest difficulty is in PDI, was 1.09; the greatest decrease in healthful PDI was 1.10; and the greatest decreasing in unhealthful PDI was 0.93. For CVD mortality, the risk was 7% lower for our 10 point increase in PDI, and 9% lower for HPDI and 8% higher for UPDI.

Dr. Megu Baden: In summary, we found that improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.

Dr. Carolyn Lam: Could I ask, Shilpa, to maybe add a line of ... have you applied this information in any way yourself or with patients, or is there an overwhelming take-home message you'd like people to remember?

Dr. Shilpa Bhupathiraju: Yeah, I'm not a clinician myself, but I'm a public health researcher. I'm in India currently and I'm giving a talk to South Asians and the emphasis on vegetarianism. But, again, the quality of the vegetarianism is important. Being a vegetarian is not enough, but what goes into it is really important. If it's a white rice and sugar-sweetened beverages, it's not good, so really the emphasis should be on whole grains, consuming more nuts and legumes. I think that's important.

Dr. Carolyn Lam: Oh, that's great. Mercedes, we've discussed this paper as associate editors, so proud to be publishing this in circulation. Could you share some of your thoughts on the implications of these findings?

Dr. Mercedes Carnethon: The authorship team has done an outstanding job of clarifying a very complicated issue. I think what we really like about this and the ways in which it really adds to the literature, what you point out, that every vegetarian diet isn't the same. I was very impressed with the thought that went into classifying vegetarian foods as healthy or unhealthy. I would be interested in hearing more from the authors, particularly, since I feel they did a good job of how they dealt with complicated foods or mixed foods. I think one example given was a pizza, which has tomato sauce, but it also has other things, so I would love to hear from the authors how they classified complicated foods.

Dr. Shilpa Bhupathiraju: The decision to classify pizza as an animal food was somewhat, I would say, arbitrary. I do agree that there's lots of tomato sauce, but again, I think the decision that went to it, it does have a ton of cheese, processed cheese, I think that's why we classified that as an animal food. The other complicated foods are mixed dishes that we struggled with were cream soups. We thought about what the base was or what the general preparation of that would be. Given that heavy cream is a major ingredient, so those were again, classified as animal foods.

Dr. Mercedes Carnethon: I think there's a lot of logic in that and I really like the thought and care that you put into that. The other questions I have, I feel that you did a really nice job of, are even portion sizes. Tell me how you handled portions.

Dr. Megu Baden: We basically take the information from our food frequency questionnaire. All of them are per the serving sizes, so we considered how participants reported how often on average they had consumed each food of our standard portion size in the past year. I know it's difficult to indicate the portion size. Shilpa, would you add something for the portion size for that?

Dr. Shilpa Bhupathiraju: Yes. Like Megu said, we use standardized portioning sizes, so a cup of fruit, a cup of vegetables, an eight-ounce, or a cup of tea or coffee, so that's how we use what people use in general. The portion sizes are all specified on the food frequency questionnaire, so the nurses or the health professionals, they understand exactly what they're reporting. Is it a glass of fruit juice or half a glass? Then, we can word those frequencies into standardized serving sizes onto servings per day.

Dr. Carolyn Lam: Great. Shilpa, could I follow up from Mercedes very important question? How does the index account for portion size too, as an is too much of even a good thing become a bad thing? You know what I mean?

Dr. Shilpa Bhupathiraju: The index itself is a score. The way we capture it, as you know, everything is converted from frequencies into servings per day for each participant. Then, what we did was we divided the participants based on the distribution of the data into quintiles. Those in the highest category of the healthy plant foods received the highest points. The scoring varied a little bit based on which index we were calculating. But, in general, what we did was we divided everybody into five groups or quintiles. Then, the scoring varied depending on what we were calculating. For the HPDI, which is the healthy plant-based diet index, those in the fifth group or the highest intake received the maximum number of points, which was five. For the unhealthy plant-based diet index, those people received the reverse scoring, so they received zero points. Essentially, the participants were divided into quintiles and the scoring was done accordingly.

Dr. Carolyn Lam: Maybe I could ask you a question on a different track, and I'm not sure if you have some answers here, but I noticed that your study population was impressive, almost 49,500 women from the Nurses' Health Study, almost 26,000 men from the Health Professionals Follow-up Study. Did you find any sex differences?

