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In this issue, author Monika Safford and Associate Editor discuss the article “Number of Social Determinants of Health and Fatal and Nonfatal Incident Coronary Heart Disease in the REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).” Then authors Jennifer Ho and Timothy Churchill discuss their Research Letter “Evaluation of 2 Existing Diagnostic Scores for Heart Failure With Preserved Ejection Fraction Against a Comprehensively Phenotyped Cohort.”   TRANSCRIPT BELOW: 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 co-hosts, I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Dr. Carolyn Lam: Guess what, Greg? We're going to talk to a lovely friend and wonderful colleague Dr. Jennifer Ho soon regarding her research letter on the HFpEF diagnostic scoring criteria. Dr. Greg Hundley: Very nice, Carolyn. Well, I've also got another feature discussion in this issue involving the reasons for geographic and racial differences in stroke. It's from the REGARDS study. But first, how about we grab a cup of coffee and jump into the next articles in the issue. Dr. Carolyn Lam: I've got my coffee, Greg and I'm ready to tell you about acute infection and endotoxinemia. We know that infections are a well-established risk factor for cardiovascular inflammation, increasing the risk for a cardiovascular complication within the first weeks after that infection. However, what is the mechanism underlying such an association? Well here, Dr. Soehnlein from Germany and colleagues utilized a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation. Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice. Dr. Greg Hundley: So, Carolyn, what did they find? Dr. Carolyn Lam: Well they found that neutrophils and specifically neutrophil extracellular traps controlled accelerated atherosclerosis during endotoxinemia. These neutrophil extracellular traps or NET-resident histone H2a, heightened arterial monocyte recruitment in endotoxinemia in a mechanism involving electrostatic charge interaction. The clinical implications are that therapeutic neutralization of NET-resident cationic molecules, including histone H2a by use of antibodies or peptides may protect patients at cardiovascular risk during an acute infection from secondary events. Dr. Greg Hundley: Wow, Carolyn. Really interesting. Well, my paper comes from Dr. David Park from New York University School of Medicine. Carolyn, elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling in the left atrium that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The authors sought in this study to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling. Dr. Carolyn Lam: Nice. And so what did they find, Greg? Dr. Greg Hundley: Well Carolyn, using the Cleveland Clinic Biobank of human left atrial specimens and their mouse models, these authors found that ETV1 is down regulated in the left atrium during cardiac pressure overload, thereby contributing to both electrical and structural remodeling of the left atrium. Dr. Carolyn Lam: Nice. Well Greg, let's talk about what else is in today's issue. There's a Perspective piece from Dr. Delgado on “Changing the Paradigm in the Management of Valvular Heart Disease: In Addition to Left Ventricular Ejection Fraction, Focus on the Myocardium. There's a Research Letter from Dr. Lurz on closure of iatrogenic atrial septal defect following transcatheter mitral valve repair, the randomized MITHRAS trial. There's an exchange of letters between Dr. McAvoy and Dr. Kim regarding the article, Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults. And an ECG challenge by Dr. Avila on complete AV block cured by atrial pacing. Dr. Greg Hundley: Very nice, Carolyn. Dr. David Saadoun has an In Depth review on medium and large vessel vasculitis and Dr. Christy Avery has a Research Letter reporting on the trends in US cancer and heart disease mortality from the period of 1999 through 2018. Well, Carolyn, how about now we jump into those feature discussions? Dr. Carolyn Lam: Yep, double features. Here we go. Dr. Greg Hundley: Well listeners, this is the first of our double feature on this January 19th and we're so fortunate today to have Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern University in Chicago. Monika, we'll start with you. Could you tell us a little of the background information pertaining to this study and what hypothesis did you want to address? Dr. Monika Safford: Sure. Well, thank you first of all, for the opportunity. We've been studying social determinants of health. I think there's a lot of attention that has come on social determinants of health from health system perspectives in recent years but I think there's less of a recognition of individual practicing physicians of what they can do. What's happened is that there are population managers at most health systems and it seems like it's a fairly distant undertaking compared to day to day clinical care. We wondered whether there was a way to begin to integrate social determinants of health more in the day to day management of patients. And that was really the major motivation here was to take this fairly late recognition, I think, compared to the sociology world of the importance and the relative importance of social determinants to see if we could help clinicians actually use this information to inform their clinical management.   Dr. Greg Hundley: Very nice. And so what was the study population that you worked with? And what was your study design? Dr. Monika Safford: Sure. The REGARDS study, REGARDS stands for reasons for geographic and racial differences in stroke, is a large national cohort, more than 30,000 people who live all over the 48 contiguous United States. About 44% of them are African-Americans and the rest are whites. Everybody was 45 and older at the time of their recruitment between 2003 and 2007. And we're now following them longitudinally for outcomes and among the outcomes are coronary heart disease and a causes of death. It's a terrific cohort to study racial disparities, if you're interested in differences between African-Americans and whites. Dr. Greg Hundley: And what did you find? Dr. Monika Safford: We did find, which was our initial hypothesis, that the greater the burden of social determinants that an individual is exposed to, the greater the independent risk. There's a definite graded risk. If you just simply count up social determinants, that should really be part of the social history that we're all taught to take in medical school. The greater