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Circulation February 15, 2022 Issue Feb 14, 2022

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This week's episode is special: Circulation is proud to present the 6th annual Go Red for Women issue podcast. Please join Sana Al-Khatib and James de Lemos as they welcome authors Michelle Albert and Sadiya Khan as they discuss their articles "Shining a Light on the Superwoman Schema and Maternal Health" and "Geographic Differences in Prepregnancy Cardiometabolic Health in the United States, 2016 Through 2019." Then Sana presents an overview of the other exciting articles in this important issue. Dr. Sana Al-Khatib: Hello, and welcome to this special Circulation on the Run podcast, focused on the sixth Go Red For Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I have the pleasure of co-leading the sixth Go Red for Women issue with, my friend and colleague Dr. Biykem Bozkurt. Very excited to introduce Dr. James de Lemos, the executive editor for Circulation, who will co-host this part of the podcast with me. Welcome, James. Dr. James de Lemos: Well, Thanks. I'm delighted to be here. Dr. Sana Al-Khatib: The theme of our podcast today is social determinants of health. We will discuss a perspective article in the issue, titled The Interplay of Sex with Social Determinants of Health in Cardiovascular Diseases, led by Dr. Michelle Albert, who is a cardiologist at the University of California in San Francisco. We will also discuss a research letter on geographic disparities in pre-pregnancy cardiometabolic health in the United States from 2016 to 2019, led by Dr. Sadiya Khan, a cardiologist at Northwestern Medicine in Chicago. Welcome, Doctors Albert and Khan. Dr. Michelle Albert: So pleased to be here. An honor to be part of the Go Red issue. Dr. Sadiya Khan: Thank you for having us. Dr. Sana Al-Khatib: Wonderful. So we'll start with the discussion and turn it over to you, Dr. de Lemos, to ask the first question. Dr. James de Lemos: Well, thanks, Sana. Michelle, let's start with you. I love the title of your essay. I'd like you to sort of orient our listeners as to why this title, why the topic and what you write about in your piece. Dr. Michelle Albert: Thank you, James. The title of the essay or Perspective is "Shining a Light on the Superwoman Schema and Maternal Health." We felt, along my coauthors, Dr. Rachel Bond and Dr. Annette Ansong--Dr. Ansong is a pediatrician, actually. Dr. Bond is also a cardiologist. We felt that it was really important to put forward the psychological parts of the maternal health crisis as a major social determinant of health. Most often, the focus is only on the other risk factors that we know of, like hypertension, diabetes and obesity. And while those are also extremely important, it is actually the interplay between those risk factors and social factors, including racism, including access to care, that actually drive the maternal health crisis for women of color. Particularly for black women, who have about three to four times the mortality and pregnancy complications, compared to white women. Dr. James de Lemos: Michelle, one thing that you've really defined your career by is moving to the biology of adversity. I thought the figure in your paper was striking. Can you expand a little bit on what you mean by this, and how these social determinants and the pernicious effects of things like racism and psychological stress, translate into the biology that I think Sadiya will tell us about, even in her research letter? Dr. Michelle Albert: Yes, James. As you know, I've had a longstanding research history and portfolio, looking at the interplay between biology and social factors, coined the biology of adversity. The adversity part of this is something, we often think about the ACEs, adverse childhood experiences, and think about how those relate to health outcomes, including cardiometabolic and cardiovascular health outcomes. But as we think about adults, actually, it's the adult environment that actually defines adversity for children. Certainly, as it pertains to black women and other women of color, there are certain special circumstances that get embedded into the whole framework of the biology of adversity, that lead to poor overall cardiovascular outcomes, but also maternal and non-maternal health outcomes. So conceptually speaking, the framework of the biology of adversity is the incorporation of stressors into the brain. That then results in a hyper inflammatory milieu, combined with dysregulation of the hypothalamic pituitary access, as well as the flight or fright hormones or the up-regulation of the sympathetic nervous system. And actually importantly, the down-regulation of the parasympathetic nervous system, which is an area that is actively under research currently, that then results in the downstream cascade of health effects. For black women, this is characterized by, in part, the Superwoman Schema, which includes several major themes. The first major theme is the history of oppression and racism and sexism. Also, a history of disappointment, the influences of spiritual values and form other influences, interplayed. These are stressors that incorporate with other stressors. And then there's an interplay with subscales, that focus on the ability to succeed, despite limited resources. Putting others ahead of yourself. So less self-care for yourself, but putting self-care of others ahead of your self-care, the lack of showing vulnerability, as well as suppressing one's emotions. So, all of these things interact with behavior and genetics, as well as epigenetics, to flow into that cascade of the biology of adversity. For me, I gave this presentation four years ago now, at American Heart Association, where I sort of reformatted this whole biology of adversity to incorporate the Superwoman Schema, which was first defined or characterized by Cheryl Woods-Giscombé, who is a PhD scientist in the United States. Dr. Sana Al-Khatib: Now, that was very helpful and insightful, Michelle. Could you tell us about, what are the main next steps that need to be done in this area, that you think are going to be important to move this line of research forward, so that we can actually change this situation and really improve healthcare for these women? Dr. Michelle Albert: Well, I like to think of the answers to that question on several levels. So, I think one of the first levels is ensuring that women, especially women of color and specifically black women, are aware of the fact that hypertension, preeclampsia and eclampsia are risk factors, not only for their pregnancy, but also for cardiovascular disease later on, and for their children developing hypertension and cardiovascular disease later on. So, I think education is really important, on one level. On the next level is, actually having a continuum of care, where women are asked to get early prenatal care, even when they're contemplating pregnancy. So that they can be screened for hypertension, diabetes and their stressors, assessed and put in contact with resources. Having doulas, midwives involved in this process, as well as cardiologists who are involved in the pregnancy setting, as well as post-pregnancy for these women. Then, there's an advocacy initiative that has to take place, that focuses on getting aid. Kamala Harris has put forward a bill to actually do just that for maternal health, focusing on racism and bias in healthcare, because black women across the spectrum of socioeconomic status, experience poor maternal health outcomes. So, this is not only an access to care issue. It's not only a socioeconomic status issue. It is an issue that pertains to the women not being listened to, with racism and other stressors. I can't stress those first two things more, the whole discrimination part of it, and dumbing down the concerns of black women. Then, I think on a research perspective, certainly the American Heart Association has got now this HERN Network, which is a network that's going to focus on research around maternal health. So in that context, figuring out the best care models for women. Understanding the biology and how it interplays with poor outcomes later on, is also very important. One point around the biology that I want to point out for, let's say, African American women and actually Asian women as well, is that there's a higher prevalence of fibroids. There's very little research focusing on fibroids and its importance on maternal health outcomes and even the care for those women. Frankly, in my mind, a lot of that has to do with bias and how we value the healthcare of certain groups of women over other groups of women. So, those are some of the things, in terms of the solutions. Dr. Sana Al-Khatib: Absolutely. Before we move on to the presentation by Dr. Khan, are there any final words Michelle, that you'd like to share with the group, in terms of any final wisdom, so to speak, that you want to leave the listeners with? Dr. Michelle Albert: Yeah. I would just say that the maternal health crisis is preventable and it is tied into... Much of our audience are going to be healthcare providers. To the healthcare providers, I'm going to say, you really, really need to listen to these women when they tell you that they're experiencing certain symptoms. You also need to dig deeper to find out about their concerns, especially their stressors, in addition to making sure their blood pressure is controlled and that their weight is managed. Dr. James de Lemos: Well, thank you, Michelle. We'll turn to Sadiya now, and her team's research letter on geographic differences in pre-pregnancy cardiometabolic health in the US. For our listeners, I think what you'll see, if you read this paper, is how remarkable the research letter format is, and how much information Dr. Kahn and her team have conveyed in this really, really powerful letter, that I think has major public health implications. Sadiya, do you mind orienting our listeners to what you studied and how you did it? Dr. Sadiya Khan: Thanks, James. And again, thank you for the opportunity to join you guys in this podcast. I think Michelle very eloquently set up the preface for this research letter, which was understanding that health in pregnancy begins before conception. That was really the reason we wanted to focus on health factors, particularly cardiometabolic health factors, like body mass index, diabetes status and hypertension status in the pregnant individual, prior to pregnancy. The second piece of this that we were really interested in, is that we had observed that there are significant differences across the United States, in maternal morbidity and mortality outcomes. There are much higher rates of pregnancy-related deaths occurring in the South and Midwest, compared with other states in the US. That led us to ask this question, if we're able to better describe or define health prior to pregnancy, will we see similar patterns? We used the Centers for Disease Control Natality database, which includes all live births in the United States. So, the strength of this dataset, is that this is a surveillance system employed by the CDC, to monitor and record health outcomes of the pregnant individual and the newborn in the United States. Using this dataset, we were able to display maps for pre-pregnancy cardiometabolic health and look at changes from 2016 to 2019. Unfortunately, there's not much positive news, in that we've seen continued declines in favorable or optimal pre-pregnancy cardiometabolic health, which we defined as having a normal BMI and the absence of diabetes or hypertension. In addition, we saw that the levels of favorable pre-pregnancy cardiometabolic health were lower in the South and Midwest. It starts to set up some questions about upstream social determinants of health, that may be playing an important role as we start to address this problem at the individual level, but also at the societal and population level. Dr. Sana Al-Khatib: Very interesting and important findings there, Sadiya. Are you planning to work on additional research, to build on the research that you were publishing in this issue? Dr. Sadiya Khan: One of the most important questions that came from this are, what are the potential ways to start to address and support care for pregnant individuals, or as I think is Michelle really nicely put it, is for preconception care. So, thinking more about the reproductive life course before pregnancy, as well as during and after pregnancy. For that, one of the things that seems to be potentially really important, could be how Medicaid expansion has helped in states that have expanded, and differences between states that have or have not expanded Medicaid. Knowing that, that probably isn't sufficient, but it has that been helpful. Dr. James de Lemos: Yeah. I was struck, Sadiya. I mean, Michelle's essay and your research project really shine a bright and distressing light on maternal health in the US, I think and the crisis that we're under, that many of us don't even maybe recognize is happening. The time trends you showed were, to me, striking, giving over such a short period of time, how much maternal cardiovascular health has declined. It seems, indirectly at least maybe, that declining at a higher rate than overall cardiovascular health. I first applaud you for writing on this topic because I think it brings this issue to light, in terms of a public health crisis, frankly. But I wonder if you have any thoughts on why specifically, things are declining at such a higher rate for pregnant women or pre-pregnant women, maybe relative to national trends? Maybe they're not. Maybe this is what's happening across all age and gender demographics. Dr. Sadiya Khan: It's a really important observation. I agree with you. It seems like it's much more striking in this concentrated and focused group of individuals, that are pregnant and giving birth. It's possible because of the age range that we focus on, the 20 to 44 year old age range, that there are potentially more significant declines happening during this time period. We know cardiovascular health in general, appears to have some age-dependent dips, generally around adolescence. That early adulthood, college age period seems to be where a lot of cardiovascular health decline happens. So, I think that's what we're observing, as we're seeing these more striking trends in this age group. But it would be interesting to know, compared to non-pregnant individuals and across the life course, if that is in fact, the case. Dr. Sana Al-Khatib: Then I'll ask you what I asked Michelle, Sadiya. Any final words of wisdom that you'd like to share with our listeners? Dr. Sadiya Khan: I don't know if I'll be able to speak as eloquently as Michelle did. I think her responses really capture both of these papers and thinking about ways forward, about how we can dress the maternal health crisis. But I think that the word that she used, that really sticks with me and is one of the reasons that I'm so passionate about this work, is that this is preventable. That there are so many different things that could be in place, whether it's at the individual clinician and patient level, at the individual health system level, at the state level, as we looked at here, but really at the national level as well. I think we have a lot of work to do, but there's a lot of things that we know can help. Dr. Sana Al-Khatib: Great. Wonderful. James, any final words from you before we wrap up this part of the podcast? Dr. James de Lemos: First, Sana and the rest of the Circulation team, I congratulate you on another spectacular Go Red issue, that really is such…

