Circulation on the Run

Follow Circulation on the Run
Share on
Copy link to clipboard

Each 15-minute podcast begins with an overview of the issue’s contents and main take-home messages for busy clinicians on the run. This is followed by a deep dive into a featured article of particular clinical significance: views will be heard from both author and editor teams for a “behind the scen…

Carolyn Lam, MBBS, PhD


    • Jan 3, 2022 LATEST EPISODE
    • weekly NEW EPISODES
    • 24m AVG DURATION
    • 183 EPISODES


    Search for episodes from Circulation on the Run with a specific topic:

    Latest episodes from Circulation on the Run

    Circulation January 4, 2022 Issue

    Play Episode Listen Later Jan 3, 2022 26:39

    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, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event. Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article? Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly. I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were. I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease. Dr. Greg Hundley: Brendan, tell us a little bit about those risks. Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes. And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases. I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo. And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern. And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect. I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects. Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research? Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty. I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed. So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around. Dr. Greg Hundley: Very good. Brendan, anything to add? Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction. And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive. Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes. Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run. Dr. Greg Hundley: This program, this copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

    Circulation December 28, 2021 Special

    Play Episode Listen Later Dec 27, 2021 28:19

    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. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most. Dr. Amit Khera: Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all. Dr. Amit Khera: Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space? Dr. Sonia Shah: Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals. Dr. Amit Khera: Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months? Dr. Xiaoming (Ming) Jia: I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well. Dr. Amit Khera: We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes. Dr. Amit Khera: Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it. Dr. Peder Langeland Myhre: Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing. Dr. Peder Langeland Myhre: So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family. Dr. Amit Khera: Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media? Dr. Pishoy Gouda: Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me. Dr. Amit Khera: Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore. Dr. Amit Khera: So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit. Dr. Vanessa Blumer: Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out. Dr. Vanessa Blumer: I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it. Dr. Amit Khera: Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so. Dr. Sonia Shah: Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved. Dr. Amit Khera: Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal. Dr. Amit Khera: Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

    Circulation December 21/28, 2021 Issue

    Play Episode Listen Later Dec 20, 2021 21:41

    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. Christine Albert: Yeah. Dr. Mercedes Carnethon: You know, the second question that builds off of that is I thought that the figure where you display the heterogeneity by the dosage of omega-3's really underscores the argument that you were just presenting. What I was wondering is, did you happen to study heterogeneity by any other characteristics, particularly sex or age? Dr. Christine Albert: That would be fantastic to be able to do, unfortunately, because it's a summary level meta-analysis, we really can't do that. And that's one of the things that we'd love to do in collaboration with some of these authors if they would like to do that, is to really get that sort of paid participant level data, so we could do those kinds of analysis. Dr. Christine Albert: But what we did do is sort of separate out studies that had like confirmed AF, studies that had incident AF versus recurrent AF, so things where the studies were completely different, we were able to look for heterogeneity and we didn't find anything that suggested that there was heterogeneity on that basis. But there's a number of things that I would love to look at and age is definitely one of them, and also sex. And actually looking at, which would be really interesting, is to look at the omega-3 or EPA and DHA levels in these individuals. And again, I think each study has sort of tried to do it on their own and you can't because there's just not enough data. So putting all this data together would be great to have a better understanding of what's going on. Dr. Mercedes Carnethon: Oh, it sounds speaks to a number really thoughtful future directions for this work. One of the benefits of me being able to speak with you today in my role as a guest podcast host, but I was also the Associate Editor for the piece and was really excited when it came in. The discussions that we had amongst the editors about this were really very stimulating and raised a number of questions that led to you responding and making some modifications and explaining certain things. Could you tell our audience, why did you select trials over a certain size? You know, quite often we do meta-analyses in order to pull together smaller studies, but why did you choose larger studies? Dr. Christine Albert: I think it was so that, there were two criterias, one was larger and one was long term, because we felt that the smaller studies had been merged together previously and we wanted to have at least some data on atrial fibrillation. One of the problems I think that I think I want to emphasize a little bit here about research in general in cardiovascular disease is that until now, most studies hadn't really measured atrial fibrillation, and I think it's really important. And I think you can see, you can find off target effects of some of the agents that we use for cardiovascular disease on atrial fibrillation. So for instance, the Statin Trials, everybody said, "Oh, well statins might lower atrial fibrillation," but then nobody measured atrial fibrillation, so we never knew. And then people went back and tried to measure it as a side effect or something that has all kinds of biases to it. Dr. Christine Albert: So I think that what is exciting about this work is that both reduce it and strength and vital, pre-specified that they were going to look at atrial fibrillation. And so if we do that, we may actually find other agents that are beneficial, not just harm, but beneficial, like the SGLT2 inhibitors, there's lots of hypotheses. So the reason that we did pick the bigger trials was that we wanted to find trials that really kind of looked at atrial fibrillation, had enough power to look at atrial fibrillation and then over a long term, a follow up to gather enough events. Dr. Mercedes Carnethon: Again, it has been such a pleasure to hear directly from you. I really hope that our listeners today and our readers of The Journal will dig into this in the same way that we have as editors and really appreciate the thoughtfulness with which you've presented this outstanding work. So I want to thank you so much, Dr. Albert for joining us today. Dr. Christine Albert: Thank you for having me. Dr. Mercedes Carnethon: I guess I will sign off now. This is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine and Associate Editor for Circulation. Disclaimer: This program is copyright of the American Heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart Association. For more, visit ahajournals.org.

    Circulation December 14, 2021 Issue

    Play Episode Listen Later Dec 13, 2021 25:48

    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 these results, I guess. Dr. Mercedes Carnethon: Yeah. Dr. Jason Roberts: But we were…Yeah. So I guess we were pleasantly surprised that our hypothesis was born out. It's important to note that the epigenetic clocks don't tell the full story with chronological aging. So after we insert the clock into the model, chronological age continues to remain associated with instant atrial fibrillation. So this measure biological aging is just part of the story. So I think that's very important. I had wondered whether or not inserting the epigenetic clocks would that potentially eliminate the subsequent association of chronological aging. So that finding suggests it's part of the story. Dr. Jason Roberts: I think that in terms of the overall concept, the idea of this being reversible really excites me. In terms of the approach of how to reverse biological aging. Right now healthy lifestyle seems to be very important. I think it provides more evidence to suggest to patients with atrial fibrillation, living healthy from a diet perspective, from exercise, keeping your weight under control, all of these things that seem to impact epigenetic aging and biological aging can be helpful for preventing atrial fibrillation. So I think that can help reinforce this message to our patients. Dr. Jason Roberts: I think ultimately in terms of where we'll be at in 15 to 20 years, it's possible that new therapies in the future are developed that are able to more powerfully address biological aging. As you alluded to, will it be possible to reverse biological aging as you and Vlad are experiencing that? Dr. Mercedes Carnethon: Most definitely. Yes. Dr. Jason Roberts: I think it may be possible. This is an intense area of investigation that's being pursued and it's still in its relative infancy. But I think that could it be small molecules? Could it be potentially gene editing that can help adjust biological aging and not only increase lifespan, but also health span? I think those concepts are really exciting. Dr. Mercedes Carnethon: I completely agree. There's a lot of richness in this paper and I think our readership is going to really enjoy digging in. Part of the richness is the use of three different cohorts and the use of multiple measures of epigenetic age. And I think you provided a really nice description of the unique information that each of these markers of epigenetic age provide. One thing I note are differences in the strength of association across the different measures of epigenetic age, which I think makes sense, because you said they characterize different aspects of the phenomenon, but I also see what looks like some variability across the cohorts with Framingham in particular seeming to stand out. And that being the only cohort that is 100% one race. It's white. Versus both the cardiovascular health study and the Eric study, which have more diverse study populations. I'm wondering what your hypothesis is about the differential strength of association that it seems Framingham is demonstrating and what you think is possibly the source of those differences. Dr. Jason Roberts: Yeah. I think those are great questions for all of genetics. The question is, does it apply to all races? For example, polygenic risk scores. It seems like when a polygenic risk scores develop for one race, it may not perfectly translate over to other races. So how relevant is that for epigenetic age acceleration. In this study, I think it's difficult to make definitive conclusions about it. We needed the three cohorts to have adequate statistical power in terms of being able to determine a differential effect of race. I think it would really be primarily hypothesis generating. We weren't really powered to look at the different races. So it's difficult for me to comment. Dr. Jason Roberts: I think ultimately and I want to believe anyways, that epigenetic age acceleration is relevant to all races, but in terms of, was it race that drove the differential impacts that we saw to some extent in terms of the magnitude of the hazard ratios, it's difficult to know in terms of tests for interaction and were these actually truly statistically different. We weren't adequately powered to address that hypothesis. So it's difficult for me to comment in a definitive matter I'd say. And sorry to cop out on… Dr. Mercedes Carnethon: No, not at all. I mean, I think there are a lot of things where there is no firm answer and that was just one of my hypotheses when I saw what was going on differently across the cohorts. I think that's a perfectly reasonable answer that sets us on a course for thinking about how we set up future studies. So I wanted to turn to you Vlad for the closing frame around this. As the editor, how do you hope that our readership will use these findings? Dr. Vlad Zaha: That is an excellent question. I was going to follow on this excellent unpacking of the core messages of the manuscript by Jason here to get his perspective as an electrophysiologist into what these type of work may represent for the everyday life of an electrophysiologist in the connecting with the patients and how would this type of approach influence, and maybe now, maybe later when our treatment for atrial fibrillation. Dr. Jason Roberts: Yeah. So that's a great question. I think, as I alluded to some extent before, as far as reinforcing healthy lifestyle, I think this provides more evidence in that respect. So we know that things like excessive alcohol consumption, being excessively obese, poor diets, not engaging in enough exercise, all of those things seem to accelerate your epigenetic age. And those are all things that we think or feel that are important with atrial fibrillation in terms of driving the path of physiology and people progressing. So I think this gives more data to us to reinforce the patients that in addition to the treatments that we're offering in terms of catheter ablation and antiarrhythmic drugs, the concern is that the substrate can continue you to progress. And that's likely driven by to some extent these modifiable risk factors. So keeping all of these under best control as possible, and hence trying to slow your biological aging as much as possible. Dr. Jason Roberts: I think that this will provide us more motivation to push these messages to our patients. A lot of patients can sometimes be like, "Let's just get on with a catheter ablation and I want to get on with my life…" but it really I think, provides more data to suggest that modifying these very important risk factors that can lead to accelerated biological agents, is very important. And in terms of the future as mentioned, so chronological aging, as people get older, people view it as, "Well, there's nothing I can do, and I'm just going to get gradually more and more unhealthy." I think, and this is somewhat futuristic, but to what extent can we slow biological aging? Can we potentially reverse it in the future? There's certainly lots of very compelling and interesting animal work and people are starting to delve into this in a big way. Dr. Jason Roberts: And not only to increase lifespan, will we some day live until we're 200. Who knows? But the concept of prolonging your health span as well. So the number of healthy years that you have before your body starts to gradually give way, I guess to some extent. Hopefully in the future will have therapies that will help keep us healthy. And if we do that increased health span, I think this data suggests that atrial fibrillation will be one thing that benefits from this. So hopefully in the future, maybe in terms of curbing the AFib pandemic, being able to address biological aging will help push things in the right direction. Dr. Mercedes Carnethon: Well, thank you so much Jason. And thank you so much Vlad for your thoughtful questions. I really like that the final bottom line leans towards my area as an epidemiologist, which is maintaining and promoting healthy lifestyles as a way to hopefully help prevent some of the difficulties of atrial fibrillation and its long-term outcomes. Really pleased to have you on this episode of Circulation on the Run, Jason, and thank you again Vlad, and I hope everyone enjoys this episode of the journal and has an opportunity to really dig into this piece. This is Mercedes Carnethon from Northwestern University Feinberg School of Medicine, saying thanks for listening today. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.

    Circulation December 7, 2021 Issue

    Play Episode Listen Later Dec 7, 2021 23:20

    Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD." 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 Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start? Dr. Greg Hundley: Very good. Dr. Carolyn Lam: Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG. Dr. Greg Hundley: Ah, Carolyn. So what did they find in this subgroup of patients? Dr. Carolyn Lam: So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery. Dr. Greg Hundley: Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go. Dr. Greg Hundley: All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery. Dr. Greg Hundley: So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection. Dr. Carolyn Lam: Wow, fascinating. So what did today's paper find? Dr. Greg Hundley: Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper? Dr. Carolyn Lam: Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right? Dr. Greg Hundley: Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn. Dr. Carolyn Lam: Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs. Dr. Carolyn Lam: The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation. Dr. Carolyn Lam: But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit. Dr. Greg Hundley: Okay. Carolyn, what a beautiful summary here. So what's the take home message here? Dr. Carolyn Lam: So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases. Dr. Carolyn Lam: Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention. Dr. Greg Hundley: Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study? Dr. Carolyn Lam: Let's go, Greg. Dr. Mercedes Carnethon: Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization. Dr. Mercedes Carnethon: And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you. Professor Gregory Lip: Hello there. Dr. Connie Hess: Thank you for having me. Dr. Mercedes Carnethon: Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study? Dr. Connie Hess: Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about. Dr. Connie Hess: And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI. Dr. Connie Hess: And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. Dr. Connie Hess: And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out. Dr. Connie Hess: And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction. Dr. Connie Hess: Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication. Dr. Mercedes Carnethon: All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind? Professor Gregory Lip: Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes. Professor Gregory Lip: So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding. Professor Gregory Lip: We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well. Dr. Mercedes Carnethon: Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study? Dr. Connie Hess: Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt. Dr. Connie Hess: I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic. Dr. Connie Hess: A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it. Dr. Connie Hess: I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy. Dr. Mercedes Carnethon: I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal. Dr. Mercedes Carnethon: This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation November 30, 2021 Issue

    Play Episode Listen Later Nov 29, 2021 22:09

    Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS 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 and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial? Dr. Greg Hundley: Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there? Dr. Carolyn Lam: The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina. Dr. Greg Hundley: Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research? Dr. Carolyn Lam: Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function. Dr. Greg Hundley: Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that. Dr. Carolyn Lam: No, we don't (laughs). Dr. Greg Hundley: Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome? Dr. Carolyn Lam: Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs). Dr. Greg Hundley: Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification- Dr. Carolyn Lam: (laughing) Dr. Greg Hundley: Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. Dr. Carolyn Lam: Wow, you've really, really piqued my interest. So what did these investigators do and what did they find? Dr. Greg Hundley: Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types. Dr. Greg Hundley: Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Wow, just fascinating, but, okay. What is the clinical take home message? Dr. Greg Hundley: Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results. Dr. Greg Hundley: Oh wow, Carolyn, I can't wait. So tell us about this novel methodology. Dr. Carolyn Lam: Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat? Dr. Greg Hundley: Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods? Dr. Carolyn Lam: A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool? Dr. Greg Hundley: Absolutely, Carolyn. Beautifully explained. Dr. Carolyn Lam: Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom. Dr. Greg Hundley: Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address? Dr. Cecilia Bahit: Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke. Dr. Greg Hundley: Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population. Dr. Cecilia Bahit: So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation. Dr. Greg Hundley: Very good. And what were your results? Dr. Cecilia Bahit: So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation. Dr. Cecilia Bahit: So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small. Dr. Greg Hundley: Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk. Dr. Graeme Hankey: Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy. Dr. Graeme Hankey: And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up. Dr. Graeme Hankey: And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin. Dr. Greg Hundley: Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research? Dr. Cecilia Bahit: Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area. Dr. Greg Hundley: Very nice. And Graeae, what are your thoughts? Dr. Graeme Hankey: Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities. Dr. Graeme Hankey: Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation. Dr. Greg Hundley: Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event. Dr. Greg Hundley: Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

    Circulation November 23, 2021 Issue

    Play Episode Listen Later Nov 22, 2021 24:40

    Please join first author Yuan Lu and Guest Editor Jan Staessen as they discuss the article "National Trends and Disparities in Hospitalization for Acute Hypertension Among Medicare Beneficiaries (1999-2019)." Dr. Carolyn Lam: Welcome to Circulation on the Run: your weekly podcast, summary and backstage pass to the journal and it's 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, and director of Pauley Heart Center at VCU health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature discussion is about the national trends and disparities and hospitalizations for hypertensive emergencies among Medicare beneficiaries. Isn't that interesting? We're going to just dig deep into this issue, but not before we discuss the other papers in today's issue. I'm going to let you go first today while I get a coffee and listen. Dr. Greg Hundley: Oh, thanks so much, Carolyn. My first paper comes to us from the world of preclinical science and it's from professor Christoff Maack from University Clinic Wursburg. Carolyn, I don't have a quiz for you, so I'm going to give a little break this week, but this particular paper is about Barth syndrome. Barth syndrome is caused by mutations of the gene encoding taffazin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Now beyond the first months of life, Barth syndrome cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, one of your favorites, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced Barth syndrome cardiomyopathy to mitochondrial formation of reactive oxygen species. Since mitochondrial function and reactive oxygen species formation are regulated by excitation contraction coupling, these authors wanted to use integrated analysis of mechano-energetic coupling to delineate the pathomechanisms of Barth syndrome cardiomyopathy. Dr. Carolyn Lam: Oh, I love the way you explained that so clearly, Greg. Thanks. So what did they find? Dr. Greg Hundley: Right, Carolyn. Well, first defective mitochondrial calcium uptake prevented Krebs cycle activation during beta adrenergic stimulation, abolishing NADH regeneration for ATP production and lowering antioxidative NADPH. Second, Carolyn, mitochondrial calcium deficiency provided the substrate for ventricular arrhythmias and contributed to blunted inotropic reserve during beta adrenergic stimulation. And finally, these changes occurred without any increase of reactive oxygen species formation in or omission from mitochondria. So Carolyn what's the take home here? Well, first beyond the first months of life, when systolic dysfunction dominates, Barth syndrome cardiomyopathy is reminiscent of heart failure with preserved rather than reduced ejection fraction presenting with progressive diastolic and moderate systolic dysfunction without relevant left ventricular dilation. Next, defective mitochondrial calcium uptake contributes to inability of Barth syndrome patients to increase stroke volume during exertion and their vulnerability to ventricular arrhythmias. Lastly, treatment with cardiac glycosides, which could favor mechano-energetic uncoupling should be discouraged in patients with Barth syndrome and left ventricular ejection fractions greater than 40%. Dr. Carolyn Lam: Oh, how interesting. I need to chew over that one a bit more. Wow, thanks. But you know, I've got a paper too. It's also talking about energetic basis in the presence of heart failure with preserved ejection fraction, but this time looking at transient pulmonary congestion during exercise, which is recognized as an emerging and important determinant of reduced exercise capacity in HFpEF. These authors, led by Dr. Lewis from University of Oxford center for clinical magnetic resonance research sought to determine if an abnormal cardiac energetic state underpins this process of transient problem congestion in HFpEF. Dr. Carolyn Lam: To investigate this, they designed and conducted a basket trial covering the physiological spectrum of HFpEF severity. They non-invasively assess cardiac energetics in this cohort using phosphorous magnetic resonance spectroscopy and combined real time free breathing volumetric assessment of whole heart mechanics, as well as a novel pulmonary proton density, magnetic resonance imaging sequence to detect lung congestion, both at rest and during submaximal exercise. Now, Greg, I know you had a look at this paper and magnetic resonance imaging, and spectroscopy is your expertise. So no quiz here, but could you maybe just share a little bit about how novel this approach is that they took? Dr. Greg Hundley: You bet. Carolyn, thanks so much for the intro on that and so beautifully described. What's novel here is they were able to combine imaging in real time, so the heart contracting and relaxing, and then simultaneously obtain the metabolic information by bringing in the spectroscopy component. So really just splashing, as they might say in Oxford, just wonderful presentation, and I cannot wait to hear what they found. Dr. Carolyn Lam: Well, they recruited patients across the spectrum of diastolic dysfunction and HFpEF, meaning they had controls. They had nine patients with type two diabetes, 14 patients with HFpEF and nine patients with severe diastolic dysfunction due to cardiac amyloidosis. What they found was that a gradient of myocardial energetic deficit existed across the spectrum of HFpEF. Even at low workload, the energetic deficit was related to a markedly abnormal exercise response in all four cardiac chambers, which was associated with detectable pulmonary congestion. The findings really support an energetic basis for transient pulmonary congestion in HFpEF with the implication that manipulating myocardial energy metabolism may be a promising strategy to improve cardiac function and reduce pulmonary congestion in HFpEF. This is discussed in a beautiful editorial by Drs. Jennifer Hole, Christopher Nguyen and Greg Lewis. Dr. Greg Hundley: Great presentation, Carolyn, and obviously love that MRI/MRS combo. Carolyn, these investigators in this next paper led by Dr. Sara Ranjbarvaziri from Stanford University School of Medicine performed a comprehensive multi-omics profile of the molecular. So transcripts metabolites, complex lipids and ultra structural and functional components of hypertrophic cardiomyopathy energetics using myocardial samples from 27 hypertrophic cardiomyopathy patients and 13 controls really is the donor heart. Dr. Carolyn Lam: Wow, it's really all about energetics today, isn't it? So what did they see, Greg? Dr. Greg Hundley: Right, Carolyn. So hypertrophic cardiomyopathy hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic arrangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced crystal density coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, the hypertrophic cardiomyopathy hearts failed to up-regulate mitophagic clearance. Dr. Greg Hundley: So Carolyn, in summary, the findings of this study suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with hypertrophic cardiomyopathy, and these results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing myocardial injury. Dr. Carolyn Lam: Wow, what an interesting issue of our journal. There's even more. There's an exchange of letters between Drs. Naeije and Claessen about determinants of exercise capacity in chronic thromboembolic pulmonary hypertension. There's a "Pathways to Discovery" paper: a beautiful interview with Dr. Heinrich Taegtmeyer entitled,"A foot soldier in cardiac metabolism." Dr. Greg Hundley: Right, Carolyn, and I've got a research letter from Professor Marston entitled "The cardiovascular benefit of lowering LDL cholesterol to below 40 milligrams per deciliter." Well, what a great issue, very metabolic, and how about we get onto that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today. We have a paper that is going to address some issues pertaining to high blood pressure, or hypertension. With us, we have Dr. Yuan Lu from Yale University in New Haven, Connecticut. We also have a guest editor to help us review this paper, Dr. Jan Staessen from University Louvain in Belgium. Welcome to you both and Yuan, will start with you. Could you describe for us some of the background that went into formulating your hypothesis and then state for us the hypothesis that you wanted to address with this research? Dr. Yuan Lu: Sure. Thank you, Greg. We conducted this study because we see that recent data show hypertension control in the US population has not improved in the last decades, and there are widening disparities. Also last year, the surgeon general issued a call to action to make hypertension control a national priority. So, we wanted to better understand whether the country has made any progress in preventing hospitalization for acute hypertension. That is including hypertension emergency, hypertension urgency, and hypertension crisis, which also refers to acute blood pressure elevation that is often associated with target organ damage and requires urgent intervention. We have the data from the Center for Medicare/Medicaid, which allow us to look at the trends of hospitalization for acute hypertension over the last 20 years and we hypothesize we may also see some reverse progress in hospitalization rate for acute hypertension, and there may differences by population subgroups like age, sex, race, and dual eligible status. Dr. Greg Hundley: Very nice. So you've described for us a little bit about perhaps the study population, but maybe clarify a little further: What was the study population and then what was your study design? Dr. Yuan Lu: Yeah, sure. The study population includes all Medicare fee-for-service beneficiaries 65 years and older enrolled in the fee-for-service plan for at least one month from January 1999 to December 2019 using the Medicare denominator files. We also study population subgroups by age, sex, race and ethnicity and dual eligible status. Specifically the racial and ethnic subgroups include Asian, blacks, Hispanics, North American native, white, and others. Dual eligible refers to beneficiary eligible for both Medicare and Medicaid. This study design is a serial cross sectional analysis of these Medicare beneficiaries between 1999 and 2019 over the last 20 years. Dr. Greg Hundley: Excellent. Yuan, what did you find? Dr. Yuan Lu: We actually have three major findings. First, we found that in Medicare beneficiaries 65 years and older, hospitalization rate for acute hypertension increased more than double in the last 20 years. Second, we found that there are widening disparities. When we look at all the population subgroups, we found black adults having the highest hospitalization rate in 2019 across age, sex, race, and dual eligible subgroup. And finally, when we look at the outcome among people hospitalized, we found that during the same period, the rate of 30 day and 90 day mortality and readmission among hospitalized beneficiaries improved and decreased significantly. So this is the main findings, and we can also talk about implications of that later. Dr. Greg Hundley: Very nice. And did you find any differences between men and women? Dr. Yuan Lu: Yes. We also looked at the difference between men and women, and we found that actually the hospitalization rate is higher among females compared to men. So more hospitalizations for acute hypertension among women than men. Dr. Greg Hundley: Given this relatively large Medicare/Medicaid database and cross-sectional design, were you able to investigate any relationships between these hospitalizations and perhaps social determinants of health? Dr. Yuan Lu: For this one, we haven't looked into that detail. This is just showing the overall picture, like how the hospitalization rate changed over time in the overall population and by different population subgroups. What you mentioned is an important issue and should definitely be a future study to look at whether social determine have moderated the relationship between the hospitalization. Speaker 3: Excellent. Well, listeners, now we're going to turn to our guest editor and you'll hear us talk a little bit sometimes about associate editors. We have a team that will review many papers, but when we receive a paper that might contain an associate editor or an associate editors institution, we actually at Circulation turn to someone completely outside of the realm of the associate editors and the editor in chief. These are called guest editors. With us today, we have Dr. Jan Staessen from Belgium who served as the guest editor. He's been working in this task for several years. Jan, often you are referred papers from the American Heart Association. What attracted you to this particular paper and how do you put Yuan's results in the context with other studies that have focused on high blood pressure research? Dr. Jan Staessen: Well, I've almost 40 years of research in clinical medicine and in population science, and some of my work has been done in Sub-Saharan Africa. So when I read the summary of the paper, I was immediately struck by the bad results, so to speak, for black people. This triggered my attention and I really thought this message must be made public on a much larger scale because there is a lot of possibility for prevention. Hypertension is a chronic disease, and if you wait until you have an emergency or until you have target organ damage, you have gone in too late. So really this paper cries for better prevention in the US. And I was really also amazed when I compared this US data with what happens in our country. We don't see any, almost no hospitalizations for acute hypertension or for hypertensive emergencies. So there is quite a difference. Dr. Jan Staessen: Going further on that, I was wondering whether there should not be more research on access to primary care in the US because people go to the emergency room, but that's not a place where you treat or manage hypertension. It should be managed in primary care with making people aware of the problem. It's still the silent killer, the main cause of cardiovascular disease, 8 million deaths each year. So this really triggered my attention and I really wanted this paper to be published. Dr. Greg Hundley: Very nice. Jan, I heard you mention the word awareness. How have you observed perhaps differences in healthcare delivery in Belgium that might heighten awareness? You mentioned primary care, but are there any other mechanisms in place that heighten awareness or the importance? Dr. Jan Staessen: I think people in Belgium, the general public, knows that hypertension is a dangerous condition. That it should be well treated. We have a very well built primary care network, so every person can go to a primary care physician. Part of the normal examination in the office of a primary care physician is a blood pressure measurement. That's almost routine in Belgium. And then of course not all patients are treated to go. Certainly keeping in mind the new US guidelines that aim for lower targets, now recently confirmed in the Chinese study, you have to sprint three cells. And then the recent Chinese study that have been published to the New England. So these are issues to be considered. I also have colleagues working in Texas close to the Mexican border at the university place there, and she's telling me how primary care is default in that area. Dr. Jan Staessen: I think this is perhaps part of the social divide in the US. This might have to be addressed. It's not only a problem in the US, it's also a problem in other countries. There is always a social divide and those who have less money, less income. These are the people who fell out in the beginning and then they don't see primary care physicians. Dr. Jan Staessen: Belgium, for instance, all medicines are almost free. Because hypertension is a chronic condition prevention should not only start at age 65. Hypertension prevention should really start at a young age, middle age, whenever this diagnosis of high blood pressure diagnosis is confirmed. Use blood pressure monitoring, which is not so popular in the US, but you can also use home blood pressure monitoring. Then you have to start first telling your patients how to improve their lifestyle. When that is not sufficient, you have to start anti hypertensive drug treatment. We have a wide array of anti hypertensive drugs that can be easily combined. If you find the right combination, then you go to combination tablets because fewer tablets means better patient adherence. Dr. Greg Hundley: Yuan we will turn back to you. In the last minutes here, could you describe some of your thoughts regarding what you think is the next research study that needs to be performed in this sphere of hypertension investigation? Dr. Yuan Lu: Sure. Greg, in order to answer your question, let me step back a little bit, just to talk about the implication of the main message from this paper, and then we can tie it to the next following study. We found that the marked increase in hospitalization rate for acute hypertension actually represented many more people suffering a potential catastrophic event that should be preventable. I truly agree with what Dr. Staessen said, hypertension should be mostly treated in outpatient setting rather than in the hospital. We also find the lack of progress in reducing racial disparity in hospitalization. These findings highlight needs for new approaches to address both the medical and non-medical factors, including the social determinants in health, system racism that can contribute to this disparity. When we look at the outcome, we found the outcome for mortality and remission improved over time. Dr. Yuan Lu: This means progress has been made in improving outcomes once people are hospitalized for an acute illness. The issue is more about prevention of hospitalization. Based on this implication, I think in a future study we need better evidence to understand how we can do a better job in the prevention of acute hypertension admissions. For example, we need the study to understand who is at risk for acute hypertensive admissions, and how can this event be preempted. If we could better understand who these people are, phenotype this patient better and predict their risk of hospitalization for acute hypertension, we may do a better job in preventing this event from happening. Dr. Greg Hundley: Very nice. And Jan, do you have anything to add? Dr. Jan Staessen: Yes. I think every effort should go to prevention in most countries. I looked at the statistics, and more than 90% of the healthcare budget is spent in treating established disease, often irreversible disease like MI or chronic kidney dysfunction. I think then you come in too late. So of the healthcare budget in my mind, much more should go to the preventive issues and probably rolling out an effective primary care because that's the place where hypertension has to be diagnosed and hypertension treatment has to be started. Dr. Greg Hundley: Excellent. Well, listeners, we've heard a wonderful discussion today regarding some of the issues pertaining to hypertension and abrupt admission to emergency rooms for conditions pertaining to hypertension, really getting almost out of control. We want to thank Dr. Yuan Lu from Yale New Haven and also our guest editor, Dr. Jan Staessen from Louvain in Belgium. On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions express by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit aha journals.org.

    Circulation November 16, 2021 Issue

    Play Episode Listen Later Nov 15, 2021 32:01

    Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review." 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 at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%? Dr. Greg Hundley: All right, Carolyn, I'm going to guess here. I'm going to go 10%. Dr. Carolyn Lam: Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days. Dr. Carolyn Lam: Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use. Dr. Carolyn Lam: Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern. Dr. Greg Hundley: Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Dr. Greg Hundley: While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells. Dr. Carolyn Lam: Interesting. So what did Dr. Loscalzo and colleagues find? Dr. Greg Hundley: Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance. Dr. Greg Hundley: Whoa. Okay, Carolyn. Now what is filamin-C? Dr. Carolyn Lam: I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found. Dr. Carolyn Lam: First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms. Dr. Carolyn Lam: Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy. Dr. Carolyn Lam: And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy. Dr. Greg Hundley: Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease. Dr. Carolyn Lam: Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please? Dr. Greg Hundley: Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease. Dr. Carolyn Lam: Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study. Dr. Greg Hundley: And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy? Dr. Carolyn Lam: Yay. All right, let's go, Greg. Dr. Greg Hundley: Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease? Dr. Babken Asatryan: Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease. Dr. Babken Asatryan: The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease. Dr. Babken Asatryan: Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy. Dr. Babken Asatryan: Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease. Dr. Babken Asatryan: The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: And patients present generally when, in terms of lifespan? Dr. Babken Asatryan: So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria. Dr. Greg Hundley: And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family? Dr. Babken Asatryan: Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging. Dr. Greg Hundley: Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking?   Dr. Anwar Chahal: Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us. Dr. Anwar Chahal: Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging. Dr. Anwar Chahal: So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this. Dr. Anwar Chahal: As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens. Dr. Anwar Chahal: That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this. Dr. Anwar Chahal: Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies. Dr. Anwar Chahal: It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury. Dr. Anwar Chahal: There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link. Dr. Greg Hundley: Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article? Dr. Ntobeko Ntusi: Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM. Dr. Ntobeko Ntusi: The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see. Dr. Ntobeko Ntusi: The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two. Dr. Ntobeko Ntusi: The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events. Dr. Ntobeko Ntusi: Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD. Dr. Ntobeko Ntusi: Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed. Dr. Ntobeko Ntusi: So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg. Dr. Greg Hundley: Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space? Dr. Babken Asatryan: I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well. Dr. Greg Hundley: Very nice. And Anwar, do you have anything to add? Dr. Anwar Chahal: Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques. Dr. Anwar Chahal: The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

    Circulation November 9, 2021 Issue

    Play Episode Listen Later Nov 8, 2021 21:55

    Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.” 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 feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first? Dr. Carolyn Lam:             I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not? Dr. Greg Hundley:           Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us? Dr. Carolyn Lam:             Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet. Dr. Greg Hundley:           Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease. Dr. Carolyn Lam:             Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke. Dr. Carolyn Lam:             Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute. Dr. Greg Hundley:           Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find? Dr. Carolyn Lam:             The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.” Dr. Greg Hundley:           And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease. Dr. Carolyn Lam:             Yay. Let's go, Greg. Dr. Greg Hundley:           Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Maria Nunes:             Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy. Dr. Greg Hundley:           Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study. Dr. Maria Nunes:             We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease's screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers. Dr. Greg Hundley:           Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long? Dr. Maria Nunes:             Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019. Dr. Greg Hundley:           Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results? Dr. Maria Nunes:             We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too. Dr. Greg Hundley:           Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women? Dr. Maria Nunes:             Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages. Dr. Greg Hundley:           And your results confirmed what was previously known in that regard. Dr. Maria Nunez:             Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking. Dr. Greg Hundley:           Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described? Dr. Ntobeko Ntusi:          Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field. Dr. Greg Hundley:           Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation? Dr. Ntobeko Ntusi:          Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels. In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world. Dr. Greg Hundley:           Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research? Dr. Maria Nunes:             We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup. Dr. Greg Hundley:           Very good. And Ntobeko, anything to add? Dr. Ntobeko Ntusi:          Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story. Dr. Greg Hundley:           Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on The Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation November 2, 2021 Issue

    Play Episode Listen Later Nov 1, 2021 21:04

    Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter 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 in Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this? Dr. Carolyn Lam: I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo. Dr. Carolyn Lam: Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome. Dr. Greg Hundley: Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find? Dr. Carolyn Lam: Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients. Dr. Carolyn Lam: Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction. Dr. Greg Hundley: Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury. Dr. Carolyn Lam: Oh, very interesting. What were the results? Dr. Greg Hundley: Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury. Dr. Carolyn Lam: Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.   Dr. Greg Hundley: Very interesting, Carolyn. What did they find here? Dr. Carolyn Lam: IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University. Dr. Greg Hundley: Very nice, Carolyn. Dr. Carolyn Lam: Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis. Dr. Greg Hundley: Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction. Dr. Carolyn Lam: Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results. Dr. Ole Fröbert: Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease. Dr. Ole Fröbert: The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial. Dr. Ole Fröbert: Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI. Dr. Carolyn Lam: Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because- Dr. Ole Fröbert: Yes, this was- Dr. Carolyn Lam: That's amazing. Dr. Ole Fröbert: ... an idea that just popped up, and then yeah, we did it, but it was seven years of work. Dr. Carolyn Lam: Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out? Dr. Dharam Kumbhani: Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time. Dr. Ole Fröbert: Thank you very much. Dr. Dharam Kumbhani: Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines? Dr. Ole Fröbert: Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist. Dr. Dharam Kumbhani: Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients. Dr. Ole Fröbert: I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it. Dr. Carolyn Lam: Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise? Dr. Ole Fröbert: There is influenza seasons in all parts of the world, I'm sorry. Dr. Carolyn Lam: True. Dr. Ole Fröbert: For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study. Dr. Carolyn Lam: Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit? Dr. Ole Fröbert: Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups. Dr. Carolyn Lam: Thank you. Dharam, any final responses to that? Dr. Dharam Kumbhani: No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.   Dr. Carolyn Lam: I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation October 26, 2021 Issue

    Play Episode Listen Later Oct 25, 2021 26:58

    Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials." 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 couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets. Dr. Greg Hundley: This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives. Dr. Carolyn Lam: Ooooh, You so got my attention, Greg, a very important topic and so, what did they find? Dr. Greg Hundley: Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings. Dr. Carolyn Lam: Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes. Dr. Greg Hundley: Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find? Dr. Carolyn Lam: Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention. Dr. Greg Hundley: Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR. Dr. Carolyn Lam: Oh, very interesting. And what were the results? Dr. Greg Hundley: An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability. Dr. Carolyn Lam: Very nice, important stuff. Dr. Carolyn Lam: Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice. Dr. Greg Hundley: Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia. Dr. Greg Hundley: Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial? Dr. Carolyn Lam: Let's go Greg. Dr. Carolyn Lam: Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper, Dr. Jonathan Newman: Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD. Dr. Carolyn Lam: Great, thanks for lining that up so nicely. So what, Dr. Jonathan Newman: So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up. Dr. Jonathan Newman: And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that. Dr. Carolyn Lam: I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts. Dr. Sandeep Das: Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes. Dr. Sandeep Das: And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper. Dr. Sandeep Das: I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials. Dr. Jonathan Newman: It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested. Dr. Jonathan Newman: And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design. Dr. Carolyn Lam: Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh? Dr. Jonathan Newman: Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world. Dr. Jonathan Newman: So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials. Dr. Carolyn Lam: Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan? Dr. Sandeep Das: Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management. Dr. Sandeep Das: And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can Speaker 3: Love it, Jonathan. Dr. Jonathan Newman: Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals. Dr. Jonathan Newman: And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge. Speaker 3: Thanks so much, Jonathan, and thank you Sandeep for joining us today. Speaker 3: And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit AHJjournals.org.