Dr. Shilpa Bhupathiraju: We didn't find any sex differences. We did some sensitivity analysis by cohort and we didn't find a statistically significant interaction, which is I think good to note because we would expect the effects to be similar in men and women.

Dr. Carolyn Lam: I think both men and women need to hear that. None of us are excused from, I suppose, trying to gear towards a healthy plant-based diet. I think that's what I'm hearing. Mercedes, do you have more thoughts to add?

Dr. Mercedes Carnethon: I do. One thing I really like about this particular paper is the way the you acknowledge some of the limitations that we face when interpreting findings from observational studies, particularly observational studies of a health behavior when we know that health behaviors often cluster or correlate with other health behaviors. Can you tell us a little bit about some of the cautions and interpretation that you certainly acknowledged and presented very well?

Dr. Shilpa Bhupathiraju: Sure. Our primary analysis was looking at changes, so long-term changes. When people change a diet or their lifestyle, they change something else. As you can see from our paper, those who improve the plant-based diet quality, we're also, in general, tended to be healthier. This being an observational study, we tried to control for those as to the greatest extent possible, but again, they could be residual confounding. We maybe failed to measure for certain things that we were unaware of or that we did not measure. I think we really can't get at causality, but I think the consistency of the evidence from our previous papers and from this paper point to a suggestion that improving plant-based diet quality is definitely associated with better health outcomes and a lower risk of death. But, again, it is important to know that this is observational and there could be changes in other health behaviors that we did not measure that could explain this association. But, we did as well of a job as we could in trying to control for these changes and other behaviors, lifestyles or even health conditions.

Dr. Mercedes Carnethon: Thank you.

Dr. Carolyn Lam: Thank you so much, Meg and Shilpa. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Carolyn Lam: This program is copyright American Heart Association 2019

Sep 9, 2019


Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. 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 Poly Heart Center at VCU health in Richmond, Virginia.

Dr. Carolyn Lam: Greg, I'm so excited about the feature paper this week. You know it deals with machine learning. It's such a hot topic now, and this one particularly deals with machine learning and the prediction of the likelihood of an acute myocardial infarction. So everyone's going to want to listen to it. Let's discuss a couple of papers and get to it, shall we?

Dr. Greg Hundley: Absolutely Carolyn, would you like to go first?

Dr. Carolyn Lam: I sure would. So my first pick is the first study to investigate the overall importance of translational regulatory networks in myocardial fibrosis. This is the study from doctors Rackham and Cook from Duke NUS Medical School here in Singapore.

Dr. Carolyn Lam: What they did is they generated nucleotide resolution translatome data during transforming growth factor beta one, or TGF beta one-driven cellular transition of human cardiac fibroblasts to myofibroblasts. So this technique identified the dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early responder genes.

Dr. Carolyn Lam: Now, very remarkably about one third of all the changes in gene expression in activated fibroblasts was subject to translational regulation and dynamic variation in the ribosome occupancy, affected protein abundance independent of RNA levels. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggest that the same post-transcriptional regulatory network, which was underlying cardiac fibrosis. Now key network hubs included RNA binding proteins such as PUM2 and QKI that worked in concert to regulate the translation of target transcripts in the human disease hearts.

Dr. Carolyn Lam: Furthermore, the authors showed that silencing of both PUM2 and QKI inhibited the transition of fibroblasts towards profibrotic myofibroblast in response to TGF beta one.

Dr. Greg Hundley: You know, Carolyn, this whole aspect of fibroblasts and how they turn on and turn off, become myofibroblasts, such a hot topic in heart failure. What are the clinical implications of this work?

Dr. Carolyn Lam: Yes, I agree. Well, threefold. First, these authors identified previously unappreciated genes under translational control, which could be novel candidates for disease biology and therapeutic targets.

Dr. Carolyn Lam: Number two, they found that critical fibrosis factors impacted cellular phenotypes at a protein level only, and hence these cannot be appreciated using single cell, or bulk RNA sequencing approaches. So that was significant. Finally, RNA binding proteins was shown to be central to the fibrotic response and represent unexplored gene expression regulators, and of course potential diagnostic or therapeutic targets.