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Circulation February 8, 2022 Feb 07, 2022

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Please join author David Webb and Editorialist Steven Smith as they discuss the original research article "Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?" Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries. Dr. Carolyn Lam: The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Dr. Carolyn Lam: The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment. Dr. Carolyn Lam: The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada. Dr. Carolyn Lam: The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction. Dr. Carolyn Lam: So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] "Why Are We Still Prescribing ACE Inhibitors?" and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion. Dr. Carolyn Lam: For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that. Dr. David Webb: So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure. Dr. Carolyn Lam: Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found? Dr. David Webb: So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer. Dr. Carolyn Lam: And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension? Dr. David Webb: Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated. Dr. Carolyn Lam: So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be? Dr. Steven Smith: Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results. Dr. Steven Smith: As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen Dr. Carolyn Lam: Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David? Dr. David Webb: Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures. Dr. David Webb: And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects. Dr. Carolyn Lam: And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most im…

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Circulation February 1, 2022 Issue Jan 31, 2022

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Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged." 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, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful. Dr. Carolyn Lam: So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable. Dr. Carolyn Lam: The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable. Dr. Carolyn Lam: And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes. Dr. Carolyn Lam: The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker. Dr. Carolyn Lam: Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis. Dr. Carolyn Lam: High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift. Dr. Carolyn Lam: There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address? Dr. Louise Olde Nordkamp: Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks. Dr. Greg Hundley: Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial. Dr. Louise Olde Nordkamp: Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication. Dr. Greg Hundley: Very nice. And so tell us your study results. Dr. Louise Olde Nordkamp: Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups. Dr. Louise Olde Nordkamp: So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm. Dr. Greg Hundley: Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Mark Link: Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community. Dr. Greg Hundley: Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing. Dr. Sana Al-Khatib: Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes. Dr. Sana Al-Khatib: And so, this study certainly makes us question some of those findings, but really I feel like it wil…

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Circulation January 25, 2022 Issue Jan 24, 2022