    Circulation October 19, 2021 Issue

    Play Episode Listen Later Oct 18, 2021 27:21

    Please join author Khurram Nasir and Associate Editor Sandeep Das as they discuss the article "Social Vulnerability and Premature Cardiovascular Mortality Among US Counties, 2014-2018." 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 in Duke-National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm really excited about today's feature discussion. It's really meaningful on so many levels. It discusses social vulnerability. In other words, social determinants of health and its association with premature cardiovascular mortality among US counties. Now, even as an ex-US person I learned a lot, so everyone is going to want to listen in. But now let's start with going through some exciting papers in today's issue, shall we? Dr. Greg Hundley: You bet Carolyn. So, I'm going to grab a cup of coffee and we'll get started with the first article. And really gets into the world of cardiovascular risk and prostate cancer management. Dr. Greg Hundley: So, Carolyn in the light of improved prostate cancer survivorship, and the competing risk of cardiovascular disease, there's an ongoing need for rigorous cardio oncology clinical trials. As you probably know, androgen deprivation therapy is a cornerstone of prostate cancer therapy. Through different pituitary gonadotropin releasing hormone receptor mediated mechanisms both GnRH agonists, as well as antagonists, either indirectly or directly inhibit luteinizing hormone secretion, consequently inhibiting testosterone production. These GnRH agonists are the most commonly prescribed form of androgen deprivation therapy with only 3 to 4% of patients receiving a GnRH antagonist. Dr. Greg Hundley: So, Carolyn the relative cardiovascular safety of gonadotropin releasing hormone antagonists compared with gonadotropin releasing hormone agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains somewhat controversial. And therefore these authors led by Dr. Renato Lopes from both Brazil, as well as the Duke University Medical Center in Durham, conducted an international multicenter, prospective randomized open label trial, and men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomized one to receive gonadotropin releasing hormone, antagonist degarelix or the gonadotropin releasing hormone, agonist leuprolide for 12 months and the primary outcome was time to first educate major adverse cardiovascular event that combined the endpoints of composite death MI and stroke over these 12 months. Dr. Carolyn Lam: Nice Greg, and what did they find? Dr. Greg Hundley: Right Carolyn, due to slower than projected enrollment and fewer than projected primary outcome events enrollment was stopped before the 900 plan participants were accrued from May 3rd, 2016 to April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were really balanced between the two study groups. Now Mace occurred in 5.5% of the patients assigned to degarelix and 4.1% assigned to leuprolide and so in summary, Carolyn, this pronounced study is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a gonadotropin releasing hormone antagonist as well as agonist in patients with prostate cancer. And the study was terminated prematurely due to smaller than planned number of participants and events. And so no difference in mace at one year was noted between the two groups and this pronounced study really provides a model for interdisciplinary collaboration between urologists, oncologists and cardiologist with a sheer goal of evaluating the impact of cancer therapies on cardiovascular outcomes. Dr. Carolyn Lam: That's so cool, Greg. I heard the presentation of these results at the ESC by Dr. Renato Lopes and it's a really cool and important study, but a paper I want to present is an analysis from Emperor preserved on inpatient and outpatient heart failure events. Dr. Greg Hundley: Great. Carolyn, so remind us, what did the Emperor preserved trial show? Dr. Carolyn Lam: Emperor preserved showed that in patients with heart failure and preserved ejection fraction empagliflozin reduce the primary endpoint of cardiovascular death or hospitalization for heart failure, primarily related to a lower risk of hospitalizations for heart failure. Greg you're smiling, because you can see me beaming because we finally have a robustly positive outcomes trial in have pep in this trial. Nonetheless in the current analysis, Dr. Milton Packer from Baylor Heart and Vascular Institute and others used prospectively collected information on inpatient and outpatient events, reflecting worsening heart failure, and pre specified their analysis in individual and composite end points. Dr. Greg Hundley: I've been in suspense here. What did they find? Dr. Carolyn Lam: Empagliflozin reduced the risk of severe hospitalizations as reflected by admissions requiring the use of ionotropic or vasopressor drugs and the need for intensive care. Empagliflozin also reduce the risk of outpatient worsening heart failure events, including the need for urgent care visits, diuretic, intensification, and unfavorable changes in functional class. So, basically benefit across the spectrum. Furthermore, because there's controversy about the effect across the spectrum of ejection fraction. The benefit on total heart failure hospitalizations was found to be similar in patients with an ejection fraction of above 40, but less than 50% and between 50 to 60%, although it was attenuated at the higher ejection fractions and we'll hear a lot of discussions about this.   Dr. Greg Hundley: Wow, Carolyn. Just more information that keeps coming out about SGLT-2 inhibition. My next paper comes from the world of preclinical science and angiogenesis is a dynamic process, involves expansion of a preexisting vascular network that can incur in a number of physiologic and pathologic settings. But despite its importance, the origin of the new angiogenesis vasculature is really poorly defined in particular, the primary subtype of endothelial cells, whether they be capillary, Venus or arterial that might be driving, this process really remains undefined. These authors led by Dr. Michael Simmons at Yale University school of medicine, fate mapped endothelial cells using genetic markers specific to arterial, Venus and capillary cells. Dr. Carolyn Lam: What did they find Greg? Dr. Greg Hundley: This team study results found that Venus endothelial cells were the primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterial, venous malformation, and pathologic angiogenesis. And these observations highlight the central role of the Venus endothelium in normal development and disease pathogenesis. Dr. Carolyn Lam: Wow. That's really interesting. I don't think I've ever really paid attention to that bit. Venus endothelium. Thank you for that. Now what else is in today's issue? Well, there's an exchange of letters between Doctors Zhang and Liao regarding the article anti hypertrophic memory after regression of exercise induced physiologic, myocardial hypertrophy is mediated by the long noncoding RNA M heart 779, then ECG Challenge by Dr. Ahmed on challenges of interpreting smart watch and implantable loop recorder, tracings. There's cardiology news by Tracy Hampton and Highlights from the Circulation Family of journals by Sara O'Brien. These regular articles are just really worth a read. You learn so much from just these short lovely summaries. There's On My Mind paper by Dr. Meyer on a targeted treatment opportunity for taking advantage of diastolic tone. And there's also a Research Letter by Dr. Brozovich on a rat model of heart failure with preserved ejection fraction changes in contractile proteins, regulating calcium cycling and vascular reactivity. Dr. Greg Hundley: These journal issues, there's so much information. I'm in a close out with an in depth piece from professor entitled antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. I really look forward to your feature discussion on the social vulnerability and premature cardiovascular mortality in US countries. Dr. Carolyn Lam: Thanks Greg. It's good. Dr. Carolyn Lam: Today's feature discussion focuses on an extremely important topic of social vulnerability and premature cardiovascular mortality. So pleased to have the corresponding author of the feature paper, Dr. Khurram Nasir from Houston Methodist and Dr. Alana Morris, who is the editorialist for this paper. And she's joining us from Emory University in Atlanta, Georgia. So thank you both of you for joining and Alana if you don't mind, I'm going to borrow some of the words from your really-excellent editorial to bring us into the discussion. You very nicely brought up that early race and ethnic disparities and a death toll from COVID 19 really, laid the foundation for us having Frank conversations about vulnerable populations and has really brought to light social determinant of health and social economic inequality as risk factors. Now that's, COVID 19. And frankly, if we put everything in a global view of what kills most of us, it's still cardiovascular disease, which is why this paper is just so important, but current recognizing I'm not from the US, lots of our audience are not from the US. Could you please walk us through what your paper looked at and what it means? Dr. Khurram Nasir: Sure. Klan, thank you so much for having us today and what a wonderful editorial by Dr. Morris on this. As you pointed out about the COVID challenges, we were all touched by the significant disparities, really in a one of the lifetime crisis, such as COVID. But the reality is that even in times of calm the benefits, for example, cardiovascular disease prevention access have not been shared equally among vulnerable groups. So I'm a preventive cardiologist, and it gives me immense pride that despite being the number one cause of morbidity mortality for so long as a cardiology community, we have made significant strides over the last three decades, cutting into our losses. And if you look at the trends it's appeared and I'm very hopeful that we'll soon be losing the number one killer tag in US. At the same time we are seeing that those cuts are being lost, especially in the young individuals. Dr. Khurram Nasir: And at one point while we celebrate these decline. But the thing that bothers many of us that unfortunately these gains have not been equal, especially for our more vulnerable patients. And apart from the well documented, I think racial disparities that we all know and are becoming more aware. I think health disparities also form across various fourth lines and I believe the deepest and more persistent divides is around income. And you can even go a step further in US, unfortunately for our international group is unfortunate fact that in US, your zip code may hold more sway than your genetic code. And an example was made famous in St. Louis, Missouri Del marble award, which is known as the Delmer divide, a title that was made famous by a four minute BBC documentary that showed, that a sharp dividing line between the poor predominantly African American neighborhoods in the north and more affluent, largely white neighborhood in the south with health falling across this divide. Dr. Khurram Nasir: And in our practice, we see this phenomenon clearly in our own backyard. So, inspired by this sterling. We wanted to determine that a mirror geographical measure, where we can get insights of conditions where people live, learn, work, play, grow, and age, and commonly now known as the social determinants of health. Can that explain some of these rising risks, especially in the premature cardiovascular disease. So to design this study, we reached out to the CDC social vulnerable, the index that has been created that ranks communities and zip codes based on 15 factors across food domains, socioeconomic status, household composition of disability, that in includes single parents, elderly or children, minority status and language and housing type and transportation, all of them are put together and for each census. And then eventually at the county level, you can classify what their social vulnerability is. And as you know, this was really developed in to identify places where in times of disaster and emergencies, you can focus a little bit more, but we thought about how do we connect this to, for example, our data on mortality from CDC wonder. Dr. Khurram Nasir: And once we did that, we found very interesting patterns that across the scale social vulnerability, there is a risk dose dependent fashion and the age adjusted mortality rates for premature cardiovascular disease, which we define as less than 65, went from the least vulnerable and became the worst across the most vulnerable. At the same time, we also found this double jeopardy issues where this association was varied by race, gender, and ruler. And what we found that specifically Non-Hispanic lack individuals were more likely for certain types of cardiovascular, premature, such as stroke and heart failure, mortality, as compared to the rest, even if you were from the least vulnerable to the most women also unfortunately had a twofold higher risk of CBD mortality. And what is becoming clearly this whole ruler urban that a two to five fold risk of CBD mortality was seen among the least vulnerable. So this is in just the motive of our study, what we did and what we found. Dr. Carolyn Lam: That is so wonderful. Thank you for setting the context and then just to reiterate, so this was all within the US. Alana, could you maybe help frame how important these findings are for us? Dr. Alana Morris: Yes. I think that this analysis is so important, particularly within the context of some of the things that we see happening politically in our country and our landscape right now. And I think we tried to touch on some of those issues in the editorial. Again, I think that the COVID 19 pandemic, if you want to put that against this landscape has really brought into the forefront of our minds, this issue of disparities. Of course, there are many of us who have been thinking about researching and writing about disparities for a long time, but the issue of disparities really, came into the public mindset with the COVID 19 pandemic. The question now is how do we address these as we go forward? And what we're seeing politically is this question of how do we address inequalities that have been present for really since the beginning of time and maybe are widening and perhaps threaten many of the advances that we've made in terms of cardiovascular disease, morbidity, and mortality. Dr. Alana Morris: I think we have to think about in the US, universal healthcare coverage, because we have to be able to prevent disease and treat disease. And as current addressed, there are neighborhood zip codes where people not only don't have access to healthcare, but they don't even have access to the ability to promote health. They don't have access to things like parks, where they can exercise. They don't have access to healthy foods or grocery stores and in a country like the United States where there's so much wealth, you need to think about the fact that certain individuals, don't have the ability to access a grocery store, to access healthy food. It's just really striking and mind boggling that we have this, the difference in rural versus urban locations where some of our US residents, unfortunately don't have access to primary care clinicians, certainly not specialty clinicians is really very mind boggling. And we've seen this play out with the pandemic, but hopefully once we get past the COVID 19 pandemic, we still have to come back to a place where again, we're taking care of not only preventives or services to prevent the onset of cardiovascular disease, but certainly once people are diagnosed with cardiovascular disease, we want to get them access to specialty care. So we have to think as a community, how do we prevent disease, but also treat disease once disease is diagnosed within our country.   Dr. Carolyn Lam: What you just said about the zip code being more powerful about, than the genetic code, that's like a quotable code. It's incredible. And for those of us coming outside of the US, we don't even realize how much that plays a role, even just within the US. But now let's get to exact point that Alana pointed out, which is what are the next steps. And could you maybe suggest Khurram, and Alana maybe come first, but what's the one thing you want to get out or the one next thing that should happen after this Dr. Alanna Morris: We put a figure in to the editorial that I think really gets to the heart of the matter, I think that those of us who are in healthcare or those of us who think about public health really would ask the question of, why in a country that has as much wealth as the United States, do we not have universal healthcare, most countries across the world that are in an economic position similar to the United States do have universal healthcare coverage for their residents. And you see much better statistics in terms of longevity for their residents as compared to what we have in the United States. And what you see when you look at the United States is that where there is the most vulnerable residents as per analysis identifies those states are the ones that actually don't have, Medicaid expansion. Dr. Alanna Morris: They don't have a safety net for their residents. And so there's really contrast and this disparity that just does not make sense. It does not make sense where there are residents in the United States, which need the most help and they just don't have it. They just are not able to get access to preventive services as well as diagnostic services. And it really just doesn't make sense what we're doing in the United States, in my humble opinion. And I think in the humble opinion of many of us who want to take care of patients, but just cannot, Kern and I both practice in states where this is an issue. And I think that's one big driver. But again, I think when we also think about the built environment in the US and how we think about promoting health and how we talk to patients, when we talk about individuals in the US, we try to give them advice about therapeutic lifestyle changes, how to exercise, how to eat healthy, to prevent disease. That's easier for certain individuals as compared to others, depending upon where you live, depending upon those five digits that make up your zip code. So if we really want our residents to be healthy, we have to create an environment that enables them to do that. Dr. Carolyn Lam: Wow, thank you very much. And as I let Khurram have the final words even about where you think mixed research should be. I just want to highlight that incredible figure from your editorial Alana. I mean, it is really started, there are three panels to it, everyone. The first one chose the social vulnerability index, the second, the premature cardiovascular disease mortality, and then the third, the status of Medicaid expansion. And you can see the colors are just vivid in, how it all makes sense and goes together. So pick up our journal and have a look, but then finally Khurram? Dr. Khurram Nasir: So, Alana, your figure was fantastic and so much add perspective to our findings. As you were saying, it took me back to 35 years back when, where we are before Medicare disparities, even in access to hospitals were dramatic. So where we practice in the south one third of the hospitals would not admit African Americans even for emergency. Now, this is where the policy comes in and suddenly in 1965 using the carrot of Medicare dollars, the federal government virtually ended the practice of racially segregating patients, doctors, and medical staffs, blood supplies so that is the direction that we need to go from the policy perspective and trying to affect the upstream determinants. Now moving forward, as I think more, and especially as a physician, I think while the census level measures are extremely useful to help refine these policy and focus programs in vulnerable areas. Dr. Khurram Nasir: I also think that there is a parallel need to start focusing on similar efforts at the individual level. The first thing is how do we even identify social determinants at this patient level? Are there three main categories, income, education, possibly healthcare, but I think that we need to broaden this. And in the past we have been challenged because we didn't have a set of consensus of the defined SDUH framework. But thankfully now in 2021, we have the healthy people, 2020. Actually for international community, the WHO there is a WHO framework of identifying SDOH at an individual level and in US a more comprehensive Kaiser family foundation. And not only that, we looked at superficially broadly, but we have to go deeper beyond these components of economic instability, education, housing, social context on healthcare beyond insurance, and even food. Dr. Khurram Nasir: For example, income and employment are predominant pillars of income stability, but it may not capture the full picture. For example, difficulty paying bills out of pocket cost and death related to medical care, same in education, where we captured the highest degree, but issues around health and digital literacy and language proficiency may be even more important. So not only we have to broaden the scope, but we have to go in depth. And thirdly, what I've realized from these kind of studies that we have to go a step further, that social disparities don't occur in silos. And we have to look at the aggregated information. And maybe it's time to potentially learn from advances in genetics, in what we have learned that manifestation of disease, especially cardio metabolic rather than being influenced by few major genes is manifested secondary to multiple interacting genes. So can we create similar to a poly genetic risk score, which is an aggregation of genetic smaller risk to a relevant something similar called poly social risk score. Dr. Khurram Nasir: Now, this is an area that our group has been extensively working. And over the last 12 months, we have tried to construct a comprehensive poly social risk score at an individual level based on almost about 50 sub components of the social determinants. And we have suddenly finding very interesting associations with premature CAD stroke. Almost one in two young individuals with stroke, have the worst poly social risk code at the individual level. I think so the next steps will be definitely validation of this tool, incorporation in practice, whether it's adoption and effective interventions can be tied. But the final thing, what I truly want to say is that I'm hopeful that these efforts, the census level at an individual level, at a societal level and the health system are waking up to the importance of social determinants that we can think outside the box and have strong community partnerships. Multi Pro strategies driven largely by social economic environmental factors. So we can all make a lead towards the mission of achieving social justice and equity that eventually cascades through the health system and beyond. So we had enough time to illuminate the issues and challenges. Now it's the time to act. Dr. Carolyn Lam: Thank you so much Kern for a beautiful paper. We are so proud to be publishing it in circulation. And thank you, Alana lovely, editor that we've said so many times. Thank you audience for joining us today. You've been listening to Circulation on the Run from Greg and I please tune in again. Next week, Dr. Greg Hundley: This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.

    Circulation October 12, 2021 Issue

    Play Episode Listen Later Oct 11, 2021 27:23

    Please join author Milton Packer and Associate Editor Justin Ezekowitz as they discuss the Perspective "Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials." 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. 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, it really is so great to be back with you chatting about the papers here in the Journal. Thank you for going solo and for just being the greatest partner on earth. Thank you for that. For everyone listening in, we are back with some gusto and especially with this feature discussion today. You are not going to want to miss it. We are talking to Dr. Milton Packer as well as Dr. Justin Ezekowitz. We are going to compare PARAGON and EMPEROR-Preserved trials in heart failure with preserved ejection fraction. A really interesting discussion you're not going to want to miss, but now let's start with some papers in today's issue. I'd like to start, please. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Greg, you know the optimal duration of antiplatelet therapy in patients with high bleeding risk with or without oral anticoagulation after coronary stenting? Well, that still remains a question. Today's paper is a pre-specified subgroup analysis of the MASTER DAPT trial and reports on the outcomes of patients with or without an oral anticoagulation indication in this study. Dr. Greg Hundley: Right, Carolyn. Remind us. What was the MASTER DAPT trial? What did it test? Dr. Carolyn Lam: Ah. MASTER DAPT investigated an abbreviated or one-month versus a non-abbreviated or three to 12-month dual antiplatelet therapy and a stopping of antiplatelet therapy at six months strategy after coronary stenting in an all-comer population at high bleeding risk. Dr. Greg Hundley: Carolyn, what did this subgroup analysis of outcomes in patients with and without oral anticoagulation show? Dr. Carolyn Lam: At 12 months of follow-up, ischemic and net risk did not differ with abbreviated versus non-abbreviated anti-platelet regimens in both subgroups, although significantly fewer clinically relevant bleeding events occurred in the group without an oral anticoagulation indication. Whereas only numerically fewer bleeding events occurred in the group with an oral anticoagulation indication that did not reach statistical significance. This subgroup analysis from the MASTER DAPT trial really adds additional evidence that dual antiplatelet therapy beyond one month in patients with or without an indication for oral anticoagulation really has no benefit and only increases bleeding risk. Dr. Greg Hundley: Oh, very important finding, Carolyn. Great research. Well, Carolyn, how the extracellular matrix microenvironment modulates the contractile phenotype of vascular smooth muscle cells and confers vascular homeostasis really remains elusive. Thus, these investigators led by Professor Wei Kong at Peking University applied protein-protein interaction network analysis to explore novel extracellular matrix proteins associated with the vascular smooth muscle cell phenotype. Dr. Carolyn Lam: Huh. Interesting. What did they find, Greg? Dr. Greg Hundley: Right, Carolyn. By combining an in-vitro and an in-vivo genetic mice vascular injury model, they identified nidogen-2, a basement membrane glycoprotein, as a key extracellular matrix protein for maintenance of vascular smooth muscle cell identity. Nidogen-2 exerted its protective function via direct interaction and modulation of Jagged1-Notch3 signaling. Dr. Carolyn Lam: Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What are the clinical implications, Greg? Dr. Greg Hundley: Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate Jagged1-Notch3 signaling, well, that may provide novel therapeutic strategy for atherosclerosis and post-injury restenosis. Dr. Carolyn Lam: Very nice. Well, in the next paper, we discuss inflammation in heart failure. We know that inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Interesting, huh? Well, these authors, Dr. Wollert and colleagues from Hannover Medical School in Germany, identified an adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against persistent afterload stress-induced heart failure in mice. Monocytes and macrophages produced myeloid-derived growth factor in the pressure overloaded myocardium to augment SERCA2a expression in cardiomyocyte's calcium cycling and contractility. Myeloid-derived growth factor plasma concentrations were also found to be elevated in patients with aortic stenosis and to decline after aortic valve implantation indicating that pressure overload also triggers myeloid-derived growth factor release in humans. Dr. Greg Hundley: Carolyn, really informative preclinical science, but what are the clinical implications? Dr. Carolyn Lam: Ah. These observations molecularly defined a feature of the inflammatory response to hemodynamic overload that protects against heart failure development. Inflammation's beneficial trade therefore need to be considered when developing inflammation as a therapeutic target in heart failure. All of this is really discussed in a lovely editorial entitled Inflammation and Heart Failure: Friend or Foe? That's by Drs. Hajjar and Leopold. Dr. Greg Hundley: Great job, Carolyn. Well, my next paper focuses on resistant hypertension. Carolyn, although lifestyle modifications generally are effective in lowering blood pressure among patients with unmedicated hypertension or those treated with one to two antihypertensive agents, the value of exercise and diet for lowering blood pressure in patients with resistant hypertension is unknown. To address this, Professor James Blumenthal and co-authors at Duke University Medical Center enrolled 140 patients with resistant hypertension with an average age of 63 years, 48% women, 59% black, 31% diabetes, and 21% with chronic kidney disease and randomly assigned them to A, a four-month cardiac rehab center-based program of lifestyle modification. We're going to call that C-LIFE, consisting of dietary counseling, behavior and weight management, and exercise. Or number 2 or the B, a single counseling session providing standardized education and physician advice. We'll call that SEPA. Dr. Greg Hundley: The primary endpoint was clinic measured systolic blood pressure. Secondary endpoints included 24-hour ambulatory blood pressure and selective cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of baroreflex on heart rate; high-frequency heart rate variability to assess vagally-mediated modulation of heart rate; flow-mediated dilation to evaluate endothelial function; and pulse wave velocity to assess arterial stiffness; and then finally left ventricular mass to characterize left ventricular structure and remodeling. Dr. Carolyn Lam: Wow! That is a very, first of all, important clinical question. Then also, just very intricate methodology in assessing this. What did they find? Dr. Greg Hundley: Right, Carolyn. Between-group comparisons revealed that the reduction in clinic systolic blood pressure was greater in C-LIFE compared with SEPA. Next, 24-hour ambulatory systolic blood pressure also was reduced in C-LIFE with no change in SEPA. Then next, compared with SEPA, C-LIFE resulted in greater improvements in baroreflex sensitivity, high-frequency heart rate variability, and flow-mediated dilation. There was no between-group differences in pulse wave velocity or LV mass. Dr. Greg Hundley: Carolyn, diet and exercise can lower blood pressure in patients with resistant hypertension. When delivered in a cardiac rehabilitation setting, a four-month program of diet and exercise as adjunctive therapy, results in a significant reduction in clinic and ambulatory blood pressure, and improvement in selected cardiovascular disease biomarkers. Dr. Carolyn Lam: Wow! Really nice, Greg. Okay. Well, looks like we're all going to round up already with what else there is in today's issue. Let me start. There's an exchange of letters between Drs. Fang and Vinceti regarding the article Blood Pressure Effects on Sodium Reduction: Dose-Response Meta-analysis of Experimental Studies. Dr. Greg Hundley: Right, Carolyn. I've got a few things in the mail bag. First, Professor Anker has a Research Letter regarding the Kidney Function After Initiation and Discontinuation of Empagliflozin in Heart Failure Patients With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge entitled Atrioventricular Block with Narrow and Wide QRS: The Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an AHA update regarding the American Heart Association's focus on primordial prevention. Well, Carolyn, I can't wait to hear this fantastic feature discussion with you and Dr. Packer. How about we jump to that? Dr. Carolyn Lam: Great. Let's go, Greg. Dr. Carolyn Lam: Because side-by-side exam of PARAGON and EMPEROR is like side-by-side of... Dr. Justin Ezekowitz: You can compare our new and our old prime minister much like your paper did. Dr. Milton Packer: Yeah, yeah. Dr. Justin Ezekowitz: There are [crosstalk] and it could be viewed until they perform in the broader world how it goes. You don't quite know. Dr. Milton Packer: The only problem is you can't do a head-to-head comparison of the old prime minister and the new prime minister. Dr. Justin Ezekowitz: That is true except that the head-to-head comparison includes excellent care by both the new and the old. I think that comparison's going to be pretty equal. I think we can case-control that one. Dr. Carolyn Lam: I really liked that that was politically correct because we are recording. Everybody, welcome to the feature discussion. I am here with Dr. Milton Packer from Baylor and he really needs no introduction. We're discussing heart failure with preserved ejection fraction. As well as our associate editor, Dr. Justin Ezekowitz from University of Alberta. Hence, in case anybody's wondering, we were talking about the Canadian elections. Let's just launch straight into it, a side-by-side comparison of PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may, what in the world drove you to do this? Dr. Milton Packer: My God. Oh, my God. Yes. Dr. Carolyn Lam: Tell us about what drove you to do this and please, if you could just summarize the results. Dr. Milton Packer: Well, let me just say from the outset that this was a commentary, not an original research article. Dr. Carolyn Lam: Yes. Dr. Milton Packer: The commentary was motivated by two very straightforward observations. We had two large scale outcome trials of two different drugs in heart failure with a preserved ejection fraction. I was privileged to serve as you were, Carolyn, on the leadership committees of both trials. It's not as if we have involvement in only one trial. We have involvement in both trials and we are very proud of that involvement. Dr. Milton Packer: One trial came in with a effect size of about 13% on its primary endpoint with a borderline P-value. A second trial, EMPEROR-Preserved, came in with a 21% reduction and its primary endpoint with a really small and persuasive P-value. The two patient populations in the two trials were really amazingly similar. We wanted to understand why it was 21% in one trial and persuasively so and why it appeared to be smaller in the PARAGON trial with sacubitril/valsartan. We thought, well, maybe that difference was related to how endpoints were defined or maybe that difference was related to the influence of ejection fraction. The reason we got excited about that was that as almost everyone knows, PARAGON found an influence of ejection fraction on the effect of sacubitril/valsartan in patients with HFpEF. We found an influence of ejection fraction on the effect of empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to understand whether that influence was similar in the two trials. Dr. Milton Packer: Just to make life simple, PARAGON had created certain cut points for ejection fraction. They had presented and previously published in Circulation endpoints based on those cut points of ejection fraction. All we did was we used their endpoints and their cut points, and we put the two trials side by side. We did not do a statistical comparison of the effect size. There're actually no P-values in the whole commentary. But what we wanted to see was: Was the shape of the ejection fraction influence relationship similar or different in the two trials? Well, very simple. In PARAGON, as has been reported, there was a linear relationship: as ejection fraction increased, the effect of sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was also an attenuation at a highest ejection fraction, but the relationship wasn't linear. It was like a hockey stick. It was flat and then went up at an ejection fraction over 62.5, which was the cut point that PARAGON used. Dr. Milton Packer: When we compared patients between the low 40s and the low 60s, the effect size in empagliflozin appeared to be larger than the effect size of sacubitril/valsartan in that ejection fraction group using the same endpoints. In fact, for hospitalizations for heart failure, which is really what SGLT2 inhibitors do, it was twice as great with empagliflozin in EMPEROR-Preserved than with sacubitril/valsartan in PARAGON-HF. We thought this was really interesting. We put the pictures up side by side. We wrote a commentary and Circulation was so kind to accept it. Dr. Carolyn Lam: Oh, but Milton, you were very, honestly as always, very clever to have done this analysis. But if I could reiterate a few things for the audience, which is very important. First of all, as you rightly first pointed out, it's a perspective piece. It is not a head-on comparison with P-values. It could not be. Let's just also give the audience a bit of background in that PARAGON included patients with an ejection fraction of 45% and above. EMPEROR-Preserved was above 40. PARAGON looked at total heart failure hospitalizations and cardiovascular death as a primary outcome. EMPEROR looked at first cardiovascular death or heart failure hospitalization. Dr. Carolyn Lam: Let's just remember the designs were different. Of course in the comparison, PARAGON compared sacubitril/valsartan versus valsartan. I like the way you very carefully wrote in your study that it was more a study of neprilysin inhibition since it's sacubitril/valsartan against valsartan and it was empagliflozin versus placebo. We know that it's important to state that as a basis. Then really important to say to everybody out there, pick up our journal. You must look at this bigger. I myself have already cited it at least twice already, Milton, because people will just naturally ask that. "Are the results different because of ejection fraction or different endpoints?" What you did there in that beautiful figure is that you tried as best as you can to match it up in terms of ejection fraction bins and match it up in terms of hospitalizations. There. I just wanted to state those few things, but I'm really- Dr. Milton Packer: Oh, no. No. Carolyn, you're 100% right. That's why there are couple of things. I just want to underscore what you said because I think your points were spot on. First of all, we really lined up the endpoints and the ejection fraction. We tried our best to compare apples and apples. It would not have been a useful exercise for us to compare different endpoints and different ejection fraction subgroups. But I just want to make sure that everyone understands: I'm a big fan of sacubitril/valsartan and I'm a big fan of neprilysin inhibition. As you know, both PARADIGM-HF and PARAGON-HF weren't really tests of sacubitril/valsartan; they were tests of neprilysin inhibition. They were great tests at that. PARAGON in particular was a great test of that. We're comparing neprilysin inhibition and SGLT2 inhibition. Dr. Milton Packer: But here's my most important point: we do not want people to choose one over the other. That was not the intent. We think that there are data in patients with certain ejection fractions, let's say between 40 and 60, I'm just creating a range, where both interventions are appropriate. Now I understand there are cost considerations and I don't want to minimize that, but we are not suggesting that anyone prefer one drug over the other. All we wanted to do was we wanted to ask the question: Since the effect size in one trial seemed to be different than the effect size in the other trial, what were the ejection fraction subgroups that represented that difference? We found that the patients with ejection fractions greater than 60, 65% did not contribute to that difference. It was the patients with lower ejection fractions that contributed to the difference. I hope that's helpful. Dr. Carolyn Lam: Ah. That's wonderful. Justin, have you recovered from the talk about the Canadian elections? Dr. Justin Ezekowitz: Oh. I have indeed. Dr. Carolyn Lam: I'm on swinging. Dr. Justin Ezekowitz: I have indeed. Thanks for recognizing that Canada just had a major election we carried out in six weeks. But, Milton, I really enjoyed reading this. Maybe I can just ask you about two elements within this perspective piece, which is number 1, what's incredibly concordant is a lack of difference across cardiovascular death for both agents in both trials regardless of the trial differences and the potential differences in patient populations recruited; that's number 1. It's incredibly flat for cardiovascular death. Dr. Justin Ezekowitz: But number 2 is there is a danger in comparing trials even non-statistically. That's often a pitfall we get into, but we have to put some frame of reference on that. What is the one or two key things you think differ between PARAGON and EMPEROR-Preserved that you say, "You really need to look at these trials differently"? Those two questions came to mind when looking at this great figure that you produced. Dr. Milton Packer: Okay. The first question is so much easier and that is that these drugs don't reduce cardiovascular deaths. Full stop. It's really interesting because sacubitril/valsartan reduces cardiovascular death in people with ejection fractions of 40% or less, but not in patients with ejection fraction greater than that. The primary effect is heart failure hospitalizations. Empagliflozin didn't reduce cardiovascular death even in patients with the ejection fraction less than 40% or greater than 40%. What we're really, really talking about two drugs where the major effect is a reduction in heart failure hospitalizations. That comes out whether you do the analysis as time-to-first-event or total heart failure hospitalizations. Dr. Milton Packer: Of course, we're looking forward to the DELIVER trial with dapagliflozin. My own personal expectation is they're going to come out with a very striking effect on heart failure hospitalizations and not on cardiovascular deaths. Cardiovascular deaths in patients with HFpEF is really... It's a hard goal because only half of the deaths are cardiovascular. These patients have so many comorbidities that influence prognosis. The other thing, which is really important, is that heart failure hospitalizations only represented 18% of all hospitalizations in these patients; it's really small. I think of empagliflozin as being a treatment of the heart failure of HFpEF, not a treatment for HFpEF. I hope that makes sense. Justin, what was your second question? Dr. Justin Ezekowitz: Absolutely. Dr. Milton Packer: Oh, the differences between- Dr. Justin Ezekowitz: Yeah. Thank you, Milton. Dr. Milton Packer: Okay. There's always differences between two trials. As I said before, Carol and I were involved in both trials. They were done slightly at different times. They didn't overlap. Remember that the cut points in the two trials, one was 40%, one was 45%, really didn't matter to our analysis because we corrected for that in our ejection fraction subgroups. I was actually really much more impressed by the similarities than by the differences, but here's the catch. HFpEF is an incredibly heterogeneous disease. When we look at baseline characteristics, we're looking at means, medians, percentages. We're not picking up on any heterogeneity and there's a lot of heterogeneity. I actually think that HFrEF is a reasonably homogeneous disease. I think HFpEF is an incredibly diverse disease with a whole host of different disorders. What I'm amazed by is that we actually got an effect size that was greater than 20% in an all-comers HFpEF analysis. Dr. Milton Packer: But in all honesty, Justin, it wasn't really all-comers. We excluded people with BMIs over 45. There are a lot of patients who are obese and had BMIs greater than 45 who have HFpEF. By the way, especially in Texas. I didn't say that. We didn't enroll those patients. In all honesty, if I had to do it all over again, I would have. By the way, PARAGON didn't enroll them either. Dr. Carolyn Lam: Well, this is an incredible conversation. I know that we could just do a whole hour of chatting about what this implies for the higher ejection fraction, what this implies for how we should be treating heart failure. I don't even dare to ask for some last words maybe from both Justin and Milton, but recognizing that the time is short, anything else to add? Dr. Milton Packer: I think Justin should do last words. Dr. Justin Ezekowitz: Well, let me summarize by saying there is a hockey stick. We love hockey sticks in Canada. A simple and an excellent comparison. I think people should really look at that figure to understand it, but do not undertreat your patients with HFpEF and look at these with a grain of salt. Thanks for joining us, Milton. Thanks, Carolyn. Dr. Milton Packer: Thank you so much. Dr. Carolyn Lam: On behalf of Greg and I, you've been listening to Circulation on the Run. Thank you so much for joining us today and don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.