Dr. Greg Hundley: Very nice Carolyn. Well, my next paper is also from the world of basic science, and it comes from Dr. Joseph Hill. Have we ever heard of him? Well of course, he's our Editor in Chief. He's going to discuss, he and his team investigated Polycycstin-1. Well, what is Polycycstin-1? It's a trans membrane protein, originally identified in autosomal dominant polycystic kidney disease, where it regulates the calcium permeate cation channel polycystin-2. So autosomal dominant, polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, atrial fibrillation and other cardiovascular disorders. These individuals harbor PC1 loss of function mutations in their cardiomyocytes, but the functional consequences of this are relatively unknown.

Dr. Greg Hundley: Now PC1 is ubiquitously expressed in its experimental ablation in cardiomyocyte specific knockout mice reduces contractile function, and in this paper the authors set out to determine the pathophysiologic role of PC1 in these cardiomyocytes.

Dr. Carolyn Lam: Huh--very interesting. I liked the way you laid that out. So what did they find?

Dr. Greg Hundley: What the investigators identified is that PC1 ablation reduced action potential duration in cardiomyocytes. They decreased calcium transients and therefore myocyte contractility. PC1 deficient cardiomyocytes manifested a reduction in sarcoplasmic reticulum calcium stores due to reduced action potential duration and circa activity, an increase in outward potassium currents decreased action potential durations in cardiomyocytes lacking PC1. PC1 coimmunoprecipitated with a potassium 4.3 channel and modeled PC1 C terminal structure suggested the existence of two docking sites for PC1 within the end terminus of K4.3. Supporting a physical interaction between the cells. Finally, a naturally occurring human mutant PC1 manifested no suppressive effects on this potassium channel activity. Thus, Carolyn, Dr Hill and colleagues' results help uncover a role for PC1 in regulating multiple potassium channels, governing membrane repolarization and alterations in circa that reduce cardiomyocyte contractility.

Dr. Carolyn Lam: Oh wow. What a bonanza of really interesting papers in this week. Now my next pick is a secondary analysis of the reveal trial. It hinges on the hypothesis that was generated from prior trials that the clinical response to cholesterol ester transfer protein or CETP inhibitor therapy may differ by ADCY9 genotype. So in the current study, authors Dr. Hopewell and colleagues from Nuffield Department of Population Health, University of Oxford examine the impact of ADCY9 genotype on the response to the CETP inhibitor Anacetrapib within the reveal trial.

Dr. Greg Hundley: Tell me, I've forgotten a little bit, but can you remind me a little about what was the reveal trial?

Dr. Carolyn Lam: Yes, of course. So the randomized placebo controlled reveal trial actually demonstrated the clinical efficacy of the CETP inhibitor Anacetrapib among more than 30,000 patients with preexisting atherosclerotic vascular disease. Now, in the current study, among more than 19,000 genotyped individuals with European ancestry, 13% had a first major vascular event during four years median follow up. The proportional reductions in the risk of major vascular events did not differ significantly by ADCY9 genotype. Furthermore, the authors showed that there were no associations between the ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or any meaningful differences in lipid response to Anacetrapib.

Dr. Carolyn Lam: So in conclusion, the reveal trial being the single largest study to date to evaluate the ADCY9 pharmacogenetic interaction provided no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor Anacetrapib. The ongoing dal-GenE study, however, will provide direct evidence as to whether there's any specific pharmacogenetic interaction with dalcetrapib.

Dr. Greg Hundley: Oh, very good. So we've got some results coming from dal-GenE.

Dr. Carolyn Lam: Mm.

Dr. Greg Hundley: Well, Carolyn, my last selection relates to a paper regarding the incidence of atrial fibrillation among those that exercise, and I mean really exercise.

Dr. Carolyn Lam: Ooh.

Dr. Greg Hundley: So the paper comes from Dr Nicholas Svedberg from Uppsala University, and studies have revealed a higher incidence of atrial fibrillation among well trained athletes. The authors in this study aim to investigate associations of endurance training with the incidents of atrial fibrillation and stroke, and to establish potential sex differences of such associations in this cohort of endurance trained athletes. They studied all Swedish skiers, so 208,654 that completed one or more races of the 30 to 90 kilometer cross country skiing event called the Vasaloppet from 1989 through 2011, and they had a matched sample of 527,448 non-skiers, and all of the individuals were followed until their first event of either atrial fibrillation or stroke.