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Please join authors Christopher Granger and Anthony Carnicelli, as well as Associate Editor & Editorialist Shinya Goto as they discuss the article "Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex" and accompanying Editorial "Patient Level Meta-Analysis: End of the Era for DOAC Developmental Trial in AF Patients?" 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 Dr. Carolyn Nam, 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. Dr. Carolyn Lam: Greg, I'm so excited about our feature discussion today. It is about DOACs versus warfarin in patients with atrial fibrillation, a really important patient-level network meta-analysis of randomized control trials with interaction testing by agent six. So you can already tell something very, very clinically relevant and important discussed by not only the authors, but our dear associate editor and editorialist. Dr. Carolyn Lam: Okay. You just got to tune in, but first I'm going to start us off with some coffee, as well as a description of this first paper in today's issue. The 2018 AHA ACC multi-society cholesterol guidelines states that statin therapy may be withheld or delayed among intermediate risk individuals in the absence of coronary artery calcium. Dr. Carolyn Lam: However, two traditional cardiovascular risk factors associate with incident atherosclerotic cardiovascular disease events among individuals with zero coronary artery calcium over the long term? Well, this is the question that investigators decided to answer in today's paper and they're led by Dr. Virani from Baylor College of Medicine in Houston, Texas. Dr. Carolyn Lam: They studied 3,416 individuals with coronary artery calcium score of zero at baseline from the MESA study, which is a prospective cohort study of individuals free of clinical atherosclerotic cardiovascular disease at baseline. Among these individuals with zero coronary artery calcium, cigarette smoking, diabetes and hypertension were found to be independently associated with incident atherosclerotic cardiovascular disease events over long-term follow up. Dr. Greg Hundley: Ah, very interesting. Another piece of information relating to how we might use coronary artery calcium scores in, it sounds like, a high-risk patient population. So, Carolyn, what's the take-home message here? Dr. Carolyn Lam: Well, even if individuals have a coronary artery calcium of zero, if they are current smokers, if they have diabetes melitis or hypertension, initiation and long-term use of statin therapy, along with a heart healthy lifestyle and risk factor modification may still be warranted as part of the patient/clinician risk discussion. Dr. Greg Hundley: Very interesting Carolyn. Well, I've got a clinical study to tell you about. And, Carolyn, as you know, obesity and diabetes are associated with a higher risk of heart failure and the inner relationships between different measures of adiposity, including overall obesity, central obesity, fat mass, and diabetes status for heart failure risk, are not well established. Dr. Greg Hundley: And so this investigative group, led by Dr. Ambarish Pandey, from UT Southwestern Medical Center, looked at the ARIC, the visit five in ARIC and CHS, the visit one, and cohorts together, and they were obtained from the NHLBI BioLINCC. They were harmonized and pooled for the present analysis, excluding individuals with prevalent heart failure. Dr. Greg Hundley: So using multi-variable adjusted fine-grade model models were created to evaluate the associations of body mass index, waist circumference, and fat mass with risk of heart failure in the overall cohort, as well as among those with, versus without, diabetes at baseline. Dr. Greg Hundley: And the population attributable risk of overall obesity with BMI greater than 30 kilograms per meter squared, abdominal obesity with waist circumference greater than 88 and 102 centimeters in women and men, respectively, and high fat mass above the sex-specific median for incident heart failure, was evaluated among participants with and without diabetes. Dr. Carolyn Lam: Ooh, I'm so in interested in this topic. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So a large study, it included 10,387 participants, about 53% from ARIC, 25% had diabetes, and the median age was 74 years. And higher levels of each adiposity measure were significantly associated with higher heart failure risk. The population-attributable risk percentage of overall obesity, abdominal obesity, and high fat mass for incident heart failure was higher among participants with diabetes versus those without diabetes. Dr. Greg Hundley: And so, Carolyn, we can conclude from this research that higher BMI, higher waist circumference and higher fat mass, are strongly associated with greater risk of heart failure among older adults, particularly among those with prevalent diabetes. Dr. Carolyn Lam: So, so nicely done. Thank you, Greg. Well, the next paper talks about common ancestry-specific ion channel variants and how they predispose to drug-induced arrhythmias. Now, we know that multiple reports associate the cardiac sodium channel gene Scn5a variants, and these are the specific variants, S1103Y and R1193Q, with Type 3 congenital long QT syndrome and drug-induced long QT syndrome. Dr. Carolyn Lam: These variants are, however, two common in ancestral populations to be highly arrhythmogenic at baseline. The S1103Y allele frequency, for example, is 8.1% in Africans and the R1193Q is 6.1% prevalent in East Asians. So the investigators, led by Dr. Roden from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues, determined the effect of the S1103Y variant on QT intervals among 1,479 Africans from a large electronic health record with no confounding medications or diagnosis of heart disease. Dr. Carolyn Lam: Now, while both the specific variants generated increased late sodium current, baseline action potential durations in cardiomyocytes from induced pluripotent stem cells carrying these variants were unexpectedly normal. The re-polarizing potassium current, IKR, was markedly increased in these induced pluripotent stem cells with the variants, accounting for normal baseline action potential duration but, with exposure to an IKR blocker, they displayed exaggerated action potential duration prolongation and after depolarizations. Dr. Greg Hundley: Wow, Carolyn, interesting. So tell us, what are the clinical implications of this really exciting research? Dr. Carolyn Lam: Yeah. So here's the take-home message. These common ancestry-specific variants do not affect baseline re-polarization, despite generating an increased late sodium current. So the authors propose that increased re-polarizing potassium current, IKR, serves to maintain normal re-polarization, but increases the risk of manifest QT prolongation with IKR blocking in these variant carriers. So we need to be aware of that and, further, these findings highlight the need to include ancestral diversity in genomic and pharmacogenomic studies. Dr. Greg Hundley: Oh, wow. Beautifully described, Carolyn. I really appreciate that. Just excellent discussion. Well, Carolyn, my next paper comes to us in an investigation regarding doxorubicin or anthracycline-associated induced cardiotoxicity. So, Carolyn, multiple pharmacogenetic studies have identified the synonymous genomic variant rs7853758 and the intronic variant rs885004 and SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity. Dr. Greg Hundley: However, the true causal variant, or variance, of this cardioprotective mechanism at this locus, the role of SLC28A3 and other solute carrier transporters in anthracycline-induced cardiotoxicity and the suitability of solute carrier transporters as targets for cardioprotective drugs has not been investigated. Dr. Carolyn Lam: Wow. Got it. So what did these investigators do and find, Greg? Dr. Greg Hundley: Right. So Paul Burridge and his colleagues at Northwestern University found that the patient-specific cardiomyocytes recapitulate the cardioprotective effect of the cGAS-identified SLC28A3 locus, and the authors functionally confirmed for the first time, the role of SLC28A3 in doxorubicin-induced cardiotoxicity. Dr. Greg Hundley: And a novel genetic variant, the rs11140490, is the potential causal variant in the SLC28A3 cardioprotective locus. And finally, Carolyn, the solute carrier transporter inhibitor desipramine protects against doxorubicin-induced cardio toxicity through decreasing the intracellular uptake of doxorubicin into the heart. Dr. Carolyn Lam: Wow. That is a lot of data. Could you summarize it for us, Greg? Dr. Greg Hundley: Right, Carolyn. So these investigators provide two potential therapeutic options to attenuate doxorubicin-induced cardiomyopathy, either repurposing FDA-approved desipramine, or therapy with long non-coding RNA SLC28A3-AS1. Also, Carolyn, they propose that a simple clinical test to detect the presence of rs11140490 can be used to predict that a patient will be less likely to experience doxorubicin-induced cardiomyopathy, and that, perhaps with future clinical trials, it may be possible for these patients to be treated with a longer duration, that is a higher accumulative dose of doxorubicin, to enhance the efficacy of their chemotherapy. Dr. Carolyn Lam: I love the way you took that home for us. Thank you, Greg. Well, also in today's issue is a Research Letter by Dr. Chen on multifaceted spacial and functional zonation of cardiac cells in an adult human heart. Dr. Greg Hundley: Right, Carolyn. And Professor Constantine has a Letter to the Editor entitled Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Well, Carolyn, how about we get onto that feature article and learn about DOACs versus warfarin in this very large network meta-analysis? Dr. Carolyn Lam: Yes, yes, yes. Let's go, Greg. Thanks. Dr. Greg Hundley: Welcome, listeners, to our feature discussion today. And we're very fortunate. We're going to review the utility of DOACs in patients with atrial fibrillation. And we have with us two of the authors of this original research, Dr. Anthony Carnicelli from Duke University, and Dr. Chris Granger from Duke University. Dr. Greg Hundley: Additionally, we have with us our associate editor, Dr. Shinya Goto, from Japan. Welcome, gentlemen. Anthony, we'll start with you. Describe for us a little of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Anthony Carnicelli: Yeah, thanks so much, Greg, for having us here to discuss this. I started working in the DOAC space when I was a resident at Brigham and Women's Hospital with mentorship from Dr. Bob Guigliano there, and was really fortunate to connect with Dr. Granger when I came to Duke for a fellowship, and we had this unique opportunity to take data out of the four largest trials of anticoagulants in the atrial fibrillation, and take individual patient data from these international centers and combine them to form the combined AF database from which we did this analysis. Dr. Anthony Carnicelli: So a very unique opportunity here to have individual patient-level data from over 70,000 patients, and perform this analysis. And, really, what we aimed to do was to do the kind of highest quality meta-analysis using network meta-analysis methods to investigate the relative safety and efficacy of DOACs versus warfarin and a broad and diverse, but randomized, population of patients with atrial fibrillation. Dr. Greg Hundley: Very good. So you started to describe for us your study population and your study aligns. So tell us a little bit more, who were these patients, and then maybe specifically give us a little bit of the outline of your meta-analysis. Dr. Anthony Carnicelli: Yeah, so these were, again, a very broad patient group, but from kind of 10,000 feet, this was a population of patients with atrial fibrillation who were at risk of stroke, from CHADS score perspective. So there are some nuances from each of the included studies, of course, regarding the individual risk of stroke from one study to the next. But largely, as I mentioned, in patients with non-valvular atrial fibrillation randomized to either DOAC or warfarin. Dr. Anthony Carnicelli: And, from a method standpoint, we are fortunate at Duke and at DCRI, to have an expert in the network, meta-analysis methodology, whom we've worked with, Dr. Bonnie Huang, who helped to put together the analysis here and to proceed with this kind of network methodology. Dr. Anthony Carnicelli: And so, again, our goal was to evaluate the overall safety and efficacy of DOACs versus warfarin, but then also to dive into some specific subgroups, both from a categorical covariant perspective, and then also to evaluate some continuous covariants, specifically age, and to assess gender across the entire spectrum of continuous age in our population, which, of course is a unique opportunity in the individual patient-level data. Dr. Greg Hundley: And, Anthony, you had, gosh, it looks like over 70,000 patients in this particular analysis. Tell us a little bit about the results. Dr. Anthony Carnicelli: Yeah, so interesting, actually, and I agree that the biggest strength of our meta-analysis is the individual patient-level data and also the profound number of randomized patients included. So I think, from a high level, the most important results to highlight are the fact that there is a 19% relative risk reduction in stroke or systemic embolism among patients who are randomized to DOACs compared to warfarin, with an 8% reduction in all-cause death and a 55% reduction in intracranial hemorrhage. Dr. Anthony Carnicelli: So a massive reduction in the most feared complications of both atrial fibrillation and then also those associated with systemic oral anticoagulation. We also found a trend towards less bleeding in patients randomized to the standard-dose DOAC group, as well. Dr. Greg Hundley: Very good. Well, Chris, we're going to turn to you. What an exciting discovery here, and beautiful methodology. I wonder, in addition to what Anthony has shared with us, were there particular outcomes that were pertinent to men versus women or perhaps related to age? Dr. Christopher Granger: Yeah, Greg. So, again, we're proud of this as being really the state-of-the-art ability to evaluate safety and efficacy in this incredibly important population of patients with Afib and at risk for stroke, and to be able to dive into the subgroups and to the individual outcomes, even the less common outcomes. And one of the most striking things, and this really reinforces prior data, but with the greatest confidence of any study ever done, there was this 55% at reduction in intracranial hemorrhage and 19% reduction in total stroke and systemic embolism, really highlighting that these drugs are clearly better than warfarin, from reinforcing the guidelines. Dr. Christopher Granger: And the message with the subgroups is there was really a remarkable amount of consistency. And specifically in the older population where people are really concerned about anticoagulation, there was a clear and consistent major advantage of DOACs over warfarin. Men versus women, clear, clear, compelling benefit of DOACs over warfarin across each of these outcomes, including mortality, by the way, 8%. But…