the number, the higher the risk. And what was really quite concerning was that once you adjusted for all of the things that are available in a typical cohort study, physiologic measures, past medical history, health behaviors. There still was this massive, independent effect, 50% greater after accounting for all of those wonderful phenotypic markers that we have available in a cohort study. Dr. Greg Hundley: And what were some examples of these social determinants that we should all be thinking about? Dr. Monika Safford: Sure. Educational level. We all ask our patients, what was their educational attainment? Income has come a little bit under scrutiny. We don't typically ask our patients what's your annual household income? But there are lots of proxy markers so we are aware of what our patients can afford and can't afford when we prescribe medications. We have to know whether or not this is something that is within the realm of possible for individual patients. We should get a very good sense of what their financial situation is. Their social circumstances. Are they isolated? Do they live alone? Are we living in a state that is one of those states that doesn't really have a robust public health infrastructure? Are we living in a rural area? Are we in a health professional shortage area? Most physicians are aware of these types of variables. Dr. Greg Hundley: Very nice. Well, Mercy, let's turn to you. Can you help us put these findings that Monika is sharing with us today in the context with other studies that have performed really related to this topic?   Dr. Mercedes Carnethon: Certainly. I'd love to summarize that as well as ask the question. We've known for some time that social determinants of health are associated with many different health outcomes, primarily cardiovascular diseases. We know that the access that individuals have to resources to promote their health and protect themselves really do influence what happens to them in the long run. I was extremely pleased to read this paper prepared by Monika and her group in the REGARDS study because it had many strengths that exceed those of prior studies, namely the large sample size, the significant representation of both Blacks and whites, as well as the ability to study both fatal and non-fatal outcomes. And I think that the summary provided by Monika was excellent and I would love to follow with a few questions if I might. Namely, were the social determinants similarly associated with outcomes in Blacks and whites? We know certainly in this country that the two are correlated. And I just wondered whether or not you saw similar patterns of association whereby those who had adverse social determinants of health also had higher rates of mortality in both Blacks and whites? Dr. Monika Safford: Yeah. Wow, what a great question. There's only so much that you can cover in one paper. In this paper, we were really focused on this concept of the burden and a simple count of social determinants of health. And we actually did not stratify by race. We didn't examine this separately by race, but that is exactly what we're doing in another similar study right now. That is a really, really important question because some of these determinants may not be similarly associated for Blacks and whites. Dr. Mercedes Carnethon: I'd like to follow as well, so what surprised you about the findings in this study? Dr. Monika Safford: Probably the biggest surprise was the difference in the association or the strength of the association between incident fatal CHD. This is primarily sudden death and this is what we all want to try to avoid because this is people who we don't yet recognize having coronary disease. And then when they die at their presentation, it's very frustrating. We sure would love to be able to intervene. We have gotten very good at intervening after people survive a myocardial infarction but the surprising thing was that the strength of this association was really much more pronounced for incident fatal CHD than it was for non-fatal MI. We don't understand the reason for that. That's a puzzling finding that we're definitely diving into as we speak. Dr. Greg Hundley: Monika, what do you see is the next study to be performed in this space? Dr. Monika Safford: What we're doing right now is we are demonstrating that this is a robust finding across a number of different endpoints. We have a very similar study on stroke, showing large magnitude of exactly the same finding. And we have one that's about to come out on diabetes, hypertension. We are really looking to demonstrate that this approach, this very simple approach of just counting up the number of social determinants, really is a cross cutting observation across a number of different cardio-metabolic outcomes, which would then lend credence to the possibility that physicians could really integrate this into their clinical care management. There's a whole host of studies that need to be done to better understand nuances such as those that Mercedes mentioned. We are really taking a deep dive into how to integrate social determinants of health on the ground into clinical care management, not just for larger health system population managers, but for individual clinicians. Dr. Greg Hundley: Mercedes, would you like to add anything? Dr. Mercedes Carnethon: I'm very pleased to see this work and I think that I really like the practical nature of it and with the counting of the social determinants of health. I think you're right that we often can go very deep in cohort studies and look at things in very nuanced way. However, I like that this presents an opportunity for clinicians interfacing with patients to have a quick and easy tool to recognize some of the background risks that they face. Thank you for this important work. Dr. Greg Hundley: Yes. Well listeners, we really appreciate the opportunity to speak today with Monika Safford from Weill Cornell in New York and our own associate editor, Mercedes Carnethon from Northwestern in Chicago and helping us to understand how social determinants can be used clinically to help identify those at increased risk of adverse cardiovascular events. Dr. Greg Hundley: Well, now we're going to turn to our second in our double feature and we'll get to that in just a moment. Dr. Greg Hundley: Well listeners, we're now on to our second feature discussion. It's a double feature on this January 19th. And we have with us Dr. Tim Churchill and Dr. Jennifer Ho, both from Massachusetts General Hospital in Boston, Massachusetts. Well Tim, we're