    Circulation October 5, 2021 Issue

    Play Episode Listen Later Oct 4, 2021 30:44

    This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue. Dr. James de Lemos: Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue. Dr. Marc Ruel: Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward. Dr. Marc Ruel: Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery. Dr. Marc Ruel: Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation. Dr. James de Lemos: Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece? Dr. Marc Ruel: It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery. Dr. Marc Ruel: It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage. Dr. Marc Ruel: And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far. Dr. Marc Ruel: Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well? Dr. Michael Fischbein: Yeah. Thanks, Marc. I think that's an excellent question. Yeah, now, every patient after this trial, I talk to them ahead of time and offer them to have their appendage ligated in this setting if they have a history of atrial fibrillation. I don't think this adds much to our operation, it doesn't increase much the clamp time. And especially, although the trial was more surgically excising with some of the newer clips out there, it really doesn't add much time to the operation. So I think this is really an important paper that will change what we do as surgeons. Dr. James de Lemos: Can I just comment that I think the trial has indirect implications well beyond surgery, because the demonstration of combined benefit for oral anticoagulation with left atrial appendage occlusion really suggests that, even for patients not going for cardiac surgery, at some point in the future, we may be thinking about not and either/or between the devices and anticoagulation, but maybe both. Dr. James de Lemos: Mike, let me come back to you. There's a really fascinating paper by DeCarlo evaluating penetrating aortic ulcers that really change my thinking on this. Can you talk a little bit about this paper and your thoughts? Dr. Michael Fischbein: Thanks very much, James. I think this is really an important paper that's going to change what we do as surgeons. As you know, symptomatic penetrating aortic ulcers are grouped with dissections in tremula hematoma where we treat those patients immediately. None of us know what to do though with the asymptomatic aortic ulcer, which is actually more common. A lot of us are basing our reports on some observational studies. Many of these studies are mixed, symptomatic and asymptomatic. And so the treatment really varies, from watching them conservatively to treating them with open or endovascular approaches. Dr. Michael Fischbein: However, this paper by DeCarlo's really excellent. They followed 273 asymptomatic penetrating ulcer patients over time following their CT scans. And they really had two key important findings. One that these ulcers really didn't change much over time, and two, the risk of some complication occurring, whether that's rupture, symptoms or progression of disease was very low at 6.5% over 10 years. And so I think this is really going to be important, because we know that these asymptomatic penetrating ulcers, we can watch them conservatively. They do have to be still followed, but we don't have to go immediately to perform some surgical procedure. Dr. James de Lemos: Marc, any thoughts from you on this paper? Does this change what you guys will be doing in Ottawa? Dr. Marc Ruel: Absolutely. Yeah, I think this is, as Mike was saying, a very germane finding that's very helpful. I think the key word here, as Mike was alluding to, is really the word asymptomatic and how do you define that? Right? I mean, many of these findings are incidental findings. Someone comes in with a bit of shortness of breath or this or that, gets a PE protocol CT scan and then a penetrating aortic ulcer is found. Dr. Marc Ruel: So where do you draw the line between symptoms that may be a small left lateral effusion or a bit of shortness of breath. And it's also, I think that nuance will have to be determined going forward, what is truly asymptomatic versus a few symptoms that may be less specific and perhaps not relate to the penetrating aortic ulcer. But I think it's tremendously helpful in guiding practice going forward. Dr. James de Lemos: Fantastic. Thank you both. Mike, I want to come back to you on another really important paper from the vascular surgery standpoint, which is the paper from the Voyager investigators on the combination of rivaroxaban and aspirin for patients with surgical treatment of peripheral arterial disease. Dr. Michael Fischbein: Yeah, no, I think this is another or provocative paper. And as you know, peripheral arterial disease is a really highly-significant clinical problem. We say that affects 200 million people globally. And this includes patients with claudication, arrest pain, limb threat ischemia. And currently, the treatment for this is to either a open surgical or endovascular revascularization of the lower extremity. And the problem is while these patients, they have immediate symptomatic relief where you can save their limb, we say that one out of five will develop some sort of symptom or limb ischemia by three years. Dr. Michael Fischbein: And so the field is really looking for some sort of adjuvant therapy to help prevent these occurrences later on. And so the Voyager trial randomized over 6,000 patients who underwent surgery, whether it was open or endovascular, and then they randomized to either receiving rivaroxaban plus aspirin, versus aspirin and a placebo. And they showed that if you received riva, that those patients had a significant reduction in the instance of their primary endpoint, which included ischemia, limb loss or symptoms. And importantly, there was not an increase in major bleeding risk in these individuals. Dr. James de Lemos: So fascinating. I mean, this does this change practice and is this now the standard for surgically-treated peripheral arterial disease? Dr. Michael Fischbein: Yeah, I think there's still some questions that we have to answer. Yeah, I think definitely this, I think will be used after the bypass surgery, but some of the things in the trial that we would have to figure out is how applicable is this to everyone. In the trial, the open surgical arm had patients with less risks. Also, some patients received vein conduit versus a prosthetic conduit. And so, I think we'll have to look at some of the sub-analysis to see who we can apply this to. Dr. James de Lemos: Fantastic. Marc, any thoughts from your perspective on this one? Dr. Marc Ruel: Yeah. Mike provided a great summary. I think one other take-home message to me is that, really, these patients should be viewed as having panvascular disease, a little bit like our CABG patients. And essentially rivaroxaban or DOACs in general have a role, like in the COMPASS trial, in preventing other complications. So here, part of the composite endpoint was myocardial infarction, right? And we know that these peripheral vascular disease patients are very much at risk of it. So it may have an effect locally, but it really, probably, has most of its effect with regards to the panvascular disease that these patients present. Dr. James de Lemos: Excellent. And I'll just point out that just today, the FDA released news that they've granted an indication for this combination therapy for patients with peripheral arterial disease. Let me come back to Marc for a really interesting randomized controlled trial, from China, evaluating no-touch vein graft interventions for cardiac surgery. Marc, can you talk to us about this trial and your impressions on this? Dr. Marc Ruel: Absolutely. Thank you, James. So this is a trial from seven hospitals in China that randomized 2,600 patients between April, 2017 and June, 2019. And patients were randomized with the use of saphenous vein grafts between a no-touch technique and a conventional saphenous vein graft harvest technique. And I'll explain a little bit what this no-touch technique is. It actually consists of two things. You take the vein by a complete incision. Often, in fact, it's more invasive, and you take the actual saphenous vein with a surrounding layer of fat and connective tissue around it. And because of that, it's not easily amenable to endoscopic vein harvest or even using small incisions. Dr. Marc Ruel: The other component of no touch of vein harvesting is to really preserve the anterior layer by not using any syringe inflation and letting the conduit be rinsed, but flow naturally and not be distended at all. So the trial was positive, and the trial already showed a lesser incidence of saphenous vein graft closure at both three months and 12 months on CT scan. So to give you an example, the three months saphenous vein closure was 4.8% in the conventional harvest group, versus 2.8% in the no-touch group. Dr. Marc Ruel: Now what's interesting to here is twofold. There may be a couple of aspects in the benefits of the therapy, and one may relate, in fact, to the lack of pressure syringe dilatation. So it's hard to tease out, is it really the surrounding layer of fat or is it the fact that the syringe dilatation procedure is not being performed in the no-touch group? The second issue is the technique is definitely more invasive. The authors found in the trial more local complications, about 50 to a hundred percent increase in terms of a local numbness, exudation, et cetera, delayed wound healing. Because you have to make bigger incisions and you have to take more tissue around where the vein that you're harvesting. Dr. Marc Ruel: So it is a very intriguing trial. Obviously, graph patency is something that's tremendously important around the CABG operation. But unfortunately, it steers us towards a more invasive approach. In a nutshell, it is a positive trial, but it does require the surgery to be slightly more invasive, albeit, in most cases, with addressable issues with regards to delayed wound healing and exudation. But it would be ideal if we could combine the benefits of a no-touch technique with a less invasive approach to harvesting. Dr. James de Lemos: Mike, this is fascinating to me because you've got a procedure that probably improves the long-term outcomes of the operation, but is associated with a longer surgical time and more local complications. Mike, I'm wondering, what are your surgeon's going to do at Stanford? Are they going to adopt this or is this too difficult and associated with too much inconvenience for the patient to become something that's done routinely? Dr. Michael Fischbein: Brilliant, great question, James. Because I think, often, our patients, previous to endoscopic vein harvesting, they often complained more issues with their leg incisions than their actual sternotomy. And I always tell my patients now, though, one of the incredible things is that we can take their vein endoscopically. And now, we're talking about, while we do have improvement in graft patency for the vein, we're going to go backwards and maybe have some of these wound issues again. And I'd be curious what Marc thinks, though. We are trying to do more and more arterial grafts. And so, if we're just using one vein, is it worth accepting these higher wound complications? Dr. Marc Ruel: It's a great point, Mike, and perhaps exactly, as you say, perhaps an increased use of arterial grafts can be combined with lack of a pressure syringe dilatation of the vein after harvest, right? And there's already some data suggesting, as provided in the excellent editorial by Vidal, that this may be mechanistically important to enhance patency. So the study is very intriguing and still remains to completely unfold. Dr. James de Lemos: Excellent. Really important contribution to the surgical science. Marc, I want to come back to you with another important randomized control trial, this with a really novel therapeutic compound designed to address kidney injury after cardiac surgery. Marc, can you talk about the trial with the small interfering mRNA for renal protection? Dr. Marc Ruel: Absolutely. Thank you, James. This is an important trial, in my opinion. It's a Phase II study of a compound named, teprasiran, which is a interfering RNA, which modifies the p53 mediated cell death response in the renal tubal cells. So what does that do, essentially, is that the thought is that it may prevent acute renal injury after cardiac surgery. We know that's a tremendous problem. Most busy cardiosurgical ICUs would have at least between 15 to 25% of the patients requiring dialysis postop, depending on the level of risk acuity that your unit is presenting. Dr. Marc Ruel: And it's no different whether you're in Stanford or Ottawa or Germany, in my opinion. So we need solutions here. And this is a relatively simple compound, which is administered within four hours of completion of surgery. So for instance, if the surgery was performed on pump, it was given within four hours of completion of surgery. So, for instance, if the surgery was on-pump, it was given within four of hours completion of CPB, cardiopulmonary bypass. If it had been performed off-pump, it was within four hours of the last anastomosis. Dr. Marc Ruel: It's a two-minute infusion, 10 milligrams per kilo, and essentially in the trial, it was not associated with any safety concerns. And quite conversely, it was actually associated with the benefit, with regards to the development of early acute kidney injury, which was 50% prevalence in the patients who were treated with placebo, versus 37% in patients who received the compound, again, named teprasiran. So I think this is quite important. It has led to a Phase III which is currently ongoing, and I think this is a very instrumental finding in the field. Dr. James de Lemos: Fantastic. I mean really a testament to the progress in clinical science for cardiac surgery, that we've got these randomized controlled trials moving through a development phase that may be actionable in years to come. Let's finish the discussion of the original research articles, Mike, with a review of the Yang paper, really, which also, I think, is in Circulation's real sweet spot, where we're highlighting the very best of basic and translational science coming from Surgeon Laboratories. Can you talk about that paper for us? Dr. Michael Fischbein: Thanks very much, James. I think this is really an exciting paper. Qiong Yang's lab at University of Michigan, they're studying Loeys-Dietz syndrome. As you know, Loeys-Dietz syndrome is one of the connective tissue disorders. There's five subtypes, and these individuals form aortic root aneurysms. Importantly, it's specific to the aortic root that these aneurysms primarily develop. Although later on, you can see them in other locations, including intracranial and some of the branch vessels. Dr. Michael Fischbein: But these root aneurysms can dissect and this is life threatening. Currently, the only treatment strategy for these individuals is surgical, where you perform a prophylactic replacement of the aortic root. Unfortunately, there are no real medical therapies, primarily because we don't understand the mechanisms why these aneurysms form. So Dr. Yang's lab, they model this disease using a induced pluripotent stem cell model, where cells are differentiated into the different embryologic origins of the aorta. Dr. Michael Fischbein: The aortic group comes primarily from the second heart field. And so, when they studied these smooth muscle cells, they were able to show that there is lineage-specific smooth muscle cell defects, and they discovered some interesting pathways that might explain why aneurysms form specifically in the root in these in individuals. They also came up with some potential pharmacologic strategies to block some of these mechanisms. Dr. Michael Fischbein: And so, I think this is really exciting because this is using pluripotent stem cells more as a model to study disease states. And I could see the potential, also, for precision medicine, where you take an individual cells, make their iPSCs and study that individual's mechanisms, and perhaps come up with unique medical strategies for that individual. Dr. James de Lemos: So let's, Marc, finish, that's really all of the original research articles we covered. Really, an amazing spectrum of clinical translational and basic science that is a Testament, both to what you all have done to recruit content, but the tremendous growth in science and the surgical specialties. Marc, let's talk a little bit about the two terrific in-depth reviews that you picked for this issue and what their contributions are. Dr. Marc Ruel: Thank you again, James. We have two excellent reviews in this themed issue of Circulation. One is a frontiers piece about cardiac surgery in women in the current era, going over what are the gaps in care. And this is spearheaded by Leslie Cho, from the Cleveland Clinic, and it really goes over, very comprehensively, many of the issues around not only clinical trial enrollment of women, but specific issues pertaining to the care, and which goes back even to basic science of the sex and gender of animals being used in research for reasons that I said, that are very comprehensively, again, I want to emphasize highlighted by the authors. Dr. Marc Ruel: And I'll give you an example, for instance. In off-pump surgery, there are some discrepancies with regards to the use of off-pump versus on-pump surgery between males and females. And we off-pump surgeons know that there are really two very different ways from the surgery. Women, for instance, have a smaller heart which is easier to expose, for instance, for lateral and inferior territories. But in the same token, the coronary targets can be smaller. So there's really a number of discrepancies here, which can be anatomic, it can be sometimes due to the disease presentations. Dr. Marc Ruel: For instance, women have more tricuspid valve disease, and at a certain age start having an increased incidence of aortic problems versus males. And there's also some what I would call logistical issues with regards, for instance, to clinical trial recruitments from VA centers that typically have very, very few women being eligible for enrollment there. So these issues, again, are comprehensively addressed by Dr. Cho and her colleagues. And it's a very interesting read. Dr. Marc Ruel: The other piece you were referring to is a state-of-the-art paper around the use of transit time flow measurements during coronary bypass. And I think our cardiology colleagues and everyone in the cardiovascular field will be very interested to learn a bit more about this. Because essentially, when we perform bypass surgery, we don't have a validated easy way to ascertain whether the grafts that we just built are doing their job. And you may say, "Well, the surgeon's great at cutting and doing anastomosis," but as I like to tell my trainees, there's much more than suturing that might be happening. Dr. Marc Ruel: An anastomosis may have an unforeseen flap into it. There could be a small clot that's blocking something. There could be a kink or a twist in the graft that's not readily recognized. So I think it's very important to have a thorough assessment in everybody. I'm the last author of this piece, so I'm obviously somewhat partial to it. But I think it is important for the field to have quality checking of all grafts that are performed at something, especially something as invasive as bypass surgery. The patient should come out with functional grafts and that should be validated and objectively verified. Dr. James de Lemos: Fantastic. Marc, and we also have two research letters in this issue of Circulation. These are small pieces, but they pack a really powerful punch. Do you want to just briefly tell us about those two? Dr. Marc Ruel: Absolutely. Thank you, James. As a surgeon, I love research letters. I think they are a great venue. They're under a thousand words. Certain, sometimes we're busy, we don't want to always read a 5,000-word manuscript. And they're really, they are well-suited to what I would say are surgical follow-up studies. Once a technique has been described and you want to look at what are the late outcomes of this technique, I think they're an excellent format for that. And precisely, this corresponds to the two research letters that we have in the 2021-themed issue. Dr. Marc Ruel: One is a long-term, 10 year analysis of the SAVE RITA trial by Kim and Kim in South Korea. The SAVE RITA trial is a fairly famous trial in our specialty, which essentially, randomized patients to have a Y graft on the left internal thoracic artery, using either a saphenous vein conduit or the right internal thoracic itself. And essentially the early results were neutral. So the two groups were comparable, which is naturally neutral. I would say non-inferior for the saphenous vein graft. Dr. Marc Ruel: Now we have 10-year data in over 200 patients, equally randomized between receiving a saphenous vein graft versus the right internal thoracic artery. And the results are 10 years are equally excellent between the saphenous vein graft and the right internal thoracic artery. So this is quite non-intuitive to many. Essentially, what we're showing here is that a vein graft at 10 years has amazing patency. We're talking 90%-plus in those patients who received an angiogram. So I think there's a couple of messages to remember here. Dr. Marc Ruel: There may be a biologic role of connecting a saphenous vein graft onto the left internal thoracic artery with regards to nitric oxide dilution. Also, technically, the authors have readily acknowledged that the harvest the vein, again, back to this saphenous vein harvest issue, they harvest it from the lower leg. Therefore, the diameter of the vein is more suited to a Y graft. And, in fact, using a vein over right internal thoracic artery may have technical advantages, because the diameter is a little bit more facile to use with regards to complex composite grafting. So it may actually be something that, if you can maintain it with patency based on say, nitric oxide dilution, is a little bit easier to maneuver and build at the time of surgery. Dr. James de Lemos: Marc, can I ask a question here? Does this change your practice with regard to how often you're using Y graphs, in general, and the vein on artery Y? Because, Mike, outsiders experiences that these graphs aren't used and do these data suggest that we should be using why Y graphs, in general, and this particular type of Y more often in surgery? Dr. Marc Ruel: Absolutely. I think these data suggest precisely that. Whether the adoption will follow is another story. There's not a lot of groups, much to your point, that are using this configuration, but it's used commonly as a bailout strategy. Let's say, one of the arteries has been injured or is not available, or you have a porcelain aorta, I think based on these important data, you can now know that you can, if well-constructed, use a saphenous vein graft as a Y graft onto the LITA with relative impunity. In fact, excellent results, if done in the way that Kim and Kim are reporting. Dr. Marc Ruel: Our second research letter is actually a follow-up of hybrid palliation for hypoplastic left heart syndrome. This comes from the UK, where a number of centers had used several years ago the concept of a hybrid palliation in patients who were mostly high risk for hypoplastic left heart. So here, again, much to the research letter format, we have a follow-up series with regards to following all these children who had received either a initial Norwood approach or a hybrid approach progressing to a Norwood stage two. And essentially, the overall survival, which is about, between two thirds to 75% of children at three, four years, is no different between an initial Norwood stage one approach versus hybrid palliation. Dr. Marc Ruel: So I think this is obviously very intriguing data. It's used to be that a hybrid palliation would only be used in very high-risk cases. I think this would provide credence to using it in a more liberal fashion. There's still the possible caveat that the centers that use hybrid palliation have a little bit of a "expertise bias," if you will, because they have both modalities being available. But I think this is a very important and very intriguing data for this extremely challenging condition. Dr. James de Lemos: Well, thank you. And I'd like to thank both you, Marc, and Mike for just tremendous insight. I think for somebody that doesn't live in the cardiac surgery world, having the privilege, not just to hear you explain these terrific studies, but also provide your insights in pearls about cardiac surgery and vascular surgery care in 2021 has been invaluable. And I think our listeners will feel the same way. I'd like to turn it over to you, Marc, as our leader in cardiovascular surgery to close us out today from a wonderful podcast. Dr. Marc Ruel: Well, thank you very much, James. Again, I want to reiterate, I think this is really a tremendous issue. It's our best ever. And I want to thank you, James and Joe Hill, as well, our Editor-in-Chief, for your support of surgery within Circulation. I also want to thank Sarah, Molly, Nick, and Augie, really, for their in their indefatigable support of our issue. I want to, again, extend our gratitude to Tim Gardner and to Mike for their tremendous help with this issue. I think this is, again, very important. Do send your best work, and I'm speaking to our readership community and all surgeons to Circulation. Dr. Marc Ruel: Circulation is our premier journal and surgery's tremendously important. And the interface together is a strong one, because Circulation realizes that surgery provides, and I'm a bit biased when I say this, but I think it is true. It provides the most robust and durable treatment for advanced heart disease, so it is very important to be featured prominently in Circulation. And I think this is what our current leadership and staff at Circulation are supporting, and I'm tremendously thankful on behalf of all surgeons. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation September 28, 2021 Issue

    Play Episode Listen Later Sep 27, 2021 29:39

    This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque." Dr. Greg Hundley: Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started. Dr. Greg Hundley: The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear. Dr. Greg Hundley: And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning. Dr. Greg Hundley: Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types. Dr. Greg Hundley: Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death. Dr. Greg Hundley: Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases. Dr. Greg Hundley: Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial. Dr. Greg Hundley: Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone. Dr. Greg Hundley: Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design. Dr. Harmony Reynolds: Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality. Dr. Harmony Reynolds: We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature? Dr. Harmony Reynolds: So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year. Dr. Greg Hundley: And what did you find? Dr. Harmony Reynolds: There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me. Dr. Greg Hundley: Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication? Dr. Nicholas Mills: Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation. Dr. Nicholas Mills: Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study. Dr. Greg Hundley: Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper? Dr. Harmony Reynolds: Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment. Dr. Harmony Reynolds: Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these. Dr. Harmony Reynolds: So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study. Dr. Greg Hundley: Very good. And what did you find here? Dr. Harmony Reynolds: Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite. Dr. Harmony Reynolds: When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy. Dr. Greg Hundley: Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published? Dr. Sandeep Das: So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be. Dr. Sandeep Das: So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract. Dr. Sandeep Das: So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing. Dr. Sandeep Das: So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper. Dr. Greg Hundley: Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers? Dr. David Newby: Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault. Dr. David Newby: And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients. Dr. David Newby: And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms. Dr. David Newby: And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are. Dr. David Newby: And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box. Dr. David Newby: But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event. Dr. Greg Hundley: Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony? Dr. Harmony Reynolds: Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice. Dr. Harmony Reynolds: And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know. Dr. Greg Hundley: Nick? Dr. Nicholas Mills: Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms. Dr. Greg Hundley: Sandeep? Dr. Sandeep Das: Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients. Dr. Greg Hundley: And finally, David. Dr. David Newby: Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation September 21, 2021 Issue

    Play Episode Listen Later Sep 20, 2021 25:13

    This week's episode features author Benjamin Levine and Guest Editor Walter Paulus as they discuss the article "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage-B HFpEF." Dr. Greg Hundley: Well, welcome listeners. This is the September 21st podcast for Circulation on the Run. Sadly, I'm without Carolyn today, but I am your host today, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Greg Hundley: Our feature discussion today is really interesting. It's from Dr. Ben Levine, and he's evaluating the utility of exercise training and actually trying to reverse abnormal left ventricular myocardial stiffness in individuals that have stage B, it's a very early heart failure and preserved ejection fraction. But before we get to that, let's grab a cup of coffee and we're going to work through some of the other articles in this issue. Dr. Greg Hundley: So the first one comes to us from Göran Bergström from University of Gothenburg in Sweden. He and his team used coronary computed tomography angiography or CCTA to determine the prevalence, severity and characteristics of coronary atherosclerosis and its association to coronary artery calcification scores in a general population of greater than 25,000 individuals all aged 50 to 64 years and without known coronary heart disease. It really comes to us from the Swedish CArdioPulmonary BioImage Study or SCAPIS. Well, Carolyn would ask me that is a really large study, and what did they find? Well, let's get to the results. Dr. Greg Hundley: So using CCTA to detect silent coronary atherosclerosis, the investigators showed that any coronary atherosclerosis was actually quite common, 42% of individuals and significant stenosis of greater than 50% was less common, only 5% of individuals. More severe forms were rarely found, only 1.9% in this very large, random sample of middle-aged individuals. Dr. Greg Hundley: Now disease onset was delayed by 10 years in women and a higher prevalence of coronary atherosclerosis was observed with higher age and accumulation of risk factors. Interestingly, CCTA detected atherosclerosis increased with an increasing coronary artery calcium score. All those with a high CAC score of greater than 400 had atherosclerosis and 45% had significant stenosis. 5.5% of those with no coronary artery calcification had atherosclerosis and 0.4% had significant stenosis. So although there was a strong association with high coronary artery calcium scores and significant stenosis, atherosclerosis was not excluded in those with zero coronary artery calcification especially in those with high baseline risk. Dr. Greg Hundley: Well, our second article comes to us from the world of preclinical science and it's from Dr. Nathan Palpant from the University of Queensland. So the article pertains to ischemia reperfusion injury, and it's one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Now during cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6 to 6.5, and the resulting tissue acidosis exacerbates ischemia injury and significantly impacts cardiac function. Dr. Greg Hundley: So the authors today use genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a or ASIC1a, we'll call it from now, in cardiac ischemia reperfusion injury at the cellular and whole organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of ischemia reperfusion injury were used to test the efficacy of ASIC1a inhibitors as pre-imposed conditioning therapeutic agents. Dr. Greg Hundley: So what did the authors find in this study? Well, they demonstrated for the first time that acid-sensing ion channel 1a or that ASIC1a mediates cardiac ischemia reperfusion injury. The authors identify that ASIC1a inhibition is a novel therapeutic strategy for preventing acute injury response to myocardial ischemia reperfusion injury. Dr. Greg Hundley: So what are the clinical implications of this research? Well, first there are currently no drugs in clinical use that prevent acute injury response to myocardial ischemia, despite many promising candidates identified over decades of research, all of which ultimately failed in subsequent clinical trials. Second, the identification of new therapeutic targets for preventing the injury response to myocardial ischemia reperfusion injury would therefore have profound implications in cardiovascular medicine. Therefore, the results of this study reveal that ASIC1a inhibiting drugs, they're safe and they have potential applications in heart transplant and myocardial infarction with potential use in other clinical scenarios where myocardial ischemia reperfusion injury is a risk such as those that undergo cardiac surgery. Dr. Greg Hundley: Well, our next article comes from Robin Choudhury from the University of Oxford. Have you ever wondered why cardiovascular risk and diabetes remains elevated despite glucose-lowering therapies? Well, these authors hypothesized that trained immunity in response to elevated glucose accounts for diabetic hyperglycemic "memory", we'll call it, in relation to atherosclerosis. So accordingly, the author sought to determine if hyperglycemia-induced disease relevant changes in monocyte and macrophage function and whether these changes persisted after restoration of normal glucose, thereby implying fundamental reprogramming. So the team combined studies of cellular function, metabolomics, transcriptomics and epigenomics to define how hyperglycemia altered metabolism to modulate long-term activation through epigenetic modifications. Dr. Greg Hundley: Well, what did they find? First, hyperglycemia induced a trained immunity in bone marrow progenitor cells by inducing persistent epigenetic modifications. Second, hyperglycemia-induced trained immunity persisted after differentiation into those macrophages. Finally, hematopoetic stem cells transplanted from mice with diabetes to euglycemic mice promoted exaggerated atherosclerosis. So therefore, the findings of this study may explain the resistance of macrovascular complications of diabetes to conventional glucose-lowering treatments. Dr. Greg Hundley: Well, in the mailbag this week, there are some other articles. Professor Huang has a Research Letter entitled, “Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.” Dr. De Caterina has an In Depth article on coronary artery anomalies. Finally, Professor Merid has a Perspective piece entitled, “Digital Redlining and Cardiovascular Innovation.” Dr. Greg Hundley: Well, listeners, what a great group of articles, and now we're going to turn to that feature discussion with Dr. Ben Levine. Dr. Greg Hundley: Welcome listeners to our feature discussion today and we're very fortunate. We have with us, Dr. Ben Levine from UT Southwestern in Dallas, Texas and also Dr. Walter Paulus from Amsterdam. Welcome gentlemen. Dr. Greg Hundley: Ben, we'd like to start with you. Could you describe for us a little bit of the background related to your study and what was the hypothesis that you wanted to test? Professor Benjamin Levine: Sure. Oh, nice to talk with you, Greg. As you know, our lab has been very interested in the effects of both aging and physical activity on cardiac mechanics. To cut a very long story short, what we know is that sedentary aging leads to stiffening of the heart. We also know that HFpEF, heart failure with preserved ejection fraction, is a disorder predominantly of the aged. I don't know about you, Walter, but I've never seen any lead masters athlete HFpEF. Professor Benjamin Levine: What we've shown is that if you regularly exercise over a lifetime that the heart can preserve its youthful compliance and flexibility. But if you wait until somebody is older, meaning over 65, 70, regardless of how hard or intense we train, the heart seems to lose its plasticity. It can't actually get that much better. But if we start in late middle age, it turns out that you can actually reverse some of the adverse effects of sedentary aging. So we said, "Okay, we know what the dose is, how much exercise you need to do. We know what the sweet spot in time. Now how do we find those people who are most likely to go on to develop HFpEF in whom getting them on a regular exercise program might help forestall this very challenging syndrome." Professor Benjamin Levine: So as part of an AHA-funded strategically focused research network and prevention, we identified a group of patients who had left ventricular hypertrophy, but evidence that they were on the wrong path. Their biomarkers were elevated. They have an elevated NT-BNP or a high sensitivity troponin. We did a right heart catheterization and we looked at their cardiac stiffness using a technique that we've done now for the past 25 years or so, and showed that indeed those patients' hearts are clearly stiffer than healthy, but otherwise sedentary middle-aged individuals. Professor Benjamin Levine: So our key question was what happens if we put them on a long sustained high intensity exercise program? Can we reverse the effects of sedentary aging superimposed with hypertension, left ventricle hypertrophy and elevated biomarkers? Dr. Greg Hundley: Really interesting, Ben. So describe your study design for us. How are you going to set up? It sounds like a very elaborate experimental setup here. Then also, maybe just define for us your study population. Did you have men and women or- Professor Benjamin Levine: Yeah, we started by going to the Dallas Heart Study. We're blessed here in Dallas by having this room access to our remarkable population where we know a lot about them. So we picked people in late middle age of all races, both sexes, and we reached out to the members of the Dallas Heart Study if they had left ventricular hypertrophy by echo or MRI and were of the right age range. We enriched that database by going to an EKG database and looking at the Ecolab database, trying to find people who did not have heart disease already. That was important. They couldn't have had a heart attack. They couldn't have had heart failure. They couldn't have had infiltrative disease. They had to be generally healthy except had left ventricular hypertrophy. Professor Benjamin Levine: We screened a lot of patients to get there, I have to acknowledge that, almost 4,000 of them or so to get the small number who were interested in doing a one-year exercise training program. But as we eventually got a good solid number that because we use such high resolution techniques, we were able to define the key outcome variable, which is cardiac stiffness. Professor Benjamin Levine: Briefly in our lab, we put a right heart catheter in to measure wedge pressure. We use 3D-echo to measure volume and then we use something called lower body negative pressure to unload the heart. It's almost like standing up progressively or tilting upright and then we give them a rapid saline infusion, 200 mls a minute. So a lot of saline, 15 and 30 mls/kg. We can get the left atrial pressure from about three or four up until about 18 to 20 and define the entire physiologic range of left ventricular filling. We look not just at the wedge pressure of course, but the transmural pressure. Professor Benjamin Levine: John Tyberg and his colleagues in Canada have shown clearly that the pericardial pressure is pretty close to right atrial pressure. So transmural pressure, which is the distending pressure of the heart, is left atrial minus right atrial pressure. We use that as the input into a pressure volume relationship. Dr. Greg Hundley: Very nice, and then what did you find? Professor Benjamin Levine: Well, what we found is after demonstrating that these patients with LVH and elevated biomarkers have increased stiffness, what we found quite remarkably actually was that we were able to reverse that by a year of training. Professor Benjamin Levine: Now when I say training, I mean, we do use the optimal approach to training that we've demonstrated in our lab. We didn't just pick one thing, get on a bike, do that for 30 minutes three times a week, right? These were sedentary people so we built them up slowly over about seven months. We added frequency, we added duration, we added intensity. Professor Benjamin Levine: I am enamored by the four by four in old Norwegian ski team workout, which is four minutes at 95% of max followed by three minutes of recovery repeated four times. We added interval training and long slow distance battle lasting about an hour on the weekends and a little bit of strength training, too. Professor Benjamin Levine: So what we consider the ideal prescription for life, four to five days a week, one long session, one high intensity session, two or three moderate intensity sessions and a little bit of strength. We did it for a year. It took a lot of effort. We had dedicated trainers. We gave them all heart rate monitors. Each person had a trainer to follow them. Professor Benjamin Levine: We did have a control group. We randomly assign them to a group that did stretching and yoga and mindfulness and a little bit of strength training, which makes people feel better. But we know from experience, it doesn't make them fitter and doesn't change their cardiac compliance. Dr. Greg Hundley: What happened with the treatment group? Professor Benjamin Levine: Oh, they got much more compliant. They got as compliant as if they had been training most of their lives. It was quite remarkable, actually, frankly, better than we expected it to be. We check the data multiple times by multiple people to make sure that this was a real finding. We really reversed much of the effects of the adverse effects of sedentary aging plus LVH. We hope that if that would be sustained over more than a year, years of long training study, there are very few training studies that go that long. But it's not a lifetime and at least we've set the stage for the concept that if this were to be sustained over a lifetime that we think it could forestall HFpEF. Dr. Greg Hundley: Very nice. Well, Walter, I know serving as a guest editor for us at Circulation and we're most appreciative for you doing that task. What struck you about this particular article and really enticed you to want to help us move it toward publication? Professor Walter Paulus: Well, I felt that the article was very visionary. Of course, as it comes from Ben, I didn't expect anything else. But what struck me were two points. Professor Walter Paulus: First of all, he looks at patients which we would label type B HFpEF. Most of our efforts have always been focusing on sick people, stage C HFpEF, stage D HFpEF. Now Ben was so clever to go to an early stage, and I believe that many of the so-called neutral outcomes in therapy for HFpEF are related to the fact that we actually address patients population who is quite far out on its natural history. So I think this was the first point to me. He, Ben, was addressing a population at the early stages of HFpEF. Professor Walter Paulus: The second point that struck me was that the variable he was looking at is in my opinion the key variable in HFpEF. It's the main reason I appreciated that this is the disease of myocardial compliance of left ventricle stiffness, and then very nicely addressed the stiffness of the heart as its primary outcome. This is something what we miss in all the pharmacological trials. I have always been curious when are we going to see the pharmacological trial whereby somebody is going to evaluate a compound in terms of its effects on left ventricular stiffness on myocardial compliance. Professor Walter Paulus: So these were for me two very salient features and very visionary in terms of treatment of a HFpEF population. Also, a couple of things that need to be clarified for me and I did. The patient's entry criteria were very demanding, has been also already said. I have the feeling that if you have LVH and then you will try NT-proBNP to be elevated and all your required troponins to be elevated, it's probably be very hard to get such a patient population and that may be then the only remark that could come up toward an extent in such a patient population still reflective of everyday health. Dr. Greg Hundley: Very good. Well, Ben, coming back to you, what's your next study? Professor Benjamin Levine: Well, we have a large program project grant, Greg, funded by the NIH, looking at the mechanisms of dyspnea and HFpEF. We're now just entered our third year. We're looking at a strategy to try to lower cardiac filling pressures acutely to see if that improves exercise tolerance and reduce dyspnea. We're looking at peripheral mechanisms of oxygen uptake and utilization and vascular control. We're looking at autonomic function, sympathetic nerve recordings, regulation of the sympathetic nervous system. We have a group focused on pulmonary mechanics, particularly on the effects of obesity. Professor Benjamin Levine: Our team with Tom Sarma is our recruitment core expert and one of the Circulation editors and is really the lifeblood of our study and leads our effort. We have Paul Fidel from UT Arlington who's leading our peripheral function studies, Qi Fu from UT Southwestern leading our autonomic group, and Tony Babb also from Southwestern in the pulmonary division leading our pulmonary mechanics. Professor Benjamin Levine: So we're entering this phase where we're trying to say, "Are there other components?" We know myocardial stiffness is a key factor, but what else in patients with the already manifest HFpEF is causing them to be so short of breath and can we change that? Professor Benjamin Levine: So that's what we're doing next, Greg. I think that if you ask what is the next step from this study, I think it has to be population-based and pushing the concept that exercise is medicine. When you find patients who have hypertension in general, and most of these had hypertension or diabetes, I mean, Walter has led this field and in emphasizing these comorbidities and what they do to the heart and the vasculature and the rest of the body, we have to catch people early. We can't wait until they have full-blown manifest HFpEF. We have to get them to include exercise as part of their personal hygiene. Professor Benjamin Levine: I know that that's a major effort from the American Heart Association. But I think that for the long-term health of our population and preventing this disease that is so difficult to treat when it's firmly established, we have to as cardiologists and as a healthcare system, we have to start by including incentives for reducing healthcare costs to get people to use exercise as part of their personal hygiene and daily life. Dr. Greg Hundley: Very nice. Walter, from your perspective, what do you see are the next studies that need to be performed in this sphere of research? Professor Walter Paulus: Well, I will be very curious to see how many patients would actually go on to develop HFpEF in their life. It should be as if Ben's hypothesis holds, then the control group probably would have an access development of HFpEF compared to his exercise training group. I think that would really extend to study from above, from a mechanical observation to a clinically, epidemiologically more relevant endpoint. So I think that to me would be the first question, how many patients will evolve to clinical HFpEF. Professor Walter Paulus: Second point I would be very intrigued in is, are there SIP groups in the patients who have a positive response to exercise? For instance, what happens with the different ejection fractions? Because we are very intrigued at present in HFpEF that at high ejection fractions nothing seems to work. Sacubitril was notable at high ejection fractions. Empagliflozin was also neutral to ejection fractions. What would happen with exercise? Do the patients who present with the 70% ejection fraction at the angio study, do they still have a positive response? This would be a game change because this would then be the only intervention that is able to cure the HFpEF with high ejection fraction. These are some future projects that come into my mind. Professor Benjamin Levine: Let me just add that we have studied and put patients with HFpEF on a yearlong exercise program with not as much effect as we would like. I think that's one of the things that pushed us to getting earlier into the course of HFpEF, as Walter said earlier. Professor Benjamin Levine: Ambarish Pandey and Jarett Berry, also from UT Southwestern, of course are very interested in this effect of fitness at different points in the lifespan, our fitness test, for example, measured in mid-life and what means for heart failure later. I think it's hard to do the kind of studies that we do and follow patients for 20 years to see if they're going to develop heart failure, and that's where I think being creative and looking at the studies that incorporate an assessment of fitness and that follow people over time will be very informative. I hope with me, Walter's hope and hypothesis that these patients are less likely to develop HFpEF. We've got to get in there early. Dr. Greg Hundley: Very good. Well, listeners, we want to thank Professor Benjamin Levine from UT Southwestern in Dallas and also Dr. Walter Paulus from Amsterdam for bringing us this really interesting study, indicating that in patients with LVH and elevated cardiac biomarkers, sort of the stage B HFpEF that one year of exercise training reduces left ventricular myocardial stiffness. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation September 14, 2021 Issue