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Circulation January 18, 2022 Issue Jan 18, 2022

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Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial." 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 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, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first? Dr. Carolyn Lam: I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues. Dr. Greg Hundley: Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about? Dr. Carolyn Lam: Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations. Dr. Greg Hundley: Very interesting Carolyn. Now you've got another study. Is this one on EMPA? Dr. Carolyn Lam: You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status. Dr. Greg Hundley: Very nice, super review Carolyn. So what were the results of this study? Dr. Carolyn Lam: In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year. Dr. Greg Hundley: Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed. Dr. Carolyn Lam: Wow, interesting. So what did they enroll in? How did they do this? what did they find? Dr. Greg Hundley: Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations. Dr. Carolyn Lam: Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper? Dr. Greg Hundley: Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk. Dr. Carolyn Lam: Huh? Okay. Well, I'm super excited to hear what these investigators did Greg. Dr. Greg Hundley: Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk. Dr. Carolyn Lam: Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on "The Long-Awaited Revascularization Guidelines are Out. What's In Them?" A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic. Dr. Greg Hundley: Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion? Dr. Carolyn Lam: Very Cool. Closure devices after TAVR. Here we go. Dr. Greg Hundley: Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address? Dr. Mohamed Abdel-Wahab: Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced. Dr. Mohamed Abdel-Wahab: And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR. Dr. Greg Hundley: Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study? Dr. Mohamed Abdel-Wahab: So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible. Dr. Mohamed Abdel-Wahab: Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores. Dr. Greg Hundley: Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization? Dr. Mohamed Abdel-Wahab: Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry. Dr. Greg Hundley: Very nice. And can you describe for us, Mohamed, your results? Dr. Mohamed Abdel-Wahab: Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant. Dr. Greg Hundley: And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age? Dr. Mohamed Abdel-Wahab: Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups. Dr. Greg Hundley: Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future? Dr. Mohamed Abdel-Wahab: I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future. Dr. Mohamed Abdel-Wahab: For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies. Dr. Greg Hund…

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Circulation January 11, 2022 Issue Jan 10, 2022