going to start with you. Could you describe for us a little bit of the background related to your study? And what hypothesis did you want to address? Dr. Timothy Churchill: Absolutely. The background behind this study that we wanted to look at was the recent emergence of the H2PEF score and the HFA-PEFF diagnostic algorithm coming out of the European Society just about a year ago. And we wanted to look at how these two diagnostic tools perform in terms of diagnosis of HFpEF, which as we all know, is a really challenging and complicated, varied and challenging to diagnose condition. And so our specific question, as more than a hypothesis per se, was really to investigate the diagnostic performance of both of these tools against what we consider really a gold standard hemodynamic definition of HFpEF using the patients who were undergoing comprehensive level three cardiopulmonary exercise testing with invasive hemodynamics. Dr. Greg Hundley: Very nice. Tell us a little bit, how did you configure your study population? And what was your study design? Dr. Timothy Churchill: At our institution, we have a large cardiopulmonary exercise testing program and we took patients coming in from there and who had a preserved ejection fraction, which we defined in line with guidelines as 50% or above and then available transthoracic echocardiography that we could review. And we performed a detailed research over read on the clinical transthoracic echo that had been performed. And we coupled that with the lab data that was drawn on the day of the exercise test, coupled that with the medical history that was previously collated and we tried to look at a population that had all of the necessary score components to assess each of these two scores. Dr. Timothy Churchill: And then what we did was we calculated each of the two scores and compared their outputs against, again, as I said, what we consider our gold standard definition of HFpEF, which is a invasively defined definition that accounts for both filling pressures, as well as the relationship of the pulmonary capillary wedge pressure to cardiac output with exercise. Trying to account for the changes in the wedge with increases in flow, increases in cardiac output with exercise. Dr. Greg Hundley: Very nice. And just quickly, how many patients did you include in this study? And did you have an equal representation of men and women? Dr. Timothy Churchill: We ended up including a 156 patients and there was a female predominant in line with the overarching with both our overarching exercise testing cohort, but also in line with, I would say, the overarching prevalence of HFpEF in many other studies. We ended up with 67% women with an average age of 59 years old. Dr. Greg Hundley: Very nice. What did you find? Dr. Timothy Churchill: I would say our biggest message, our biggest takeaway was that we found that both of these scores performED quite well overall and performed in a broadly similar fashion. We did note however, that there was a significant under ascertainment of HFpEF at some of the lower scores, which we highlighted as a potential weakness in terms of using these scores for the diagnosis of community HFpEF in that there was a certain number of patients with low scores who would be classified as either not having HFpEF or a low probability HFpEF, who we found to fit our hemodynamic definition. And so we highlighted that as a potential weakness or potential consideration of these. That's one area where these scores might potentially miss people. Dr. Greg Hundley: Very nice. Well, let's turn to Jennifer. Jennifer you are spending much of your career helping the world understand more or bringing to light more information really in this field of heart failure and specifically focusing on patients with preserved ejection fractions. How do you put your findings here in the context with some of the other world's literature relative to patients with heart failure preserved ejection fraction? Dr. Jennifer Ho: Thank you, Greg. First off, I just want to say that we greatly appreciate the opportunity to participate in this podcast and on behalf of all of our coauthors, we're just thrilled to be here. I guess there are a couple of points that I would take away to try to place our study within the clinical context of HFpEF in general. Number one, we know that HFpEF diagnosis is challenging, which I think is something so fundamental to our field and needs a lot further work. But a lot of other groups have really struggled with trying to define HFpEF and really figuring out who these patients are. There's a lot of work going on there. Dr. Jennifer Ho: I would say that our findings really show that these non-invasive tools developed by other groups do help enrich for individuals with HFpEF and that they perform quite well with some potential of misclassification in these lower risk individuals. I'll also say that what's new in our study is that we were able to show a direct relationship of these scores and functional implications that really affect how our patients feel. And so we were able to show that these noninvasive scores really enrich for patients with lower exercise capacity as measured by peak VO2, two worse chronotropic response to exercise, and also worse hemodynamic responses to exercise. And so I think that that's really powerful in taking these noninvasive scores that have been developed by other groups and really showing that there are direct functional consequences for our patients depending on where you're scoring. Dr. Greg Hundley: Very nice. Jennifer, where do you think we take these scoring systems next? What do you think is the next research that needs to be performed in this particular space? Dr. Jennifer Ho: That's a great question, Greg. I think we do recognize that our sample may be subject to referral bias. These are all patients who were referred for clinical indications for a cardiopulmonary exercise test with invasive hemodynamic monitoring. And so I do think that validation of these scores is necessary across wider samples so we can really affirm generalizability overall. I think on a more fundamental level, so much more work is needed in the HFpEF space in general to better understand disease pathogenesis. We recognize that there's heterogeneity with respect to clinical presentation, with respect to cardiac and extra cardiac organ involvement, with respect to how we even define the disease in the first place. I think a lot of work needs to really focus on potential deep phenotyping approaches and other approaches