    Play Episode Listen Later Sep 14, 2021 20:40

    This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Miriam Cortese-Krott and Associate Editor Charles Lowenstein as they discuss the article "Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure." 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. Dr. Carolyn Lam: Greg, today's feature paper is one of those really, really landmark papers that really advance our understanding of Nitric oxide signaling. And it's about red blood cell and Endothelial eNOS, and how they independently regulate circulating nitric oxide, metabolites, and blood pressure. A real, real must, but let's go on and look at the other papers in this issue first. Greg, you want to go first? Dr. Greg Hundley: You bet, Carolyn. Better grab a cup of coffee. And my first paper is from professor Nathan Mewton from Hôpital Louis Pradel Hospices Civils de Lyon. Carolyn, these authors hypothesized that Colchicine a potent anti-inflammatory agent may reduce infarct size in left ventricular remodeling at the acute phase of STEMI. And so to address this hypothesis, they performed a double-blind multi-center trial and randomly assigned patients admitted for a first episode of STEMI referred for primary PTCA to receive oral Colchicine two-milligram loading dose followed by 0.5 milligrams twice a day, or matching placebo from admission to day five and the primary efficacy outcome was infarct size determined by cardiovascular magnetic resonance imaging at five days. And the relative left ventricular end-diastolic volume change at three months and infarct size at three months was also assessed by cardiac MRI. And these were secondary outcomes. Dr. Carolyn Lam: Nice. Okay. So what were the results? Dr. Greg Hundley: Right, Carolyn. So 192 patients were enrolled. 101 in the Colchicine group and 91 in the controls. And as a result of this trial, the oral administration of high dose Colchicine at the time of Reperfusion. And for five days thereafter did not reduce infarct size assessed by cardiac MRI. And so Carolyn, the clinical implications of these results suggest that other studies exploring the timing, pharma kinetics, and dose-response of Colchicine, as well as other anti-inflammatory agents are needed to identify an effective method to reduce infarct size and limit remodeling in this group of patients. Dr. Carolyn Lam: Wow, it's just such a rich field done with all this about Colchicine. Well, our next paper is a pre-specified sub-analysis of the randomized EAST-AFNET 4 Trial and the sub-analysis assess the effect of systematic early rhythm control therapy that is using Antiarrhythmic drugs or catheter ablation compared to usual care, which means allowing rhythm control therapy to improve symptoms in patients with heart failure. And this was defined in the sub-analysis as the presence of heart failure symptoms of New York Heart Association status two to three or a left ventricular ejection fraction of less than 50%. Dr. Carolyn Lam: Now, the authors led by Dr. Kirchhof at University Heart and Vascular Center UKE in Hamburg, Germany included 798 patients in this sub-analysis of whom 442 had HFpEF, 211 had heart failure with mid-range ejection fraction and 132 had HF-rEF over a median of 5.1 years of follow-up the composite primary outcome of cardiovascular death stroke or hospitalization for worsening heart failure, or for acute coronary syndrome occurred less often in patients randomized to early rhythm control therapy compared with patients randomized to usual care. And this was not altered by heart failure status with an interaction P-value of 0.6. Left ventricular function, symptoms, and quality of life improved equally in both treatment strategies. Dr. Greg Hundley: Wow, Carolyn, a lot of information here. So what can we take away from this? Dr. Carolyn Lam: Well, let's remember that this is a sub-analysis, albeit pre-specified of that randomized trial of the EAST-AFNET 4 Trial, but nonetheless, the data supports a treatment strategy of rhythm control therapy with Antiarrhythmic drugs or ablation within a year of diagnosing atrial fibrillation in patients with signs and symptoms of heart failure to reduce cardiovascular outcomes. Dr. Greg Hundley: Very nice, Carolyn. So, Carolyn, my next paper pertains to Alarmin Interleukin-1 Alpha, and it comes to us from Dr. Thimoteus Speer at Saarland University. So, Carolyn, Alarmin Interleukin-1 Alpha is expressed in a variety of cell types, promoting sterile systemic inflammation. And the aim of the present study was to examine the role of Alarmin Interleukin-1 Alpha in mediating inflammation in the setting of acute myocardial infarction and chronic kidney disease. Dr. Carolyn Lam: Wow, sterile inflammation. It's a really hot topic now. So what did these authors find? Dr. Greg Hundley: Right, Carolyn. So we're going to call Alarmin Interleukin-1 Alpha. Let's just call it IL-1 Alpha and so increased IL-1 Alpha surface expression on monocytes from patients with acute myocardial infarction in patients with chronic kidney disease was found to be associated with cardiovascular events. Next, IL-1 Alphas itself served as an adhesion molecule, mediating leukocyte-endothelial adhesion, and finally, abrogation of IL-1 alpha prevented inflammation after myocardial infarction and ameliorated chronic kidney disease in Vivo. Dr. Carolyn Lam: Wow. So what does this mean clinically? Dr. Greg Hundley: Right, Carolyn, so perhaps targeted therapeutic inhibition of IL-1 Alpha might represent a novel anti-inflammatory treatment strategy in patients with myocardial infarction and in patients with chronic kidney disease. Dr. Carolyn Lam: Amazing. Thanks, Greg. Well, in today's issue, there's also an exchange of letters between doctors Lother and Filippatos on Finerenone and risk of hyperkalemia in CKD and type two diabetes. There's an On My Mind paper by Dr. Sattler on the single-cell immunology and cardiovascular METs in, do we know yet what we don't know? Dr. Greg Hundley: And then Carolyn, from the mailbag, a Research Letter from Professor Wehrens entitled “Atrial Specific LK Beta One Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation.” Well, Carolyn, how about we turn our attention to those red blood cells and endothelial nitric oxide synthase. Dr. Carolyn Lam: Yeah. Can't wait. Dr. Mercedes Carnethon: Well, welcome to this episode of Circulation on the Run. Our podcasts, where we have an opportunity to speak with authors of important papers that are appearing in the journal of circulation. I'm pleased to introduce myself. My name is Mercedes Carnethon, professor and vice-chair of preventive medicine at the Northwestern University Feinberg School of Medicine. And I'm pleased today to invite our guest author, Miriam Cortese-Krott, who is the faculty of the University of Duesseldorf, and a guest professor at the Karolinska Institute in Stockholm. And we have with us as well the other associate editor who handled the piece for circulation, Dr. Charlie Lowenstein from Johns Hopkins University. So welcome to each of you this morning. Miriam Cortese-krott: Thank you. Dr. Charles Lowenstein : Thanks for having me. Dr. Mercedes Carnethon: Well, thank you. I'm really excited to jump right into this piece, Miriam, can you tell me a little bit about the rationale for carrying out the study, why you pursued it? Professor Miriam Cortese-Krott: The reason is because when I was working as a post-doc, I had to isolate an enzyme from red blood cells, which is a very, very difficult. And if you know, this enzyme is endothelial nitric oxide synthase, which produce nitric oxide, and actually, the red blood cell is full of the worst enemy of nitric oxide, which is hemoglobin. So actually, when I was talking about my project, everybody was asking, "Why are you doing that?" And I was actually able to isolate the enzyme and look at activity and be sure that the enzyme was fine, but the function of this enzyme was absolutely unknown. Professor Miriam Cortese-Krott: And the only way to study proteins in red blood cells is to make modification in the bone marrow of the mice. So in the Erythroid cells, because you can not, of course, if there are cells without nucleus you don't have any chance to modify them in culture, something like that. So the only way was to generate mice with modification specifically in the red blood cells. And I had the chance to create, to generate red cell-specific eNOS knockout mice. And of course, as a control endothelial-specific eNOS knockout mice by using the Cre-loxP technology. And with this technology, I could really understand what's happening to the physiology of the mouse if you remove this protein from the red blood cells. And so this was the whole idea. Dr. Mercedes Carnethon: Thank you so much. It was really exciting for me to read this piece. We are on opposite ends of the scientific inquiry spread as I'm an epidemiologist who does things at the population level, and you're identifying things at the basic science level. I thought the paper was extremely well-written and that encouraged people to dig in, even if you're unfamiliar, and in part that's because you provided such a great explanation of how your findings are used and how they're relevant to the process. Do you mind sharing a little bit about your findings and how you expect that they will be used by our scientific community? Professor Miriam Cortese-Krott: I think the main finding of this paper is that if you remove eNOS from the red blood cells if the mice are hypertensive, have hypertension, and this is completely something that you actually will not expect, as I told you that indeed red cells are full of the enemy of nitric oxide that remove it immediately. So you can ask yourself how it is possible. But I think the key finding here in this paper was that I also generated the opposite model. So I created the model a conditional eNOS Knockout model where you can decide in which tissue you want to have your enzyme. And of course, I applied for red blood cells. And what you see in this model is that you start from a global knockout mouse with hypertension, you reintroduce the eNOS just in the red blood cells, you have normal tension. So this means, this is the main finding. You have a switch in the red blood cells, which is the enzyme eNOS, which it's behaving in a completely different way clearly as compared to the vessel wall eNOS and still regulating blood pressure. Dr. Mercedes Carnethon: Well, thank you so much. I think this is the point at which I like to turn to the associate editor who handled the piece. Charlie, you and I don't get to talk as often given the diversity of work that we each pursue, but Charlie, tell me a little bit about what excited you about this piece? Dr. Charles Lowenstein: Thanks, Mercedes. So I love this piece. I thought Miriam, your article is so great. So a couple of thoughts. One is nitric oxide and nitric oxide synthase are so important in biology and medicine, nitric oxide regulates blood pressure. It regulates neurotransmission. It regulates inflammation. And this is true, not only in the lab, looking at cells in mice, but also in the human. So genetic variance in the endothelial nitric oxide synthase gene or NOS3 are associated with risks for diseases like coronary artery disease. So eNOS is just so important in biology and medicine. And now some ancient history. When I was a cardiology fellow, about a hundred years ago, I worked in the lab that first purified nitric oxide synthase proteins, and we cloned two of the nitric oxide synthase genes that was in the lab of Dr. Solomon Snyder at Johns Hopkins back in the 1700s. Dr. Charles Lowenstein: So when we cloned the nitric oxide synthase genes, when we and others did, we made a huge mistake. We chose the names for these isoforms from the tissue where they were first isolated. So we called the brain nitric oxide synthase nNOS, because it's a neurons, macrophages MCnos we called it MCnos and in endothelial cells, we called it the nitric oxide synthase eNOS or endothelial NOS. But in the last 20 years, lots of investigators have found these isoforms are in other cells, not just the original cells at discovery. And so Miriam's question is just so important, which cells make endothelial NOS also called NOS3. That's the history. Now what Miriam has discovered is just so important. I was so fascinated by her work because as she just said, she made two amazing discoveries. One, red blood cells make endothelial nitric oxide synthase. Dr. Charles Lowenstein: And that's been a controversy for a long time. Some people have said, "Yes." Some, "No." And Miriam made the definitive answer. Yes, red blood cells make eNOS, and secondly, she has discovered so much about the physiology of ENO coming from red blood cells, the nitric oxide that's made inside red blood cells regulates blood pressure. What a magical, interesting, and important finding. That's a little bit about the history. Nitric oxide and NOS are important in medicine. The people who originally cloned and purified the nitric oxide synthase isoforms named them after the tissue in which they discovered. And Miriam has made a major discovery that it's not only endothelial cells that make nitric oxide but also red blood cells. Dr. Mercedes Carnethon: Thank you so much for that summary. And I guess, I would have thought perhaps this was something of an Elixir of youth because if you've been working in this area for 200 plus years and Miriam, you started working on this as part of your dissertation work, you both have a lot of insight and background on where we've been and what the advances are. Miriam, can you tell me a little bit about how you'd like to see these findings used by the scientific community? Professor Miriam Cortese-Krott: I think I would like that the scientific community would use my mice first because I think, as Charles has said, it's not only red cells that express eNOS and it's not only endothelial cells. There are other cells producing eNOS and the function in the other cells is not known even in leukocytes, even when they have iNOS of course, but also have eNOS. So you can use my mice since it's a flux model. You can choose whatever you want, what cell you want, and then knock it in and knock it out. So this is one thing that I think the community could really do. I cannot do everything. So I'm happy to give my mice away. Professor Miriam Cortese-Krott: And the second thing is I would like too that in particular, the clinical community would see this link between Emathology and cardiovascular disease. This is something that was started, of course, there are studies looking at anemia and cardiovascular disease, but these studies have sometimes some issues I of course cannot speak as a basic scientist. I cannot speak about huge clinical trials, but I think this link exists and exists at the molecular level and it can be a target for pharmacological therapy. So I think this is what I would like to transport with this study to the clinical community and the basic science community. Dr. Mercedes Carnethon: Yeah. I think this is the point at which Charlie, I turn it to you because you really stand at the intersection of both of those communities. What questions do you have for Miriam going forward, as you think about spreading the word on this important work? Dr. Charles Lowenstein: So Miriam's discovery is just so important and she now has the tools to help answer really, really important questions. How is nitric oxide made in red blood cells? How is it stored in red blood cells? How is it transported throughout the body in red blood cells? What is the chemistry of nitric oxide, when it is stored, when it combines with oxygen when it forms nitrite and nitrate, how is it released from red blood cells? How is it targeted from a red blood cell to the vasculature? So there're these great basic science questions that Miriam and her colleagues are now poised to answer. So there's the science part of it. Then there's the medicine part of it because Miriam's mice and her great discovery have really huge implications for medicine. And so the question is, how can we use ENO? How can we deliver it? How can we target ENO to human tissues? Dr. Charles Lowenstein: How can we turn on erythrocyte, nitric oxide synthase? How can we turn it off? Because there are all these medical diseases where too much nitric oxide is bad, like in sepsis or inadequate amounts, don't protect the vasculature like atherosclerosis. Then there are all these other interesting questions. When we transfuse red blood cells, sometimes if you transfuse aged red blood cells, it's not good. You can harm people. Maybe we can load up or activate eNOS in stored red blood cells and then help deliver more ENO to patients who need red blood cells. So there are all these fascinating medical questions that we can look at based on Miriam's really important discovery. Dr. Mercedes Carnethon: Well, thank you so much. We're coming to the end of this wonderful and informative podcast. And I guess, I'd just ask Miriam, do you have anything else you'd like our listeners to know about your work and about the findings from this study? Professor Miriam Cortese-Krott: I would like people know that hard work help a lot, and that you have to believe in what you are doing and the quality of your science at the end would bring their true discoveries. So I think it's important specifically, for the young women in science that having this message too. So the science per se must be excellent and to proceed, you need a lot of work, but then the work goes to a good end. Dr. Mercedes Carnethon: Miriam, thank you so much for that inspirational note. The hard work that scientists need, the persistence across one's career and building from earlier discoveries, and bringing those forward through one's career are always critically important. And so I hope everyone has really enjoyed this episode and this opportunity to hear from Dr. Cortese-Krott. Miriam, you've done such wonderful work, and thank you as well, Charlie, for your insights about the intersection of this work with clinical care and basic science. Professor Miriam Cortese-Krott: Thank you. Dr. Charles Lowenstein: Thank you. Dr. Mercedes Carnethon: Thank you all very much for joining us today in this episode of Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation September 7, 2021 Issue

    Play Episode Listen Later Sep 7, 2021 29:02

    This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry." 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, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first? Dr. Carolyn Lam: All right. I got my coffee. Dr. Greg Hundley: So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown. Dr. Carolyn Lam: Wow. Okay. And what did the current paper do and find? Dr. Greg Hundley: Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.   Dr. Carolyn Lam: Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample. Dr. Carolyn Lam: However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm. Dr. Greg Hundley: Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear. Dr. Carolyn Lam: So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter. Dr. Carolyn Lam: And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.   Dr. Greg Hundley: Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.   Dr. Greg Hundley: Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations. Dr. Carolyn Lam: Oh, okay. And what did the authors find? Dr. Greg Hundley: Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling. Dr Carolyn Lam: Okay, Greg, that was super summarized but what are the clinical implications? Dr. Greg Hundley: Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias. Dr. Carolyn Lam: Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection. Dr. Greg Hundley: And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”   Dr. Carolyn Lam: Nice. Well, let's go on to our feature discussion. Can't wait. Dr. Greg Hundley: You bet.   Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it. Dr. Mercedes Carnethon: Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you? Dr. Sung-Min Cho: Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study. Dr. Mercedes Carnethon: Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you? Dr. Sung-Min Cho: Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3. Dr. Mercedes Carnethon: Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece. Dr. Marc Ruel: Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration. Dr. Marc Ruel: Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it? Dr. Sung-Min Cho: Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data. Dr. Sung-Min Cho: So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through. Dr. Marc Ruel: Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD. Dr. Marc Ruel: Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events. Dr. Marc Ruel: So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera. Dr. Marc Ruel: So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this? Dr. Marc Ruel: Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found. Dr. Sung-Min Cho: Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3. Dr. Sung-Min Cho: So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3. Dr. Mercedes Carnethon: Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more? Sung-Min Cho: Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market. Sung-Min Cho: So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah. Dr. Marc Ruel: Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team. Dr. Marc Ruel: If you still have a minute or two, I had a couple of more secondary questions? Dr. Marc Ruel In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this? Dr. Sung-Min Cho: Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript. Dr. Sung-Min Cho: And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke. Dr. Sung-Min Cho: There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications. Dr. Marc Ruel: Mercedes, if I'm so allowed, I do have one final comment and question. Dr. Mercedes Carnethon: Most definitely. This has been delightful, so yes. Dr. Marc Ruel: Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that. Dr. Marc Ruel: And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question. Dr. Sung-Min Cho: Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.   Dr. Sung-Min Cho: We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients. Dr. Sung-Min Cho: But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into. Dr. Sung-Min Cho: Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent. Dr. Mercedes Carnethon: Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it. Dr. Mercedes Carnethon: I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation August 31, 2021 Issue

    Play Episode Listen Later Aug 30, 2021 26:53

    This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy." 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 cohost. 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, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue? Dr. Carolyn Lam: Yep. Dr. Greg Hundley: Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms. Dr. Greg Hundley: And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort. Dr. Carolyn Lam: Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find? Dr. Greg Hundley: Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes. Dr. Greg Hundley: So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%. Dr. Carolyn Lam: Okay, Greg, but what's a take-home message? Dr. Greg Hundley: Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed. Dr. Carolyn Lam: Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy. Dr. Greg Hundley: Wow. Carolyn, so tell me a little bit more about HINT 1. Dr. Carolyn Lam: I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control. Dr. Carolyn Lam: Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction. Dr. Carolyn Lam: Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure. Greg Hundley: Great, Carolyn. So, we get a hint for future cardiac hypertrophy. Dr. Carolyn Lam: Hahaha. Dr. Greg Hundley: Couldn't resist. Dr. Carolyn Lam: Bravo. Dr. Greg Hundley: Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension. Dr. Greg Hundley: And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells. Dr. Carolyn Lam: Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension. Dr. Greg Hundley: So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF. Dr. Carolyn Lam: Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family. Dr. Carolyn Lam: There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative. Dr. Greg Hundley: Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy. Dr. Carolyn Lam: And all by AI. Very, very cool. All right, let's go. Dr. Victoria Delgado: Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance. Dr. Victoria Delgado: With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it? Dr. Qiang Zhang: Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast. Dr. Qiang Zhang: And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI  method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement. Dr. Victoria Delgado: Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology? Dr. Qiang Zhang: Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials. Dr. Victoria Delgado: And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement? Dr. Qiang Zhang: Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients. Dr. Victoria Delgado: Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article? Dr. Greg Hundley: Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial. Dr. Greg Hundley: So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation. Dr. Greg Hundley: And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features. Dr. Greg Hundley: One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that. Dr. Greg Hundley: Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it. Dr. Greg Hundley: And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean? Dr. Greg Hundley: But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors. Dr. Victoria Delgado: Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated. Dr. Victoria Delgado: And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement. Dr. Victoria Delgado: Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis? Dr. Qiang Zhang: Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment. Dr. Qiang Zhang: And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions. Dr. Victoria Delgado: Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice? Dr. Greg Hundley: Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that. Dr. Greg Hundley: I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes? Dr. Greg Hundley: And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward? Dr. Greg Hundley: And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work. Dr. Victoria Delgado: Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us. Dr. Victoria Delgado: But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation August 24, 2021 Issue

    Play Episode Listen Later Aug 23, 2021 25:26

    This week's episode features special Guest Host Victoria Delgado, as she interviews author Qiang Zhang and Greg (who was the editorialist and handling editor) as they discuss the article "Towards Replacing Late Gadolinium Enhancement with Artificial Intelligence Virtual Native Enhancement for Gadolinium-Free Cardiovascular Magnetic Resonance Tissue Characterization in Hypertrophic Cardiomyopathy." 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 cohost. 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, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. And Carolyn, this week's feature actually is a magnetic resonance imaging paper, which you know, of course, I'm very fond of. And these authors have come up with a new methodology to get information equivalent to a late gadolinium-enhanced exam without administering gadolinium. But before we get to that feature discussion, how about we start in with some of the other articles in this issue? Dr. Carolyn Lam: Yep. Dr. Greg Hundley: Well, how about if I go first? So Carolyn, the first paper I'm going to discuss is from Dr. Paul Welsh from the University of Glasgow, and it pertains to abdominal aortic aneurysms, which you know can occur in patients who are ineligible for routine ultrasound screening. A simple abdominal aortic aneurysm risk score was derived and compared to current guidelines used for ultrasound screening of abdominal aortic aneurysms. Dr. Greg Hundley: And so, this study comes to us from the UK Biobank, and they examined participants without previous, and let's just abbreviate this as AAA or AAA. So without previous AAA, we're split into a derivation cohort of 401,820 individuals, and a validation cohort of 83,000 individuals. An incident AAA was defined as a first hospital, inpatient diagnosis of AAA, death from AAA, or a AAA-related surgical procedure. And, of course, they used multivariable Cox models to develop the derivation cohort, and then apply that to the validation cohort. Dr. Carolyn Lam: Wow, Greg, that is a large number of people, the power of the UK Biobank, huh? So, what did they find? Dr. Greg Hundley: Right. So, Carolyn, components of the AAA risk score were age, stratified by smoking status, weight, stratified by smoking status, any hypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and then diabetes. Dr. Greg Hundley: So, Carolyn, in the validation cohort, over 10 years of follow-up, the C index, for the model for the USPSTF guidelines, was 0.705, whereas, the C index of the risk score as a continuous variable was 0.856. And in the validation cohort, the USPSTF model yielded a sensitivity of 63%, and a specificity of 71%. Dr. Carolyn Lam: Okay, Greg, but what's a take-home message? Dr. Greg Hundley: Right, Carolyn. So the take-home message is that in an asymptomatic general population, a risk score based on patient age, height, weight, and a medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. And also, these results highlight that further development and validation of risk scores to detect asymptomatic AAA are needed. Dr. Carolyn Lam: Wow, and that was a great summary with a lot more data in the article, huh? Let's refer the readers to it. But for my paper, it highlights the key role of histidine triad nucleotide-binding protein 1, or HINT 1, in the pathogenesis of cardiac hypertrophy. Dr. Greg Hundley: Wow. Carolyn, so tell me a little bit more about HINT 1. Dr. Carolyn Lam: I thought you may ask. HINT 1 is a highly-conserved 14 kilodalton protein that belongs to the histidine triad super family. It was previously shown to play a role in diverse neuropsychiatric diseases. Loss of HINT 1 increased susceptibility to carcinogenesis in mice, suggesting, as well, a tumor suppressor role. So recently, HINT 1 has emerged as a tumor suppressor with multiple molecular mechanisms, involving regulation of apoptosis, gene transcription, and cell cycle control. Dr. Carolyn Lam: Now, with that as a background, today's paper from co-corresponding authors Drs. Ji, Xie and Han, from Nanjing Medical University, used animal models and cell models of hypertrophic growth, and found that HINT 1 deficiency aggravated overload-induced cardiac hypertrophy and fibrosis and deteriorated cardiac dysfunction in mice, whereas, cardiac-specific HINT 1 over-expression attenuated cardiac hypertrophy, and rescued cardiac dysfunction. Dr. Carolyn Lam: Furthermore, the more the authors uncovered Homeobox A5, or Hox A5, as a HINT 1 target gene, which contributed to hypertrophy through activating the TGF beta signal pathway. Combined, these findings demonstrate HINT 1 may be a prognostic biomarker, and this may establish a foundation for future investigation of its potential as a therapeutic target for cardiac hypertrophy and heart failure. Greg Hundley: Great, Carolyn. So, we get a hint for future cardiac hypertrophy. Dr. Carolyn Lam: Hahaha. Dr. Greg Hundley: Couldn't resist. Dr. Carolyn Lam: Bravo. Dr. Greg Hundley: Couldn't resist. So, Carolyn, my next paper comes to us from Dr. Mark Gladwin from the University of Pittsburgh. And, as you know, many patients with one of your faves, heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension. Now, increases in pulmonary vascular resistance, in patients with HFpEF portend a poor prognosis. This phenotype is referred to as combined pre- and post-capillary pulmonary hypertension. Dr. Greg Hundley: And therapeutic trials of exercise-induced pulmonary hypertension, and pre- and post-capillary pulmonary hypertension, have been disappointing, suggesting the need for strategies that target upstream mechanisms of the disease. And so, this work reports novel rat exercise-induced pulmonary hypertension models and mechanisms of pulmonary vascular dysfunction, centered around the transcriptional repression of the soluble guanylate cyclase enzyme in pulmonary artery smooth muscle cells. Dr. Carolyn Lam: Ooh, so much of this is of interest to me, from HFpEF to soluble guanylate cyclase. Ah, all right, so what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, in the HFpEF and in the pre- and post-capillary pulmonary hypertension models, metabolic syndrome contributed to pulmonary vascular dysfunction and exercise-induced pulmonary hypertension through enhanced reactive oxygen species and MIR193B expression, which downregulates NFYA-dependent soluble guanylate cyclase beta-1 expression, and adenovirus mediated NFYA over-expression and SGLT-2 inhibition restored NFYA soluble guanylate cyclase beta-1 cyclic GMP signaling, and ameliorated exercise-induced pulmonary hypertension. Dr. Greg Hundley: So Carolyn, after all of that, these results uncover a molecular explanation for the unsolved clinical associations linking metabolic syndrome with exercise-induced pulmonary hypertension in patients with pre- and post-capillary pulmonary hypertension, as well as HFpEF. Dr. Carolyn Lam: Wow. That is super, Greg. Thanks. Now, other articles in today's issue include a research letter by Dr. Schunkert on identification of a functional PDE5A variant at the chromosome 4q27 coronary artery disease locus in an extended myocardial infarction family. Dr. Carolyn Lam: There is a policy front paper by Dr. Lackey on applying decision analysis to inform FDA's benefit risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke, based on the THEMIS trial. There's an exchange of letters between Drs. Olson and Reiffel regarding the article emulating randomized controlled trials with non-randomized real-world evidence studies, the first results of the RCT Duplicate Initiative. Dr. Greg Hundley: Great. Carolyn. Well, I've got two other papers. There's an ECG challenge from Professor Macherey entitled, Wide QRS complex bradycardia in a hemodynamically unstable young woman. And then, finally, one of our nice perspective pieces from Dr. Armstrong entitled, Extending the product label for ticagrelor: Looking under the FDA hood. Well, Carolyn, now we're going to learn a little bit more about that non-contrast method of MRI to get, maybe, the equivalent to late gadolinium enhancement in patients with hypertrophic cardiomyopathy. Dr. Carolyn Lam: And all by AI. Very, very cool. All right, let's go. Dr. Victoria Delgado: Hello, I'm Victoria Delgado, associate editor of Circulation, and working at the University Medical Center, and I have the privilege to welcome Dr. Zhang from the University of Oxford, division of cardiovascular medicine, and first author of the article published in Circulation, which presents a new technology that has the potential to change our clinical practice, and how do we assess myocardial tissue characteristics, particularly fibrosis with cardiac magnetic resonance. Dr. Victoria Delgado: With us, we have also Dr. Greg Hundley from VCU Pauley Heart Center, associate editor of Circulation, and host of Circulation on the Run and editorialist of this article. And Greg has handled this article in the review process and guided Dr. Zhang and coworkers to finally get a very impactful, in my opinion, and novel paper that has the potential to change clinical practice. He will help us to put in perspective the main message of this article. But first, Dr. Zhang, why don't you tell us briefly, what is this new technology for myocardial tissue characterization with cardiovascular magnetic resonance, and why did you develop it? Dr. Qiang Zhang: Well, first, I want to say thank you very much for the invitation. Well, as we know, CMR late-gadolinium enhancement, or LGE, has been the imaging gold standard for micro tissue catheterization. However, LGE requires the injection of a contrast agent, which prolongs the scan, increase the cost, and is cautioned in some patient groups. It is therefore desirable to develop a contrast-free technique to replace LGE. A native or pre-contrast CMR such as cine imaging, T1-mapping and the T2-mapping are alternative means for myocardial tissue characterization without the need for contrast. Dr. Qiang Zhang: And notably, T1-mapping can detect a wider range of pathology, but its clinical application is hindered by confounding factors and a lack of clear interpretation. So we thought that since MRI is inherently multimodal and multiparametric, with different modalities reflecting complimentary information about micro tissue, therefore can we use the ones of an AI  method to combine the enhanced pre-contrast and modalities to produce a virtual LGE image without the need for contrast, and this leads to our concept of CMR virtual native enhancement. Dr. Victoria Delgado: Excellent. And in which population did you evaluate this technology? Why did you choose? So, can you tell us a little bit the characteristics of the population where you choose to assess the performance of this new technology? Dr. Qiang Zhang: Yes, so we validated this concept first on the hypertrophic cardiomyopathy patients using the image data from HCMR study, which is a larger multinational study. We trained the new network models on about 2,700 images, and then we tested independently on 124 patient materials. Dr. Victoria Delgado: And what were the results? Can you summarize them for us to understand what you found, how you evaluated the performance of this new technology compared to classical late gadolinium enhancement? Dr. Qiang Zhang: Yeah. So, we found that first, the VNE image had significantly better image quality than the traditional LGE, and the secondly, the VNE revealed characteristic HCM lesions in hypertrophic segment and added the anterior and the inferior right ventricular insertion point, and those VNE lesions were in high visual spatial agreement with the lesions detected by LGE. And thirdly, VNE correlated strongly with LGE in quantifying hyperintensity, micro lesions, but also more subtle intermediate-intensity lesions as often observed in the HCM patients. Dr. Victoria Delgado: Exciting. And now I would like to turn to Greg. You are a renowned expert on CMR. What did this article attract you? What were the main findings that you found interesting in this article? Dr. Greg Hundley: Yes. Thank you so much, Victoria. And just first, before I get started, I wanted to thank Zhang for sending us this work, and his entire team really spanning several institutions around the globe. Victoria, I want to thank you for leading this discussion. And Victoria, we work as a team looking at imaging, and what's very impressive is this caught multiple of us on the imaging team, but also the editorial board. So want to thank you Victoria. And then, finally, I want to thank Dr. Charlotte Manisty and Jennifer Jordan who helped with the editorial. Dr. Greg Hundley: So, just to take a little bit of a step back in the year 2000, Dr. Ray Kim, Dr. Bob Bono, Dr. Bob Judd at Northwestern University, in Chicago, administered gadolinium contrast. It's an extra cellular agent and they were examining myocardial perfusion, and then they noticed if they took images 10 or so minutes after that administration, they appreciated this late enhancement of the myocardial tissue that was associated with two things, one myocardial injury, and then, also, scar formation. Dr. Greg Hundley: And for the last 21 years, that technique has been very valuable in assessing infarct size in those with ischemic cardiomyopathy, and then also recognizing extracellular fibrosis or forms of myocardial injury in a variety of non-ischemic cardiomyopathy processes. And one of those is hypertrophic cardiomyopathy. And so, Zhang and his group have been working on a technique that did not utilize gadolinium anymore. And they based this on, really, had two important features. Dr. Greg Hundley: One is, some examination of the T1 relaxation that's available when you acquire magnetic resonance images, and then also applying artificial intelligence to analysis of these images. Those two factors allowed this investigative team to produce images that are very similar to what we appreciate with gadolinium enhancement in patients with hypertrophic cardiomyopathy. And why is that significant? So administration of gadolinium, we think about two things, again, that are an issue with that. Dr. Greg Hundley: Well, one, we've got to give the contrast agent, and some patients are not well-suited. If you have renal dysfunction, you can develop nephrogenic systemic fibrosis, a scleroderma-like syndrome when the gadolinium is not cleared, and it's stays in your body a long time. The other thing we tend to worry about much more recently was accumulation of gadolinium in the brain stem. We don't know that that has an adverse effect, but we're certainly aware of it. Dr. Greg Hundley: And finally, I guess there is a third point. There are a few patients, one in 20 to 40,000 that have allergic reactions. So, for all those patients that really can't get gadolinium, this is another potential opportunity moving forward. The second point is time. So during an MRI scan time, or process, we administer the gadolinium. And remember what I said, we've got to wait about 10 minutes to then collect these images. Well, if you can have a technique where you don't have to administer gadolinium, you get the same administration and you don't have to wait that 10 minutes, we might be able to save a large amount of time. And you say, well, 10 minutes, what does that mean? Dr. Greg Hundley: But if you're doing many patients during the day, that really could equate to a big time-savings. So what attracted us to this article? A technical innovation that perhaps may obviate the need for the administration of gadolinium in many cases, and here in these patients with hypertrophic cardiomyopathy, I think the images were quite stunning in that they appreciated the extent of the fibrosis and scar in patients with hypertrophic cardiomyopathy to the same degree, and maybe even with higher image quality than we had in the gadolinium-enhanced comparitors. Dr. Victoria Delgado: Yeah. I agree with all those comments, indeed. For these 20 years, there have been other developments, in terms of assessing diffuse fibrosis with T1-mapping techniques after administration of gadolinium, but also before administration of gadolinium. And this technology Dr. Zhang and co-workers have shown actually reduces the time of acquisition because you only need 15 minutes to acquire the cine images and the T1 images. And the analysis is not very long in terms of post-processing, because it's also very short. As seen the paper was indicated. Dr. Victoria Delgado: And as you said, the administration of gadolinium enhancement is not free of potential risks. And in these patients, for example, we have hypertrophic cardiomyopathy that can undergo repetitive evaluations during follow-up. The use of this imaging technique can help to reduce the exposure to gadolinium enhancement. Dr. Victoria Delgado: Now, the question for you, Qiang, will be, what are the next steps for you and your team to further develop this technique, to further convince the community to implement this technique in clinical practice, and that can have an impact in our management of these patients with hypertrophic cardiomyopathy, or with other patients on whom we also evaluate the presence of myocardial fibrosis? Dr. Qiang Zhang: Thank you, Victoria. And thank you Greg, for the very insightful comments. So we think that the immediate future work would be to validate the VNE HCMR study clinical outcomes as a potential new contrast-free biomarker for HCM patients. And in the meantime, we are working on extending the method to other pathologies, particularly myocardial infarction, for viability assessment. Dr. Qiang Zhang: And we also think that the concept of AI virtual contrast agent maybe apply it to other post-contrast images, such as early gadolinium enhancement and extracellular volume refraction mapping, or even, maybe, first perfusion. And also in collaboration with MR vendors, we plan to implement VNE as inline sequence on the scanner to display lesions immediately after the pre-contrast cine and the T1-mapping acquisitions. Dr. Victoria Delgado: Very interesting. And Greg, another group of patients, for example, that I'm thinking of where this technology can be very helpful, and you have expertise on this, are patients undergoing treatment with chemotherapy, what we need to address, for example, or to evaluate the presence of cardiac toxicity. Would you see in this population the value of this technique, or how do you see the future of these technique in clinical practice? Dr. Greg Hundley: Yeah. Great questions, Victoria. I think probably five things and many of those Qiang has already just brought up. One, with the current study, it's going to be great to follow these patients over time and look at the outcomes. What did amount, presence, location of the findings with this new technique, how did they equate to outcomes in patients with hypertrophic cardiomyopathy? So we're going to anxiously await that. Dr. Greg Hundley: I think once we move out of the current study, thinking about other vendors, using this and acquiring images from General Electric and Phillips, and multiple vendors around the world and multiple field strengths, how do we going to understand the findings there? I think another particular issue will be different diseases as Qiang ha said, ischemic cardiomyopathy. Well, what about amyloid? Victoria, you've mentioned using the other possibility here is, can this technique help us produce something similar to extracellular volume fraction measures? And could that be used to identify interstitial disease processes? Dr. Greg Hundley: And, for example, as you mentioned, the fibrosis that's associated with the administration of certain chemotherapeutic agents or radiation therapy. I think another thing is, Qiang, can we go back and use retrospectively-collected data? Can your technique be modified so that many of the studies that have been performed in the past, large population studies, like Mesa or a Framingham or Jackson heart study, and could we use that to develop forecasting and algorithms moving forward? Dr. Greg Hundley: And then, lastly, I think as you mentioned, the artificial intelligence component of what you've described and how's that can compare when Victoria and I look at the images, and could we get into combining reads from one institution, reads from another, reads from another, tracking outcomes? And so, when a patient comes in and has a study performed, your artificial intelligence, not only does it read that study and highlights the increased signal in the myocardium, but then goes and looks at outcomes across multiple sites, and what would that mean for a given patient with a different condition? So, oh my goodness, the horizon is just so expansive here. The future is very bright. And just to congratulate you on, I really think this could be another landmark technical innovation, so fantastic work. Dr. Victoria Delgado: Indeed. Thank you very much, Greg, for all these insightful comments and these perspectives that we have in the future, particularly with the use of this technique in retrospective studies in large cities, that where we can develop these algorithms. And I would like also to thank Qiang for submitting your article to Circulation, for giving us the opportunity to present this new technology and make this article, like the landmark article, where there will be many other articles to follow. We hope that you also choose us. Dr. Victoria Delgado: But with this, I would like to thank both of you, Greg and Qiang, for the excellent discussion that we have had in this new technology, based on artificial intelligence, that can identify myocardial fibrosis without the use of gadolinium enhancement, that maybe by now will be obsolete in the future, and that can impact on how we do our clinical practice. Many thanks to all of you and happy to discuss in the future other articles. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers, and then also, wish everyone a great week. And we will catch you next week On the Run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation August 17, 2021 Issue

    Play Episode Listen Later Aug 16, 2021 21:45

    This week's episode features author Philippe Gabriel Steg and editorialist Gregg Stone as they discuss the article "International Observational Analysis of Evolution and Outcomes of Chronic Stable Angina: The Multinational Observational CLARIFY Study." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation 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 here with my other co-host, a little bird that you can hear I think in the background and then my real co-host, Greg. Dr. Greg Hundley: Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the bird this week. Associate editor, director of the Pauley Heart Center in Richmond, Virginia. Carolyn, so this week, our feature discussion is really going to be on the importance of stable angina and what that means prognostically. But before we get to that, how about we grab a cup of coffee, talk to our other bird friends and then we jump in and talk about the other papers in the issue. Would you like to go first? Dr. Carolyn Lam: Love it, Greg. Thank you so much. This first paper, very important question. We know that while the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It's still unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. And so today's paper is really important from Dr. Mills from the University Center for Cardiovascular Science Royal Infirmary of Edinburgh in the University of Edinburgh and colleagues. Dr. Carolyn Lam: What they did was a secondary analysis of the high stakes trial of more than 46,000 consecutive patients with suspected acute coronary syndrome. They evaluated the performance of the 99th percentile rule in threshold and thresholds of 64 ng/L and five times the upper reference limit for the diagnosis of type 1 myocardial infarction. They found that troponin concentrations at presentation have a low, positive predictive value for type 1 myocardial infarction and a threshold of 50 times the upper reference limit is required to achieve a positive predictive value of more than 70%. A change in troponin on serial testing only marginally improved positive predictive value for type 1 myocardial infarction over the presenting troponin alone. Dr. Greg Hundley: Interesting, Carolyn. Very important data. What's our take home message here. Dr. Carolyn Lam: Well, troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction and should not be used in isolation to guide management decisions in patients with suspected ACS. Consideration of other important clinical factors may be more helpful than any particular rule in threshold to guide initial triage and management. Dr. Greg Hundley: Wow, Carolyn, so really great new data and more data on the utility of these troponin concentrations. Dr. Greg Hundley: Well, my next paper comes from the world of preclinical science and it's from Professor Vladimir Kalinichenko from Cincinnati Children's Hospital Medical Center. Carolyn, as we know, pulmonary hypertension is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a severe congenital disorder associated with mutations in the Foxf1 gene. Now, while the loss of alveolar microvasculature causes pulmonary hypertension in, and we're going to abbreviate this ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent pulmonary hypertension and right ventricular hypertrophy in these subjects. Dr. Carolyn Lam: Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar capillary dysplasia and misalignment of pulmonary veins. Really cool stuff. What did they find, Greg? This sounds like a first of its kind study. Dr. Greg Hundley: Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed pulmonary hypertension and RV hypertrophy after birth. The severity of pulmonary hypertension in these mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Second, increased fibrotic remodeling was found in the human ACDMPV lungs. Third, the mouse endothelial cells carrying the S52F Fox1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that the Foxf1 wild type S52F endothelial cells have a propensity to differentiate into pulmonary myofibroblasts. And then finally, intravascular delivery of nanoparticles carrying Stat3 copy DNA protected the Foxf1 wild type S52F mice from RV hypertrophy and pulmonary hypertension, improved their survival and decreased that fibrotic lung remodeling. Carolyn, nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent pulmonary hypertension in alveolar capillary dysplasia with misalignment of pulmonary veins. Dr. Carolyn Lam: Wow, thank you, Greg. Such incredibly hopeful papers here. The next paper identified a key role of a particular amino acid in cardiac aging. Dr. Greg Hundley: Ah, Carolyn, so you didn't ask me the quiz but I guess it's implied here. Okay, I give up. Which amino acid is it? Dr. Carolyn Lam: Spot on, Greg. Well, the answer is phenylalanine. This is an essential amino acid whose levels are regulated by the tetrahydrobiopterin or BH4 dependent rate limiting enzyme, phenylalanine hydroxylase and whose expression is physiologically restricted to the liver and the kidney. Well, co-corresponding authors Dr. Czibik and Derumeaux from Paris, France, hypothesized that phenylalanine plays a causal role in promoting cardiac senescence and dysfunction based on prior evidence from human metabolomics that shed light on a link between amino acids, aging and heart failure, as well as data showing that plasma levels of phenylalanine increase with age and inversely correlate with leukocyte telomere length. In addition, increased serum phenylalanine levels are associated with heart failure. Here, the authors tested their hypothesis in a series of elegant mouse experiments and showed for the first time that a decline in hepatic phenylalanine catabolism was a causal contributor to a rise in systemic levels, leading to cardiac ectopic phenylalanine hydroxylase activity and resultant cardiac aging. Dr. Carolyn Lam: They demonstrated that phenylalanine administration induced a remarkable premature cardiac deterioration in young mice, closely mimicking that of aged mice and leading to cellular senescence in vitro. They identified hepatic phenylalanine catabolism to decline with age in a p21 dependent manner, while demonstrating that p21 deficiency prevented age related cardiac dysfunction. Administration of phenylalanine hydroxylase cofactor BH4 or dietary phenylalanine restriction, both abrogated the age related rise in the plasma levels and reversed age associated cardiac alterations. This study really identifies phenylalanine and its hydroxylase modulation as a potential therapeutic strategy to promote cardiac health and prevent age related cardiac impairment. Amazing, isn't it? Dr. Greg Hundley: Yeah, Carolyn. Really interesting about phenylalanine and while it may impact cardiovascular health and the aging process. Dr. Greg Hundley: Well, I know we've got some other articles in this issue, so how about I'll go and dip into the mailbag first? The first is from Professors Wong and Finn and they're exchanging letters regarding the prior publication entitled, Microthrombi as a Major Cause of Cardiac Injury in COVID-19 and it's a pathologic study. There's a nice Research Letter from Dr. Zhu entitled, “Catheter Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication Control Trial.” There's a Perspective piece from Dr. Stehlik entitled, “The Long and Winding Road to an Effective Left Ventricular Assist Device: The Demise of Medtronic's HVAD.” And then finally a report from Dr. Mehta and colleagues, really Carolyn, thinking about clinicians' wellbeing and addressing global needs for improvements in the healthcare field. And it's a Joint Opinion representing the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the World Heart Federation. Really a nice report on really addressing physician stress in the workplace. Dr. Carolyn Lam: Nice. Well, there's also an ECG Challenge by Dr. Shi entitled, “An Acutely Breathless Patient with Inferior St-Segment Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn describe studies detailing heart risks for firefighters. Wow, what an interesting issue, but let's go on now to the feature discussion shall we, Greg? Dr. Greg Hundley: You bet. Dr. Greg Hundley: Welcome listeners to our feature discussion. And today we have with us Dr. Gabriel Steg from Paris, France, Universite de Paris. And also Dr. Gregg Stone, an editorialist from Mount Sinai in New York. Welcome gentlemen. And Gabriel, we'll start with you first. Could you describe for us some of the background related to your study and what was the hypothesis that you wanted to test? Dr. Gabriel Steg: Thank you, Greg. As you know, there have been tremendous changes in cardiology over the past 25 years with the advent of effective anti-anginal therapy, with the advent of myocardial revascularization and the dramatic changes produced by widespread availability of percutaneous coronary intervention and finally the availability of evidence based secondary prevention therapies. And there has been really a sea change in the presentation and treatment, management and outcomes of patients with coronary artery disease. And when we started off, we asked ourselves, is angina pectoris really prognostic in patients with stable coronary artery disease? Is the symptom of angina really prognostic? That was the question we tried to address. Dr. Greg Hundley: And Gabriel, what was your study population and your study design? Dr. Gabriel Steg: It was a very simple descriptive design. We use a large international registry of patients with stable coronary artery disease called the CLARIFY registry, which enrolled almost 35,000 patients with stable coronary artery disease and followed them up for five years. Now, how was stable coronary artery disease defined? It was defined as any of the following conditions, a prior MI, more than three months before enrollment, a prior PCI or a CBG, angina pectoris was a demonstration of myocardial ischemia on noninvasive stress testing or finally the presence of a fixed stenosis of the coronary arteries on an angiogram. And you could get any of these criteria. Of course you could have more than one at the same time. And the design was to describe the anginal status at baseline and every year based on investigator reports, not a formal angina questionnaire, as there are several, including the Seattle angina questionnaire. We had a very simple assessment of angina and angina severity based on presence or absence and then Canadian class of angina. Dr. Greg Hundley: Did you follow these individuals too? Did they experience specific events? Dr. Gabriel Steg: Yes. We collected all the cardiovascular hospitalizations events, revascularizations. We followed the medications and we collected the biological results, although there was no core lab but we collected the results of the tests that were done. We essentially aimed was that registry to describe the population, their management and their outcomes over five years. And this is over 40 plus countries. And fortunately does not include any patient from the United States but has a substantial contribution from Canada and Mexico. Dr. Greg Hundley: Very nice. And so what did you find, Gabriel? Dr. Gabriel Steg: Well, the first observation is the prevalence of angina at baseline and it's 22%. We found that in a patient population selected for having stable coronary artery disease, approximately a fifth to a quarter will have anginal symptoms. I don't think that's a major surprise but what was a big surprise to us is that angina resolved very, very substantially, 40% of the patients who had angina at baseline had no longer angina by one year. And what was even more surprising is what caused the resolution of angina. And it was rarely changes in anginal medications, rarely revascularization. It was largely spontaneous. Almost 80% of the patients had spontaneous resolution of angina. And so, yes, it's been known that angina can regress but we did not expect that it would regress that often and that much spontaneously without intervention or need for increasing medications. Dr. Gabriel Steg: And the other aspect is then we looked at what happened for those patients who had angina resolution at one year and what were the subsequent outcomes? And we found they were indistinguishable from those who had no angina at baseline. And then we looked at those patients who had persistent angina at one year or occurrence of angina at one year, despite not having angina at baseline. And again, we found that having angina at one year was detrimental to the longterm prognosis. It's really good that you either not have angina or that your angina resolve. That's really important. Dr. Greg Hundley: Did you find any differences, Gabriel, between men and women? Dr. Gabriel Steg: No. We looked at a variety of subgroups. We looked by criteria for enrollment. We looked across geographic locales. We looked according to the presence or absence of diabetes and sex and other variables and there were really no major differences. The results were remarkably consistent. Dr. Greg Hundley: Very nice. Well listeners, one of the advantages of some of the publications that we pursue at Circulation is the ability to bring in an editorialist. And with us today, we have Dr. Gregg Stone from Mount Sinai in New York. And Gregg, we want to turn to you. How do we put the results of this study in perspective with other studies that have been involved in this sphere of research? Dr. Gregg Stone: Well, thank you, Greg. First off, I'd like to congratulate Gabriel and his colleagues for a tremendous study and thank you and Circulation for offering David Waters and I, the chance to provide our perspectives. I think this study raises a lot of important issues. Angina is kind of like the common cold to cardiologists. We're always dealing with it but it can be very difficult to diagnose. There's typical angina, atypical angina, anginal equivalent disease, non-anginal chest pain, et cetera. And we've learned in the last several years or decade that the etiology of angina can be very complex. It's not just epicardial coronary disease. There can be microvascular disease, macro or microvascular spasm and other causes. I think that we have to, when we're thinking of angina, we have to try to understand the mechanism and know whether or not it's really due to at least epicardial coronary artery disease, which is the type of disease that may respond to revascularization. Dr. Gregg Stone: In this regard, both David and I were struck with the fact that the CLARIFY even though a very large population, is a very mature population of patients with coronary disease, who I believe were diagnosed at least approximately seven years ago, most had undergone a prior revascularization therapy, about 50% ahead of myocardial infarct and the minority interestingly had inducible ischemia. We wondered is this real angina? Is this true angina that these patients are having? Because they've been effectively revascularized. In contrast, I was one of the co-principal investigators of the ISCHEMIA trial, which was a very different population because we took only with exercise induced moderate or severe ischemia. And while we excluded most patients with class three or four angina because we know those patients basically don't tolerate medical therapy without frequent crossovers. We found that in our trial, angina was more persistent and was substantially reduced by revascularization, by an interventional approach. Much more so than in the medical therapy arm. I think that it really does depend on the patient population and the likelihood of which the angina is due to true inducible ischemia that may respond to a revascularization approach. Dr. Greg Hundley: Very nice. And so Gabriel, want to turn back to you, what do you think is the next study that really needs to be performed in this space? Dr. Gabriel Steg: Well, I think it's really in line with Dr. Stone's comments. I think that what we need to do is to have a much more formal prospective assessment of a broader population of patients with angina using formalized questionnaire, such as the Seattle angina questionnaire, which allow a much better and thorough characterization of the presence, type and severity of symptoms and to look across the whole spectrum of patients with and without myocardial ischemia and look at the prognostic importance of the symptoms. I think that teasing out the relationship between the anginal symptoms, their severity, myocardial ischemia and outcomes is really critical to our interpretation of the series of recent trials, the last of which being ISCHEMIA, which have revolutionized our thinking regarding management of coronary artery disease. And we're still somewhat in the dark as to how to incorporate that information relative to the symptoms and outcomes of our patients. And I think we still have a lot of work to do in that respect. Dr. Greg Hundley: Very Good. And Gregg, do you have anything to add to that? Dr. Gregg Stone: Yeah. I would certainly echo Gabriel's comments. In addition, I think we have to think of angina as a collection of different diseases. And we have to do a better job at trying to understand the mechanisms underlying angina. First, we have to be able to determine whether it's really cardiac in origin versus non-cardiac. And then second, we have to understand again, whether it's coming from epicardial coronary disease, microvascular disease or other mechanisms. We've just been struck in even many of our simple stent studies, how often patients redevelop angina after treatment with no re-stenosis whatsoever, suggesting that many of them may have other etiologies of angina. I think these studies to me are very important because they really highlight, yes how much we've learned but how much more work there still is to do for us to be able to effectively diagnose and treat these patients. Dr. Greg Hundley: Well listeners, we want to thank both Dr. Gabriel Steg, the author of this paper and also Dr. Gregg Stone, who provided his editorial expertise, in bringing us information from these 32,000 plus individuals from the CLARIFY registry, of patients with stable coronary artery disease and helping us answer really two questions regarding the presence of angina. One, both that angina may resolve spontaneously and then second, persistent angina is associated with future cardiovascular events. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers and then also wish everyone a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation August 10, 2021 Issue