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This week's Feature is a Panel Discussion. Circulation invited the Young Investigator Finalists who had a Simultaneous Publication for AHA's 2021 Sessions. Please join authors Amgad Mentias, Matthew Burrage, Shaan Khurshid, Sevedeh Maram Zekavat, and Neel Butala as they discuss their articles. Dr. Greg Hundley: Welcome listeners to this very special January 11th issue of Circulation on the Run. And I'm going to tell you why it's special. I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia and also associate editor at Circulation. Why is this issue special? Because we have the opportunity to speak with finalists for several of the awards that were presented or that these investigators presented for at the American Heart Association sessions. And so we have with us today, five early stage investigators and we are going to hear about each of their research projects and the manuscripts that are coming out and are published in this issue. Want to welcome all five of you and we'll introduce one at a time as we work through their research projects. And the first is Dr. Amgad Mentias from Cleveland Clinic and he was in the session competing for the Elizabeth Barrett-Connor Research Award for early career investigators in training. Welcome Amgad. And we'll start with you. Can you tell us a little bit about the background for your study and what was the hypothesis that you wanted to address? Dr. Amgad Mentias: Hi, Dr. Hundley. How are you? Thank you so much for inviting me today. A little background, we know that community economic distress affects outcomes in patients with heart failure. It actually affects both short term and long-term outcomes. What was not studied on a nation level before is how is that impact different or if it's actually different between different races. In White patients and Black patients and Hispanic patients, what would be the differentiated effect of community economic distress on their short and long-term outcomes with heart failure after a heart failure admission? Dr. Greg Hundley: Absolutely. And so that hypothesis that you were going to address, what were you hypothesizing here? Dr. Amgad Mentias: We were hypothesizing that each race has probably some shared risk factors but also some specific risk factors. We were hypothesizing that the community level economic distress effect on heart failure outcomes is not homogeneous or not exactly the same between all races. Dr. Greg Hundley: Very nice. And so what was your study design? And describe a little bit for us the study population. Dr. Amgad Mentias: We included the Medicare population. We included patients who were admitted with a primary diagnosis of heart failure from the years 2014 till 2019. We included patients from Black and White and Hispanic races or ethnicities. And we only included the first admission for a patient if the patient was admitted more than once during these years. That was the study population. And we had about 1.6 million White patients and about 205,000 Black patients and around 89,000 Hispanic patients. Dr. Greg Hundley: Great. And so was this a cohort design? Dr. Amgad Mentias: Yes, it was a cohort design. The study start date was when they were admitted to the hospital for our mortality outcome and when they were discharged from the hospital for readmission outcomes. And then we followed them in time up to one year. Dr. Greg Hundley: Very nice. And so tell us, what did you find? Dr. Amgad Mentias: Our primary exposure of interest, like we said, was economic distress and race and our primary outcome was three things, mortality, the second thing is readmission burden, which is number of admissions over time the patient is alive and third thing is home time how many days the patient spends at home, out of the hospital and out of skilled nursing facilities and LTACs. And we looked at these outcomes at three different points, at 30 days, at six months and at one year follow up. Initially we did an interaction and that is to see whether our hypothesis, that the effect is different or not between a race and term and the economic distress term. And the interaction was significant, in all three outcomes. Then we went deeper and we started to study each race separately and see how economic distress affects their outcomes. We defined economic distress by distress score called the distressed community index, which is a composite measure of seven things, including education of the people in the zip code, unemployment, poverty rate and income in the zip code compared to the state level and that stuff. Dr. Amgad Mentias: We actually found that in White patients, economic distress was actually associated with adverse outcomes in the short and long term. In Black patients, it was affecting the outcomes more robust and more evident in the long term, not in the short term. We also found the geographic location and their approximate location, whether it's urban or rural, residential zip code also affected outcomes. We found that in all races being in a rural distressed community had the highest posterity and the highest admission burden and the worst home time compared to other communities. In fact, people in distressed urban communities had comparable outcomes. People in rural, non-distressed communities had comparable outcomes to urban distressed. We found that the rural location and approximate location near resources affected outcomes in all races but specifically also in Black patients. Dr. Greg Hundley: Very nice. And how do you put your results in context with others that are doing research in this area? Dr. Amgad Mentias: We show that the interplay between economic distress and societal factors and different things for heart failure is very complex and there is a complex interplay between different factors. I think it's very important for health policies that targeting improvements in community with economic distress and access to care, they are key to improving outcomes and reducing racial disparities among patients with heart failure. Dr. Greg Hundley: Beautiful. Well, Amgad, we want to congratulate you on this just excellent work in identifying associations between community level economic distress and risk of adverse outcomes across different race ethnic groups. Congratulations to you. Dr. Greg Hundley: Well listeners, next we're going to turn to Matthew Burrage from University of Oxford. And Matt was a finalist for the Melvin Judkins Early Career Clinical Investigator Award. Matt, just like with Amgad, could you tell us a little bit about the background that went into your research project? And what was the hypothesis that you wanted to address? Dr. Matthew Burrage: Yeah, certainly. And thank you very much for the invitation to take part in this discussion. Really it's a pleasure to be here. The inspiration for this study was really driven by the difficulties that we've been having in trying phenotype heart failure with preserved ejection fraction or HFpEF, given that until very recently, there were really no therapeutic agents that have significantly improved outcomes for this population. This is despite the fact that around half of all heart failure is classified as HFpEF. And so the thought is that this is a very heterogeneous population but when you dig down into the physiology, there seems to be a central mechanism which involves impairment of myocardial relaxation and in a subsequent rise in intracardiac filling pressures. And this is something that's often unasked by exercise and typically this then results in pulmonary congestion and symptoms of breathlessness. And so some recent translational studies suggests that abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of HFpEF. Dr. Matthew Burrage: And given that we know myocardial contraction is dependent on cardiac energy metabolism and that diastolic relaxation is even more energy dependent, we hypothesized that impairment of myocardial energetics may underpin a lot of the physiological changes in the heart that occur during exercise and thus could potentially present a metabolic basis that underlies symptoms in patients with HFpEF, with the hope that this could then lead to new translational drug targets for HFpEF in the future. But then alongside this as well, there's been some really pivotal work on pulmonary congestion during exercise in HFpEF that's been led by Barry Borlaug's group at the Mayo Clinic as the main determinant of patients' symptoms. This has been very well validated against invasive hemodynamics. The second component of our study was to see if we could noninvasively assess pulmonary congestion during exercise and HFpEF. And so to do this, we developed and implemented a new MRI sequence that could quantitatively assess changes in lung water. Dr Greg Hundley: Very nice. How did you address the hypothesis in terms of your study design and your methodology? Dr. Matthew Burrage: This was a prospective study that followed essentially a basket trial design, where we recruited four distinct groups of participants that were felt to really encompass the spectrum of worsening diastolic dysfunction in HFpEF, which was based on clinical scoring systems, blood biomarkers and echocardiography. We recruited 43 participants split across this group and so we had a cohort of age matched, healthy controls. We had patients with cardiometabolic risk factors for HFpEF like diabetes and obesity who were included essentially if you think of it like a pre-HFpEF group, patients with carefully clinically phenotyped HFpEF and then a cohort of patients with cardiac amyloidosis. And the amyloid group was recruited really as a positive control, that the proof of principle lung imaging sequences, as the presence of restrictive physiology in those patients meant they would be the group that would be far most likely to develop pulmonary congestion during exercise. Dr. Matthew Burrage: And so each participant underwent blood sampling, a targeted echocardiogram, they had magnetic resonance spectroscopy to assess myocardial energetics and cardiac metabolism. We do this by measuring the phosphocreatine to ATP ratio and also a cardiopulmonary exercise MRI. The exercise protocol for the study was a fixed low intensity workload of 20 Watts for six minutes with the patient supine within the MRI scanner using an ergometer. And then during exercise, we did whole heart free breathing cine stacks to assess cardiac volumes at rest and exercise, as well as performing our custom proton density weighted lung imaging sequence to look at changes in pulmonary congestion. And if you're interested, the whole rest and stress protocol together can be done within about 15 minutes. Dr. Greg Hundley: Wow. Boy, very exciting. Exercise during an MRI scan. Matt, we're very anxious to hear, what did you find? Dr. Matthew Burrage: The key findings from this study is that there really is a clear gradient myocardial energetic impairment that exists across the spectrum of diastolic dysfunction and HFpEF phenotypes of increasing clinical severity and worsening diastolic function. And this gradient of impaired myocardial energetics was associated with progressively abnormal exercise responses compared to normal physiology in the age matched controls. And so a greater degree of energetic deficit was linked to impaired left ventricular systolic and diastolic functional reserve. It was also linked to altered right ventricular reserve and abnormal RV-PA coupling and also to exercise induced pulmonary congestion. Dr. Matthew Burrage: And we also showed that the pulmonary congestion or changes in lung water could be quantitatively assessed using our new proton density lung imaging sequence and that there is a subgroup of patients with HFpEF who do demonstrate transient pulmonary congestion during exercise that we can assess noninvasively. Overall, the findings suggest a pathway where impaired energetics are linked to patient symptoms and they do this by limiting cardiac reserve during exercise and promoting pulmonary congestion. There seems to be a really important role of resting cardiac energetics in signaling the abnormal ability of the heart to perform high energy consuming processes like active diastolic relaxation and augmentation of contractility and then this leads of course to the downstream effects that we see. Dr. Greg Hundley: Very nice. And you were able to even also observe the lung water. It sounds like, help us put this in context for our listeners of how do your results really advance some of the understanding of the pathophysiology of heart failure with preserved ejection fraction? Dr. Matthew Burrage: I think one of the key impacts of this study is the fact that the heterogeneity of clinical HFpEF syndromes has been such a major challenge to efforts to develop new therapies to improve symptoms and prognosis in these patients. Pathophysiological phenotyping may represent an important step towards targeting the right therapies to the right patients and specifically targeting myocardial energy metabolism may be a promising therapeutic strategy to improve cardiac reserve and potentially reduce pulmonary congestion in patients with HFpEF. And this really builds on all the translational studies that exist today and have gone before it. Dr. Matthew Burrage: Hopefully the mechanistic insights that we get from this could lead to some new translational drug targets, which can be tested against myocardial energetics in patients to see if this metabolic substrate is modifiable. And if this then leads to improvements in symptoms and outcomes. The second aspect very quickly, relates to the evaluation of patients with breathlessness, particularly because invasive hemodynamic assessments may not be possible in all patients who have breathlessness on exertion. The lung water imaging represents a potentially new diagnostic tool that can help to differentiate HFpEF from other causes of dyspnea and I think this is some something that may have a lot of direct clinical applications for patient diagnostics for a wide range of conditions in future. Dr. Greg Hundley: Very nice. Well, thanks so much for what outstanding work, identifying this myocardial energetic deficit and then linking that to both cardiac performance, as well as the development of pulmonary congestion. Dr. Greg Hundley: Well listeners, we are going to switch to our third author today, Dr. Shaan Khurshid from Mass General and Shaan was a finalist for the Samuel A. Levine Early Career Investigator Award. And so, Shaan, can you give us a little bit of the background information pertaining to your study? And what was the hypothesis that you wanted to address? Dr. Shaan Khurshid: Thanks for having me, it's a pleasure to be here. A little bit of background that predicting the risk of atrial fibrillation or AF, may increase the efficiency of AF screening and effectively prioritize individuals for preventive interventions that are designed to reduce the risk of incident AF in the first place. And to that end, risk of AF can be estimated with reasonable accuracy using clinical factors. We already know that. And for example, the CHARGE-AF score is a well validated score that been used in multiple settings. More recently, work suggests that artificial intelligence or AI enabled analysis of the 12 lead electrocardiogram can extract latent information that may be relevant for predicting AF risk. Past models however, have had some limitations. They've utilized very short time intervals. They have not incorporated survival time and censoring with is important for prognostic models. They are kind of a black box and therefore difficult to interpret and they haven't undergone a broad external validation. Dr. Shaan Khurshid: Therefore, in this curre…

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Circulation January 4, 2022 Issue Jan 03, 2022

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Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article "Colchicine in Cardiovascular Disease." 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 Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor? Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials. Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find? Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia. The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor. However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials. Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center. Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils. In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils. Dr. Carolyn Lam: Ah, okay. So what did they find, Greg? Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells. Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis. Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction. So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes. Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction. The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF. These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling. Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events. Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications? Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF. Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis. Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis. Dr. Carolyn Lam: Cool. So what did they find, Greg? Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver. And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis. So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid. Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial. Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled "Dancing Bundles with Stable Sinus Rhythm." And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers. And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease. Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone. Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic. This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease? Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later. The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it. Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis? Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that. Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress. I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area. Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation? Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there. To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients. Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention? Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in. The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been. There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways. But several studies have been, again, very,…

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Circulation December 28, 2021 Special Dec 27, 2021