Dr. Carolyn Lam: Wow. What an interesting and what a big study. So tell us, what are the results and especially were there any sex differences?

Dr. Greg Hundley: Well, interesting that you ask about those sex and gender differences. So female skiers had a lower incidence of atrial fibrillation than female non-skiers, independent of their finishing time and the number of races, whereas male skiers had a similar incidence to that of non-skiers. Second, skiers with the highest number of races or fastest finishing times had the highest incidents of the AFib, but skiers of either sex had a lower incidence of stroke than non-skiers independent of the number of races and finishing time. Third, skiers with atrial fibrillation had a higher incidence of stroke than skiers and non-skiers without atrial fibrillation. That's true for both men and women. We would think that. Finally after one had been diagnosed with atrial fibrillation, skiers with atrial fibrillation had a lower incidence of stroke and a lower mortality compared to non-skiers with atrial fibrillation.

Dr. Carolyn Lam: Very interesting. Could you sum it up for us? What's the take home?

Dr. Greg Hundley: Couple things. One, female endurance athletes appear to be less susceptible to atrial fibrillation than male endurance athletes. Second, both male and female endurance athletes have a lower risk of stroke independent of their fitness level. Third, after the diagnosis of atrial fibrillation, participants in a long distance skiing event with atrial fibrillation had a 27% lower risk of stroke and a 43% lower risk of dying compared to individuals from the general population with the diagnosis of atrial fibrillation.

Dr. Greg Hundley: So there's some clinical implications. Although very well trained men have a higher incidence of atrial fibrillation than less trained men, the incidence is on par with that of the general population and not related to a higher incidence of stroke at that group level. This indicates that exercise has very beneficial effects on other risk factors for stroke. Then lastly, atrial fibrillation in well trained individuals should be treated according to our other usual guidelines for the population at whole.

Dr. Carolyn Lam: Wow. What a fantastic study to end our little coffee chat on, but it's time to move on to our feature discussion.

Dr. Carolyn Lam: Today's feature discussion touches on super-hot topics. First of all, the perennially interesting and hot topic of the prediction of acute myocardial infarction, or should I say the more precise predictions that we can do these days. The second part of the hot topic is machine learning. Oh my goodness. This is creeping into cardiovascular medicine like never before. So I'm so glad to welcome to this discussion corresponding author of the featured paper Professor Nicholas Mills from the University of Edinburgh, as well as our Associate Editor Doctor Deborah Diercks from UT Southwestern. So welcome both, and Nick, if I could start with you, tell us about MI Cubed.

Prof Nicholas Mills: First thing to say, it was a major international collaboration, involved researchers from over nine different countries and we got together to develop and test an innovative algorithm that estimates for individual patients the probability when they attend the emergency department with acute chest pain that they may or may not have had a myocardial infarction.

Prof Nicholas Mills: Machine learning is a really new area in cardiovascular medicine as you say. Our algorithm called MI Cubed uses a fairly simple algorithm which is a decision tree. It takes into consideration really important patient factors such as age, sex, troponin concentration at presentation, and troponin concentration on subsequent testing, and the change in troponin in between those two tests in order to estimate or calculate the probability of the diagnosis. One of the really interesting aspects of this is it's not just an algorithm for research, it's a clinical decision support tool as well. So what we've done is taken the output from that algorithm and translated it into something that is meaningful for clinicians. We've kept it quite simple. It gives an output between zero and a hundred, which is directly proportional to the likelihood of the patient having a myocardial infarct. We also provide estimated diagnostic metrics. So sensitivities and specificities that relate to that individual patient. It's really going to change the way we think about the interpretation of cardiac troponin in clinical practice.

Dr. Carolyn Lam: Indeed, and first audience please, please look up the beautiful figures of this paper. I think it summarizes it all. The algorithm shows you what MI Cubed is and then compares it to the ESC three hour algorithm, one hour algorithm. Then I love the last figure, where you actually show us that very important component that you just said. As a clinical support tool, how it's going to work. So we actually have pictures of your cell phone and showing you the pictures that you're going to get from it. So super cool. Beautiful paper.