    Play Episode Listen Later Aug 9, 2021 36:25

    This week's episode features a panel discussion in regard to Covid-19. Please join authors Kathryn Larson, Christopher deFilippi, James de Lemos, and Biykem Bozkurt as they discuss their articles regarding temporary myocarditis and Covid-19 vaccination. 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. Dr. Greg Hundley: Carolyn, this week, oh my goodness. It's a forum, almost a triple or quadruple feature, and you know what we're going to be discussing? COVID-19 vaccinations and their relationship potentially to myocarditis. We're going to have our associate editors and our deputy editor involved, be really interesting. But before we get to that, how about we start in with the papers in the issue. Would you like to go first? Dr. Carolyn Lam: Absolutely. And my first paper is so interesting. It identified a novel underlying mechanism of graft arteriopathy, or otherwise known as coronary allograft vasculopathy, a devastating development of heart transplant in which arterial intimal thickening limits coronary blood flow and could lead to transplant failure. Dr. Greg Hundley: Oh wow, Carolyn. So, what did they find? Dr. Carolyn Lam: Well, this was Dr. Martin from Yale Cardiovascular Research Center and colleagues. What they did is they used both human coronary allograft vasculopathy and renal transplant samples as well as murine models, basically, and found that TET methylcytosine dioxygenase 2, or TET2, is a critical negative regulator of vascular smooth muscle cell apoptosis in graft arteriopathy and vascular injury. Enhancing smooth muscle TET2 activity with a high dose of ascorbic acid rescued donor vascular smooth muscle cells apoptosis and intimal thickening in murine transplant vasculopathy. Furthermore, TET2 expression and activity were repressed in arterial vascular smooth muscle cells in human and mouse graft arteriopathy compared to controls. Dr. Carolyn Lam: Interferon gamma signaling in vascular smooth muscle cells resulted in TET2 repression. Preventing donor vascular smooth muscle cell apoptosis with high dose ascorbic acid may therefore represent a safe and cost-effective therapeutic strategy for limiting graft arteriopathy in patients undergoing solid organ transplant. Neat, huh? Dr. Greg Hundley: You bet, Carolyn. Really an interesting article on limiting graft arteriopathy. Dr. Greg Hundley: Well, Carolyn, my next paper comes to us from Dr. Greg Stone and colleagues at the Cardiovascular Research Foundation. It involves the randomized COAPT trial. Remember that in the COAPT trial, there were 614 heart failure patients with 3+ or 4+ secondary mitral regurgitation and had trans-catheter mitral valve repair with the MitraClip, reduced mitral regurgitation, heart failure hospitalizations and mortality as well as improving quality of life compared with guideline directed medical therapy alone. So the authors here, Carolyn, sought to examine the prognostic relationship between mitral regurgitation reduction and outcomes in trans-catheter mitral valve repair versus guideline directed medical therapy alone. Dr. Carolyn Lam: Wow, okay. So, what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, among patients with heart failure and severe, grade 3+ or 4+ secondary mitral regurgitation randomized to trans-catheter mitral valve repair with the MitraClip versus guideline directed medical therapy, the reduction of MR to 2+ was strongly associated with subsequent two year freedom from death and heart failure hospitalization and improved quality of life regardless of whether this reduction to 2+ MR was achieved by trans-catheter clip or guideline directed medical therapy alone. And the improvement in long term prognosis was similar after this mitral regurgitation reduction to grade 2+ compared with grade 0 or 1+ in both arms, although the mitral regurgitation reduction was a little more durable over time after the trans-catheter mitral clip. Dr. Greg Hundley: So Carolyn, the take-home message is that substantial benefits are realized even if mitral regurgitation is reduced to only 2+. Dr. Carolyn Lam: Nice, Greg. Thanks. Dr. Carolyn Lam: Now, this next paper, oh, close to my heart. We know that individuals of South Asian ancestry actually represent 23% of the global population, corresponding to 1.8 billion people, and that they have a substantially higher risk of atherosclerotic cardiovascular disease compared with most other ethnicities. However, what is the magnitude of that enhanced risk, the extent to which it is captured by existing risk estimators, and what are its potential mechanisms? Dr. Carolyn Lam: This was studied in this beautiful paper. Dr. Khera from Massachusetts General Hospital and colleagues used data from the large UK Biobank prospective cohort study to investigate the relationship between South Asian ancestry and incident atherosclerotic cardiovascular disease within the context of contemporary medical care. Their findings confirmed an approximate doubling of atherosclerotic cardiovascular disease risk among South Asian compared with European individuals that was not captured by the pooled cohort equations. The higher risk of atherosclerotic cardiovascular disease persisted despite adjustment for a broad range of potential clinical, anthropometric, and lifestyle mediators. Hypertension, diabetes, and central adiposity explain a greater proportion of risk of atherosclerotic cardiovascular disease in South Asian compared with European individuals. Dr. Greg Hundley: Wow, Carolyn. So, a lot of data here. How do we take all this and put it together clinically? Dr. Carolyn Lam: Well, the results confirm and extend the current guidelines that consider South Asian ancestry a risk-enhancing factor in assessing future risk for atherosclerotic cardiovascular disease. Residual risks that persisted after accounting for a range of potential mediators may relate to differences in social determinants of health, unmeasured risk factors and genetics and so on, that this warrants further investigation. Whether a targeted intervention can attenuate the outsized impact of diabetes or central adiposity among South Asian individuals also warrants further attention. Dr. Carolyn Lam: This is accompanied by a beautiful editorial entitled The South Asian Enigma: Solving a Puzzle of Global Importance, love that, from Drs. Kandula from Northwestern University Medical Center and Kanaya from University of California San Francisco. Dr. Greg Hundley: Very nice, Carolyn. I just want you to know, after being quizzed last week on phospholamban, I went and did a little bit of studying, okay? So I get to bring to you, Carolyn, this week, a paper on phospholamban. But I'm going to spare you from the quiz. Dr. Greg Hundley: All right. Dr. Carolyn Lam: Yay! Dr. Greg Hundley: This comes to us from Professor Fadi Akar from Yale University. Carolyn, arginine 14 deletion is the calcium regulatory protein phospholamban, so hPLN R14 deletion. It has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy, and mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling really remain unclear. Dr. Carolyn Lam: Interesting, Greg. So, what did they find? Dr. Greg Hundley: Right, Carolyn. Adverse electrophysiological remodeling was evident in the absence of significant structural hemodynamic changes, and the R14 deletion hearts exhibited increased arrhythmia susceptibility compared to their wild-type counterparts. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to beta-adrenergic stimulation. A steep repolarization gradient at the LV/RV interface provided the substrate for inter-ventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. And then once sustained, these circuits evolved into high frequency rotors, which in their majority were pinned to the right ventricle. Importantly, these rotors exhibited unique spatio-temporal dynamics that promoted their increased stability in the R14 deletion compared to the wild-type hearts. Dr. Greg Hundley: So Carolyn, in summary, this research found the crucial role of primary electrical remodeling caused by the hPLN R14 deletion mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of the PLN R14 deletion induced a cardiomyopathy. Dr. Carolyn Lam: Oh, and ties up very nicely about how we mentioned that this dilated cardiomyopathy is associated with lots of ventricular arrhythmias that we discussed last week. Really cool. Dr. Carolyn Lam: Well, let's do a little tour around what else there is in today's issue. Tracy Hampton presents from the literature discussing how excessive exercise may damage mitochondria and impair glucose control in a publication from Cell Metabolism. Data on an oral antisense oligonucleotide for PCSK9 inhibition was published in Science Translational Medicine. Dr. Carolyn Lam: And there's a paper on structuring clinical text with AI. How very interesting, published in Patterns. There's an On My Mind paper by Dr. Berger on summoning strength to question the placebo in reducing. Dr. Greg Hundley: Right, Carolyn. Also in the mail bag, there is a reply to the Quintao and Cazita from Professor Brunham entitled High-Density Lipoprotein Cholesteryl Ester Transfer Protein and Sepsis. And then finally, from Dr. Goldstein, an ECG challenge. Does this ischemia pattern look right? Dr. Greg Hundley: Well, Carolyn, this is going to be a really interesting feature forum discussion today on COVID-19 vaccinations and myocarditis. How about we get on to that discussion? Dr. Carolyn Lam: Yep. A really important issue now. Yup, let's go. Dr. Greg Hundley: Welcome, listeners. We have a very exciting, really series, of feature discussions. We're going to call it a forum, and focusing on COVID-19 vaccine associated myocarditis. We really have four manuscripts to discuss today. We have Dr. Kathryn Larson from the Mayo Clinic in Rochester. We have another author, Dr. Chris deFilippi from Inova Health, really in the Washington DC metro area. We have our executive editor, Dr. James deLemos from UT Southwestern in Dallas, Texas. And then also one of our senior associate editors, Dr. Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Welcome to everyone. Dr. Greg Hundley: Well, first, listeners, we're going to start with Dr. Larson. So, Kathryn, can you tell us a little bit about the background and the hypothesis that you were testing in your research project, and then a little bit about your study design and what were the results of your study? Dr. Kathryn Larson: Absolutely. Well, first off, thank you so much for having me, Greg. It's a pleasure to be here and in such good company. My study really grew out of a clinical interest in a number of patients that had presented to our institution and other institutions that we had been in discussion with of really young male patients with no significant past medical history who were coming in two to three days after receiving their COVID vaccines, most often the second dose, and presenting with laboratory and clinical findings consistent with myocarditis. I think in a lot of arteriosity and what the course of their illness may be and what the best course of treatment may be, that really drove our hypothesis to try and describe other cases that were coming up and that we had heard about from a lot of our colleagues around the country and around the world. Dr. Kathryn Larson: Our paper really grew out of a case series of eight patients, and they're from the United States and from Italy, and they're of eight patients who were diagnosed with laboratory and clinical and imaging findings consistent with myocarditis after receiving their COVID-19 vaccines. Our patients had received either the Pfizer BioNTech or the Moderna vaccines, the mRNA vaccines. Really, only two of our patients had previously been infected with COVID at all, and so most of these patients were coming in with really no relevant medical history. They were really young in age, between 21 and 56 years old, and basically all patients except for one developed their symptoms after receiving the second dose of the vaccine. Dr. Kathryn Larson: The timeline was generally about two to three days after that dose and was often accompanied by other symptoms which we have seen and heard about things like myalgias, subjective fevers, chills, and kind of a general malaise. They presented really with very typical features of myocarditis, chest pain, one of the patients had a more pleuritic type of chest pain, and had ECG changes, troponin elevations, elevated inflammatory markers, and most importantly cardiac MRI findings that were significant and really diagnostic of myocarditis. Dr. Kathryn Larson: There was a good amount of investigation into other potential causes and none other identified in any of those eight patients. All thankfully had a relatively unremarkable course clinically and all are currently doing very well. There was mild reductions in LV function, no clinically significant heart failure, and at last known contact, those patients really had recovery of LV function and are essentially back to baseline. Dr. Greg Hundley: Excellent. Well, listeners, we're going to move to another part of the country, and again, Dr. Chris deFilippi is in the Washington metro area. Chris, you also have a case series. Can you describe for us what you were looking at with your study, and then what were your study results? Dr. Chris deFilippi: Greg, first, thank you for having me here today. As a regular listener to Circulation on the Run, it's really a privilege to actually be able to participate and contribute to it. First, I would have to say was a little bit of serendipity. We recognized one case out of the ordinary with respect to suspected myocarditis in early March, and given our location around Washington DC, some of our faculty were former active military and serve in the reserves and one returned and said, "The military is beginning to find a small series of cases." Dr. Chris deFilippi: We've worked hard within our academically oriented independent health system to develop a research clinical trials network, and we called upon our cardiologists and cases started coming forward actually fairly rapidly, drawing upon five hospitals in our network. Combining our efforts with UT Southwestern, we identified seven individuals. They were all men or young adults in their 20s and 30s. Six out of seven had received the mRNA vaccines. Most of them had developed symptoms between three to seven days after their second vaccination. Dr. Chris deFilippi: Very similar to Kathryn's presentation, we did an extensive evaluation, of course including advanced imaging with MRI using the Lake Louise criteria, but also did a lot of serologic measurements. I think it was remarkable that troponin values using still a conventional assay ranged from mild elevations, 0.34 to as high as 44 milligrams per milliliter. Dr. Chris deFilippi: All patients fortunately had resolution of symptoms within several days and returned back to normal life and then all return follow-ups seemed to remain symptom-free. Again, we looked for multiple other etiologies including autoimmune disease, other respiratory infections, and these were all effectively negative. Dr. Greg Hundley: Very nice. Well now, listeners, we're going to head south, down to Dallas, Texas and bring in Dr. James deLemos. James, you also have a case report and did some extensive study, I believe, in your patient in terms of investigating perhaps mechanisms. Could you share with us your study and some of your findings? Dr. James deLemos: Yeah. Thanks, Greg. Ours was like Kathryn and Chris's experience, purely serendipitous. I was on service in late January at our university hospital and we had a case that came in three days after receiving the Moderna vaccine with what appeared to be clearly myocarditis in temporal association with the vaccine. At that time, we reported it to the CDC, but there was really not much, if anything, and so what we decided to do was pull together a translational team. We brought together clinical pathologists, immunologists, infectious disease experts, and a panel of folks to think about how we might get at a potential mechanism, obviously in a highly exploratory fashion because this was one case and at this point we really didn't know whether this was a true causal association or just circumstance. Dr. James deLemos: What we did was really a broad exploratory analysis, comparing our index case with a number of vaccinated controls, COVID infected controls, and normal controls. We did autoantibody panels, cytokine panels. We looked at flow cytometry for cell fractions, and really tried to see if there was a signature for our case that distinguished it from these other control groups. Dr. James deLemos: I think one important thing we didn't see was an exuberant or over exuberant response in terms of the spike antibody. That was also not seen in several other cases from Chris and Kathryn. The antibody response seemed to be in the normal range of what would be expected after the vaccine. We also didn't see broad spread inflammation in our case compared to controls. There were several cytokines that were upregulated, some of which have been reported in myocarditis, and there were some natural killer cell subsets that would seem to be upregulated, and then several autoantibodies as well that have been reported in myocarditis. But interestingly, none of the poor prognosis autoantibodies that had been reported, which may in part, we think, explain why these cases seem to be doing quite well. Dr. James deLemos: I'd emphasize it's one case, so we recognize this is purely exploratory and hopefully will set the stage for other people as they try to investigate this in more depth. Dr. Greg Hundley: Thank you, James. Well, Biykem, you've been spending a large segment of time, the last year, really year and a half, trying to put together for us at the American Heart Association what may be operative in these patients receiving these vaccines, and also really studying COVID-19. It sounds like what we're hearing amongst all three of these, young men, really a myocarditis that develops after the second vaccine. We have typically elevated troponins, there's MRI findings. You've put together a review. Maybe you could start to share with us what have you learned over this past year and a half? Dr. Biykem Bozkurt: Thank you, Greg. As my colleagues have alluded to, the characterization of the presentation is pretty concordant. What I did in the review was to review all the case reports and case series published to date, which summed up to 61 cases. Additionally, I looked at what has been reported by the Vaccine Adverse Event Reporting System by the CDC and their internal analyses, and also looked at the reports that came from Israel as well as the US military, which is a large cohort and population base reporting. Dr. Biykem Bozkurt: The messages for the clinicians, number one, the presentation in most of these reports have been pretty unified in the sense that most patients presented day two or day three after the second dose of mRNA vaccination. Secondly, most if not all had cardiac troponin elevation along with chest pain on presentation. The majority of the patients, more than 90, 95 in the case series, had EKG abnormality, usually with ST elevation. When we're to examine the echo findings, about two thirds or sometimes in the case series about 40% of abnormalities and only a small percentage had LV systolic dysfunction with EF less than 50. Dr. Biykem Bozkurt: When done as was the case in all the case series and case reports, cardiac MRI was always abnormal. They were very self-limited. Important concepts are, these were very self-limited cases. All of them recovered and were discharged and had resolution of their symptoms, biomarker findings as well as imaging findings. Dr. Biykem Bozkurt: Now, let's look at the benefits versus risk concept that was examined at the CDC level. The current reporting in the VAERS system, the Vaccine Adverse Event Reporting System, is about 12.6 cases per million doses of vaccination. This is after 300 million doses being given in the US and about 170 million individuals being vaccinated in the US. Of those, when compared to what we have been expecting in the population, there appears to be a temporal association that the CDC has confirmed. If we were to look at the risk versus benefits ratios, it's very clear that COVID-19 is a deadly disease. It results in mortality even amongst the younger population, somewhere at the order of 0.1 to 1% per 100,000 people being infected. So for 12 to 39 years old, where the myocarditis risk is felt to be higher, still we need to keep in mind, that risk is very low. 12 per million doses, compared to about 0.1 to 1 death for about 100,000 infections. Dr. Biykem Bozkurt: And of course, if we were to add the number of hospitalizations, ICU stays, cardiac involvement, which we know is seen in about 12 to 20% of hospitalized patients by cardiac troponin elevation, as well as multisystem inflammatory syndrome that is seen in young populations, the benefits significantly outweigh the risks. In terms of mechanisms which James has alluded to, the things that are coming as potential signals or hypothesized mechanisms include the following. There could be molecular mimicry between the spike protein and the self-antigens. Currently, that experimental data, antibodies against spike protein have been reported to cross react with human proteins including alpha myogen. Other mechanisms could be vaccine and it making a response triggering a pre-existing dysregulated immunopathological pathway in predisposed patients. But mind you, we don't right now have a pattern of who's predisposed to myocarditis. It doesn't look like comorbidities as we have seen with COVID-19 infection. Dr. Biykem Bozkurt: And in James' case, there was no predisposition to cardiomyopathy identified by a gene variant that are known to be associated, so those were negative in the case reports that James had mentioned. There was increased frequency of autoantibodies in that case report that James had published. Again, this may be in reaction to the inflammation or injury rather than being the cause. It may be the outcome, but still it raises a concern whether autoantibody formation is one of the mechanisms. Dr. Biykem Bozkurt: Male predisposition is a known risk for myocarditis. We've known this even before the vaccine related myocarditis cases. In the experimental as well as population based studies in the past, young males have a higher predisposition than females or older age, and it's thought to be due to the differences related to sex hormones, especially testosterone, being pro-inflammatory. But of course, in the passive vaccine adverse event reporting, we also do know that the chest pain presentation did not appear to be as different among males compared to females and the imaging and studies were done in less frequency in females, so there may be also a bias toward work-up in females which needs to be further examined. Dr. Biykem Bozkurt: The most important message we'd like to put out there is the benefits highly outweigh the risks, but there needs to be recognition that there is such a risk for clinicians, and definitely do an appropriate work-up for patients presenting with chest pain to the emergency room or to the clinical setting for an appropriate work-up to be carried out including EKG, cardiac troponin in all patients, followed by imaging, such as cardiac MRI and/or other imaging as necessary depending on the symptomatology, the age, as well as the findings on the troponin and EKG. And cardiology moment is essential for those ones who are diagnosed with myocarditis. The treatment strategies in the case reports range all the way from non-steroidal colchicine to IV steroids to intravenous immunoglobulin. Probably the way to approach these cases is if it's very self-limited with resolution of symptoms and biomarkers within two or three days, they may not need to resort to very intensive therapy, but if the case is with unrelenting symptoms, persistent biomarker abnormality, an imaging finding higher level of intense geo-treatment with intravenous steroids or IV immunoglobulin may be considered. Dr. Biykem Bozkurt: So far in the published reports, there have not been any bad outcomes such as death and/or requirement for mechanical circulatory support, but again, further research is needed. Dr. Greg Hundley: Very nice, Biykem. Well, listeners, we're going to go back through our authors and just really quickly, Kathryn, Chris, James, Biykem, what study, maybe in 15 seconds, do you think might need to be performed next in this sphere of research? And then second, what's the one point that you think we ought to emphasize as we close out going forward? So, both questions for each author. Kathryn, we'll start with you. Dr. Kathryn Larson: Okay, cool. I think I'll bring a little bit of an imaging bias as that's my personal interest. I'd really like to see a lot of the data that's already out there from these patients both at their baseline studies, and I'd really like to see their follow-up studies in terms of what happens to things like LV function and in terms of their MRI findings. I think that could be really helpful given the amount of weight that imaging has in the diagnosis of these patients. Dr. Kathryn Larson: I think the biggest take-away for me in a lot of these discussions that we were having is, these are very rare issues and incidents when patients are presenting with these, and I think the vast majority of the information we have at hand is that these are self limited, there's good recovery of any decline in LV function, and that I think overall the clinical course is favorable. Dr. Greg Hundley: Very nice. Chris? Dr. Chris deFilippi: First, I shouldn't be promoting my colleague's work, but I've got to say that Biykem's review was terrific. I know I did a lot of background reading in this case presentation. I've gone through that review a couple times and it's clearly, I think, helped my thinking on this topic. As Biykem mentions in that review, the recording of myocarditis can have a number of biases either under or over reporting, basically what's available in the public and what sort of people are thinking about. I think looking at it from a population health standpoint, the risk benefits are so favorable for the benefits of vaccination. We knew that even a month ago, we know that even more today. But I think it would be great to get an understanding, recognizing that there may be cases of unrecognized myocarditis, myocardial fibrosis, at a population level in what we would assume would generally be very healthy, young adult males, do we see more cardiac related hospitalizations over time? Do we see more sudden death? I think we should just affirm that, hopefully we can affirm that isn't the case and keep moving forward. Dr. Chris deFilippi: That being said, I'm still really a big advocate for vaccination and the benefits of vaccination combined with these very small risks. Dr. Greg Hundley: Very nice. James? Dr. James deLemos: I'd say really two avenues for research. I'd echo Kathryn's point that we need longer term follow-up data for patients that have this syndrome. To do that we're going to have to collaborate, because each of us individually see very few cases, because fortunately this is rare, and we're going to need registries that look at longer term follow-up of patients with vaccine associated myocarditis. And then really getting to Chris' point on the front end, I think that's what's needed are prospective studies measuring high sensitivity troponin and cardiac MRI in younger individuals who get vaccinated, so we study them not once they get the disease, but trying to determine whether there might be even less severe versions of myocardial injury that are occurring after the vaccine and try to understand why that's the case, because mRNA vaccines are here to stay. They're remarkable advances. And let's understand what this apparently self limited myocarditis is all about. Dr. James deLemos: The take-home message I'd echo is that this is important and all of us even had angst about recording and talking about this, because we don't want this ever to be misconstrued to suggest that these vaccines, which are absolutely remarkable, don't have a favorable risk benefit, even for our cardiac patients. These data in no way affect the safety and efficacy of the vaccine, even in people with underlying cardiac disease, who are some of the ones that have the greatest priority to get vaccinated. Dr. Greg Hundley: And finally, Biykem. Dr. Biykem Bozkurt: I think I echo all my colleagues' sentiments in the necessity for prospective and imaging and biomarker. The way to do that, as James alluded to, is we should right now develop a consortium for a registry, and we should have a bioregistry. I would urge us to not solely consider it for vaccine related entity, but also COVID-19. So I think we need to straddle the whole concept of COVID-19 itself, the infection plus the vaccinated individuals and follow them in a prospective manner with the known biomarkers, the cardiac biomarkers as well as imaging, but also the thing that is lacking right now is to characterize them with a specific immune cell populations as to what is rising, what kind of response we've seen, with the changes that we're seeing in males and others, and capture further mechanistics, perhaps signaling. Quite a few of this phenotyping is needed in these individuals as well as perhaps a genotyping characterization and maybe a tissue characterization. Dr. Biykem Bozkurt: I think the consortium will need to entail pathologies as well as immunopathology along with biomarkers and imaging. And of course, prospectively following these individuals. As was done in certain other vaccines in the past may give us a totally different signal and prevalence. Dr. Biykem Bozkurt: Take-home message, I fully agree. Being able to get a message of the risk is low compared to benefit. While we're calling for, the necessity for further research is a delicate balance of what the scientists have to straddle. Yes, the vaccine is very safe. It's been shown in numerous, several randomized clinical trials. Current data actually validates that because it's a few cases in millions of doses of the safest vaccine. But for those very few cases, for those very few cases we need to be on the alert and treat them appropriately and not miss those diagnoses. Dr. Biykem Bozkurt: One other message I'm going to share is the rapidly evolving conceptualization of myocarditis. The lymphocytic myocarditis concept that historically was the gold standard characterization of myocarditis with other viruses is, I think, rapidly changing now with the recognition of what we saw with COVID-19 itself, as well as now with the vaccine. It does not seem to be the classical characterization of myocarditis, so again, understanding of myocardial injury, cardiomyocyte injury is now a continuum beyond what we used to call the path to MI and injury, now straddling all the way to a concept of injury that is much different than the lymphocytic myocarditis we've seen with other viruses, which we need to embrace. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Kathryn Lawson, Dr. Chris deFilippi, Dr. James deLemos, Dr. Biykem Bozkurt, for this wonderful forum discussion on COVID-19 vaccine associated myocarditis. Dr. Greg Hundley: Well, thank you so much and on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. Dr. Greg Hundley: The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAJournals.org.  