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In this week's edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation. Dr. Amit Khera: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do. Dr. Amit Khera: And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself. Dr. Vanessa Blumer: Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US. Dr. Vanessa Blumer: I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure. Dr. Amit Khera: Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself. Dr. Pishoy Gouda: Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training. Dr. Pishoy Gouda: Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome. Dr. Amit Khera: Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome. Dr. Xiaoming (Ming) Jia: Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology. Dr. Amit Khera: Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome. Dr. Peder Langeland Myhre: Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago. Dr. Amit Khera: Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please. Dr. Sonia Shah: Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now. Dr. Amit Khera: Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works. Dr. Amit Khera: And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing? Dr. Vanessa Blumer: Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media. Dr. Vanessa Blumer: So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way. Dr. Amit Khera: Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research. Dr. Xiaoming (Ming) Jia: Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts. Dr. Amit Khera: Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art. Dr. Amit Khera: And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet? Dr. Pishoy Gouda: Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content. Dr. Pishoy Gouda: So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future. Dr. Amit Khera: Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both. Dr. Amit Khera: And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians. Dr. Peder Langeland Myhre: Yes.…

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Circulation December 21, 2021 Issue Dec 20, 2021

Show notes

Please join Guest Host and Associate Editor Mercedes Carnethon and author Christine Albert as they discuss the article "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We are your co-hosts, 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, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is such an important question clinically. It's something I've asked myself and so I cannot wait to discuss it in greater detail. It refers to the effect of long-term marine omega-3 fatty acid supplementation, and the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. So it talks about a systematic review and meta-analysis published in this week's issue. Dr. Carolyn Lam: All right. Okay. You got to wait in suspense, as do I, and let's discuss other papers, very important papers in today's issue too. I'd like to start with a bit of a quiz. So Greg, for converting atrial fibrillation, is the anterior-lateral or anterior posterior electrode position better? What's your guess? Dr. Greg Hundley: Oh, wow, Carolyn. That's interesting. We put these pads on and we kind of just follow the directions on whatever the particular device says. Interesting question. It's a guess, Carolyn, it's a guess. Antro-lateral? Dr. Carolyn Lam: Smarty pants. Well, let's see. Frankly I didn't know the answer. It's just such an elegant question, isn't it? To answer in a study. And this is exactly what Professor Løfgren from Randers University Hospital and Denmark and colleagues did. They performed a multi-center investigator initiated open label trial, where they randomly assigned 468 patients with atrial fibrillation scheduled for elective cardioversion to anterior-lateral versus anterior-posterior electrode position. Dr. Carolyn Lam: The primary outcome was the proportion of patients in sinus rhythm after the first shock. And so drum roll. The primary outcome occurred in 54% assigned to an anterior-lateral electrode position. And in 33% assigned to an anterior-posterior electrode position, a significant risk difference of 22% in favor of the anterior-lateral electrode position. Dr. Carolyn Lam: Cheers, Greg. There were no significant differences between groups in any safety outcomes and the superiority of the anterior-lateral electrode position was statistically significant both after the initial low energy shock and after a final high energy shock. So this study really suggests a practice change in the standard approach to electrode positioning for cardioversion in favor of anterior-lateral electrode position. Dr. Greg Hundley: Very nice, Carolyn. Very nice. Well, I'm going to come at you using your heart failure expertise and ask you a quiz here in just a second. But first I want to introduce this paper from Dr. Javier Barallobre-Barreiro from King's College London. Okay, Carolyn, here's your quiz. Do you think that the extracellular matrix fibrosis contributes to LV dysfunction in heart failure patients? Dr. Carolyn Lam: Absolutely. Dr. Greg Hundley: Very nice. I think, of course, you are correct. So Carolyn, remodeling of the extracellular matrix is a hallmark of heart failure and this team's previous analysis of the secretome of mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5 as one of the most abundant proteases. So ADAMTS5 cleaves chondroitin sulfate proteoglycans such as Versican. The contribution of ADAMTS5 and its substrate Versican to heart failure is unknown. Dr. Carolyn Lam: Ah, so what did the authors find, Greg? Dr. Greg Hundley: Well, first Carolyn, there was a methodologic advance here. Left ventricular tissues from 86 heart failure patients and non-failing controls were analyzed by quantitative mass spectrometry, constituting the largest proteomics analysis on human heart failure today. And so what did they find? Accumulation of proteoglycan Versican was regulated by ADAMTS5, that disintegrin and metalloproteinase with thrombospondin motifs 5, and was associated with the reduction in proteins involved in intercellular communication. And Carolyn, interestingly, proteoglycan accumulation in ischemic heart failure was attenuated by beta blocker administration. Dr. Carolyn Lam: Oh, that's very interesting. Could you put that all together for us? What's the clinical implications, Greg? Dr. Greg Hundley: You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast constitutes an important component of cardiac fibrosis after ischemic heart failure, just like you stated at the beginning with your quiz answer. This contributes to impaired cardiac function and besides their negative chronotropic and inotropic effects, beta blockers may modulate extracellular matrix remodeling. Dr. Carolyn Lam: Wow, nice, Greg, thank you for that. I've got another original paper and it deals with the very important topic of endothelial to mesenchymal transition. Now it has been reported that cardiac endothelial cells contribute to a substantial proportion of myofibroblast through this process called endothelial to mesenchymal transition. Lineage tracing studies have demonstrated that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation from endothelial cells. Dr. Carolyn Lam: However, it remains unknown whether endothelial cells can transdifferentiate into myofibroblast reversibly or would these endothelial to mesenchymal transition genes just transiently activated in endothelial cells during cardiac fibrosis? So these authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong University School of Medicine, Dr. Lui from Price of Wales Hospital and Chinese University of Hong Kong, as well as Dr. Zhou from the University of Chinese Academy of Sciences in Shanghai and their colleagues. Dr. Carolyn Lam: What they did is they used the dual recombination technology to generate a genetic lineage tracing system for tracking endothelial to mesenchymal transition in cardiac endothelial cells and their genetic fate mapping results basically showed that although mesenchymal gene expression was activated in cardiac endothelial cells throughout the endothelial to mesenchymal transition in the developing heart, the endothelial cells do not transdifferentiate into myofibroblasts, nor do they transiently express some known mesenchymal genes during homeostasis or fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblast by activating mesenchymal gene expressions are in