to tease apart potential subgroups of individuals that have HFpEF that might be more uniform so we can understand all the contributors that really lead to this disease. Dr. Greg Hundley: Very nice. Tim, would you like to add anything? Dr. Timothy Churchill: I would really echo. I think the biggest immediate question in my mind would be replicating this model and or similar approaches to really using invasive validation in other contexts that may or may not have the same referral population. One of the biggest things that drove this original study originally was that many of the other validation efforts that have formed so far have been based on consensus. And so we think there's a lot of value added by the invasive hemodynamics. And so I think extending that approach, I think can offer a lot of additional value as well in different contexts. Dr. Greg Hundley: Very nice. Well listeners, we really want to thank both Dr. Jennifer Ho and Dr. Tim Churchill for bringing us this very informative study and helping us evaluate these new noninvasive scoring methods and comparing them with really well done invasive measures to best characterize patients with HFpEF. And then as Dr. Ho said, perhaps identify groups that further phenotyping may be indicated in other research studies to identify those that are best suited for specific therapies to improve their overall condition. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.

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 Dr Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week relates to an international multi-center evidence-based reappraisal of genes reported to cause congenital long QT syndrome. But, before we get to that, how about if we grab a cup of coffee and start on our other papers? Do you have one you'd like to discuss? Dr Carolyn Lam: Yes. My favorite part of the week. So this first paper really asks the question, "What's the association between HDL functional characteristics, as opposed to HDL cholesterol levels, and acute coronary syndrome?" The paper comes from Dr Hernáez from IDIBAPS in Barcelona, Spain and colleagues who conducted a case control study nested within the PREDIMED cohort. Originally a randomized trial where participants followed a Mediterranean or low-fat diet. Cases of incident acute coronary syndrome were individually matched one is to two to controls by sex, age, intervention group, body mass index, and follow-up time. The authors measure it the following functional characteristics, which were HDL cholesterol concentration, cholesterol efflux capacity, antioxidant ability, phospholipase A2 activity and sphingosine-1-phosphate, apolipoproteins A1 and A4, serum amyloid A and complement 3 protein. Dr Greg Hundley: Wow Carolyn, a detailed analysis. What did they find? Dr Carolyn Lam: They found that low values of cholesterol efflux capacity, and levels of sphingosine-1-phosphate and apolipoprotein A1 in HDL or all associated with a higher risk of acute coronary syndrome in high cardiovascular risk individuals, irrespective of HDL cholesterol levels and other cardiovascular risk factors. Low cholesterol efflux capacity values and sphingo-1-phosphate levels were particularly associated with an increased risk of myocardial infarction, whereas HDL antioxidant or anti-inflammatory capacity was inversely related to unstable angina. Now this is significant because it's the first longitudinal study to comprehensively examine the association of several HDL function related biomarkers with incident acute coronary syndrome beyond HDL cholesterol levels in a high-risk cardiovascular risk population. Greg Hundley: Very nice. Carolyn. It sounds like function over just the levels is important. Dr Carolyn Lam: Exactly, you summarized it well. Well Greg, I've got another paper and I want to pick your brain first. Is it your impression that type 2 myocardial infarction, the type that occurs due to acute imbalance in myocardial oxygen supply versus demand in the absence of atherothrombosis, do you think that this type of MI is on the rise? It seems more and more common in my country. Dr Greg Hundley: Do we want to say it's on the rise? Certainly by measuring all these high sensitivity troponins, et cetera, we're finding, I think, more evidence of type 2 MI. So, all in all, yeah it probably is on the rise, but likely related to some of our measurement techniques. Dr Carolyn Lam: Oh, you are so smart, Greg. Because this paper that I'm about to tell you about really addresses some of these issues and it's from corresponding author Dr Gulati from Mayo Clinic in Rochester, Minnesota. And they really start by acknowledging that despite being frequently encountered in clinical practice, the population base incidents and trends of type 2 myocardial infarction is unknown and long-term outcomes are incompletely characterized. So they prospectively recruited 5,640 residents of Olmsted County, Minnesota who experienced an event associated with cardiac troponin T greater than 99th percentile of a normal reference population, which is greater than or equal to 0.01 nanograms per milliliter. And this was between 2003 and 2012, so very careful to talk about which Troponin T assay exactly to the point you discussed earlier, Greg. The events were retrospectively classified into type 1 versus type 2 MI using the universal definition. Dr Greg Hundley: So Carolyn, what did they find? Dr Carolyn Lam: They found that there was an evolution in the types of MI occurring in the community over a decade with the incidence of type 2 MI now being similar to type 1 MI. Adjusted long-term mortality following type 2 MI is markedly higher than after type 1 MI and that's driven by early and non-cardiovascular deaths. Mortality of type 2 MI is associated with a provoking factor and is more favorable when the principle provoking mechanism was an arrhythmia compared with postoperative status, hypotension, anemia or hypoxia. And these findings really underscore the healthcare burden of type 2 MI and provide benchmarks for clinical trial design. Dr Greg Hundley: Very nice, Carolyn. Well, my paper comes from type 5 long QT syndromes and an analysis. And it's from Dr Jason Roberts from Western University. Through an international, multi-center collaboration, improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in long QT 5 was sought across 22 genetic arrhythmia clinics and four registries from nine countries that included 229 subjects with autosomal dominant long QT five. So there were 229 of those subjects. And then 19 individuals