Dr. Carolyn Lam: Now I just have so much to talk about, first the machine learning bit, always sexy sounding, but a bit scary for clinicians. So I really like the fact that you broke it down to actually say what components go in so that people aren't afraid of this black box. We don't know what's going on. Is there like a set time between samples, or how does this work? Do you need to have it within a certain timing? How does that fall in? Is it a particular type of troponin, what are some of the specs of the model that a practicing clinician needs to know?

Prof Nicholas Mills: Well, in order to answer that question, I might explain to you the rationale for developing it. So when you're assessing a patient in the emergency department, we all recognize in our daily practice that patients differ. So interpreting troponin has been challenging. One threshold for all may not be the right way to approach this really important clinical diagnosis. Troponin concentrations differ in men and women. They differ by age, and as a surrogate of the presence of comorbidities. They differ depending on the timing of when you take that sample and when you repeat that measurement, and that has introduced some complexity. So many interesting pathways have been developed for guidelines which try and apply fixed thresholds and fixed time points, and it's pretty tough to deliver in the real world setting of a super busy emergency department. So the premise for developing this algorithm was we wanted something that was really flexible, that recognized that patients are different, they're not all the same.

Prof Nicholas Mills: That's why we went for a machine learned approach rather than a more conventional statistical model. So you asked about the specification. You can do your two troponin tests whenever you like. So I had across the 11,000 patients huge variation in the timing of samples, but that is okay for MI Cubed. If you repeat the test within an hour, two hours, three hours, six hours, it still provides the same diagnostic performance. I think that's really important.

Prof Nicholas Mills: You also mentioned specification about the assay. This algorithm has been developed using a particular high sensitivity cardiac troponin assay developed by Abbott Diagnostics. It will be effective for other high sensitive troponin assays, but it's unlikely to be as effective using a contemporary assay. So if your hospital uses a contemporary or conventional cardiac troponin assay, this might not be the right algorithm for you.

Dr. Carolyn Lam: Great. Thank you for breaking down the issue so beautifully and practically. It really makes me think, oh my goodness, this paper's just far more than about MI. Because you know, natriuretic peptides, you could say the same thing. A prediction of heart failure is the same thing, you know? So the whole approach is novel. Deb, could you please share your thoughts and perspectives on where this is going perhaps?

Dr. Deborah Diercks: I think this study is terrific because I think it does, as Dr. Mills stated, reflect reality. We don't draw measures at zero, exactly at zero, and exactly at one and exactly at three, especially in a busy emergency department. So I think it provides flexibility to the physician and provider in using it to be able to interpret values in a world that doesn't fit complete structure like the guidelines are written out. What I find really interesting about this study, and I'd love to hear more about, is how you decided the thresholds of where low risk and high risk were cut at. It mentions by consensus, and I guess I would have loved to have been a fly on the wall to hear how those discussions went, and would love to hear more from you Dr. Mills about that.

Prof Nicholas Mills: Fascinating discussions amongst all the investigators on this project as to how we would define that. The first point I would make though is we designed the algorithm to provide a continuous output, a continuous measure of risk. So your MI Cubed score is between zero and a hundred. You don't have to apply a threshold, but we are used to in clinical practice having processes that support our triage of patients, and identifying people as low risk and high risk. Therefore we felt upfront that we should evaluate specific low risk and high risk thresholds.

Prof Nicholas Mills: So low-risk, we were completely unanimous on how to define that, and it was based on some really nice work done by emergency physicians in New Zealand. Martin Fan, who's the first author on this paper, surveyed many emergency physicians and asked about their acceptance of risk. They came up with the concept that an algorithm to be considered safe in emergency medicine would be acceptable if the sensitivity was greater than 99% or the negative predictive value was greater than 99.5%.