    Circulation August 3, 2021 Issue

    Play Episode Listen Later Aug 2, 2021 25:59

    This week's episode features author Shih-Chuan Chou and editorialist Alexander Sandhu discuss the article "Impact of High-Deductible Health Plans on Emergency Department Patients With Nonspecific Chest Pain and Their Subsequent Care." 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 at VCU health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I am so excited about today's feature discussion that's going to be about high deductible health plans and their impact on emergency department patients with chest pain and their subsequent care. Now, I can tell you as coming from outside of US, I learned so much from this discussion so everybody's going to want to hear it. But before we go there, let's discuss the other papers in today's issue. Greg, do you have a paper? Dr. Greg Hundley: You bet. Thanks Carolyn. So my paper is going to really evaluate a very interesting question about the role of measuring lipoproteins and their subfractions in patients, not with coronary disease, but peripheral arterial disease. And it comes to us from Dr. Scott Damrauer from the University of Pennsylvania School of Medicine. So Carolyn lipoprotein related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, just like we said. Largely based on their role in progression of coronary artery disease, but the relative contributions of these lipoproteins to those with peripheral arterial disease really haven't been as well defined. So these authors leveraged a large scale genetic association data to investigate the effects of circulating lipoprotein related traits on peripheral arterial disease risk. Dr. Carolyn Lam: Interesting. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So ApoB was prioritized as the major lipoprotein fraction usually or almost causally responsible for both peripheral and coronary artery disease risk. Extra small VLDL particle concentration, we'll call that excess VLDLP was identified as the most likely subfraction associated with peripheral arterial disease risk while large LDL particle concentration was most likely the sub fraction associated with coronary artery disease risk. And genes associated with excess VLDLP and large LDL particle concentration included canonical ApoB pathway components although gene specific effects were quite variable. And then finally Carolyn, lipoprotein A was associated with increased risk of peripheral arterial disease, independent of Apo protein B. So therefore Carolyn, I think the take home message from this study is that ApoB lowering drug targets and ApoB containing lipoprotein subfractions had really diverse associations with atherosclerotic cardiovascular disease and distinct subfraction associated genes suggested that possible differences in the role of these lipoproteins really are involved in the pathogenesis of peripheral arterial as opposed to coronary arterial disease.   Dr. Carolyn Lam: Wow. Thanks Greg. Hey, it struck me that we haven't had a quiz in a long time. Okay, but we're not going to do it now. Don't choke because this one's kind of tough. I don't think I could even answer it. What is phospholamban? Dr. Greg Hundley: Well, let me guess. I remember having this, I think. Let's just... Carolyn I do not know what phospholamban is. Dr. Carolyn Lam: Let me just tell us all. Phospholamban is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in phosphate lanvin is associated with dilated cardiomyopathy and a high prevalence of ventricular arrhythmias. But how this deletion causes dilated cardiomyopathy is still poorly understood. And there are no disease specific therapies. And hence today's paper, which comes from Dr. Karakikes and colleagues from Stanford university school of medicine. What they did is they employed human induced pluripotent stem cells and CRISPR Cas9 gene editing technologies to create an in vitro model of dilated cardiomyopathy associated with this phosphate lanvin 14 deletion mutation. Single cell RNA sequencing revealed the activation of an unfolded protein response pathway, which was also evident by significant up-regulation of marker genes in the hearts of patients with the deletion. Pharmacological and molecular modulation of this unfolded protein response pathways suggest a compensatory role in this type of dilated cardiomyopathy. Augmentation of the unfolded protein response by the small molecule BIP protein inducer X Millia rated contractile dysfunction. Dr. Greg Hundley: So Carolyn, tell me what are the clinical implications? Dr. Carolyn Lam: Well, these findings suggest a mechanistic link between proteostasis and the phospholamban 14 deletion induce pathophysiology that could be exploited to develop a therapeutic strategy for this kind of cardiomyopathy. The study also highlights how human induced pluripotent stem cells and cardiomyocyte modeling could be combined with small molecule testing as a paradigm for studying genotype, phenotype associations in heart disease. Dr. Greg Hundley: Very nice Carolyn. Well, my next paper comes to us also from the world of preclinical science. And it's from Dr. Philip Marsden from the University of Toronto. And Carolyn endothelial nitric oxide synthase or eNOS is an endothelial cell specific gene predominantly expressed in medium to large size arteries where endothelial cells experience athero-protective laminar flow with high shear stress. Now disturbed flow with lower average shear stress decreases eNOS transcription, which leads to the development of atherosclerosis especially at bifurcations and in the curvatures of arteries. So the prototypical arterial endothelial cell gene contains two distinct flow responsive SIS DNA elements in the promoter. The shear stress response element and the Kruppel-like factor or KLF element. Previous in vitro studies suggested there're positive regulatory functions on flow induce transcription of the endothelial genes, including eNOS. However, the in-vivo function of these SIS DNA elements remains unknown. Dr. Carolyn Lam: Wow. So what did these investigators do, Greg? Dr. Greg Hundley: Right. So Carolyn the authors report for the first time that the shear stress response element and the KLF elements are critical flow sensors necessary for a transcriptionally permissive hypo methylated eNOS promoter in endothelial cells under chronic shear stress in vivo. Moreover endothelial nitric oxide synthase expression is regulated by flow dependent epigenetic mechanisms, which offers novel mechanistic insight on eNOS gene regulation in atherogenesis. Dr. Carolyn Lam: Nice. Thanks Greg. Well, let's go through what else is in this week's issue. In a cardiovascular case series, Dr. Ribeiro discusses the Platypnea-Orthodeoxia Syndrome, a case of persistent hypoxemia in an elderly patient. In ECG challenge, Dr. Challenge shows a case of diffuse St. Segment elevation with idiopathic malignant ventricular arrhythmias. There's an exchange of letters between doctors Wang and Sattler regarding the article cross priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart. And there's an On My Mind article by Dr. Mullasari Sankardas on of occlusions, inclusions and exclusions time to reclassify infarctions. So interesting. Dr. Greg Hundley: Very nice, Carolyn. So I've got a couple of things in the mail bag. There is from Professor Kunfu a Research Letter entitled PTP MT-1 is required for embryonic cardio lipid biosynthesis to regulate mitochondrial morphogenesis and heart development. And then finally our own Bridget Kuhn has a cardiology news entitled vegan diets that are culturally aligned with traditional soul food gained popularity among black individuals. Well Carolyn, I can't wait to get to your feature discussion today. Dr. Carolyn Lam: Me too. Today's feature paper is about the impact of high deductible health plans on emergency department patients with non-specific chest pain and their subsequent care. I'm so pleased to have with us the first author Dr. Andrew Chou from Brigham and Women's hospital, as well as the editorialist Dr. Alexander Sandhu from Stanford university. Welcome gentlemen, please tell us about your current study. Dr. Andrew Chou: Yeah, so I think the reason we did this study was really obviously aware of the context, but also me working as an emergency decision. So anybody in the ED will now that, there's all kinds of versions of chest discomfort that comes through the ED and they always are worried about heart attack. And we do this testing kind of day in day out, it gets kind of inundated. So a lot of people have put thought into what we should do in the emergency room. We should get ECG, we should care cardiac enzymes when we're worried about it. But what really quite remains uncertain is really what to do afterwards. We get this patient, we test them, we didn't really find heart attacks, but there's a lot of uncertainty about what to do after. Do we do stress test, do we hospitalize them to get the stress test or other testing. Dr. Andrew Chou: As a result, there's a lot of variation in care. And I think partly because of that, they're kind of the shared decision making came out of that. As a part of the solution was to involve patient via, Hey, here are your risks. Let's talk about whether or not this would make sense for you to stay, get testing among other decisions. But what's always interesting to me is that even though we have this push towards having patients have kind of needing to make these decisions because of money, we don't really talk about costs and even their sort of sense of pride about, oh, we don't want to talk about costs. We just want to be the best medical treatment for you, but cost is such a reality for the patients. So, that's kind of the motivation behind getting this study done. So the way we wanted to test it was to set it up as closely as possible to run my trial but knowing that it's not really possible in the real world to do something like that. Dr. Andrew Chou: So we had to be pretty selective about who we include as a study population. So the first thing we did was we took essentially a large national insurer and their claims database. We look at only the people who enrolled in insurance products through their employer. So employers in the US can choose what type of plan they want to offer patients. And we only chose employers that offer only one type of insurance at a time within each year of a plan. So what we did is we chose people who had essentially two years of enrollment. And in the first year, they all have to have loaded up full plans. Dr. Andrew Chou: Meaning deductibles are less than $500. It's still a lot of money, but it's less compared to... The second year either they still have low deductible plan or the experimental group is going to be a group of people who employer only offer high deductible plan, which we define as having deductible greater than $1,000. So that sort of set up a control and experimental group with a similar baseline and then a different followup period of a year. And then we also did additional matching by employer characteristics and their own, the member characteristics to kind of make them as close as possible in terms of compabilities, age, as well as employer size, which we find to be a really big factor. Because large employers tend to have lower deductibles because they can risk care a lot better among their employees where a small employers like companies with five, 10 employees tend to have high deductible plans. So we use that population to compare essentially what happens after a certain company switch to kind of calculate the effect of the high deductible plan. Dr. Carolyn Lam: Great. Very novel design. But could you please tell us your results? Dr. Andrew Chou: Yeah, so we found is that once the employees from the companies that switch, there were less ED visits that ended up with a diagnosis of chest pain. This is important to bring in also the nuance here, which is that these are ED visits that effectively are not have been seen and test it. And they don't have a severe diagnosis like a heart attack or other significant cardiac issues that were found at least during the initial ED stay. And that decreased, which sort of makes the question whether or not these decreased visits or either where they just another chest visit without really other diagnoses or are they visits that actually have diagnosis. The other thing we found was also that there's a decrease in admissions from these ED visits actually. And majority of it, even though when we did our study, we actually were looking at admissions through the 30 days after these ED visits. Dr. Andrew Chou: But we found that the majority of difference is actually the admissions directly from these initial ED visits with time is just horrible. Two more things we found was that the amount of testing that was done after the ED visits, or not really consistently decreased because of high deductible, some tests really didn't have a difference and some more invasive and expensive tests did have some differences. But if you account for the decrease in the chest pain ED visits, then they're not really that notable. But the last finding, which perhaps is the most interesting of which is that there seems to be an increase in heart attack diagnosis and admissions after these visits for chest pain and our statistics for the entire study population actually wasn't significant. But we decided to look at the subgroup patients from poor communities who presumably have lower income and found that the same findings in this group was actually statistically consistent and so we felt comfortable reporting that. So I think that was probably the most interesting finding from our study. Dr. Carolyn Lam: Right. Thanks Andrew. Alex, I have to bring you in here. I really love the editorial love that you said to go or not to go as the title. But could you put these findings in context, please? Dr. Alexander Sandhu: Yes. Happy to and thank you for having me. I think studies like this study by Andrew and colleagues are incredibly important as we make health policy decisions that have large impacts on clinical decision-making for both patients and clinicians. It's important that we study them to understand how they impact patient decision-making clinical outcomes and costs, because obviously that can have important ramifications for future design at the end detecting unintended consequences. I think this study adds to a large body of work done by Andrew and his colleagues, really helping us to understand the implications of high deductible health plans on patient decision-making and subsequent outcomes. This is an incredibly important topic because of the proliferation of high deductible health plans over time and then potentially since the advent of the Affordable Care Act with fixed premiums leading to more and more cost sharing for patients. And it's really critical that we understand how that cost sharing impacts patients. Dr. Alexander Sandhu: And I think that chest pain is a wonderful test because chest pain can be something very serious. It's almost universal that when patients have acute onset chest pain, that a clinician asks them to go to the emergency department for further evaluation. However, we also have a large body of evidence that suggests that the large majority of chest pain episodes are not serious and don't end up needing additional treatment. So it's an area that I think both you could imagine decreased utilization once you applied cost sharing to patients. But what were you very much worried about the unintended consequences of people not going to the emergency department, if it's a serious condition. I think this was a well-designed quasi experimental analysis to look at the lower risk, but majority of episodes of chest pain where they're non-specific and not resulting in acute coronary syndrome and to try to demonstrate it that the high deductible health plans do lead to reductions in those episodes. Dr. Alexander Sandhu: I think as Andrew said, one of the most fascinating findings was this increase in acute MI's it was consistently significant amongst the low-income patients, but was not related to patients that were discharged because of potentially the effects of the high deductible and then came back in with acute MI's but were actually acute MI's during the initial admission. I was wondering if Andrew could maybe both explain that nuance a little bit more, which you get into the discussion of that paper, and then also walk us through maybe some thoughts that you and your study team had for causes for that potential finding. Dr. Andrew Chou: Yeah, absolutely. Thanks for raising that. So I think going into it initially, our hypothesis was really that, but when we first saw it, our initial thought was that, oh, maybe perhaps after they're discharged, they're supposed to get testing and patients or then follow up with their doctors. So they have increased poor outcomes. And so after that thought, that's when we did the kind of subgroup analysis looking at just patients who were discharged versus those who were admitted when they were diagnosed with chest pain at their initial ED visits. And exactly what we found is that the difference is really among people who were admitted initially, which is surprising to us. So I think what that signals to us is that our initial thought was not correct in the sense that this is not really a result of lack of followup or didn't intend to the testing that they were scheduled or didn't go see their doctor afterwards. But really like patients who are showing up in the ED already are more prone to perhaps having a heart attack. Dr. Andrew Chou: And so it really points to which is what you mentioned at your program, which we totally agree as well, that more upstream factors is affecting this. Could it be that they don't tend to take their medications as they should, or they didn't go to their doctors for checkups as they should, or they could have had earlier identification of heart problems if they have more perhaps milder symptoms beforehand until before the ED visits that could have presented certain things. So, that's hard to say. I do think that there is a... One of my mentors in this paper, Dr. Wareham, who has done a ton of work in the space of high deductible plan with kind of chronic disease management, they have definitely shown a lot of differences when patients have higher cost sharing. They'd certainly defer a lot of carriers, especially in diabetics have more complications and it might be a similar scenario here that which would make the most sense and fits the best with our findings here. Dr. Carolyn Lam: So that's a great question Alex and great insight Andrew. I think at this point, I need to ask you both. So what overall do you think is the clinical implication or there'd be any practical next step that you think should follow from this? Maybe I'll let Andrew start and then Alex finish? Dr. Andrew Chou: Sure. Thank you. I think there's kind of... I think two aspects to this one is really broader policy changes. I think if anything, it's quite uncertain whether or not the reduction in ED visits for chest pain is something detrimental. It's unsure whether or not the reduce admission is detrimental. But what is certain is that especially in lower income population certainly feels the higher out-of-pocket costs a lot more. And if there is an unintended consequence, it will certainly be magnified in this population. And in fact, I think a couple of past studies who having compared really high income versus low income population has found that really, high income patients tend to do okay and they're able to pick and choose appropriately of type of care they need. Whereas low-income patients tend to have really unanticipated changes. So, really trying to minimize the impact for low-income patients is going to be important policy direction. Dr. Andrew Chou: And there are a number of ways of doing it. I think there certainly is an increasing trend for companies to fund the health savings account, which is actually a tax deferred almost like investment accounts or certain fund to help them offset some of their healthcare out-of-pocket costs. But the other aspect of it, which I think is all a bit harder to push for is really for employers and insurance to just keeping their account patient's income when they're kind of pushing forward products for a high deductible plan. So low-income patients should just not have quite as big of a deductible as the high income earners do. But a different aspect it's really clinically for clinicians. It's tough because I think insurance put this forward because they want to influence patient decisions before they even see the clinician. But after they decide to come visit clinician, I think the clinician should be aware of the financial reality for the patient when making these decisions. Dr. Andrew Chou: But it's really hard for me to think about whether or not this is going to be a good thing for the patient or not. And one of the biggest concerns for really my colleagues in the department is really whether or not if we are really talking poor patients out of certain care by reviewing their financial reality with them and by through that are we essentially discriminating against other patients. So that's really a big unknown. I think that's definitely an area that we should definitely heavily invest in research because we're just pushing forward with price discussion for care to encourage price discussion at the clinic here without really knowing what's going to happen. Dr. Carolyn Lam: Yeah. Wow. Alex? Dr. Alexander Sandhu: Yeah, I definitely agree with Andrew. I think if we want to make decisions based on cost and we want patients to make those decisions and we as clinicians, obviously should be helping them. We need more transparency around costs, current deductible status, and that has to be available at the point of care so it actually can be integrated in decision-making. But I think that's likely not enough. I mean, even for clinicians, it's hard to determine how clinically necessary it is to get emergency evaluation before you see the patient when you get a phone call. So I think, if it's hard for clinicians with all of our years of experience, it's hard to understand how we can really expect that from our patients. Dr. Alexander Sandhu: I wholly agree with Andrew that I think a critical step is it's going to be important to reduce the risk of cost sharing for low-income patients with a number of potential interventions to do that, which I think are the real policy implications here. And then more generally, I think we should make sure that deductibles aren't discouraging utilization of high value cost effective intervention. There are currently safeguards in the Affordable Care Act about that. But I think we need to think about those closely and probably expand that so we don't see high deductible health plans leading to lower stat rates or worse diabetes prevention. Dr. Carolyn Lam: Wow. Words of wisdom. I just cannot thank you both enough for publishing such a beautiful paper, important findings, as well as just a very lovely editorial in Circulation. Thank you. Learned a lot. I'm sure the audience did too. Please remember you're listening to Circulation on the Run. Please tune in again next week with Greg and I. Dr. Greg Hundley: This program is copyright of the American heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more visit ahajournals.org.  

    Circulation July 27, 2021 Issue

    Play Episode Listen Later Jul 26, 2021 25:37

    This week's episode features author Aaron Baggish and Associate Editor & Editorialist Satyam "Tom" Sarma as they discuss the article "SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes." 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 from VCU health in Richmond, Virginia. Dr. Carolyn Lam: Greg, this feature discussion is just so relevant to our current times. It talks about SARS-CoV-2 cardiac involvement in young competitive athletes. Oh, one that I'm sure we're all dying to get to. Very important. But first, let's tell you what's in this week's issue. Greg, you want to go first? Dr. Greg Hundley: You bet, Carolyn. I'm going to grab a cup of coffee, and we're going to dive into the world of preclinical science. Our first paper comes to us from Professor Naftali Kaminski from Yale University. Carolyn, these investigators reprocessed human control single-cell RNA-sequencing, or scRNA sequence data from six datasets to provide a reference atlas of human lung endothelial cells to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium. Also, the signaling network between different lung cell types was studied. Dr. Carolyn Lam: Wow. Okay. So what did they find, Greg? Dr. Greg Hundley: Six lung single-cell RNA-sequencing datasets were reanalyzed and annotated to identify over 15,000 vascular endothelial cells from 73 individuals. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous endothelial cells, the co-authors found two previously indistinguishable populations. Pulmonary venous endothelial cells, called COL15A1neg localized to the lung parenchyma and systemic venous endothelial cells, COL1581positive localized to the airways and visceral pleura. Dr. Greg Hundley: Now, among capillary endothelium cells, the authors confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1, and TBXX2 and general capillary endothelial cells. The authors confirmed that all six endothelial cell types, including the systemic venous endothelial cells and aerocytes, are present in mice and identified endothelial marker genes conserved in both humans and mice. Dr. Greg Hundley: So Carolyn, I'm going to take a question I bet you're getting ready to ask. What are the clinical implications of this research? Well, mainly that understanding the lung endothelial diversity is crucially important to identify new therapeutic approaches for vascular diseases such as pulmonary hypertension. Dr. Carolyn Lam: Wow. That was interesting, Greg. Thank you. I've got another one from basic science world as well, and this one talks about the initial functional characterization of an exercise-induced cardiac physiological hypertrophy associated novel long non-coding RNA or LncRNA. Dr. Greg Hundley: Okay, Carolyn. Quick quiz. Can you remind us what these long-coding RNAs are? Dr. Carolyn Lam: Ha. Sure. So long non-coding RNAs or LncRNA refers to RNAs that are longer than 200 nucleotides and lack the potential to encode proteins, but have still been closely related to the occurrence and development of many diseases. Dr. Carolyn Lam: The current paper comes from co-corresponding authors, Dr. Li from the First Affiliated Hospital of Nanjing Medical University and Dr. Xiao from Shanghai University. They identified a LncRNA in the heart named cardiac physiological hypertrophy associated regulator, or CPhar. This was increased following exercise training and was necessary for exercise-induced cardiac growth. In neonatal mouse cardiomyocytes, over expression of this LncRNA induced an increase in these cardiomyocytes' size and expression of proliferation markers while inhibition of the LncRNA reduced these neonatal mouse cardiomyocytes' size and the expression of proliferative markers. Over expression of the LncRNA led to a reduction in oxygen glucose deprivation reperfusion-induced cardiomyocyte apoptosis, while LncRNA knockdown aggravated the apoptosis. Dr. Carolyn Lam: In vivo over expression of that LncRNA prevented myocardial ischemia reperfusion injury and improved cardiac function. So mechanistically though, the transcription factor, ATF7, acted as the functional downstream effector of this cardiac physiological hypertrophy associated regulator, the LncRNA. Dr. Carolyn Lam: Now Greg, following your example, I'm going to ask what are the clinical implications and tell you. So these results provide new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of this LncRNA known as cardiac physiological hypertrophy associated regulator in the heart. It also expanded our knowledge and understanding of the functions and fundamental mechanisms of LncRNAs in general. Dr. Greg Hundley: Wow, Carolyn. Beautifully described. Well, my next paper comes to us from the world of clinical science and really it's kind of something that's going to get into spending. It comes to us from Dr. Brandon Bellows from Columbia University. Dr. Greg Hundley: So Carolyn, spending on cardiovascular disease and cardiovascular risk factors, in total cardiovascular spending, accounts for a significant portion of overall US healthcare spending. The author's objective was to describe US adult cardiovascular spending patterns in 2016 and changes from 1996 to 2016, and look at the factors associated with these changes over time. Dr. Carolyn Lam: Wow. Okay. So were the authors are viewing time-dependent changes in cardiovascular spending. Is that it? What did they find? Dr. Greg Hundley: Absolutely Carolyn. So a bunch of data. Just kind of some interesting facts here. So let's work through them. Adult cardiovascular spending increased from 212 billion in 1996 to 320 billion in 2016, a period when the US population increased by over 52 million people and the median age increased from 33 to 36.9 years. Dr. Greg Hundley: Next, over this period, public insurance was responsible for the majority of cardiovascular spending at 54% followed by private insurance at 37% and out-of-pocket spending at 9%. Dr. Greg Hundley: Next, health services for ischemic heart disease at about 80 billion and hypertension, 71 billion, led to the most spending in 2016. Dr. Greg Hundley: Next, increased spending between 1996 and 2016 was primarily driven by treatment of hypertension, hyperlipidemia, and atrial fibrillation flutter on which spending rose by $42 billion, $18 billion and $16 billion respectively. Increasing service price and intensity alone were associated with 51% or 88 billion, and cardiovascular spending increased from 1996 through 2016. Whereas, changes in disease prevalence was associated with a 37% or $36 billion spending reduction over the same period after taking into account population growth and population aging. Dr. Greg Hundley: So in summary, Carolyn, US adult cardiovascular spending increased by about $100 billion from 1996 to 2016. Maybe policies tailored to control service price and intensity and preferentially reimburse higher quality care, perhaps that could help counteract future spending increases due to population aging and growth. Dr. Carolyn Lam: Oh, wow. Those are staggering numbers. Thanks Greg. Now let's go through what else is in this week's issue. There's an exchange of letters between doctors Mehmood and Houser regarding the article, Cardiac Remodeling During Pregnancy with Metabolic Syndrome: A Prologue of Pathological Remodeling. There's an ECG challenge by Dr. Real on an unusual call from the urology ward. There's also a Research Letter from Dr. Molkentin on cardiac cell therapy failing to rejuvenate the chronically scarred rodent heart. And finally a Special Report by Dr. Althouse on Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report from the American Heart Association. Dr. Greg Hundley: Great, Carolyn, and I've got a Perspective piece entitled, Intravenous Iron Therapy in Heart Failure with Reduced Ejection Fraction: Tackling the Deficiency. It's from Professor Ardehali. Dr. Greg Hundley: Well, Carolyn, how about we get on to that feature discussion and learn more about SARS-CoV-2 in young competitive athletes. Dr. Carolyn Lam: Ooh, let's go. In our current COVID-19 pandemic a huge question is, does cardiac involvement in athletes with COVID-19 preclude their further participation in sports? What is their involvement after they've recovered from COVID-19? Guess what? Today's feature discussion is really hitting the spot with this question. So pleased to have with us the corresponding author of the feature paper, Dr. Aaron Baggish from Massachusetts General Hospital, as well as Dr. Satyam Sarma also known as Tom Sarma, our dear Associate Editor from UT Southwestern, who is also an editorialist for today's paper. So welcome Aaron and Tom. Aaron, could you start us off by describing your study and what you found? Dr. Aaron Baggish: Sure. So just very briefly, some historical context. As everyone is quite aware, when we first started seeing COVID-19 in the hospital, there was a lot of concern about what the virus did to the hearts in people that were sick enough to be hospitalized. Those of us in the sports cardiology community were quite concerned that when young athletes that developed COVID-19 infection got sick and then returned to sport, that we'd be seeing the adverse events associated with cardiac involvement. So that was the impetus to start the ORCCA Registry, which was really an opportunity to try to capture the large-scale experience with collegiate athletes returning to sport after COVID-19 infection. Indeed, with roughly 19,000 student athletes across 42 universities, there were approximately 3,000 that developed COVID-19 infection and then went through some form of cardiac screening prior to return to play. The registry was really about telling that story of what we found and what we think the implications are. Dr. Carolyn Lam: Aaron, I mean, first of all, more than 19,000 athletes recruited in just ... What was it? September 1st to December 31, 2020? How did you accomplish this amazing registry so quickly? That's amazing. Dr. Aaron Baggish: I need to acknowledge the fact that this was an incredible team effort. I was joined and continue to be joined in this by my co-PIs, Dr. Jon Drezner and Kim Harmon, who are sports medicine physicians out of the Seattle area, and the combination of cardiology, expertise and sports medicine expertise really able to pull in many of the large universities and colleges around the country, including most of the Power Five schools to participate in this registry. Dr. Aaron Baggish: In short order, team physicians from all these schools understood the importance of this work and agreed to partner with us to work very hard to enroll their student athletes and to provide us with the information we needed. Dr. Carolyn Lam: Incredible. But with the foresight, congratulations, this in and of itself is amazing. Now, could you please tell us what you found? Dr. Aaron Baggish: Sure. So we found that indeed, as we expected, that these student athletes were undergoing a fair bit of cardiac testing prior to being allowed to return to sport, and that there was variability in terms of what type of testing they were getting. The majority of schools were following what at that point were the recommendations, which were do, what we call the cardiac triad testing, which includes an echocardiogram, a high-sensitivity troponin, and an ECG and to use that information to either clear athletes or send them through further clinically indicated tests. A small number of early adopters had decided to do mandatory cardiac MRIs. So within that, we were able to understand what the prevalence, if you will, of cardiac involvement in these COVID-19 student athletes looked like, and it varied as a function of what type of tests people were doing. Dr. Carolyn Lam: And? Give us a sneak peek. Dr. Aaron Baggish: As people would expect, the more sensitive tests you do, the more abnormalities you detect. So among the schools that were using a mandatory cardiac MRI approach, there was a 3% prevalence, if you will, of either definitive, probable or possible COVID-19 cardiac involvement. When schools were following the triad testing first followed by clinically indicated CMR that prevalence was much less. It was approximately 0.5 or 0.6%. So I would emphasize that on the whole, regardless of which test was being used, that the involvement was at a much lower rate than we expected based on what we saw early in the hospitalized patient experience. So I think it's a very good news story. Dr. Carolyn Lam: Indeed. That's exactly, I think the title almost of Tom's editorial. Tom, could I bring you in here, please? Could you give us the context of this and then tell us what as editors we thought of the paper when it kind of reached out doors at Circulation? Dr. Satyam “Tom” Sarma: Sure. No, this was, I actually remember almost exactly when I was asked to handle this paper from an editorial standpoint. Joe texted me, Joe, our editor-in-chief texted me ... I think, the night, actually it was a Friday night I think ... That we had a really important paper, would you be able to take care of it on an expedited basis? I said, "Of course." So took a look at it over the weekend, and it's one of those papers when you're reading it, you almost wish you had a time machine because you realize if we had known this information eight, nine, 10, 11 months ago, it would have totally changed how we handle the pandemic from an athlete and young person standpoint. So from that aspect, I thought this is obviously a very high impact paper. Dr. Satyam “Tom” Sarma: Which then led me to the second challenge is finding the right reviewers for this paper because obviously this is a very controversial topic. We wanted to make sure we had the best reviewers we can get. The challenge, unfortunately, was that a lot of my usual go-to reviewers were actually members of the ORCCA Registry. So there were some issues with conflict of interest there, and so from a reviewer standpoint, I looked to sort of leaders in the field who had done something similar. The first thing that came to mind was really how the field has handled ECG screenings for our young athletes. I think there's, again, a perspective there that I think is very similar to how do you handle patients or young athletes with COVID and then how do you emphasize shared decision making? So from that standpoint, I had a narrow list of experts in shared decision making in sports cardiology, and really leaned on them to help guide us through the process because this is a complex paper. Dr. Satyam “Tom” Sarma: I think their feedback was instrumental in really helping to kind of distill the message, to kind of phrase things in a way that allowed the message to be easily digested by both the lay media, but more importantly, by sports trainers and athletic directors around the country. From that standpoint we really work hard and again, really thank you to Aaron and Jonathan on this manuscript because they worked so hard with our reviewers. They were incredibly responsive to almost every review comment. From that standpoint, I think the end result was amazing to really see it in final format. Dr. Carolyn Lam: I love that behind-the-scenes look. Thank you so much, Tom. What is the strong clinical implication of this? If you have questions for Aaron, please go ahead. Dr. Satyam “Tom” Sarma: Sure. No, I think the biggest thing for us as editors and sort of from the public health impact was, as Aaron mentioned, some schools have unlimited resources to really throw as much money as they can at the problem or what they think is the best approach to the problem. Again, when you have unlimited resources, you can get the "best tests." I think, unfortunately not every school in this country, both from a collegiate or high school level, has a capacity and more importantly, around the world. That's a really important limiting factor. Dr. Satyam “Tom” Sarma: Is there a way to distill the algorithm in a way that's both safe for the athletes, but more importantly is feasible for most schools? For us, that was the most important public health message was really to get that out there. The second of course, was that thinking back to last summer, just how many COVID myocarditis papers we handled in Circulation. Looking back with the again, in the heat of the battle, things are always challenging, but just to sort of see how the pendulum shifted in such a 180 degree sort of manner. So that also I think was important to get out there as well. Dr. Carolyn Lam: Yeah. And exactly why this paper is so important. So thank you once again for publishing it with Circulation. Tom though ... Okay. I mean, not to underestimate the MRI findings and so on. I think you had a question for Aaron in relation to that? Dr. Satyam “Tom” Sarma: I do. One of the challenges, again, being on the myocardial side is that we're not always experts in the papers we're assigned, and it's obviously been an incredible learning process. For me, I was hoping to pick your brain a little bit about the MRIs and sort of how you think the field will evolve from a sports cardiology standpoint. Especially as scanners get more powerful, as scanners get more sensitive, the challenges I think the field's going to have is really detecting the tiniest fleck of an abnormality. Dr. Satyam “Tom” Sarma: I think the context here is really the recent paper out of the Big 10 where they MRI'd, I believe, everyone in that registry ... I want to say it was over 2,000 athletes. Just out of curiosity, how was that handled, again, amongst your co-authors in deciding how best to present the MRI data? I like how you use the probabilistic language of it's either definite, probable or possible. How do you see that sort of progressing in terms of is that something practical that can be used by sports trainers and sports medicine staff to help restratify your athletes or athletes? Dr. Aaron Baggish: Tom, there's so much packed into that question. Let me try to unpack it piece by piece. So first off in our registry, there were a few schools that were early adopters in mandatory CMR screening, and so we wanted to very much responsibly report that. Again, there was about a 3% prevalence of something being abnormal with the myocardium based on the scans. We also realized that not all abnormalities were created equal, and that's why we did come up with that definitive, possible, probable nomenclature to really capture the fact that there were a few people that looked like they had overt myocarditis. But the vast majority had non-specific findings that those of us as clinicians pre-COVID would not have considered myocarditis. Dr. Aaron Baggish: The issue with MRI is a complicated one. The way I like to think about this as, as you mentioned earlier, is to go back to the historical experience we had with ECG screening in which doing that before we understood how to use it as a screening tool caused more problems than it solved. Dr. Aaron Baggish: It was really back in the mid-2000s when the Italians published their first ECG screening paper that the Americans got interested in it. What we learned is that if you used ECG, and this applies to MR too, without having good normative data, without understanding the cost implications, without having the experts prepared to interpret the test and deal with the downstream findings, that you're just not ready for prime time. Dr. Aaron Baggish: While I think the use of MRI as a screening technique during COVID was done with the best of intentions, I think the Big 10 paper, which is a very important dataset in this discussion, highlighted why MRI is just simply not a useful screening tool right now. If you look across their schools, they had tremendously variable rates of cardiac involvement, which is not a function of pathobiology. This virus is not different in Virginia than it is in Tennessee than it is in Wisconsin. It's just simply that people are using the tool in different ways and coming up with different findings. What we're now seeing clinically is that all these MRIs are finding a lot of stuff that either we don't want to care about or we don't want to know, and we're stuck dealing with it. So a challenge ahead of us, for sure. Dr. Satyam “Tom” Sarma: No, I think that's a really important point, Aaron. I think looking back even from a clinical standpoint in those, didn't not necessarily look at athletes, I think what you bring up is really important. The cognitive bias. Find something abnormal. I do wonder if you could talk a little bit about ... One of the other concerns we had behind the scenes was if you know an athlete, if you're an MRI reader and you know an athlete or the scan in front of you says 19-year-old athlete with COVID, can you talk a little bit about the cognitive biases that kind of go into sort of assuming either the worst case scenario, especially with athletes, because again, these are young, robust, healthy people who may or may not be on TV or in a very public format. How do you handle that as a sports cardiology in general, just kind of overcoming the cognitive bias, both from a public policy standpoint, but also from a lay public standpoint? Dr. Aaron Baggish: Yeah. So I think bias is such an interesting word to me because bias has a negative connotation, but bias actually also has some positive attributes associated with it. Bias really pushes people to be, in this situation, to be conservative and to try to do what they think is best. Dr. Aaron Baggish: But what I think it boils down to is going back to a very simple tenet and that's understanding the pre-test probability of disease. So when we interpret imaging data or exercise testing data, it always goes back to the question of why did this person get the test done in the first hand and what is our pre-test probability of finding something wrong? I think what we've learned through the COVID pandemic is that just simply having COVID does not equate with a high pre-test probability of having myocarditis in this young population. That it's really the kids that present, and these are the rare few and far between, that present with clinical findings that any doctor would think of as being consistent with myocarditis, where the scan is really helpful. The vast majority of time it's just simply not that case. Dr. Satyam “Tom” Sarma: No, I agree. I think that's always the challenge as well, too clinically as well too, with the diagnostic creep of you get one test that's kind of abnormal and the next thing you know, you're doing a cardiac biopsy and trying to figure out how you got to where you got to. Dr. Satyam “Tom” Sarma: I wanted to circle back to Carolyn's comment. I guess obviously COVID kind of really was the dominant health story over the last 12 to 14 months. Has there been a similar rash, in other words, I'm thinking back to H5N1 or some other pandemics in the past, was there a similar concern historically from the sports cardiology community with those viral outbreaks? Dr. Aaron Baggish: No. Not to my knowledge, and that's simply because there wasn't as much of an experience with hospitalized patients in the US in those prior pandemics. Again, our concern in sports cardiology world really stemmed from a very different population than the one we deal with on a daily basis. I think we learned that, although we thought that was a well-intending way to approach it, that it turned out to be an overreaction. Dr. Aaron Baggish: Before we end, I want to return to Tom's comments about the process and just share with the listeners what a satisfying process this was as an author. Having been through the peer review process, many hundreds of times with different journals, I don't remember one that was as satisfying nor one that led to as high quality of paper based on the feedback we got from the reviewers. So very much appreciative. Dr. Aaron Baggish: I also want to acknowledge the American Heart Association that has become a long-term partner in this effort. As we move out of the pandemic, the ORCCA Registry will be pivoting to really capture what happens to young athletes that are diagnosed with genetic and congenital forms of heart disease. We're very appreciative that the AHA has agreed to partner with us on this. Dr. Carolyn Lam: Aw, my goodness. Thank you so much, Aaron and Tom, for this incredible discussion. I really want to end with, if I may Tom, citing your editorial. I love the way you ended it by saying, "As Nelson Mandela said, 'Sports has the power to change the world. It has the power to inspire. It has the power to unite people in a way that little else does.'" We got seriously scared with COVID-19, but this paper is just so important in providing some reassurance that there has not been a single case of cardiac complication to date, documented to be clearly related to COVID-19 in this population. It's a real testament to the hard work that you've put in. So thank you. Thank you very much for this paper. For all the effort. Thank you both for being here to discuss this. Dr. Carolyn Lam: Well, audience, you've been listening to Circulation on the Run. Thanks for joining us today, and don't forget to join us again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation July 20, 2021 Issue

    Play Episode Listen Later Jul 19, 2021 19:06

    This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction." 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, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation. Dr. Carolyn Lam: Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites. Dr. Greg Hundley: Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically? Dr. Carolyn Lam: Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.   Dr. Greg Hundley: Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5. Dr. Carolyn Lam: Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study. Dr. Greg Hundley: Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility. Dr. Carolyn Lam: Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us? Dr. Greg Hundley: Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder. Dr. Carolyn Lam: Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity. Dr. Greg Hundley: Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?   Dr. Carolyn Lam: Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region. Dr. Greg Hundley: Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure. Dr. Carolyn Lam: And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address? Dr. Kieran Docherty: Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care. Dr. Kieran Docherty: Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction. Dr. Greg Hundley: Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study? Dr. Kieran Docherty: Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization. Dr. Greg Hundley: Very good. And what did you find? Dr. Kieran Docherty: So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I. Dr. Greg Hundley: Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender? Dr. Kieran Docherty: So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels. Dr. Greg Hundley: Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan? Dr. Torbjørn Omland: So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study. Dr. Torbjørn Omland: And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think. Dr. Greg Hundley: Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research? Dr. Kieran Docherty: As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest. Dr. Greg Hundley: Very good. And Torbjørn , do you have anything to add? Dr. Kieran Docherty: Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan Dr. Greg Hundley: Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland. Dr. Greg Hundley: And for all of you, we wish you a great week, and we hope to catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.  