with the recessive type 2 Jervell and Lang-Nielsen syndrome. The authors compared the effects of clinical and genetic predictors on a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter defibrillators shocks, aborted cardiac arrest, and sudden cardiac death. Dr Carolyn Lam: Wow. What did they find? Dr Greg Hundley: Well, several things, Carolyn. First, rare loss of function KCNE1 variants are weakly penetrant and do not manifest with a long QT syndrome phenotype in a majority of individuals. That's a little bit of a surprise. Second, QT prolongation and arrhythmic risk associated with type 2 Jervell and Lang-Nielsen syndrome is mild in comparison with the more malignant phenotype observed for type 1 Jervell and Lang-Nielsen syndrome. And then number three, all individuals possessing a rare loss of function KCNE1 variant should be counseled to avoid QT prolonging medications and should undergo a meticulous clinical evaluation to screen for long QTS phenotype. And then finally, Carolyn, the last finding, in the absence of a long QTS phenotype, more intensive measures, such as beta blockade and exercise restriction, may not be merited. Dr Carolyn Lam: Oh, very interesting. Well, I've got one more original paper and in this, authors describe a new cellular mechanism linking ischemia-reperfusion injury to the development of donor specific antibody, a pathologic feature of chronic antibody-mediated rejection, which mediates late graph loss. This paper is from corresponding author Dr Jane Witt from Yale University School of Medicine and colleagues who use humanized models and patient specimens to show that ischemia-reperfusion injury promoted elaboration of interleukin 18 from endothelial cells to selectively expand alloreactive interleukin 18 receptor 1 positive T peripheral helper cells in allograph tissues and this promoted donor specific antibody formation. Dr Greg Hundley: Carolyn, here's the famous question. What does that mean clinically for us? Dr Carolyn Lam: Aha, I'm prepared. Therapies targeted against endothelial cell derived factors like interleukin 18 may therefore block late complications of ischemia-reperfusion injury. Dr Greg Hundley: Very nice. Sounds like more research to come. Well, how about other articles in the issue? Dr Carolyn Lam: Well, I'd love to talk about a white paper from Dr Al-Khatib, and it's about the research needs and priorities for catheter ablation of atrial fibrillation and this is a report from the National Heart, Lung, and Blood Institute Virtual Workshop. Dr Greg Hundley: Well, I've got another arrhythmia paper, so this is from Professor Michael Ackerman at the Mayo Clinic and its minor long QT gene disease associations by coupling the genome aggregation database. It's a harmonized database of 140,000 or more exomes and genome derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large long QT syndrome registry to reassess the strength of these minor long QT syndrome gene disease associations. Next, Carolyn, in an on my mind piece, Professor Gerd Heusch from University of Essen Medical School discusses, how can the many positive preclinical and clinical proof of concept studies on reduced infarct size by ischemic conditioning interventions and cardioprotective drugs be reconciled with the mostly neutral results in regard to clinical outcomes. The author discusses the important differences between animal models that have been used a lot in this ischemia reperfusion and infarct size reduction science, and then the clinical scenarios of STEMI in humans as well as the many aspects of coronary reperfusion. How is that affecting the myocytes? How is that affecting the microcirculation, et cetera, that must be addressed? And then finally Carolyn, there is a series of letters, one from Professor Oliver Weingärtner from Universitätsklinikum Jena and another from Professor Yasuyoshi Ouchi from Toranomon Hospital. They're exchanging letters debating the utility of lipid lowering with Ezetimibe in individuals over the age of 75 years. Dr Carolyn Lam: Very nice, Greg. Thanks so much. Shall we now move to our future discussion. Dr Greg Hundley: You bet. Well, welcome everyone. This is our feature discussion and today we're going to hear more about long QT syndrome. We have Dr Michael Gollob from University of Toronto and our own associate editor, Dr Sami Viskin from Tel Aviv Medical Center. Good morning. Good afternoon, gentlemen. Before we get started with a discussion of some of the study findings and results, Michael, could you tell us a little bit about why you performed the study and what were some of the hypotheses you wanted to test? Dr Michael Gollob: As you know, long QT syndrome is probably the most recognized channelopathy associated with sudden cardiac death in young individuals and adults. And at the present time, there are 17 genes available for clinical genetic testing in cases of suspected long QT syndrome. We simply ask the question, "Is there sufficient scientific evidence to support that each of these genes are single gene causes of long QT syndrome based on our contemporary knowledge of genetics and the human genome? Dr Greg Hundley: Great, Michael. So, can you tell us a little bit about your study population? How did you go about this and what was your study design? Dr Michael Gollob: We designed a methods approach that would assure that any conclusions that were made from our working group were not based on the opinions of one or two individuals. We wanted to ensure that this was a consensus conclusion with multiple experts in the field including genomic scientists, genetic counselors, inherited arrhythmia experts, and researchers in the field. We created three independent teams of genetic experts to curate the genetic evidence reported in the medical literature for each of these 17 reported causes of long QT syndrome. This was essentially an evidence-based approach using a pre-specified evidence-based matrix or scoring system depending on the level of evidence, genetic primarily, in the reported literature for each gene. Each of these curation teams worked independently of each other and they were blinded to each other's work and they were tasked with concluding whether a gene, based on the medical literature and the resource methodologies, had sufficient evidence for disease causation. Their classifications would be one of disputed evidence, limited evidence, moderate evidence, strong or definitive evidence for claims towards disease causation. Remarkably, independently, all of these teams reached the same