Prof Nicholas Mills: So we agreed up front that we would hold our low risk thresholds to those bars. Those metrics. Where there was less agreement was how you defined high risk. That didn't surprise me hugely. The positive predictive value of troponin is one of the most controversial topics around. Most cardiologists [crosstalk 00:20:52] of troponin has been difficult for them in clinical practice because with the improvements in sensitivity we are seeing lower specificity and lower causative link to value. If I put it into context, just measuring troponin and using the 99 percentile in consecutive patients gives you a positive predictive value of around about 45 to 50% in most healthcare systems for the diagnosis of type one myocardial infarction. Therein lies the problem. So one in every two patients has an abnormal troponin result but doesn't have the condition that we have evidence based treatments for, and whom cardiologists who are often quite simplistic in their approach to the assessment of these patients know how to manage.

Prof Nicholas Mills: Every second patient we don't know how to manage, and therefore we wanted an algorithm that would help us identify those patients who can go through our often guideline-based pathways and treatment pathways for acute coronary syndromes more effectively. We eventually agreed that a positive predictive value of 75% would be ideal. So three out of every four patients would have the diagnosis that we knew how to manage and treat. That was our target. We got pretty close to it in our test set. I think the actual positive predictive value at the threshold of around an MI Cubed value of 50 was 72%, so pretty effective. Certainly a lot better than relying on a kind of binary threshold such as the 99 percentile to identify high risk patients.

Dr. Deborah Diercks.: Thanks for that great answer. My next question is how do you think MI Cubed is going to integrate, or will it even replace the need for other risk stratification tools that we often use the emergency departments such as TIMI or the heart score?

Prof Nicholas Mills: Fabulous question. In this analysis, we haven't specifically compared the performance of MI Cubed with TIMI or heart, so my answer is going to be a little speculative. You can forgive me hopefully. Both those scores were developed prior to the widespread use of high sensitive cardiac troponin tests. I think what we've learned since the introduction of high sensitive cardiac troponin is that we're using this test as a risk stratification tool, and a lot of the power of the MI Cubed algorithm comes from the way that it identifies extremely low risk patients with very low and unchanging cardiac troponin concentrations way below the diagnostic threshold.

Prof Nicholas Mills: TIMI and heart simply consider troponin as a binary test, a positive or negative test, and do not take advantage of the real power of the test to restratify patients. All the evidence to date that has compared TIMI and heart with pathways that use high sensitive troponin in this way, both to restratify and diagnose patients show that these risk tools add very little in terms of safety, but do make pathways more conservative. So they identify fewer patients that are lower risk and permit discharge of those patients.

Prof Nicholas Mills: So my concern about using an algorithm like MI Cubed with an existing tool like heart is that it will undermine much of the effectiveness of this tool which identifies around about two thirds of patients as low risk. If you were to combine that with a heart score, you would reduce the effectiveness. I don't think you get a gain in performance, but further research is required to do a head to head comparison with these sorts of traditional restratification tools.

Dr. Carolyn Lam: I'm so grateful for this discussion, both Nick and Deb. In fact, I was about to ask what are the next steps and I think Nick you just articulated it. Deb, I want to leave the final words to you. Do you have anything else to add?

Dr. Deborah Diercks: I think this study represents a real change in how we can practice medicine, where we can actually take our biomarkers that actually have really strong value and utilize them in a manner that is pragmatic. It can actually introduce and take full advantage of them, and so I think this is a great opportunity for us to rethink our usual approach, which frankly, especially for troponin has really been very binary and very static. Thank you so much Dr Mills for the innovation and the willingness to look into this area.

Dr. Carolyn Lam: Thank you so much. This paper is like a sneak peak into the future of what we'll be practicing medicine like. Well, audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

Sep 3, 2019

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr 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:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events?

Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that.

Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis.

Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis?

Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.

                                                Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.

                                                Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.

                                                They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh?

Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.

                                                So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation.

Dr Carolyn Lam:                 Nice. A lot of work. So what did they show?

Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.

                                                Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction.

Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one.

Dr Greg Hundley:             Tell us a little bit about notch signaling.

Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.

                                                So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.

                                                So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation.

Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications.

Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found.

Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.

                                                So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work.

Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion.

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that.

Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time.

Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right?

Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance.

Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me?

Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example.

Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings.

Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference.

Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts?

Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.

                                                But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk.

Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically?

Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.

                                                And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well.

Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that?

Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice.

Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct?

Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test.

Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually.

Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course.

Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.

                                                And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march.

Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs?

Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies.

Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

Dr Carolyn Lam:                 This program is copyright American Heart Association 2019.