fact the major contributors to cardiac fibrosis. Dr. Greg Hundley: Ah, Carolyn, very interesting. So can you put this together? What are the clinical implications? Dr. Carolyn Lam: So what it really says is that it's the resident fibroblasts that are converted to myofibroblast by activating mesenchymal genes. These are the ones that represent a major therapeutic target and really unraveling these mechanisms, driving endothelial to mesenchymal transition in such a detailed way, provided new insights into therapeutic development to target cardiac fibrosis. Dr. Greg Hundley: Wow, Carolyn. You know, two really good preclinical science articles speaking to us about myocardial fibrosis. Dr. Carolyn Lam: Well, there are other papers in today's issue too. There's a Perspective piece by Dr. Christopher Lamb on "Liver Cirrhosis and Hepatocellular Carcinoma After the Fontan Operation: Reaching Clarity in the Face of Uncertainty. And this is paired with a Research Letter by Dr. Toshio Nakanishi on incidents and expected probability of liver cirrhosis and hepatocellular carcinoma after the Fontan operation. Dr. Greg Hundley: Very nice, Carolyn, and I've got an "In the News" piece from Bridget Kuehn entitled "Centering Equity in Cardiovascular Care as Michelle Albert Lays Out a Roadmap for our Profession." Well, Carolyn, how about we learn a little more about those long term marine omega-3 fatty acid supplementations and the risk of atrial fibrillation? Dr. Christine Albert: Oh, I can't wait. Let's go, Greg. Dr. Mercedes Carnethon: Thank you so much for joining us for today's episode of Circulation on the Run. My Lame is Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and Associate Editor at Circulation. And I have the great pleasure today of having a conversation with a long time friend, Dr. Christine Albert from the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles. Dr. Mercedes Carnethon: And today I've got the great pleasure of hearing directly from Christine about a wonderful original research piece that is being featured in Circulation about the effect of long term marine omega-3 fatty acid supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. And the exciting innovation of this piece that we'll dig into is what we're learning from the systematic review and meta-analysis that Dr. Albert and her team carried out. So, thank you so much for joining us today, Christine. Dr. Christine Albert: Well, thank you, Mercedes. It's really great to be here. Dr. Mercedes Carnethon: Great. Well, I'd just like to launch with you telling us a little bit about the study, what you found, why you decided to conduct this meta-analysis and review. Dr. Christine Albert: Yeah. Great. So my first author, Dr. Baris Gencer and I decided to do this because we actually had participated in a randomized trial called the Vital Rhythm Trial, where we actually randomized people to omega-3 fatty acids and atrial fibrillation, and found a slightly elevated risk, but it wasn't significant. And at that time, a number of other articles came out saying that there really was an increased risk of atrial fibrillation. Dr. Christine Albert: So we wanted to put together the data to see what the combined data, our data, that's been published before, on this sort of long term treatment with omega-3 fatty acids and atrial fibrillation. As you may know, there have been studies that have looked at short term treatment, and specifically for atrial fibrillation, and did not find benefit. So this is why we went ahead and did this study. And what we did is we were able to find seven randomized trials that collected data on atrial fibrillation that had randomized people to omega-3 fatty acids over an average of about five years of follow up between all the different trials. And we found that when you combine all these trials together, you actually see that there is a slightly elevated risk of atrial fibrillation in the participants that were randomized to the omega-3 fatty acids. Dr. Mercedes Carnethon: Thank you so much for that summary, Christine. I think the findings themselves surprised me. This is not my primary area of work, but we hear so much about supplements and their benefits that I thought it was really telling to actually have these data coming from a large number of studies, and particularly large studies that suggest that there is a risk to benefit ratio that we need to consider. How would you recommend that clinicians weigh this evidence that you've generated today? Dr. Christine Albert: So I think that it's got to be individualized. There are benefit, as you said, of these omega-3 fatty acids. And I think it's just awareness, awareness that this potentially is a risk. If you have a patient on omega-3 fatty acids and they start to have atrial fibrillation, there could be a link. Also when you talk about it with patients, I think it's reasonable, especially with the higher doses, we can just discuss that this is a potential side effect. Does it prevent you from using it? I don't think so. I think you have to look at what is, again, as you said, the risk benefit ratio for the individual patient. And as I alluded to, we did do a dose analysis and we found that the risk was primarily seen, and it was higher, in those that were given more than a gram of omega-3 fatty acid a day. Dr. Christine Albert: However, I will say that the trials are very different when you take a meta-analysis, it's really hard to say, "What is the cause of the differences between trials?" You know, these trials that had the higher dose, the reduce it trial that used just a purified EPA was very different than the dose of the medication that was used in vital, different than the type of medication that was used in strength. And as you know, there's the whole debate about the placebo and reduce it versus strength. And so there are other differences, but one thing that is pretty consistent is that most of the point estimates are on the side of harm. So there is the thought that I think this is potentially very real and we should be considering it when we use these supplements. Dr. Mercedes Carnethon: You know, that's a really nice summary which really launches me into two subsequent questions. The first would give you the opportunity to speculate beyond the findings in your particular study, and this is one of the benefits to me of this Circ on the Run podcast, because you, of course, produced excellent science and weighed all of your findings based on what you found. But can you tell me, based on your experience, could you speculate about what you think the mechanism of elevated risk of atrial fibrillation is, particularly with those higher doses? Dr. Christine Albert: Yeah, no, it's interesting. You know, if you look at the epidemiology for this, Mercedes, it was totally inconsistent. When I postulated doing the vital rhythm trial, I actually have to be honest with you, I thought that there might be an increased risk, because when you look at some of the data of what these omega-3 fatty acids do, they increase vegal tone, they lower heart rate. They can actually slow conduction. So potentially those electrophysiologic actions might, might allow atrial fibrillation to emerge in people who are susceptible. Dr. Christine Albert: On the flip side, all of those things might be good for ventricular arrhythmias. So you see, if you look at the literature, there's benefits for…sudden death and epidemiologic studies and in some of the randomized trials, but then when you look at atrial fibrillation, at least the short terms, really didn't show a benefit. And again, that point estimate was more towards harm. Dr. Christine Albert: And then when you look at epidemiologic studies, looking at fish consumption, there's actually a lot of studies that suggest that people who eat more fish get more AFib. So it is really paradoxical. And we know as electrophysiologist that atrial arrhythmias and ventricular arrhythmias are not the same, we give drugs to prevent atrial arrhythmias that then cause ventricular arrhythmias. So it is interesting. And I think it's something that hopefully some of our translational scientists will help us to figure out. Dr. Mercedes Carnethon: All those contradictions are so challenging, but you were certainly speaking my language in describing the hypothesized mechanisms. It calls to mind, back in the day, in your early research on sudden cardiac death that I was citing as part of my dissertation work in epidemiology. So thank you for that. Dr. Ch…