    Circulation July 13, 2021 Issue

    Play Episode Listen Later Jul 12, 2021 27:32

    This week is a Double Feature Circulation on the Run. Please join author Patrick Serruys, editorialist Shamir Mehta, and Associate Editor Emmanouil Brilakis as they discuss their article "Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study" and editorial "Achieving complete revascularization for multi-vessel coronary artery disease." Then, please join author G. Michael Felker, and Associate Editor Mark Link as they discuss the Research Letter "Implantable-Cardioverter-Defibrillator Eligibility after Initiation of Sacubitril/valsartan in Chronic Heart Failure: Insights from PROVE-HF." 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, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: So guess what, Greg, we have another double feature this week. First, we need to talk about completeness of revascularization in patients with three-vessel disease or left main coronary artery disease. Always a question, and this time we've got insights from the SYNTAX Extended Survival Study. And then, the next feature talks about implantable cardioverter defibrillator eligibility after initiation of sacubitril/valsartan in heart failure, and these are insights from PROVE-HF. But before we get to that, I suggest, as I pick up my coffee, could you tell us what some of the papers you've spotted? Dr. Greg Hundley: Thanks so much, Carolyn. Sure. So I'm going to start from the world of preclinical science, and the paper comes to us from Dr. Vadim Fedorov from The Ohio State University Wexner Medical Center. Carolyn, up to 50% of the adult human sinoatrial node is composed of dense connective tissue, and cardiac diseases, including heart failure might further increase fibrosis within the sinoatrial node pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atrium. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inheritantly fibrotic sinoatrial node environment. Dr. Carolyn Lam: That's true. So what did these authors do? Dr. Greg Hundley: Right, Carolyn. So these authors found that increased sinoatrial node-specific fibrosis, with presence of myofibroblasts and CILP-1, and periostin-positive interstitial fibrosis only in heart failure versus non-heart failure human hearts. And comprehensive proteo-transcriptomic profiles of sinoatrial node fibroblasts identified up-regulation of genes and proteins promoting stiffer sinoatrial node extracellular matrix in heart failure hearts. Dr. Greg Hundley: And next, fibroblast specific profiles generated by the team's proteo-transcriptomic analyses of the human sinoatrial node provided a comprehensive framework for future studies to investigate the role of sinoatrial node-specific fibrosis in cardiac rhythm regulation and arrhythmias. So really very interesting preclinical science, Carolyn. Dr. Carolyn Lam: Yeah. Makes me think of arrhythmias and heart failure very differently, too. Thanks Greg. Well, for my next paper, we know that dietary high salt is bad for us. It's associated with mortality and morbidity. Serum sodium can accumulate at sites of inflammation and affect the function of both innate and adaptive immune cells. But how do changes in extracellular sodium actually affect mononuclear phagocytes? Dr. Greg Hundley: Ah. Carolyn, this is really an interesting question, but how would you even set this up or go about investigating this? Dr. Carolyn Lam: Ah, good question, Greg, and these investigators are really smart. So first, let me tell you about the co-corresponding authors, Dr. Kempa from Berlin Institute of Medical Systems Biology at Max Delbrück Center for Molecular Medicine in the Helmholtz Association, and Dr. Müller from the Experimental and Clinical Research Center in Berlin, Germany. Now, guess what they did? They used sea horse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays to characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under high salt, in vitro. Dr. Carolyn Lam: And what they found was a disturbance of mitochondrial respiration as the initial step by which high salt mechanistically influenced immune cell function. While these functional changes may help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory cardiovascular disease. A further potential implication is that mitochondrial functional analysis in monocytes and other immune cells upon a high-salt challenge, could serve as a test for salt sensitivity of immune cells in future. Dr. Greg Hundley: Oh wow, Carolyn. We don't often think about salt sensitivity in immune cells. Really informative research. Well, my next paper comes to us from the world of clinical science, and it's from Professor Derek Chew, from the school of medicine, at Flinders University, the Department of Cardiovascular Medicine at Flinders Medical Center. Dr. Greg Hundley: Carolyn, this paper reports results from a multicenter prospective, patient-level, randomized comparison of care informed by unmasked zero to one-hour, high-sensitivity troponin-T protocol, reported as less than five nanograms per liter versus standard-practice, masked high-sensitivity, cardiac troponin T-testing, reported at a value of less than 29 nanograms per liter, assessed at zero to three hours, and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. And the primary endpoint was timed to all-cause death or myocardial infarction. Dr. Carolyn Lam: Interesting experiment there. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So, while the use of the zero to one-hour, high-sensitivity, cardiac troponin T-protocol expedited discharge of patients presenting to the emergency department, with a low-event rate at 30 days, an increase in death or myocardial infarction was observed at one year in those with unmasked, high-sensitivity, cardiac troponin T-concentrations. Next, among those with intermediate cardiac troponin concentrations, where care was informed by zero to one-hour unmasked, high-sensitivity, cardiac troponin T-protocols, increases in revascularization and reductions in noninvasive cardiac investigation were observed. Dr. Greg Hundley: So these changes in practice that result from the use of rapid-discharge protocols, may be potentially associated with an increase in all-cause death or MI, by 12 months among those low-level troponin elevations. So in summary, Carolyn, this research found that unmasked, high-sensitivity, cardiac troponin T-reporting, deployed within a zero to one hour protocol, did not reduce ischemic events over a 12-month followup, and changes in practice associated with the implementation of this protocol may be associated with an increase in death in MI among those with newly-identified troponin elevations. Dr. Carolyn Lam: Wow, that's very, very interesting and clinically important. Thanks, Greg. Well, let's do a little bit of a tour around what else is available in this week's issue, shall we? I want to talk about a Special Report that I was so privileged to contribute to and was led by Dr. Gemma Figtree. And it's a Call to Action for new global approaches to cardiovascular disease drug solutions. There's also a Research Letter by Dr. Solomon on the prognostic value of natriuretic peptides and cardiac troponins in COVID-19. Dr. Greg Hundley: Great, Carolyn. So I'm going to tell you about an exchange of letters between Professors Correia and Chaitman regarding a prior published article, entitled “Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.” Also, there's a very nice Case Series from Professor Shapira entitled, “In the Heart of the Ancient Silk Road: Fever of Unknown Origin, Right Ventricular Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has a very nice On My Mind piece From Studying Heart Disease and Cancer Simultaneously to Reverse Cardio Oncology. Dr. Carolyn Lam: So interesting. Well, let's get onto our double feature, Greg. Dr. Greg Hundley: Absolutely. Well, listeners, we are here for our first feature discussion today and we have with us really, an very interesting panel. First, Dr. Patrick Serruys from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster University in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute. Welcome gentlemen. Patrick, we're going to start with you. Could you describe for us the hypothesis that you wanted to test. Dr. Patrick Serruys: Yeah. The hypothesis was that if the surgeon and the interventional cardiologist doesn't achieve a complete revascularization, there will be a penalty. The penalty is we look at the all-cause mortality because that's really a unbiased assessment. Dr. Greg Hundley: And then, tell us the design of your study for us. Dr. Patrick Serruys: So SYNTAXES, which is the extension of the SYNTAX study up to 10 years, had 1,800 patient, and then basically, we took a threshold of eight. If you have a residual SYNTAX for more than eight, you have an incomplete revascularization. We stratify for less than four, four to eight, and above eight. And clearly, the group above eight has a bad outcome, not only with PCI, but also with surgery. The score is a little bit more difficult to establish in surgery, because you don't have an angiography immediately after the procedure. Dr. Patrick Serruys: And then as I said, if you do a complete revascularization by PCI, and that's basically a residual SYNTAX score of zero, then you have an outcome which is comparable to the surgical outcome. What is interesting, if you have above eight, you have to think twice and maybe refer that patient to surgery. It's difficult to anticipate, but of course, bifurcation, total chronic occlusion, small vessel, is the three major reason to have a residual SYNTAX score. Dr. Greg Hundley: Very good. So Shamir, could you help us put these results in context with other studies that have been performed in this sphere of research? Dr. Shamir Mehta: Yeah, sure. I would be happy to. So the SYNTAX study was unique in that they were able to look at the degree of revascularization, and the key finding that PCI was comparable to CABG surgery in terms of outcomes, when complete revascularization was able to be achieved, is a very intriguing finding. In cases where PCI was not able to achieve complete revascularization, it was clear superiority of CABG surgery. And so the question is in this study, this comparison, which is a non-randomized comparison, whether or not there's any type of external validity for these findings. Dr. Shamir Mehta: And, in fact there is. It's a timely publication, because recently we had the 4,000-patient multinational COMPLETE trial, which looked at the issue of complete revascularization versus incomplete revascularization in patients with STEMI, and found that complete revascularization with multi-vessel PCI, in appropriately-chosen patients, reduced hard clinical outcomes, including the composite of cardiac mortality and/or current myocardial infarction. And it reduces it quite substantially, by about 26%, and it's a highly-significant benefit. Dr. Shamir Mehta: I think the caveats to this finding are important, though. Because in the COMPLETE trial, patients were not eligible for recruitment, unless the interventional cardiologists felt that all of the lesions were amenable to PCI. So complete revascularization had to be achieved in the trial. And in fact, over 90% of patients in the trial were able to achieve complete revascularization. So that's absolutely key, and that brings up the importance of having a heart team in evaluating these patients. Dr. Shamir Mehta: The second point is that the SYNTAX score, Patrick had referred to was relatively low in the trial, it was only 4.6. Meaning that the lesions that were attempted were relatively straightforward, meaning that there was a high probability of achieving complete revascularization. So again, I think we're starting to see from the randomized trials and from the observational studies, the types of patients that may be suitable for PCI versus suitable for CABG surgery. Dr. Greg Hundley: Very nice. Well, Manos, Shamir, what an outstanding description in helping us put this paper in context with other research in this space. Manos, I know you see a number of papers come across your desk. Also, for you, what attracted you to this particular study? Dr. Emmanouil (Manos) Brilakis: Yeah, thank you, Greg. And again, congratulations to Patrick for a phenomenal study. I think the main strength of this analysis is the clinical relevance. I think everyone is still debating this question, is complete revascularization the goal in every patient? And all of the data, as mentioned already, have several limitations. Nevertheless, they move us a little bit closer to understanding better on whom complete revascularization should be used. Dr. Emmanouil (Manos) Brilakis: So the clinical relevance is one key. I think this paper does set the stage well for a randomized trial. End of the day, we are still not hundred percent sure if COMPLETE is the best for everyone, because COMPLETE counts as a risk, and the risk is going to be higher in those patients who have more complex anatomy. But that study will give us the definitive answer about which is the best way to go for each individual base. Dr. Greg Hundley: Very nice, Manos. So that's a great segue. So I'll turn to both Shamir and Patrick, and ask them also, as well, what do you think is the next study to be performed in this particular space? Shamir, you first and then we'll finish with Patrick. Dr. Shamir Mehta: Well, I think the concept of complete revascularization has now essentially been proven in multiple trials. And don't forget, if you go back several decades, really the first proof was in the context of CABG surgery. So really, this should be the goal in patients with multi-vessel disease. The next large randomized trial that is going to be starting very soon is the COMPLETE 2 trial where we are actually looking at the lesions physiologically to see whether or not we need to revascularize lesions that are physiologically significant versus anatomically severe. Dr. Shamir Mehta: This is an important question because what it does is it has the potential to reduce the number of lesions that we perform PCI in, by about 50%. We are also looking at plaque composition in that trial with optical coherence tomography. A very, very large number of patients will be receiving that. So that will be trying to target PCI to the actual pathophysiology of the disease, by targeting unstable plaques to perform PCI on. I think this is the whole next era of coronary intervention, where we are now beginning to target our therapies to the actual pathophysiology of the disease, which is a very, very exciting idea. Dr. Greg Hundley: And Patrick, do you have anything to add? Dr. Patrick Serruys: Yeah. I think, that obviously, you have to convert the anatomical SYNTAX Score in a functional SYNTAX Score. You could do that with the pressure wire and hyperemia of diastolic resting gradient. You can also do that by QFR or FFR CT. So we are going in that direction since a few years. The second point is that we have been working on machine learning that, at some point, the segmentation of the coronary segment, the assessment of the narrowing is done. And then, the next step that we are doing right now to is to convert that to the multi-slice CT scan. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Patrick Serruys, from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster university in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute, really bringing to us this paper that, in patients with complex coronary artery disease, incomplete revascularization can be common after PCI. And the degree of incompleteness can be associated with 10-year mortality. And therefore, if it's unlikely that complete or nearly complete revascularization can be achieved with PCI in patient with three-vessel disease, maybe we should be considering coronary artery bypass grafting. Dr. Greg Hundley: Well, again, let's get on now to that second feature discussion. Well, listeners, we are now here for our second feature discussion today, and we have with us Dr. Michael Felker from Duke University, and our own associate editor, Dr. Mark Link, from UT Southwestern. Welcome, gentlemen. And Mike, we'll start with you. Tell us a little bit about the background pertaining to your study and what hypothesis did you want to address? Dr. G. Michael Felker: Great. Thanks, Greg. So I think everybody's very familiar with the concept of favorable ventricular remodeling in patients with heart failure, that we know is something that happens when we treat our patients with guideline-directed medical therapy, like beta blockers, ACE inhibitors, MRAs. Interestingly, with the introduction of sacubitril/valsartan and the landmark PARADIGM trial, we had a drug where we had clearly a major outcome benefit, but we actually had very little understanding about whether that was mediated by remodeling. Dr. G. Michael Felker: And those questions led us to design the PROVE trial, which was a single-arm trial of 794 patients, looking at whether or not patients with heart failure and reduced ejection fraction who met the FDA label for sacubitril/valsartan, the initiation of that therapy will be associated with favorable changes in ventricular structure and function, as well as favorable changes in natriuretic peptide. The current paper's really trying to put those results in a clinical context around some of the things that we make clinical decisions about, in taking care of heart failure patients in this case, whether and when patients qualify for a primary prevention ICD. Dr. Greg Hundley: Fantastic, Mike. And so you've told us a little bit about the study design, and did you have exactly the same number of patients, or what was the study population for this sort of substudy, if you will? Dr. G. Michael Felker: Yeah. So in PROVE, we enrolled people who had chronic heart failure in the EF, less than 40%, because that's the FDA label for sacubitril/valsartan. In this analysis, because we were interested in patients who qualified for ICD therapy, we limited our analysis to those who an EF plus or equal to 35%. Because, as you all know, the guideline for primary prevention ICD is people who have a EF less or equal to 35% after at least three months of optimized heart failure therapy. Dr. G. Michael Felker: And so, one of our questions was in some patients start on sacubitril/valsartan, what happens to their ventricle and how many patients might favorably remodel? This is, obviously, a question that comes up a lot clinically as more and more we're switching people from ACE inhibitors, or ARBs, to sacubitril/valsartan in line with the recommendation that's 1A from the AHA guidelines. Dr. Greg Hundley: Fantastic. ell, we're all listeners waiting to hear your results, Mike. This is very exciting. So what did you find? Dr. G. Michael Felker: I think our results were quite interesting. I mean, for one thing, the patients that were enrolled PROVE were incredibly well-treated at baseline, and they had had heart failure for quite some time, and a average median time of over six years. So this is not patients who are just recently diagnosed. A lot of these are people that you might think, clinically, we're unlikely to go on and have much favorable ventricular modeling, but that's not what we found. We actually found that after the initiation of sacubitril/valsartan, after six months, on average, we had a five point increase in injection faction. Dr. G. Michael Felker: And by 12 months, on average, that was almost 10 points. So quite a bit of favorable remodeling, even in these patients you might think were less likely to do that. And we put that in the context of ICD decision-making. By six months, 32% of the patients who would initially have been eligible based on the guidelines for primary prevention ICD, no longer met those criteria because their EF had risen to greater than 35, and by 12 months, it was up to 62% of those patients. So as we're thinking about decision-making around ICDs, I think these data have some pretty obvious direct clinical relevance to decisions we now make in the care of our patients. Dr. Greg Hundley: Really interesting. So Mark, I know you get several papers coming across your desk, and as associate editor, boy, I think I can see why this paper was attractive to you. Tell us a little bit, how do we put these results from this study into the context of how we decide whether a patient should receive an ICD? Dr. Mark Link: Yeah. The current guidelines are to wait three months after guideline-directed medical therapy, and then repeat the ECHO and see if they still qualify. I think what this study shows us is that patients can continue to improve after three months, and that improvement is somewhat continuous, actually. Because at six months, the improvement in EF was five percent, and at 12 months, it was 10%. So I think that's what this shows, the context is, if you have a patient who has a low EF and they are improving, but still haven't quite made it to 35, let's say when they went from 25 to 30 in three months, I'd probably hold off and wait another three months and repeat the ECHO again. Dr. Greg Hundley: Excellent. Well, Mike, Mark, I'm going to ask you question. And we'll start with you Mike, and then go to Mark. What study would you perform next in this space? Mike, you first. Dr. G. Michael Felker: So, I think it's important to recognize some of the limitations of any study you do, including this one. So this was not a randomized trial. PROVE was a single-arm trial, there wasn't a control group. And the question about the ICD per se was not pre-specified. It was really a post-hoc analysis. So as is often the case, I think these are intriguing and highly-suggestive results, but I think there's clearly an opportunity to confirm them in perspective studies designed to answer this specific question. Dr. G. Michael Felker: So you could imagine a trial where patients who are starting on sacubitril/valsartan who don't have ICDs, get randomized to waiting three months or waiting six months, or 12 months or whatever the interval would be. So I think these are intriguing, and that there definitely opportunities to develop confirmatory results. Dr. Greg Hundley: Excellent. Mark, do you have anything to add to that? Dr. Mark Link: I think the big thing we would really like to know are predictors, predictors of response and predictors of non-response. And that would take a larger trial perspective, and that would be very, very valuable. Because if you could have a predictor of a non-responder, they would get an ICD earlier, and predictors of responders, you might wait a while. Dr. Greg Hundley: Very nice. Well, listeners, we get rate studies here in circulation, and you'll find this one as a research letter, highlighting that in the substudy of the PROVE heart failure study, that in patients with an EF less than or equal to 35%, the introduction of sacubitril/valsartan improved EF to greater than 35%, at 62% of subjects at 12 months. Really an interesting finding, and perhaps further randomized clinical trials as suggested by both Mike and Mark here, are maybe warranted in the future. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to A, thank Dr. Mike Felker and also our associate editor, Mark Link, and wish you, as listeners, a great week, and we will catch you next week On the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

    Circulation July 6, 2021 Issue

    Play Episode Listen Later Jul 6, 2021 23:44

    This week's show features a panel discussion between authors Adrian Wells and Hyeon Chang Kim as they discuss their articles "Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy" and "Associations of Ideal Cardiovascular Health and Its Change During Young Adulthood With Premature Cardiovascular Events: A Nationwide Cohort Study." 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, also your co-host. And Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, we're starting off the month with double features, and these are just so interesting. The first paper talks about psychological interventions for depression and anxiety in cardiac rehabilitation. And the next talks about ideal cardiovascular health and its change during young adulthood and how that relates to premature cardiovascular events. Cool, huh? Dr. Greg Hundley: Absolutely. Well, Carolyn. How about we grab a cup of coffee and start discussing some of the other articles in the issue? And I could go first. Carolyn, the first article that I've got is from Mrs. Elizabeth Jordan from Ohio State University Wexner Medical Center. And it really pertains to cardiomyopathies. And remember, Carolyn, classically, we categorize hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathy. And each has a signature genetic theme. Hypertrophic cardiomyopathy and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins. But in contrast, there are over 250 genes spanning more than 10 gene ontologies that have been implicated in dilated cardiomyopathy. And therefore, it really represents a very complex and diverse genetic architecture. So to clarify this, a systematic curation of evidence to establish the relationship of genes with dilated cardiomyopathy was conducted by an international panel with clinical and scientific expertise in dilated cardiomyopathy genetics. And they evaluated evidence supporting monogenic relationships of genes with idiopathic dilated cardiomyopathy. Dr. Carolyn Lam: Oh, wow. That sounds like a lot of work. And what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So in the curation of 51 genes, 19 had high evidence. 12 are definitive strong, and seven moderate. And notably, these 19 genes only explain the minority of cases, leaving the remainder of dilated cardiomyopathy genetic architecture really incompletely addressed. And clinical genetic testing panels include most high evidence genes. However also, the panel noted that genes lacking robust evidence are very commonly observed clinically. Dr. Greg Hundley: So Carolyn, the take home message from this international panel is that while dilated cardiomyopathy genetic testing panels include an average of about 60 genes, when curating published evidence for dilated cardiomyopathy, only 19 have really emerged as high levels of evidence. And then in this study, 51 genes were evaluated. And the 19 genes appraised as high evidence were recommended to be routinely used in the genetic evaluation of dilated cardiomyopathy. And one more point. Rare variants from genes without moderate, strong, or definitive evidence should not be used in clinical practice to predict dilated cardiomyopathy risk most importantly when also you're screening at risk family members. Dr. Carolyn Lam: Wow. Very nice. Stunning numbers. Well, my paper is identifying a novel therapeutic target in pulmonary arterial hypertension. Do you want to know what that is? Dr. Greg Hundley: Ah, yes, Carolyn. Very interesting. So what is it? Dr. Carolyn Lam: It's switch-independent 3A. Which is an epigenetic modifier, which is drastically down-regulated in pulmonary arterial hypertension patients and rodent models of pulmonary arterial hypertension. And strongly associated with decreased bone morphogenic protein receptor type two, or BMPR2 expression. So this switch-independent 3A overexpression up-regulated BMPR2 expression by modulating critical epigenetic pathways and decreasing a specific transcription factor binding to the BMPR2 promoter in pulmonary vascular smooth muscle cells. Furthermore, aerosolized lung-targeted gene transfer of adeno-associated virus zero type one and containing switch-independent 3A reversed and prevented pulmonary arterial hypertension phenotype in preclinical animal models. So this beautiful study, from Dr. Hadri from Icahn School of Medicine at Mount Sinai in New York and colleagues, really suggests that switch-independent 3A can be a clinically relevant molecule for the treatment of pulmonary arterial hypertension. Dr. Greg Hundley: Wow, Carolyn. Really nice. Very intricate science for the study of pulmonary hypertension. Well, my next paper actually comes to us from Dr. Joe Hill and colleagues at UT Southwestern Medical Center. And Carolyn, as we know, cardiac hypertrophy is an independent risk factor for heart failure. Of course, the leading cause of morbidity and mortality globally. And the calcineurin NFAT, or nuclear factor of activated T-cells pathway, and the MAP kinase ERK, or extra cellular signal regulated kinase pathway, contributes to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. However, Carolyn, how these pathways interact really remains unclear. And so Dr. Hill and colleagues engineered a cardiomyocyte-specific ETS2, a member of the E26 transformation specific sequence or ETS domain family knockout mouse, and investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Dr. Carolyn Lam: Wow. Okay. So what were the results, Greg? Dr. Greg Hundley: Right, Carolyn. Three main findings. First, ETS2 is activated by ERK1/2, or extracellular signal-regulated kinase 1/2, in both hypertrophied murine hearts and in human dilated cardiomyopathy. Second, ETS2 is required for both pressure overload, and calcineurin induced cardiac hypertrophy responses involving signaling cascades distinct from, but interdependent with ERK1/2 signaling. And third, this group discovered that ETS2 synergizes with NFAT to transactivate RCAN1-4, an established downstream target of NFAT, or nuclear factor of activated T-cells. And they identified an MIR-223 as a novel transcriptional target of NFAT ETS2 in cardiomyocytes. Dr. Carolyn Lam: Wow. Wow. That sounds like a lot of detailed work. Could you tell us what the clinical implications are, Greg? Dr. Greg Hundley: You bet, Carolyn. So in aggregate, these findings unveil a previously unrecognized molecular interaction between two conical hypertrophic signaling pathways, MAP kinase-driven hypertrophy, and calcineurin driven hypertrophy. And therefore, as pathological cardiac hypertrophy is an established risk factor for heart failure development, this unveiling of novel signaling mechanisms really is of potential clinical relevance. Dr. Carolyn Lam: Thanks, Greg. Well, let's round up with what else there is in this week's issue. There's a Frontiers paper by Dr. Chris Granger. And it's a big call to action to the cardiology community, to incorporate SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and kidney disease risk reduction. There's a Joint Opinion piece from the American Heart Association, World Heart Federation, American College of Cardiology, and European Society of Cardiology on, “The Tobacco Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind. Dr. Greg Hundley: Oh great, Carolyn. Well, I've got an On My Mind piece from Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome and Torsade de Pointes Ultimately Treated With Quinidine, The Concept of Pseudo Torsade de Pointes.” And then finally, there's a Letter to the Editor by Dr. Lu regarding the article, “Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19, Results from the American Heart Association COVID-19 Cardiovascular Disease Registry.” Well, Carolyn, I can't wait to get on to this double feature. Dr. Carolyn Lam: Me too. Let's go. Dr. Greg Hundley: Welcome, listeners, to our feature discussion today. And again, we're going to create today a forum, because we have two very interesting papers to present during this timeframe. Our first is going to come to us from Dr. Adrian Wells from University of Manchester. And our second paper will come to us from Dr. Hyeon Chang Kim from Yonsei University. I want to welcome you both, gentlemen. And Adrian, I would like to start with you. Tell us a little bit about the background related to your study. And then what was the hypothesis that you wanted to address? Dr. Adrian Wells: Okay, well thank you for inviting me to take part in this podcast. Following cardiac events, around one in three individuals will develop significant anxiety and depression symptoms. And we know that anxiety and depression can have an impact on prognosis, quality of life, future outcomes. Psychological treatment isn't routinely offered in cardiac rehabilitation for anxiety and depression, despite the fact that we identified that many of our patients felt that they would benefit from a psychological intervention to address these issues. And they felt that their needs were not really being met. So our primary question was, can we improve psychological outcomes in patients with cardiovascular disease? Dr. Greg Hundley: Very nice. And Adrian, what was your study population? And also, what was your study design? Dr. Adrian Wells: So we selected patients who entered cardiac rehabilitation in the UK. So these are patients with acute coronary syndrome, revascularization, stable heart failure, heart transplantation, and so on. And so, a wide group of individuals. We recruited 332 patients, all of whom had had anxiety and depression scores of eight or more. So these were people showing mild to severe levels of psychological distress. We conducted a two arm single blind randomized controlled trial, with 332 patients who were randomly allocated to one of these two conditions. And we assessed anxiety and depression symptoms before treatment at four months and at 12 months. Dr. Greg Hundley: Describe a little bit some of the specifics of your intervention. And then what did you find? Dr. Adrian Wells: We use relatively recent new treatment called metacognitive therapy. And this was delivered in a group format over six sessions. And we trained cardiac rehabilitation staff, nurse consultants, physiotherapists, in the delivery of this intervention. Metacognitive therapy works on helping patients discover unhelpful patterns of thinking, such as worrying and ruminating ,and excessive threat monitoring. And to reduce those patterns of thinking that contribute to anxiety, depression, and poor adaptation following stressful life experiences. Dr. Greg Hundley: And what did you find? Dr. Adrian Wells: Well, what we found was that the addition of metacognitive therapy to treatment to usual cardiac rehabilitation, significantly improved outcomes at four months and 12 months. What was striking about this was that our effect sizes were modest and moderate to large. They seem to be larger than those obtained in other studies or psychological treatments. And of note, the treatment seemed to impact well on both anxiety and depression symptoms. Whereas other types of intervention evaluated in the past have tended to treat the depression, but not so much the anxiety. Dr. Greg Hundley: Very good. So it sounds like a group-based intervention. And I'm assuming maybe participants interacted not only with your staff, but with one another. How would you put your results really in the context with other research that's going on in this space? Dr. Adrian Wells: Well, there have been a number of studies in the past that have looked at individual and group-based treatments, and patient preference for different types of intervention. I think this is the first study to use a clear manualized intervention that's based on the psychological theory of mechanisms that contribute to the maintenance of psychological problems. Obviously, this tended to use more prescriptive interventions like anxiety management, stress management, taking techniques from a range of different sources. So I think there's a difference of conceptual basis to this kind of intervention. And it's something that is highly manualized and structured, and in fact can be delivered by a range of different healthcare professionals. Dr. Greg Hundley: Very nice. And also during cardiovascular rehab. Correct? Dr. Adrian Wells: Absolutely, yeah. During cardiac rehab. One interesting finding... And we were a little concerned that this might adversely affect attendance at cardiac rehab. But we found that the treatment was well tolerated, and it didn't have any negative impact on attendance at these other sessions. Dr. Greg Hundley: Excellent. Well, congratulations on this new finding. Well, listeners, we're next going to turn to Dr. Hyeon Chang Kim from Yonsei University in Korea. And Yong-Chan, could you describe for us also the background related to your study, and the hypothesis that your research wanted to test? Dr. Hyeon Chang Kim: Thank you for inviting me to this wonderful discussion. South Korea is among the countries with the lowest cardiovascular mortality in the world. And the rate is even decreasing. However, cardiovascular risk factor is worsening. Especially in younger generation in Korea. So these young people may not have a very high cardiovascular risk, but I wanted to know the potential impact of worsening cardiovascular risk profile in this younger Korean generation. And furthermore, I wanted to know how much we can lead youth cardiovascular risk by improving their cardiovascular health profile. Dr. Greg Hundley: Very nice. And so tell us about your study design and what was the study population, related to your study? Dr. Hyeon Chang Kim: My study is basically based on the national health checkup program and national health insurance claim database. In Korea, adults over the age of 20 and employed workers of all ages are required to take general health checkup every two years. The participation rate is between 70 and 80%. So we identified three and a half million adults, age 20 to 39 years, who complete the health checkup. And cardiovascular health scores was calculated as the number of ideal cardiovascular health component, which include non-smoking, moderate physical activity three times a week, body mass index below 2030, normal blood pressure, normal cholesterol and normal fasting glucose. So the score can range from zero to six. And higher score meaning better cardiovascular health. Our outcomes were myocardial infarction, stroke, heart failure, and cardiovascular deaths in about 16 years. In addition, we also evaluate the risk of cardiovascular disease. According to two year change in how the vascular health score using repeated health checkup data. Dr. Greg Hundley: Very nice. So evaluating a set of behavioral patterns and risk factors in younger individuals, and then predicting what their longer term adverse cardiovascular outcomes would be. So what did you find? Dr. Hyeon Chang Kim: So even in this relatively low risk population, better cardiovascular health score was associated with significantly lower cardiovascular risk. About 20% reduction per one point higher score. And more importantly, people with improving cardiovascular score over two years showed leading toward cardiovascular risk. Even if their baseline cardiovascular health score was very low. Dr. Greg Hundley: Really unique findings. Tell us about the impact of your results relative to other studies published in this space. And was this also.... This was unique, because it's an Asian population, Dr. Hyeon Chang Kim: Asian population. And we are among the very low risk population. And even in this low risk population, cardiovascular health score was... Fear can be a good predictor of cardiovascular risk. And compared to many Western countries, we have very low cardiovascular risk. And our population was younger than most other studies. So we can provide some evidence that even in the higher risk population, they can do much better, based on our study. Another important thing, we can check the impact of a changing cardiovascular score, even in the younger generation. Dr. Greg Hundley: Very good. And just as a frame of reference for our listeners. Give us some characteristics, if you wouldn't mind, on what really constitutes practically a low risk score, versus what would constitute a high risk score Dr. Hyeon Chang Kim: In this younger Korean population, their cigarette smoking, and their obesity, and physical inactivity are the most common causes of worsening cardiovascular profile. And the behavioral risk factor also can attack the blood glucose and cholesterol blood pressure. So in this younger generation, they're keeping the good behavior. Past behavior is very important and it's beneficial in the very long-term. Dr. Greg Hundley: Very nice, well listeners. We're going to turn to our experts here. Two very interesting studies. And ask them both, what do they think is the next study that needs to be performed in their respective areas of research? So Yong-Chan, we'll start with you. Since we just discussed your paper. What do you think is the next study to be performed really in this sphere of research. Dr. Hyeon Chang Kim: Korea is a relatively low cardiovascular risk, has a very small size, and no racial diversity. But even in this country, disparity and inequality in cardiovascular health is becoming an important issue. So I want to identify subcultural relatively poor cardiovascular health among younger population. And also I want to find ways to improve their cardiovascular score. The conventional approaches, such as education and mass campaign, are less effective oppose this younger adults have a poor socioeconomic status. So, we may need to develop newer target-specific strategies to improve their cardiovascular health. Dr. Greg Hundley: Good. And Dr. Wells, our agent will turn next to you. What do you see is the next area of investigation or research study that needs to be performed in your sphere of interests? Dr. Adrian Wells: Well, I think the next step is to look at rollout of this intervention. Is that feasible, and how acceptable is this to cardiac services? In fact, the National Institute of Health Research have just awarded us some funding to examine feasibility and barriers to implementation in the healthcare system. In addition to that, we're beginning to examine the effects of metacognitive therapy with other health conditions, such as cancer in children and adolescents. Dr. Greg Hundley: Nice. Well listeners, we have had just a wonderful discussion today from both Dr. Adrian Wells from University of Manchester. Who brought to us combining a group-mediated, psychological stress-reducing, anxiety-reducing, intervention to the cardiac rehab sphere. And how impactful that was in reducing both anxiety, and overall depressive symptoms. And then also exciting research from Dr. Hyeon Chang Kim from South Korea. Identifying for us that in Asian population, as well as what we know in other races, those individuals in their twenties to thirties with favorable lifestyle habits, have reduced cardiovascular risk much later in life. Dr. Greg Hundley: Well, on behalf of both Carolyn and myself, we want to wish you a great week. And we'll catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation on the Run: Come Meet the Team

    Play Episode Listen Later Jun 28, 2021 29:59

    This week, we have a special podcast: the interviewers become the guests! Join Digital Strategies Editor Amit Khera as he interviews Carolyn Lam, Greg Hundley, and Managing Editor David "Augie" Rivera as they provide a behind-the-scenes look at how Circulation on the Run comes to you each and every week. Come meet your favorite podcast hosts! Dr. Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation, and boy, do I have a treat today? I get to step in for Carolyn Lam and Greg Hundley, but wait, I actually get to interview Carolyn Lam and Greg Hundley today. So we have a very special Circulation on the run. Well, the interviewer becomes the interviewee. These two you get to hear every week and hear this amazing back and forth and deep insight into Science and Circulation. But, who are these folks behind the Circulation on the Run podcast? And boy, what interesting life stories they have and how they work through this. And wait, we also have a third joining us today, and that is Augie Rivera, who is the managing editor of Circulation. So we get to see the mastermind behind how all this runs. Well, Carolyn, Greg, Augie, welcome you three. Dr. Carolyn Lam: Thanks, Amit. Feels weird. Dr. Amit Khera: Good. Then mission accomplished this week. Well, first let me start with you, Carolyn. I know you and I started this long ago, with help from so many folks. People hear you every week and I'm sure many people know you quite well. I will say you have one of the most interesting backgrounds, incredible scientific and personal accomplishments, professional accomplishments. So we're very fortunate to have you as leading this podcast in the beginning, but a lot of people may not know your background story about sort of your training and your day job, because you do have a day job outside of podcasting. So tell us a little bit about yourself, about how you got here in life. Dr. Carolyn Lam: Oh my gosh. Amit, I'm humbled by your question. My goodness. I feel just very lucky to be part of the Circulation editors. And I humbly did my med school in Singapore, and did cardiology here, and traveled and lived overseas for the first time. Guess where, in Rochester, Minnesota. Tropical Singapore island to refrigerator state. Other than that, it was absolutely the most pivotal moment of my life. Met my first female mentor and Dr. Margaret Redfield. Really, really just came into my own and got involved in population-based research. And then hopped on over to Boston where actually I was working at the Framingham Heart Study. So continuing sort of the epidemiologic work, but then I think another mentor I really have to call out too is Dr. Scott Solomon, who kind of took me under his wing a little bit and showed me a little bit of the world of clinical trials. And boy, all I can say is I haven't looked back. And so here I am. Dr. Amit Khera: I think you took a detour in the Netherlands too. Am I right to say that? Dr. Carolyn Lam: Oh yes, but that was quite a late detour in life. I was really, really fortunate meet Dr. Adrian Voris who supervised my own PhD. That was a really interesting thing because I come from a family of a pediatrician in my mom, and a scientist, a biologist really, specialized in fish, in my father. And I'm saying this because my father told me never ever follow his footsteps and do a PhD. Make sure I follow my mom's footsteps and be a clinician, and go into private practice. Dr. Amit Khera: Well, it looks like you followed both of their footsteps, maybe the best of both, so they're very proud of you for that. We recently had the privilege of having you give us grand rounds and get to hear your impressive work in clinical trials. And I have to say, the work you're doing in half half and really with some great clinical trial and cohort data involving Asian populations was quite inspiring and impressive. How did you sort of get things going? You've traveled around and moved back and how did you start getting your career going and the momentum you've had so far, incredible success? Dr. Carolyn Lam: Oh goodness. Thanks for letting me share. Amit, honestly, I don't know. And I can only look back and be on my knees and be grateful for being at the right place at the right time. I think it's a combination of taking what I had learned in Olmsted County and Framingham. Coming back to Singapore and realizing that there was a need for similar epidemiologic studies. I firmly believe if I didn't do it, someone else would. I'm not that brilliant. I just get things done. And so that's what I did. I started that. And one thing led to another. It's having really friends as well. And so I really, really want to say big thanks to my mentors who have become my friends and colleagues. And to people listening. This is really, really from the heart. You don't plan these things. You just go the next step that you see, and you go with all your heart. And you make sure that you've got your eyes open to see the next opportunity, and have the energy to seize that one when it comes by as well. I think that's how it all happened. Dr. Amit Khera: Well, that is a good pivot because one of the next opportunities that came up in Circulation on the Run after you'd done it for a while, was to bring in this gentleman, Greg Hundley. And so we're so glad that you two partnered. Now, Greg, you and I have a little bit of a shared background. You were at UT Southwestern for a period of time, where I am currently. Well, tell us your story, Greg. Tell us a little bit about your background and training and where you are currently. Dr. Greg Hundley: Sure. Thanks so much, Amit. Again, I think like Carolyn, we really feel this is an incredible opportunity. The journal is a wonderful blend of collecting impactful science, both clinically and pre-clinically. And trying to bring that to the forefront. It's just been a fantastic opportunity to participate on the editorial side, but then after that, share with the rest of the world, the findings that we really develop each week. And it is truly a team effort. All the way from identifying impactful science, discussing it, preparing it, and then sharing it. And so I think like Carolyn, I just feel very privileged to have this opportunity. Now, my path, listening to Carolyn, and for listeners, you kind of move with it a little bit, and follow along seeking, I don't know, new opportunities, but also being very humble. And as they approach you, and doing kind of the best that you can in the situation. Dr. Greg Hundley: So my career path started at what was Medical College of Virginia, but is now VCU in Richmond, Virginia, and medical school there. And then, at Southwestern, did my internship, residency, and cardiology fellowship. And I would say, probably my first strong mentors was really a mentor team. There was expertise there. Jim Willerson had brought Ron P Shock and Craig Malloy on the magnetic resonance imaging side. So for those that are listening, I'm more of an imager in cardiovascular medicine. But also a key fundamental pivotal figure or figures were David Hillis, and Rick Lang in the cath lab. And at the time, magnetic resonance imaging, we were trying to figure out, well, could this noninvasive methodology help us understand problems related to cardiovascular disease that came along maybe before, or we needed to go to an interventional situation, or how they would relate to an interventional situation. Dr. Greg Hundley: And then was briefly a faculty member at Southwestern, and then recruited back to the East Coast to Wake Forest. Another really pivotal figure for me was Dr. Bill Little at Wake Forest. Now, he's passed away, but bill had again, that great insight and excellence in science, and performing research and investigations, but also clinical expertise and emphasize the world... We haven't talked a lot about this, but education. How we take the information that we gather and educate others. Began working with the American Heart Association, with the American College of Cardiology in that realm. Then after 22 or three years, another opportunity came up actually to return back to VCU, and be the director of the heart center. And so now have that position here in Richmond, Virginia. Again, very excited to be working here with Circulation on the Run. Dr. Amit Khera: Well, I hear some amazing themes from both of you about mentoring and people along the way. It's a great story obviously for our younger listeners that are thinking about life and careers and opportunity sort of finding where life takes you. I think those are great themes for both of you. Now, we won't have as much time for this story, but Greg, you and I spoke recently. You told me this most amazing story of how you were going to be an interventional cardiologist, walked over to drop off something. A patient had an MRI machine and saw this MRI and fell in love. Dr. Amit Khera: I'll paraphrase about staying up all night, drinking soda and coding zeros and ones since that's the technology back then, but what an amazing story. We'll have to do that for our next podcast. All right. I'm going to bring in Augie Rivera. Now, he is the managing editor of Circulation. Meaning he really keeps everything going, and is the engine and brains behind the operation. And one of the many things he does, is the podcast. And we'll talk more about the logistics of that. But Augie, people never get to hear your voice. So tell us a little bit about how you got into this medical publishing and circulation in the pacific, sort of your background. David “Augie” Rivera: Well, thanks, Amit. Also thanks to Carolyn and Greg for inviting me as well to participate. This is going to be shocking and maybe scary, but I only have a couple of years of scientific journal publishing experience, and that's with the Circulation family. My background for my entire career has been in educational school publishing, specifically in mathematics. And mainly grade K to 12 mathematics. So making the jump over to scientific publishing seemed a bit daunting, but after like 20 plus years, I was looking to do something else. And I was grateful that I saw something on LinkedIn. I interviewed for the position and I was very fortunate the American Heart Association that ended up hiring me. In a sense I always say, "Taking a chance on the long shot." And so that's what brought me here. So a lot of this has been very, very new to me, but at the same time, all the Circulation editors have been so helpful, as well as my staff that I work with. They've been so beneficial to me in learning the side effects. So, that's a little bit about me. Dr. Amit Khera: We're very glad that the DHA found you, Augie, and you've been obviously this incredible resource for us. I'm glad you brought up the staff because there's so many people on Circulation that make it run and we're very grateful for all their efforts, including those who help us put on this podcast. Well, I want to dig into the podcast. Carolyn, we haven't told the story in a long, long time. I think you told it on the very first podcast, but Circulation on the Run. For those that missed in earlier days, remind us how you came up with that name. Dr. Carolyn Lam: Okay, very quickly. I'm a runner, and I know a lot of us are. It's just on one of my runs that I realized, "My goodness, wouldn't it be great to be able to just feed my mind at the time?" I was on a treadmill actually, and I was trying to read, and it occurred to me, "It is impossible. I'm getting a serious headache to try to read while you're trying to run." And so I thought, "Wow, wouldn't it be great if somebody just read that to me, so I could just read the journal while I was running?" Yeah, you can join the dots. So that was exactly the idea. That, "No, I'll do that for someone. I'll give them the nuts and bolts of that issue." Dr. Carolyn Lam: At least the main papers. The way it's grown since then, it's frankly thanks to Greg. I need to make a plug here. Greg has admitted that he's humble. And in fact, that's why I need to drag this out of him. I did not realize until I interviewed him on one of the podcasts, that he is totally gifted at interviewing. And then he tells me just, by the way, in the usual Greg way, he has a history and thick experience in this. He had done the interviews like... Greg, you have to tell me, but he had done several of these. He had a show, he had ideas. He used to do it. And I was like, "Why are you hiding all this? You got to come do this with me." But he hides it. So Greg, now you have to fess up. Dr. Greg Hundley: Oh gosh. And now Carolyn, she's too kind. So Carolyn, listeners as you can tell, just has a very warm, inviting personality. And she so couples that with just brilliance and interest in science. I mean, I can't take credit for the things, but she's also open to listening. And I think one of the really exciting things, this sort of team of three with Augie and Carolyn, we have great discussions behind the scenes on how we can bring the information in the journal to you as listeners, in a way that is inviting, engaging, and educational. It's really being part of a team, that has that common goal in mind and in thought. Carolyn and Augie, I just treasure the opportunities that we get to work together every several weeks and putting together the most exciting science that our journal really brings forth. So it's a team effort for the listeners. And just to maybe anticipate the next question, how do we do that? Dr. Greg Hundley: We do get the joy of reading the journal every week, and we spend some time each of us, on our weekends and late at nights reading thoroughly the journal. And Carolyn and I kind of divide up the articles. Both of us taking and becoming enthralled with areas of expertise that we may have. Again, we've talked about Carolyn in heart failure expertise and maybe me a little bit more on the imaging side and cardio oncology and the like. And then in any way we divide up the articles, we read them thoroughly, and then we produce a script. So one of the fun parts of this is working with Augie. We're producers as well as editors, as well as the spokespersons. Dr. Greg Hundley: So it's kind of all done in one shop and put together, and interactive, if you will. And then we are able to record that in sessions with Augie, coordinating them, and involving some of our authors, editorial experts. And then other experts that we gather from around the world that are also involved in the science. And the goal is to create discussions in addition to presenting the information that's in the journal, but to create meaningful, thoughtful discussions regarding this impactful science, so that we can actually take it in as practitioners or other researchers and scientists in the field quickly. And that's sort of the general concept. Dr. Amit Khera: You jumped right in there, Greg. And that's exactly what we want to dive into, which is sort of the behind the scenes, the mechanics about the why. Now, you two have an incredible chemistry. I will say since you two have been doing this together, it's really been a joy listening to you two. Carolyn, just maybe the dovetail on what Greg just talked about, about sort of the chemistry. That back and forth that you two do, the preparation behind that. Tell us a little bit about how that works out. Dr. Greg Hundley: Oh, absolutely. I've been dying to share. You should hear the bloopers. It's hilarious. So after a while, we just totally like... We have the fun doing this. And we realize it's very serious science that we're talking about. We're so solidly proud of circulation, but it's okay to have fun. It's okay by the way, to mispronounce some of these basic science words and to call Joe Hill, which I've done by the way, literally called him to ask him how to pronounce certain things. And you know what? And have fun at the same time. And so Greg starts these quizzes. Now, that is all Greg, okay. This Carolyn quizzes and... So after a while, we started to try to hide little quizzes inside our script with the answers given just in case. But it sometimes catches us unaware, and it's just really hilarious. Dr. Greg Hundley: And once or twice, I think Greg and I have tried to quiz Augie as well. But Augie never allows us to do that. So it's really great when we're having fun. And that is exactly what I'm so grateful for Greg to showing me that. He's the one who had the experience with the back and forth and gave us the idea. He's the one who push to say, "Look beyond the original articles, I really like as a listener, to have an overview of every single article." That was Greg. He's the one who initiated the sort of forum type discussions and double bill discussions, because he got feedback and acted on it, that people really, really enjoy listening to the authors too. And finally, we're really trying to make it even more useful for the audience based on feedback by seeing if we can get CME accreditation, seeing if we can be more responsive. I just want to let people know, even if we don't manage to achieve it, that we're listening, and we're trying, and we're constantly trying to improve. And that's what I really, really thank both Greg and Augie for. Dr. Amit Khera: Thanks for that. Listen, I want to just pick up on many things that you just said. First, I think what people may not appreciate is how much work goes into this. You read all of the articles and prepare with the featured articles. You create a script, and you have fun doing it, which is the most important thing. You record and have to coordinate. Takes a lot of time. I've seen this too, then people don't realize afterwards, you listen to the entire thing and edited again. This is impressive. And it shows, because it's a fantastic product. I want to talk a little bit about some of the deeper features. So you two obviously summarized in the beginning, the original research and we talked a little bit about the back and forth. I want to talk about the featured articles and the interviews of these different folks. Tell me a little bit about that and how that goes. What do you enjoy about the interview part of that. Greg, you want to start? Dr. Greg Hundley: Well, I thoroughly enjoy what we call the feature discussions, where we bring together the authors of the paper, editorial experts that... With Circulation, there's a team of associate editors that process the papers. And actually, when you as a listener submit an article, we review these in a discussion format. And one of the associate editors is leading that through a discussion group. And so we bring in that expert. And then oftentimes, we have an editorialist, or an expert from the world, and bringing together a discussion and focusing on the content, not only in that article, but how that article pertains to the world's literature, and then where we really want to go next with research. Dr. Greg Hundley: And I think that's sort of our objective, is to bring a living discussion for us as listeners, with authors, the active researchers, with the editorial team and the experts. Why of all the papers you get did this impactful science really come to the forefront for you? And then from the editorialists, how do we take this information and put it in the context of the world's research that's going on in cardiovascular medicine? So those are sort of the main insights and as listeners, just as Carolyn said, we really enjoy receiving feedback from you, and how we can perfect that further. One of the things we've started thinking about is, if we have a basic paper and a clinical paper on the same topic, is really having even a broader discussion, a forum discussion, where we talk about several papers at one time and really embrace a topic. And I love what Carolyn said about providing not only continuing medical education credits, but for those in the United States or maybe North America in particular, maintenance of certification credit, and something we're actively looking at, trying to work through right now. Dr. Amit Khera: Thank you for that. And Carolyn, do an add to the features and the interviewing these folks and some of the... what it is that's most interesting to you in doing that process and what you've learned. Dr. Carolyn Lam: Yeah. I certainly want to add, but probably in an angle you would not expect. And here, I really, really want to point out the tremendous work of coordinating this, that Augie takes care of. It is incredible. When we have an editor in Europe, a author in California, a me in Singapore, himself in another part of the US. I do not know how Augie does it. And not only does he do it super well, it's always with a smile. Augie, you truly are amazing. Your positivity has honestly kept me going many times, when I just came on the recording half dead. Kudos to you, truly. Dr. Amit Khera: Thank you, Carolyn, because I wanted to bring in Augie back again now. Augie, it must be amazing for you. I mean, first, the logistics. Maybe you can tell us about coordinating people from all over the world, different time zones, every single week and obviously people that are quite busy and show what a hard thing to do. And then maybe seeing the process. Boy, from seeing these papers come through our meeting, to the selection, to coordinating, to seeing the final product at the end, it must be a pretty satisfying process for you. Tell us a little bit about the mechanics and what this is from your vantage point. David “Augie” Rivera: Well, indeed, it is very interesting. It's something that I did a little bit of production back in college when I did college radio, way back in the day, but I never do. I would end up doing this again, but I think as far as the logistics are concerned, I'm not by myself in this at all. I mean, a big shout out to Sarah O'Brien who trained me when I took on this job because she was covering Circulation on the Run while there was a search for a managing editor. So she was the one who taught me all the tricks of the trade, on how to make some of this happen. But also it's the two assistants for Carolyn and Greg, Afshaan and Angela, who I contact and I go, "Please let me know what their availability is, when, and what can we fit here? And what can we fit there? And can we try to move a meeting?" David “Augie” Rivera: In fact, I get to tell Greg that we were successful in moving a meeting for tomorrow, and we have another one scheduled. So we made it work. So really Afshaan and Angela really help out with those logistics as well. We also have to thank you Ishara and her team over at Learner's Digest. They're the masters who put together all of our raw audio files, and cut them all together, to make the final product of the podcast. And not only does her team do that flawlessly, but it also coordinates with having those reviewed and approved by the editors as well. So there is no way that we would ever be able to get any of our podcasts out and delivered without their awesome help and support. So a big shout out to Ishara and team. And most importantly, and the viewers can't see this, but also to the authors and associate editors, editorialists. Augie Rivera: First of all, we're grateful that they've sent and submitted their articles to circulation for peer review, and then eventual publication, but their flexibility, because I know that they are very busy during their time too, and trying to make things work. I have had an author say, "Oh yeah, 12:30 in the morning, past midnight? Oh totally. I can totally do that. No problem." Or an associate editor who says, "Yeah, I can probably do that for 5:00 AM in the morning." So the flexibility of the authors, the editorialists and the associate editors is also what makes the logistics and everything work out. So it's not me, but it's completely a team effort. And it's also thanks to Carolyn and Greg for finding those pockets of time while they're doing their day job, to also take the time to be prepped and interview our authors and editorialists. So on that end, like I said, it's not me, it's a team of all of us that put this together. Dr. Amit Khera: Well, I appreciate everyone's humility, including yours, Augie. And you are right, there's a broader team and I appreciate you calling them out, but we certainly acknowledge you're at the center of that, and appreciate all your work to make this come to fruition. Well, we're winding down. I have maybe one last question for you two, Carolyn and Greg. Tell us about the future of Circulation on the Run. Where do we go from here? What's the future of this specifically? Or maybe podcasting and Circulation in general. Dr. Carolyn Lam: Well, what I can say is, it is continuously going to improve. You've heard us commit to that. We will and promise to try to make it as short and snappy as we can. So for those of you listening, who kind of don't get to the end, please hang in there with us. We're continuously getting better. Dr. Greg Hundley: Yeah. I would just want to echo that. If listeners have suggestions and there's a pathway to gather that information from you, we are all ears. We're listeners, and we would love to shape and mold this further based on your suggestions, because really, your suggestions have shaped a lot of where we are today. Dr. Carolyn Lam: And Amit, if I could, because the podcast is only one cog in the whole wheel of what you do as overall strategy for us, digital strategy. Could I ask you to give us that last word? I have to be the interviewer again. Dr. Amit Khera: You can't get it out of your system. This one is not about me. I'll give two seconds on my role specifically, but I have a neat role. We purposefully chose the term, digital strategies, because we appreciate there's so many different things behind getting medical literature out there, including website, working with traditional media, social media, podcast, and whatever else comes in the future. Dr. Amit Khera: So I'm very lucky because I get to work with you all plus a ton of other folks to really bring this material to life. And the coolest part is, you all are so easy to work with and so creative, and have done so many amazing things with this podcast. And it's been real privilege just to watch this grow and develop. What I love that you both said, and I hope the listeners heard this, that have hung on with this, you're appreciated for feedback and you always have been. Have made tweaks along the way to make this better and better. And so if anybody has any, feel free to email any one of us, and we welcome that feedback to make this even better. Listen, I want to say what a treat this has been to interview the interviewers. Amazing, and certainly did not disappoint learning about your backgrounds and a little bit more about all of you, and about what makes Circulation on the Run come to life. Dr. Amit Khera: So that's it. There's another rap. I'm Amit Khera, stepping in and interviewing Carolyn Lam and Greg Hundley, who will join you again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation June 22/29, 2021 Issue