conclusion. In the end, their summary data was reviewed by a clinical domain expert panel with individuals with expertise, particularly in long QT syndrome and other channelopathies. So in total 19 individuals reviewed all of the literature and the data presented and came to unanimous conclusions for each gene. Dr Greg Hundley: Out of the 17, were there some that were more important than others or was it uniformly all 17 were relevant? Dr Michael Gollob: Well, I think the most relevant conclusions of our study are that nine of these genes, more than half of these genes, were felt not to have sufficient evidence to support their causation as a single gene cause for typical long QT syndrome. So nine genes that are currently tested by clinical genetic testing providers do not have enough evidence to support their testing in patients with suspected long QT. And to us, that is the most relevant observation because testing genes that do not have sufficient evidence for disease causation poses a significant risk to patient harm and family harm. We concluded that only three genes had very definitive evidence for causation of long QT syndrome. Those three genes were KCNQ1, KCNH2, and SCN5A. There were another four genes that were concluded to have strong or definitive evidence for unusual presentations of long QT syndrome. And by that, I mean presentations that typically occur in the neonatal period and are associated with heart block seizures or developmental delay or in the case of one of these genes, Triadin, an autosomal recessive form of the disease. Dr Greg Hundley: So helping us perhaps what types of genes to screen for when we have someone with this condition or suspected. So Sami, can you help us put this into perspective? How does this study help us in management of this clinical situation. Dr Sami Viskin: In Circulation, we immediately recognize the importance of the manuscript, the importance of the study because unfortunately, there are too many physicians all over who will accept the results of genetic testing essentially like gospel. Now it's in the DNA, it's in the genes, so whatever you find must be true. And too often, clinical decisions on treatment including ICD implantation have been undertaken based on results of genetic testing’s; thus are wrongly interpreted. So we recognize immediately the importance of this paper. We already had a different study by Dr Gollob and his associates. Again, reassessing the role of genes in Brugada syndrome. So we were familiar with this type of analysis. We recognize the importance and we moved ahead to accept this paper, it went fairly easily, I think only one revision. At the same time, we were getting additional paper by other groups. So in the same issue, we have two more papers, one from Jason Roberts with the International Long QT Registry of long QT 5, reaching similar conclusions that this is a gene with very limited penetrants and another study by the Mayo clinic also showing that many of the genes who are not the major genes are overrepresented in the healthy population. So we put all these three papers together with a very nice editorial by Chris Semsarian in the same issue. So everything is put in the right perspective of how we should be looking at all the genes of these disease in a different way. Dr Greg Hundley: So as a clinician quickly, how can I use this information in the issue, perhaps this paper and all three, in management of patients with either suspected or long QT syndrome? Dr Michael Gollob: First off, I would emphasize that the diagnosis of long QT syndrome or any genetic base disease for that matter, should be based on clinical phenotype and not the observation of a genetic change, particularly if genes are being tested that do not have strong evidence for disease causation, as is the case for the nine genes that we've pointed out in this manuscript. So I think clinicians need to be wary of the genetic testing panels that they are requesting be screened or used in the assessment of their patients and be knowledgeable that at this point in time, we really only have three genes with very strong evidence to support disease causation of the typical form of long QT syndrome. And that for the most part, these other genes should not be tested or should only remain in the realm of research. I think that responsibility extends further than just the clinician taking care of the patient, but also clinical genetic testing providers, companies that offer these genetic testing services. I think they should assume a responsibility to ensure that they are only offering services for genes that have strong evidence for disease causation because when they report results in genes that are not valid for the disease, that only confuses the care of the patient and that creates a risk of harm to them if that information is misinterpreted by a physician. As Dr Viskin or Sami pointed out, we do see patients who are inappropriately diagnosed. We remove the diagnosis of roughly 10 to 20% of cases in our own clinic. And unfortunately, many of these patients and their families have suffered undue anxiety. Some of them have ICDs in place that should not have been there. So I think overall, the field needs to be aware of what genes are relevant and what genes still are within the realm of research. Dr Greg Hundley: Can you tell us just quickly Michael and then also Sami, what do you see as the next study in this field? Dr Michael Gollob: We're taking a step back now. The first decade of this century saw an exponential growth in reported gene disease associations. And now in the last five or six years, we've learned a lot about human genetic variation, which has provided us an opportunity to reflect back on some of these previous and reported genes as causes for long QT and other diseases. So I think many individuals in our field may say, "Well, you know, this is disappointing. We believed in these genes. We really thought these genes were causes of long QT." And to that point I would say, we need more research. If you believe in some of these genes that have now been considered to have limited or disputed evidence, research should continue if these remain plausible candidates for the disease. So I think future research has to continue. There are probably still a few other genes that have not yet been discovered. I think we've got the vast majority. I think in most cases, at least in our experience, 90 to 95% of cases are explained by the top three genes. But there are probably other genes out there and it's always fascinating to