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Circulation December 14, 2021 Issue Dec 13, 2021

Show notes

Please join Guest Host Mercedes Carnethon, author Jason Roberts, and Associate Editor Vlad Zaha as they discuss the article "Epigenetic Age and the Risk of Incident Atrial Fibrillation." 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-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in 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, this week's feature we're going to learn more about the risk of incident atrial fibrillation, but as that pertains to epigenetics. But before we get to that feature, how about we grab a cup of coffee and get started on some of the other articles in the issue. Would you like to go first? Dr. Carolyn Lam: I would love to. And the first paper I want to highlight asks the question, are social economic variables associated with 30 day survival after out of hospital cardiac arrest. And this comes from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden, and colleagues. They linked data from the Swedish Registry of Cardiopulmonary Resuscitation with individual level data on social economic factors. In other words, educational level and disposable income, all from statistics, Sweden. And what they found was that both higher disposable income and higher educational level independently associated with better 30 day survival following out of hospital cardiac arrest. The relationship between disposable income and 30 day survival was more robust for mediating factors compared to educational level. Dr. Greg Hundley: Oh, wow Carolyn. Really interesting in a very, what I would call hot topic these days. So what are the clinical implications of this particular study? Dr. Carolyn Lam: Well, the results really highlight the importance of preventive efforts aimed at patients with lower social economic status. And these preventive actions could include both early recognition and warning signs and for example, CPR and AED training. So very lovely paper there. Dr. Greg Hundley: Absolutely. Very nice Carolyn. Well, my first paper comes to us from Dr. Nan Wang from Columbia University Medical Center. And Carolyn this paper focuses on a common genetic variant called link RS 3184504, and it is associated with increased platelet and neutrophil counts, coronary artery disease, thrombotic stroke, and autoimmune diseases. And so this research group previously has shown that hematopoietic link deficiency synergizes with hyperlipidemia to promote platelet production and activation, neutrophilia, platelet neutrophil aggregates, atherosclerosis and arterial thrombosis, all of those things. So platelet activation and platelet neutrophil interactions have been shown to promote neutrophil extracellular traps or net formations. So nets are formed when neutrophils release their contents leading to the formation web-like structures made of DNA, myeloperoxidase, citrullinated histone and proteases that entrap and kill bacteria. Now, while nets may help to suppress infection, the formation of nets called NETosis in blood vessels can promote atherosclerosis and thrombosis. And so this study was undertaken to investigate the hypothesis that linked deficiency might promote NETosis leading to formation of unstable atherosclerotic plaques, and arterial thrombosis. Dr. Carolyn Lam: Wow. What a really neat hypothesis and NETosis. I learn new things all the time. So what do they find? Dr. Greg Hundley: Right Carolyn. First of all, hypercholesterolemic mice with hematopoietic link deficiency displayed accelerated arterial thrombosis with nets in thrombi and these changes were reversed by PAD4 deficiency or OxPL antibodies. Second, linked deficient platelet from hyperlipidemic mice expose and release increased OxPL when activated promoting NETosis, when incubated with link deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL levels, NETosis and arterial thrombosis specifically in link deficient mice, and finally Carolyn targeting atherothrombotic risk using OxPL antibodies might be particularly effective in genetically defined populations with reduced link function or increased JAK-STAT signaling. Dr. Carolyn Lam: Wow. Okay. So they proved their hypothesis. Could you sum it up for us, Greg? Dr. Greg Hundley: You bet Carolyn. So this foundational work suggests that perhaps future studies targeting NETosis and OxPL in patients carrying the common link loss of function variant, could reduce atherothrombotic risk. Dr. Carolyn Lam: Wow. Thanks, Greg. My next paper is super interesting in its approach. Listen up. Now the assessment of the relationship between myocardial ATP production and cardiac workload. We know is important for better understand disease development and choice of nutritional or pharmacological treatment strategies. So what Dr. Berndt from Charity University and colleagues did, was they developed a comprehensive physiology based mathematical model of cardiac energy metabolism. And this model is called cardiokine one. And what it does is it recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. The model encompassed all pathways along, which the possible energy delivering substrates like glucose, long chain fatty acids, keto bodies, acetate, branch chain, amino acids are utilized. Dr. Carolyn Lam: They use the proteomic space, the abundance of metabolic enzymes and cardiac tissue to generate individualized metabolic models of cardiac energy metabolism. And so to prove their case, they further applied this approach to the left ventricles of controls in patients with mitral insufficiency and aortic stenosis, and showed that despite overall preserved systolic function, the ATP producing capacity of these left ventricles of patients with valvular dysfunction was generally diminished and correlated positively with mechanical energy demand and cardiac output. Dr. Greg Hundley: So Carolyn really interesting findings. Sort of linking metabolism them with ventricular dysfunction in those with valvular heart disease. So what were the clinical implications here? What's the take home? Dr. Carolyn Lam: Well, this methodology is just awesome, but what they also found I think is a very important physiological principle. And that is, while metabolic capacity have a significant correlation with biomechanical properties like myocardial power and cardiac output, they can also vary considerably between individual patients and therefore help us to understand in future perhaps why some patients develop heart failure over time while others with similar hemodynamic conditions do not. So just interesting. I think it just opens the space to a lot more. Dr. Greg Hundley: Absolutely beautiful summary there Carolyn. Well, in the rest of the mailbag for this issue, we have an exchange of letters between Professors Hu and Trifon on the previously published paper, entitled "Short Term Treatment with Aspirin plus Clopidogrel Compared to Monotherapy of Aspirin May Not Significantly Decrease the Risk of Stroke Recurrence." Also, there's a Research Letter from Professor Catalucci entitled, "Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded Induced Heart Failure." And then finally Carolyn, there's an In-Depth article from Professor Aengevaeren entitled, "Exercise-Induced Cardiac Troponin Elevations From Underlying Mechanisms to Clinical Science." Well Carolyn, how about we get onto that feature discussion and learn more about incident atrial fibrillation and the age of epigenetics. Dr. Carolyn Lam: Let's go. Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, where we're going to have a very exciting discussion about a paper on epigenetic age and the risk of incident atrial fibrillation. We're extremely excited to have the lead author here with us, Dr. Jason Roberts from the Population Health Research Institute, McMaster University and Hamilton Health Sciences in Ontario Canada. And I am really excited to host this episode alongside the handling editor. My name is Mercedes Carnethon and I'm the professor and vice chair of Preventive Medicine at the Northwestern University School of Medicine. And I'm pleased to be hosting this with Dr. Vlad Zaha from UT Southwestern Medical School, who was the associate editor who handled the piece. So I'm really excited to jump right into this because I think there's a lot that we can all learn from this. So welcome Jason, and thank you so much, Vlad. Dr. Jason Roberts: Thank you so much for having me, it's a delight to be here. Dr. Mercedes Carnethon: So Jason, tell us a little bit about the rationale for this study, what you found and what it means. Dr. Jason Roberts: Absolutely. So as a cardiac arrhythmia specialist, I see a lot of patients with atrial fibrillation. And in 2021, our understanding of its underlying pathophysiology still remains modest. Our treatment strategies for the condition are also somewhat modest, although catheter ablation and antiarrhythmic drugs can potentially be very effective. In the context of these limitations, they're also exacerbated to some extent by the prevalence of atrial fibrillation, increasing dramatically in developed countries. Part of this is related to the obesity epidemic. Things like hypertension increasing becoming more common, but because atrial fibrillation is age dependent and because of our aging populations in developed countries, this is felt to have a major contribution to the growing prevalence of atrial fibrillation. Unlike obesity and hypertension and other risk factors, which are potentially modifiable, chronological aging is viewed as non-modifiable. It's not something that we can tackle. That said, we know within the population and just from personal experience that people age at different rates. There are some people that are 65 who behave more like they're 50, other people that are 50 who behave more like they're 65. Dr. Jason Roberts: And in that context, biological aging, we wondered whether or not, does biological aging independent of chronological aging potentially impacts the risk of atrial fibrillation. If that was the case, because there are gradually accumulating to suggest that biological aging is potentially modifiable, that could potentially open up the possibility of tackling aging as a respective for atrial fibrillation. So that drove us to ask this question. In terms of what we found in the approach that we used. So we used our biological marker of aging, was something called an epigenetic clock. So it's been found that modifications to DNA, specifically methylation at CpG at dinucleotides, they correlate with aging. This has been appreciated for a few decades. It was initially felt that with aging, methylation levels gradually reduced over time. But with more careful interrogation, it's shown that there's patterns. Some methylation areas increase, other methylation areas there's decreases. Dr. Jason Roberts: And Steve Horvath, who is a scientist at UCLA has found that using mathematical algorithms, you're able to very accurately ascertain chronological age based on the patterns of DNA methylation, he's called these things epigenetic o'clock. That said, even though they very accurately ascertain chronological age, they aren't perfect in each individual in terms of matching up to their chronological age, but that's actually turned out to be a good thing. So when people, their epigenetic age is older than their chronological age, they're said to have positive epigenetic age acceleration. They may be biologically older than their actual chronological age. And then the reverse also holds. So using this concept of epigenetic age acceleration, we ask whether or not do people that are older biologically on the basis of their epigenetic age, do they have an increased risk of atrial fibrillation? And then we tackle that using a few different core works that I'm certainly happy to elaborate on in terms of what we found. Dr. Jason Roberts: So we used three population based cohorts from the United States, the well known Framingham Heart Study, the Cardiovascular Health Study and Eric as well. There were approximately just under 6,000 people from those studies that had undergone genome wide methylation analysis that in the enabled us to calculate their epigenetic ages. The follow period for these people was just under 13 years. And then we look to see whether or not these epigenetic clocks associated with instant atrial fibrillation. In these cohorts, we look at five different clocks. So there's the Horvath Clock and the Hannum clock that were designed to predict chronological aging. The more recent clocks, things like DNAm PhenoAge and DNAm GrimAge are more designed to predict aspects of clinical phenotype and also mortality. We found that in unadjusted analyses, all of these clocks were associated with atrial fibrillation. When we then adjusted for multiple different clinical variables, we found that the DNAm PhenoAge clock and the DNAm GrimAge clock continued to exhibit statistically significant associations with atrial fibrillation. Dr. Jason Roberts: Interestingly, the multi-variable adjustment, one concern is, do these clinical factors, are they confounders where we should be adjusting, or are they potentially mediators. If we adjust for mediators that potentially masks the effect of the clock. But regardless of how we treat them both DNAm PhenoAge and DNAm GrimAge, we're associated with increased risks of incident atrial fibrillation. Alluding to the possibility that biological aging independent of chronological aging is important in terms of determining risk for atrial fibrillation. And it may be that if we're able to modify biological aging, we could potentially reduce the risk of atrial fibrillation. So that's the study in a nutshell. Dr. Mercedes Carnethon: No, that is really exciting. You said something early on about chronological age being immutable. And I would have to say, both Vlad and I are not aging. And in fact, we are going in the opposite direction. If only this were not just an audio podcast, you would see that I steadily gotten younger and younger and I'm suddenly about 25 now. But no, these are really important findings. I really like the innovation of using multiple different strategies to characterize epigenetic age and genetic aging. So tell me Vlad, I want to turn to you. When this came across your desk, what excited you about this particular piece and why did you think that it would be of great interest to our readership? Dr. Vlad Zaha: Good morning Merci and Jason. This is a great question. And as in associate editor at Circulation for the bridging discipline section, it was fascinating to see this topic coming on my desk, thinking about all the genome wide association studies in nature of fibrillation and predisposition to atrial fibrillation, that in that case would not be changed by interventions because of different loci that would be determined. This was coming as a completely new perspective that was opening some new potentials. And it was very interesting to see some of the findings. Dr. Mercedes Carnethon: Certainly. So Jason, I have a question. So what surprised you about the findings of this particular study? Jason Roberts: Yeah, that's a great question. So we had hoped that biological aging would be associated with atrial fibrillation. I think the concept of being able to tackle biological aging is exciting. In terms of what surprised us, I guess we were hoping for t…

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