learn or discover new genes, but those sorts of studies have to be done with the correct methodologies and rigid protocols. Lastly, I think in the future us clinicians and geneticists and genetic counselors need to work closely with genetic testing providers to ensure that they are offering responsible genetic testing services. Dr Greg Hundley: Sami, do you have anything to add? Dr Sami Viskin: Just congratulate the authors. I think they did a very great service to the medical community by pointing out the limitations of the genetic testing and the way we interpret the results, and they deserve to be applauded for reminding us that we have to be careful when we read papers about genetic results or when we get genetic testing results ourselves. Dr Greg Hundley: I want to thank Michael from University of Toronto and Sami from Tel Aviv Medical Center for participating. And on behalf of both Carolyn and myself, wish you all a great week and look forward to chatting with you next week. This program is copyright, the American Heart Association 2020.  

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 National Heart Center and Duke National University of Singapore Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss? Dr Carolyn Lam:                You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years. Dr Gregory Hundley:       Wow, Carolyn. What did this study find? What did Josh and his colleagues find? Dr Carolyn Lam:                They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease. Dr Gregory Hundley:       Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides? Dr Carolyn Lam:                Tell us about it, Greg. Dr Gregory Hundley:       Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy. Dr Carolyn Lam:                Interesting. What did this study do Greg? Dr Gregory Hundley:       It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals. Dr Carolyn Lam:                Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins? Dr Gregory Hundley:       Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly. Dr Carolyn Lam:                Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification.                                                 Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel.                                                 Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development. Dr Gregory Hundley:       Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC. Dr Carolyn Lam:                Huh? What did they find? Dr Gregory Hundley        Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium. Dr Carolyn Lam:                Hmm. What do you think are the clinical implications of this? Dr Gregory Hundley        This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease. Dr Carolyn Lam:                Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we? Dr Gregory Hundley        You Bet. Dr Carolyn Lam:                Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found? Dr Veli Topkara:                We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart.                                                 Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD.                                                 To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes.                                                 And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale.                                                 Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy.                                                 But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy.                                                 And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are. Dr Carolyn Lam:                Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives? Dr Mark Drazner:             As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done.                                                 And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged? Dr Veli Topkara:                I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point. Dr Mark Drazner:             Do you think their continuous flow exposure is part of it? Dr Veli Topkara:                That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question. Dr Mark Drazner:             And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct? Dr Veli Topkara:                Yes. This analysis doesn't include any HeartMate 3 patients. Dr Carolyn Lam:                And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility? Dr Mark Drazner:             There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one. Dr Veli Topkara:                We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project. Dr Mark Drazner:             Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well? Dr Veli Topkara:                Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality.                                                 We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data. Dr Mark Drazner:             And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor. Dr Veli Topkara:                That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet. Dr Mark Drazner:             Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term. Dr Veli Topkara:                Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact. Dr Mark Drazner:             Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate? Dr Veli Topkara:                Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection. Dr Mark Drazner:             That's interesting. Dr Carolyn Lam:                Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now? Dr Veli Topkara:                I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out.                                                 And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question.                                                 And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts.                                                 Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients. Dr Mark Drazner:             I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question. Dr Carolyn Lam:                Thanks again, Mark and Veli. That was an amazing discussion.                                                 Thank you, audience, for joining us. You've been listening to Circulation On The Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                                Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg. Dr Gregory Hundley:                       Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors. Dr Carolyn Lam:                                Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start? Dr Gregory Hundley:                       Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings. Dr Carolyn Lam:                                Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?   Dr Gregory Hundley:                       Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results. Dr Carolyn Lam:                                Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.                                                                 However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan. Dr Gregory Hundley:                       Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin? Dr Carolyn Lam:                                Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.                                                                 So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.   Dr Gregory Hundley:                       That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?                                                                 And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.                                                                 So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels. Dr Carolyn Lam:                                 Hm. So, how can this be addressed then? How can we raise that H2S? Dr Gregory Hundley:                       That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low. Dr Carolyn Lam:                                Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.                                                                 Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events. Dr Gregory Hundley:                       So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment? Dr Carolyn Lam:                                That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.                                                                 And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.                                                                 So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?                                                                 Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.                                                                 So, Ciantel, can you just perhaps start by telling us what you found. Dr Ciantel Blyler:                               So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.                                                                 And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group. Dr Gregory Hundley:                       Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles? Dr Ciantel Blyler:                               So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there. Dr Greg Hundley:                             Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men? Dr Florian Rader:                              So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study. Dr Greg Hundley:                             And do you think that there was more compliance in this pharmacist-led group? Dr Florian Rader:                              One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed. Dr Greg Hundley:                             It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?   Dr Ciantel Blyler:                               Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program. Dr Greg Hundley:                             And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South. Dr Ciantel Blyler:                               I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.                                                                 With respect to the area of the country again, I think it translates. Dr Carolyn Lam:                                I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share? Dr Wanpen Vongpatanasin:         I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination. Dr Greg Hundley:                             Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall. Dr Florian Rader:                              Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.                                                                 And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves. Dr Greg Hundley:                             Wanpen, do you have anything to add about Ron? I think he was your mentor as well. Dr Wanpen Vongpatanasin:         Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine. Dr Carolyn Lam:                                What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!                                                                 Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.                                                                 This program is copyright American Heart Association 2019.  

This week on SWIS ROC Radio we are entertained by the Milhollands; two new and very interesting and amusing members of the SWIS Staff. Mori who was born in Israel to American parents moved to the US when she was 14 and has lived in Paris, Brazil, Costa Rica, Australia and now China. Well Greg is from Australia and used to support Carlton but has changed colors to Western Bulldogs. This doesn't sit well with unnamed members of the Drama department! We'll leave it at that! It's all on the show. They tell us about their smooth transition to life in China, their professional background, and goals for the year. It's a very informative podcast. Mark Tymchyna in Singapore gets a extra special shout out as he is missing us. Our good friends at http://www.nogogo.cn get a special shout out for delivering my order earlier than scheduled and sending in another 200 bars for the teachers. Available Monday! Mori and Greg will be signing up for https://www.shenzheneat.com to order their food after learning about this excellent delivery service. We hear about Teachers' Tuesday on at Macawleys Seaworld every week (on Tuesday) with 10% off bill with ID card. And with the manager Craig in Vietnam this week; its a great time to visit! Just joking Craig....... Enjoy the weekend and the podcast and fingers crossed for more Red Rain! SWIS ROC RADIO Listen, Like, Learn --- Send in a voice message: https://anchor.fm/eugene-leonard/message