    Play Episode Listen Later Jun 21, 2021 28:37

    First join author Marc Dweck and Associate Editor Victoria Delgado as they discuss the article "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial." Then, join authors Torbjørn Omland and Geeta Gulati as they discuss the article "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol." 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: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Hooray, it's another double feature week! And guess what, these two papers are two randomized control trials. One looking at progression of aortic stenosis and the other, looking at a prevention of cardiac dysfunction following adjuvant breast cancer therapies. Dr. Carolyn Lam: So, very interesting two papers coming right up. But Greg, why don't you start by highlighting some of your favorite papers from today's issue. Dr. Greg Hundley: You bet Carolyn. Dr. Greg Hundley: So my first study was conducted by Dr. Gabriela Trifan and colleagues from University of Illinois who performed a meta analysis of major studies that compare the efficacy and safety of dual anti-platelet therapy versus monotherapy for secondary prevention of recurrent stroke or transient ischemic attack in those previously experiencing minor non cardioembolic stroke. And their primary outcomes were stroke and the composite of stroke, TIA, acute coronary syndrome and death of all cause. And the safety outcome was major hemorrhage. Dr. Carolyn Lam: Oh, okay. Very important study. What did they find? Dr. Greg Hundley: Right Carolyn. So the analysis included 27,358 patients. And compared with monotherapy, dual anti-platelet therapy reduced the risk of recurrent stroke and the composite outcome, but increased the risk of major bleeding. And in subgroup analysis at less than or equal to 30 days, dual anti-platelet therapy increased the risk of hemorrhage relative to monotherapy. In sensitivity analyses, the risk for hemorrhage with less than or equal to 30 days of dual anti-platelet therapy, after excluding the combination of aspirin plus Ticagrelor, was comparable to monotherapy. However, the risk of stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remained decreased compared to monotherapy. Dr. Greg Hundley: And so Carolyn, the take-home message from this paper is that dual anti-platelet therapy decreases the risk of recurrent stroke and composite events compared with monotherapy. But, dual anti-platelet therapy increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus Ticagrelor. Dr. Carolyn Lam: Ah, thanks for that last take home message. Thank you. Dr. Carolyn Lam: Well, the paper I'm going to tell you about is the first to examine the role of epicardial fat derived extracellular vesicles in the pathogenesis of atrial fibrillation. And this comes from Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel and his colleagues who collected epicardial fat specimens from patients with and without atrial fibrillation during elective heart surgery. Dr. Carolyn Lam: Epicardial fat samples were grown as organ cultures and the culture medium was collected every two days. And the authors then isolated and purify these epicardial fat extracellular vesicles from the culture medium. Dr. Carolyn Lam: They found that epicardial fat extracellular vesicles of patients with atrial fibrillation had unique pro-inflammatory, profibrotic and proarrhythmic properties. Epicardial fat extracellular vesicles could in fact induce cellular, molecular and electrophysiological remodeling that could result in atrial fibrosis, myopathy and the development of atrial fibrillation. Dr. Greg Hundley: Wow Carolyn, so what are the clinical implications of epicardial fat extracellular vesicles? Dr. Carolyn Lam: Hmm, good question. Well, understanding their role in the pathogenesis of atrial fibrillation may for one lead to the discovery of new diagnostic markers or new targets for the prevention and treatment of atrial fibrillation. And that combined pro-inflammatory profibrotic and proarrhythmic effects of these epicardial fat and extracellular vesicles may in fact be relevant to the pathogenesis of other cardiovascular diseases associated with obesity and abnormal adipose tissue deposition. Dr. Greg Hundley: Very nice Carolyn. Dr. Greg Hundley: My next paper comes again to us from the world of preclinical science and these authors led by Dr. Masanori Aikawa from Harvard Medical School applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. They use global proteomics and high dimensional clustering on multiple vein graft tissues to identify potential pathogenic mechanisms. And experiments were conducted in both in vivo mouse models and in vitro human macrophages. Dr. Carolyn Lam: Oh wow. So what did they find? Dr. Greg Hundley: So Carolyn, peroxisomes proliferator activated receptors or PPAR alpha agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Dr. Greg Hundley: Now, metabolomics, lipidomics, functional metabolic assays and single cell analysis of cultured human macrophages revealed that PPAR alpha modulates macrophage glycolosis, citrate metabolism, mitochondrial membrane sphingolipid metabolism and heterogeneity. Dr. Carolyn Lam: Okay. So what is the take home message Greg? Dr. Greg Hundley: Right Carolyn, thought you would ask me that. Dr. Greg Hundley: So PPAR alpha activation suppresses the development of vein graft and arterial venous fistula lesions. And PPAR alpha reduces macrophage activation by influencing macrophage heterogeneity, mitochondrial integrity, and the metabolome. So Carolyn, given that peripheral arterial disease and chronic kidney disease prevalences are increasing, warranting needs for more vein grafts and arterial venous fistulas, this target discovery platform is applicable to investigating therapies for these diseases. Dr. Greg Hundley: And a really nice accompanying editorial is provided by doctors Reilly and Bornfeldt. Dr. Greg Hundley: Well Carolyn, how about we turn to look at what is in the mailbag this week? Dr. Carolyn Lam: Well let me tell you about it Greg. We've got a cardiovascular case series by Dr. Borlaug on things are not always as they seem, multimodality exercise assessment and evaluation of dyspnea. In cardiology news by Kuhn there's a discussion of Evinecumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. A perspective piece by Dr. Watkins on time to think differently about sarcomere negative hypertrophic cardiomyopathy. And finally a research letter by Dr. Ahn on reduction in Kawasaki disease after non-pharmaceutical interventions in the COVID-19 era, a nationwide observational study in Korea. Dr. Carolyn Lam: Wow. That wraps it up for the summaries. Let's go on to the feature discussions shall we, Greg? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: We are about to talk about the extended follow-up results of the PRADA trial. Oh, so interesting. So happy to have with us today, doctors Geeta Gulati and Dr. Torbjørn Omland, both from the Akershus University hospital in Norway, and you would probably recognize that Dr. Torbjørn Omland is also one of our associate editors, but both here are the co-corresponding authors of this beautiful paper. Dr. Carolyn Lam: Thank you so much for coming here today. Torbjørn, maybe you could start with what is the PRADA trial? Why did you decide to do an extended follow-up? Dr. Torbjørn Omland: Yeah so PRADA was a two times two factorial randomized double blind clinical trial that sought to evaluate the effects of intervention with receptor blocker Candesartan. And a beta blocker Metoprolol in patients with early breast cancer who received anthracycline therapy as part of their chemotherapy. And then we wanted to assess the effect of this sort of preventative therapy, left ventricular function and injury. Dr. Torbjørn Omland: So we reported the primary results of the trial a few years ago and showed that intervention with Candesartan most associated with a significant elevation of the reduction in left ventricular ejection fraction that these patients may experience, and also that treatment with the beta blocker Metoprolol was associated with an intimation of the increase in cardio proponents suggesting a beneficial effect on myocardial injury. However, whether these results were or these effects were sustained after termination of the study drugs was unknown. And that was what we really wanted to address with extended follow-up study. Dr. Carolyn Lam: Yeah, makes a lot of sense, especially because these injuries I suppose could still continue. And just to be very clear, the medications though were only taken during the adjuvant chemotherapy and therefore could be a variable duration from what I understand. Right? Great. Dr. Carolyn Lam: So Geeta then, could you tell us what did the extended analysis show? Dr. Geeta Gulati: The extended follow-up was interesting and it was something we really wanted to figure out because there are not many studies who have been done on the extended follow-up and you're not giving these study medications afterwards. Dr. Geeta Gulati: So very interestingly we saw that the decline in the ejection fraction was still there in the whole group. But this time there was no difference in the group who received Candesartan do those who didn't. And we show that there was a different in the primary results, but now in the extended follow-up there was no difference. And then also in the Metoprolol group that had previously shown that there was lesser rise in the troponins. Again, there was no difference in the groups now on the extended follow-up. Dr. Geeta Gulati: So this is very interesting because this shows that there is a small, modest decline in a left ventricular ejection fraction during and after the breast cancer therapy. But what does this really mean? It's a small decline and it's within the normal range and the cardioprotection is not working. So, are we perhaps looking at the wrong group? Perhaps we should look at patients who have the higher cardiovascular risk factors. Perhaps even we should look at more novel heart failure or cardiac drugs that may have a stronger effect on the ejection fraction. Dr. Carolyn Lam: Right. So Geeta though, can we unpack that a little bit? You see, the patients were not on the medication anymore at the time of follow-up. So you're saying that even though they were given adjuvant chemotherapy and covered with the drug, that even not having any more chemotherapy, their ejection fraction still fell. And if I'm not wrong, this was an MRI analysis. And so it was only by an ejection fraction of two percent on mean fall, right? How do we think about that clinically? Dr. Geeta Gulati: And that's the important question, isn't it? Because a decline in the ejection fraction of less than two percent within the normal range, what does it really mean? Well initially we thought that if there was a different in those who had cardioprotective medication compared to those that didn't, it may prevent development of further decline in the cardiac function and then heart failure in the future. But now, there is really no difference between the groups. So perhaps the clinical implication of giving cardio protection to all cancer patients is not really that useful. Perhaps they should look at those who are at higher risk because they would have a greater fall in ejection fraction and then more cardioprotective effect of these drugs. Dr. Carolyn Lam: Yeah, totally. And perhaps the metrics that we're used to seeing in the past with greater falls of ejection fraction, maybe it just doesn't apply currently or perhaps with the specific chemotherapeutic regimens perhaps that you're using now. Because with a very small fall, and I believe you only had one heart failure event, right? If I'm not wrong in this extended follow-up. So, just to let the audience know, it was very small fall, little number of events. It's hard to really tease apart what that clinically means. Now, could I ask though, does it mean we need actually a more sensitive marker? Because there was some interesting stuff about global longitudinal strain. Could you- Dr. Geeta Gulati: I would throw that question back to Torbjørn I think. Dr. Torbjørn Omland: Yes. So that's a very interesting question Carolyn. So we did observe what seemed to be a beneficial, but a sort of minor effect on global longitudinal strain. So we know that that is the more sensitive index of systolic function than left ventricular ejection fraction, that was the pre defined primary outcome. So that's raises of course questions whether a future trial should more focus on these more sensitive indices of cardiac function. Dr. Carolyn Lam: Yeah. Geeta, could I then really put it back to you? And the tough question I always get, how do we apply these results clinically then? I mean, you see these patients right? Now what? Do you give or do you don't give? And which one do you give? And how do you identify high risk patients? I don't know. Dr. Geeta Gulati: Again, I think all the patients are unique aren't they? So that's where we have to start. So in my clinic, if I have a high risk patient with hypertension, diabetes, hypercholesterolemia, yeah perhaps they even have had a cardiovascular disease before something like this. Then I will take more care of these patients and be more careful with the echo measurements I'm doing and if I find that they have a decline in their cardiac function, I may be more eager to start them on cardioprotective medication. Dr. Geeta Gulati: But then in R-Regen we follow all the HER two positive breast cancers with echo. If I don't have echoparamaties that clearly tells me that they have a decline in the cardiac function, then I may wait to start cardio protection because none of the studies has really so far show that all patients should have these cardioprotective medication or prevention. Dr. Carolyn Lam: Nice. Thank you. That was a tough one to get at. And I suppose Torbjørn I have to give you another tough one then. Because how to address the remaining unanswered questions, right? Because one of them on my mind too, is how to identify the high risk, do biomarkers play a role? And then the other is if we then start the preventive therapies like ERBs and beta blockers, should we actually continue it forever? And so on. But anyway Torbjørn please, please, what does the future hold? Dr. Torbjørn Omland: I think it's worthy of a recap or underscoring that these are really good news for many breast cancer patients that actually the risk of an important decline in ventricular function is lower than we thought. So that may be because of several things. I think in general, those whose used these cardiotoxic drugs are lower. And we also, I think that there's increased collaboration between oncologists and cardiologists. Also meaning that we are better to pick up the high-risk patients at an early stage. Dr. Torbjørn Omland: But of course, it's very important questions that you asked regarding how to identify the high risk patients. And I think that's where really future research should focus. So there we know that traditional risk factors are important. We are looking into whether biomarkers can be used, if there's more sensitive imaging in this can be used. But so far we haven't really succeeded in getting the risk model that really identifies it on the patient level. So that's work that remains to be done. Dr. Torbjørn Omland: And then we are also looking for new types of intervention, good exercise, good other drugs. We are doing now a PRADA two study where we look at the effects of Sacubitril Valsartan in this setting. And those are also very exciting, I think, and we look very much forward to present that in the future. Dr. Carolyn Lam: Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial. I've got to ask you, why do you then call it the Chanel trial? But I think I'll save that for another day. So thank you. Thank you once again, this is fabulous and congratulations to you both. Dr. Torbjørn Omland: Thank you. Dr. Geeta Gulati: Thank you. Dr. Greg Hundley: Well listeners, welcome to our second feature discussion today. And we have with us Dr. Marc Dweck from University of Edinburgh in Scotland and our own associate editor, Victoria Delgado from Leiden in the Netherlands. Welcome to both of you. Dr. Greg Hundley: Marc, we're going to get started with you. Could you tell us a little bit about the background for your study and what was the hypothesis that you wanted to test? Dr. Marc Dweck: Thanks very much Greg for the invitation. So I guess aortic stenosis is perhaps the last major cardiovascular condition where we don't have a medical therapy. We're unable to treat these patients. We're unable to prevent progression. We're only left with a valve replacement. And so we, like a lot of groups around the world, want to develop a treatment for aortic stenosis. Our group did the first SALTIRE trial, where we looked at statins seeing if we could slow aortic stenosis progression. And that, like similar trials, was neutral. No effect on the valve progression. Dr. Marc Dweck: And so actually I've spent the last 10 years looking at some of the factors associated with aortic stenosis progression in particular. The answers that we've had from those trials have kind of come back telling us that really it's a process of calcification. If you look at what triggers progressive valve narrowness is this calcific process, that seems to be a self perpetuating disease. Dr. Marc Dweck: So the question is, how do you target this calcification process? How can you interrupt it? And how can you do that without compromising bone health in these elderly patients? So in trying to come up with a solution to that we thought about using osteopetrosis agents, which we hypothesized would maintain both bone health and reduce vascular calcification on the basis of observational data and also animal data suggesting that. And that was really where we came from in the design of the SALTIRE two trial. Dr. Marc Dweck: And doing a big trial with clinical endpoints wasn't felt to be feasible and instead we decided to look at imaging end points and see whether we could slow disease progression using these agents. Dr. Greg Hundley: Very nice Marc. And so you're really leading us into, tell us a little bit more about your study population and your study design. Dr. Marc Dweck: Yeah so we wanted to take patients from our outpatient clinic with mild, moderate and even early severe disease, asymptomatic patients crucially, patients that aren't scheduled for aortic valve replacement and see the effects of these drugs on disease progression. Dr. Marc Dweck: So we did a randomized control trial. There was three arms. Patients were randomized to Alendronate, Denosumab, these are the two osteopetrosis agents, or placebo. We then did a series of baseline imaging tests. So the primary end point was based on CT calcium scoring. So they had a baseline CT calcium score. They also had a baseline echocardiogram and they had a baseline fluoride PET scan. So this measures calcification activity in the valve. And then we essentially repeated those tests after a period of time on the drugs, or on placebo. We repeated the calcium score and the echo after two years and repeated the PET scan after one year. Dr. Greg Hundley: Very nice, and so before you tell us your results, a little bit, how many patients? And maybe their average age and the rough distribution of men versus women. Dr. Marc Dweck: Yeah so study recruited roughly 50 patients in each arm. The average age was 72 and there was 21% females in the study. So, like a lot of studies in aortic stenosis, a low female prevalence. Despite our best efforts, that's something we need to attend to in the future, but otherwise, a representative age group and patients with this disease. Dr. Greg Hundley: And what did you find? Dr. Marc Dweck: Well we found that the drugs didn't have an effect on any of these imaging assessments. So, there was no effect on the progression for CT calcium score at two years, no effects on any of the echocardiographic assessments of hemodynamic severity, and no effect on calcification activity as measured with the fluoride. Dr. Marc Dweck: So a very consistent result using multiple different imaging modalities, which I think gives us confidence that there isn't at least a dramatic effect of these drugs on disease activity or disease progression, in aortic stenosis. Dr. Greg Hundley: Very good. Well listeners, we're now going to turn to one of our associate editors, Dr. Victoria Delgado, and she is really a valvular heart disease expert member of our team. Dr. Greg Hundley: Victoria, I know you see a lot of papers that kind of come across your desk. What attracted you to this manuscript? And then how do you put the results in the context of other research that's going on to halt the progression of aortic stenosis. Dr. Victoria Delgado: Thank you Greg. So first the first thing that attracted my attention for this article is the question. We know that we don't have any medical therapy for halting the progression of aortic stenosis. And even if the previous studies have been negative or neutral, still there is the interest of trying to find a less invasive therapy for these patients, or even prevent that they arrive to surgical or transcatheter aortic valve replacement. Dr. Victoria Delgado: And the second is that these are very strong analysis because it's a randomized clinical trial and using as end points imaging. So that trial also in a way answers the question of which imaging technique we need to use in order to see the effects of specific therapies. Previous studies have used mainly echocardiography, but that only gave us information on the modynamic effects of the aortic stenosis. While in this study, we have the combination of CT and a combination of a PET that he give us also information on how the calcification is happening. So that makes the study very comprehensive and give us more insights into this pathophysiology, to this pathology particularly. Dr. Greg Hundley: Very nice. So it sounds like looking at aortic stenosis from multiple different angles, whether it be echocardiography or perhaps imaging processes that look at the progression of calcification. Dr. Greg Hundley: Well, Marc, I want to come back to you. What do you think is the next, sounds like you've been working in this area for an extended period of time. What do you see as the next research study that you and your group may undertake in this area? Dr. Marc Dweck: I Think we've got the study design about right. I think if in the future studies we want to do, I think we would adopt a similar design using these imaging end points. Dr. Marc Dweck: I have to say I'm very influenced by the recovery trial that has been conducted in the UK with COVID. I mean, here's a disease where we wanted to get a treatment as quickly as we can. And in doing that, developing a platform type trial where you potentially test multiple different promising agents simultaneously across multiple centers across the world or the UK, I think that would be the quickest way to developing a treatment. And so I'm encouraged that there are five or six very good targets where we could, for a new therapy in aortic stenosis. And I think a platform type design where we engage multiple groups using imaging as that initial end point. And then, the drugs that appear to have an effect on these imaging end points we can start to recruit more patients at those sites, into those centers, looking for clinical end points. Dr. Marc Dweck: I think that kind of discussion is happening around the world now between groups that are interested because we want to crack this problem quickly. We don't want to wait and do these different studies sequentially. We want to try and do them simultaneously. And I'm excited about that. I think if we do that, we've got a real shot at developing a treatment over the next five to 10 years say. Dr. Greg Hundley: Fantastic. Dr. Greg Hundley: And Victoria, I know you have interest in this particular area. Do you have anything you'd like to add? Dr. Victoria Delgado: Yeah. I think that those studies that Mark said are really welcome and I hope that they are positive. And give us a little bit of more to treat these patients. My main fear is that these patients are not as frequent, for example, as heart failure patients. Where we have several therapies where we have possibility to enroll patients in trials for new drugs, that we know that probably are going to be effective. But for valvular heart disease it has been always the end point to reach surgery or to reach an aortic valve replacement or indication of the mitral valve and mitral valve repair. So in early phase of the disease, my main concern is that maybe the patient is not going to be well-trained to understand what are the consequences. I want to always wait until maybe when is needed for the surgical or transcatheter procedure. Dr. Victoria Delgado: But I think that increasing the awareness of the prevalence of valvular heart disease and the consequences may help people to understand, to put more attention for an early diagnosis and develop new drugs that can help, like in this case, aortic stenosis one of the most frequent valvular heart disease, to prevent the proliferation and to prevent the replacement of the valve. Dr. Greg Hundley: Very nice. Well listeners, this has been a wonderful discussion and we greatly appreciate the input that we've been able to gather today from Dr. Marc Dweck from Edinburgh in Scotland and our own associate editor, Dr. Victoria Delgado. Bringing this information from a randomized trial, evaluating osteoporosis drugs, and really indicating they did not disrupt the progression of calcification in patients with aortic stenosis. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great rest of your week and we will catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation June 15, 2021 Issue

    Play Episode Listen Later Jun 14, 2021 25:47

    Join Mercedes Carnethon as she interviews authors Brendon Bellows, Dhruv Kazi, and Kirsten Bibbins-Domingo to discuss two articles published in the special issue: “Cost-effectiveness of Hypertension Treatment by Pharmacists in Black Barbershops” (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051683 ) and “Scaling Up Pharmacist led Blood Pressure Control Programs in Black Barbershops: Projected Population Health Impact and Value” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051782. Dr. Joseph Hill: Welcome to Circulation on the Run. My name is Joe Hill and I'm the editor-in-chief of Circulation. In recent months, we witnessed horrific acts of discrimination and violence against African-Americans. We are shocked and appalled, but yet we also recognize that this is in many ways nothing new. At Circulation, we are highly committed, longstanding commitment to shining a bright light on these pervasive inequities. And we are not willing to simply catalog the woefully longstanding racism that pocks our society, but rather we intend to shine a bright light on solutions. And with that, we are launching the first annual issue on disparities in cardiovascular medicine. This will be released in mid June corresponding to the date of Juneteenth, which is the date in the 19th century when a group of slaves in Galveston, Texas was apprised of the fact that they were no longer slaves now for two years. Dr. Joseph Hill: I'm honored to have our three editors who are running this podcast and this issue with us, they are Dr. Mercedes Carnethon from Northwestern University, Dr. Karol Watson from UCLA, both of whom are associate editors with the journal. And I'm pleased that Michelle Albert, who is one of our senior guest editors at UCSF will be joining us. These three professionals have led this initiative and I would like to spend a few minutes talking with them about this. First let's turn to Michelle if I may. Michelle, what do you think is required from a workforce perspective to make headway, to eliminate these disparities? Dr. Michelle Albert: Thank you, Dr. Hill. And I would first say that it is an honor to have been able to participate in this disparities issue focused on African-Americans and health. First, I think that it is important for our audience to understand that the metrics actually behind a workforce. In cardiovascular medicine, only 13% of fellows are underrepresented fellows, meaning black or African American, Hispanic, or Latinx, native Americans, Alaska natives, and Pacific Islanders. And only 9% of faculty are UIM in cardiovascular medicine. This stems from a pipeline or pathway issues that go all the way back to kindergarten and middle school. Indeed, over the last three decades only, although there's been a 50% increase in applications for blacks and Hispanics, the applications have only increased by 1.2% and there has been a drop in Alaska native and American Indian applications by 30%. Dr. Michelle Albert: So with regards to how improve these statistics, we have to have multifaceted approaches related to understanding pipeline barriers, which include things like lack of encouragement, lack of role models and paying attention to recruitment, but not just the only recruitment at the pre-medical level, immediate pre-medical level, but way prior to the pre-med level, we have to engage middle-aged and high school students in STEM and thereafter at the pre-medical level, we have to make sure that students get the appropriate advice to ensure successful careers in college that would then engender successful applications to medical school. Dr. Michelle Albert: Once we get into the actual medical institutional systems, we have to address structural barriers to discrimination that exist, that impede the progress through pathways in medicine. And these barriers exist at the medical school level, the residency level, fellowship level and faculty to leadership levels. I would say just a couple of examples at the medical school level to address would be actually paying attention to the fact that MCAT scores, we need to pay attention to a whole range of MCAT scores that focus on success in medical school and not just a specific hard cutoff. In residency we need to focus on evaluation disparities for UIM versus non UIM that then set the pathway again for a lack of progress into extremely competitive specialties like cardiovascular medicine. At the fellowship level we know that only 6% of program directors actually value diversity as one of the top three entities when ranking applicants. Duke School of Medicine actually had a really innovative process of holistic review and at all levels there should be holistic review that pays attention to distance, travel and metrics as well as attributes. Dr. Michelle Albert: And at Duke for example, what they did was they tripled actually their UIM enrollment in cardiology fellowship from 9% to 33% after employing a holistic review process that focus less on metrics and more on a combination of metrics, distance traveled, et cetera. Once folks are in the pipeline we have to set up systems of support to help trainees and faculty thrive in clinical learning and work environments because we noted small differences and assess clinical performance, amplify to large differences and evaluations, grades, and awards that have gone toward consequences for our workforce. And then I would say these are not my recommendations here or not all inclusive. But two other things I think that we really need to pay attention to besides the mentorship and sponsorship is actually stemming isolation for trainees and faculty within our structures and systems as well as ensuring that we all have implicit bias training and also the effect of implicit bias training is measured over time on the impact on healthcare outcomes and our pipeline outcomes. I know that was a mouthful, Joe, but this is a very complicated topic. Dr. Joseph Hill: Well, it certainly is Michelle. And I think all our listeners know that you have been and are a major leader on an international scale around these topics. Thank you for your leadership. My next question has to do with building trust with black patients in terms of their willingness to engage with their physician and also participate in research studies and trials. Karol, Dr. Watson from UCLA, maybe you can comment on that. Dr. Karol Watson: Yes, I would be happy to. And I have to piggy back on what Michelle just said. You start off talking about trust, there has to be a trust between the patient and the provider, the researcher and the participant, and that trust really it's multifactorial as Michelle states, but it really does rely on having a workforce that looks like the patient population, having principal investigators that look like the participants. We have an issue with trust in medicine in many areas, but one of them is lack of trust amongst African-Americans. When surveys are done and they ask patients to endorse or not endorse certain statements, the statement I trust my healthcare provider, it's less likely to be endorsed by African-American patients than others. And much of that mistrust is well earned. We're all aware of some horrific medical injustices that were meted out to certain communities, including African-American communities. Dr. Karol Watson: We're all aware of the Tuskegee syphilis study, but there are many others. So without trust, there really cannot be a healthy, collaborative care model that ensures optimal patient outcomes. So I think one of the most important things that we have to stop doing is thinking of blaming the patient for being, "Nonadherent, non-compliant, difficult," because many things go into that equation and much of it is on our backs. And as Michelle says, we have to diversify our workforce to start off. And I think there are so many other levels of Michelle really nicely laid out, but there are really so many other levels and including getting more African-Americans into clinical trials and we can't just do the same thing we've always done and expect to get different results. So we say, "Oh, African-Americans just won't up for research." Well, maybe we're not making that research relevant, appropriate, and easy for them. Dr. Karol Watson: If we ask people to come to our research centers between 8:00 and 5:00, Monday through Friday, when they're working three jobs and they have to watch their grandkids and they have no one to help. That's a very difficult ask, when you're asking people who are struggling for basic needs and basic survival to do extra things. It's a very difficult ask and we have to make it easier for them because I am of a firm belief that everyone wants to do the right thing. They want to help medical professionals get the research needed, do the right thing to care for their own health, but it has to be accessible and that's something we haven't done a great job doing. Dr. Joseph Hill: Well, thank you. What a challenge and that's why I think this issue that the three of you have spearheaded has helped move that needle around those sorts of questions. So my last question is a broad one and maybe even the hardest one that I will throw to Dr. Carnethon and that is what are the biggest remaining threats? What does the future look like when you put your headlights on high beam to solve these problems? Dr. Mercedes Carnethon: Well, thank you so much Dr. Hill, and it's great to follow my colleagues who've offered wonderful insights from multiple perspectives. When we think about the path forward, we have to really consider how we got here. And we didn't get here solely through faults in one system, for example, academic medicine, we got here because of the broader systemic and structural issues that have led to differences in access, that have led to the mistrust we're talking about and that have led to fewer opportunities for academic advancement for black adults within this country. And the path forward is going to have to be a collaborative path. It can't just be the researchers and clinicians within academic medicine making a change because we can't make those changes and reach out in isolation of the context in which the patients who were seeking to help live in. So it requires partnerships with individuals at the community level, so that we can think about how we roll out effective interventions. Dr. Mercedes Carnethon: So those interventions that work one-on-one how do we get those out to the people who need them the most? That requires partnerships with the community and even changing the environments in which people live, making them healthier. It requires partnerships with academic institutions building off of the point that Dr. Albert made about needing to start and bolster the pipeline early so that we can get researchers and clinicians who look like the patients that they're trying to serve. And ending as well with Carol's point, when we run a study and we don't have representation from across a range of socioeconomic status from multiple individuals, black individuals, white, other races and ethnicities, we don't know how well those therapies are going to work, or whether there are unique situations that are going to lead them to be less effective in one group versus another. So I think I would end really with the point that the path forward to promoting equity is one that's going to involve partnerships across multiple different domains. And I do feel very hopeful that we can get there, especially as we're calling attention to these important issues right now. Dr. Joseph Hill: Well, I will end by saluting the three of you because you are in fact pointing away to a path forward and concrete things to make a difference. And it is my pleasure and honor to work with the three of you leaders. And I'm so proud of this issue, which will be a recurring issue and in June of every year. And thank you again for what you've done, you're making an important difference in our world. Dr. Karol Watson: And thank you so much for Dr. Hill for spearheading and supporting this effort. It is so important. Dr. Mercedes Carnethon: Yes, thank you. Dr. Joseph Hill: My pleasure. Dr. Michelle Albert: It's indeed an honor. And we have to lead by example, and I hope that we do. Dr. Mercedes Carnethon: Thank you so much. Dr. Mercedes Carnethon: I'm really excited as we move past our discussion amongst the editors to have an opportunity in this podcast to also speak with a team of authors who submitted two papers to our very special issue we have with us today, Dr. Brandon Bellows, Dr. Kazi and Dr. Kirsten Bibbins-Domingo who are sharing their findings about pharmacist led interventions to manage blood pressure among black Americans in barbershops. So thank you so much for submitting your important work to Circulation. I'd like to start with questions for you, Dr. Bellows. So your particular manuscript is addressing the cost effectiveness of hypertension treatment by pharmacists in black barbershops. Thank you for working on this very important work, because it really extends some of what we talked about earlier, which is the need to scale up and disseminate what we know to be effective interventions in populations. So can you tell us a little more about what you studied and what was unique? Dr. Brandon Bellows: Yeah, thank you so much. So we studied the value of a program to bring clinical pharmacists into black owned barbershops as you mentioned, and have the pharmacist partner with the barbers to manage hypertension in black men. As we know, black men are disproportionately impacted by both hypertension and cardiovascular disease. So our work was based on a randomized trial that was performed in barbershops in Los Angeles County. And this was led by the late Dr. Ron Victor. So we're really building upon his great foundation. In that trial they found that the pharmacist-barber collaborations substantially reduced systolic blood pressure by over 20 millimeters of mercury, relative to Barber's providing education alone over one year. So given that having pharmacist drive around barbershops and Los Angeles is a very expensive proposition, but we wanted to know if the potential benefits long-term would outweigh some of those high upfront costs and would it be a cost-effective to do this in Los Angeles? So really focused on the trial. Dr. Brandon Bellows: So to do this, we combined the data from the randomized trial with our computer simulation model to try and project long-term clinical outcomes. So upto 10 years, so for both blood pressure, cardiovascular disease events, as well as the economic outcomes. So total healthcare costs, costs of the program and so on. So what we found was that having pharmacists work with barbers and these black owned barbershops was a cost-effective way to reduce blood pressure in black men. Over 10 years, we projected that the program would cost about $2,400 more, and that's total healthcare costs than barbers providing education alone so they enter the control arm in the trial, and we found that they would prevent about 30% of cardiovascular disease events over 10 years. So the incremental cost effectiveness ratio or ICER, which is how we define cost-effectiveness was $43,000 per quality adjusted life year gained. Dr. Brandon Bellows: And this is below the threshold recommended by the American Heart Association of $50,000 per quality adjusted life year gained to define something as highly cost-effective. So doing this with a highly cost effective way to improve blood pressure in black men. So one thing that makes our study unique is that our computer simulation model allows us to explore different designs of the program to see how that might impact the cost effectiveness. So for example, if we were to use only generic antihypertensive medications, or if we were to decrease the length of the intervention from one year to six months, the pharmacist barber program was even more cost effective. So given the long-standing disparities in cardiovascular disease that have been experienced by black men in the United States, we're really hoping that how our research can help motivate healthcare payers to adopt these kinds of non-traditional approach delivering hypertension care, because if nobody's paying for it, then there's not going to be uptake in the community. Dr. Mercedes Carnethon: Yeah. Brandon, thank you so much for sharing that and sharing the details about what you found. I love this line of work because quite often we've spent a lot of time discussing and describing disparities, but less attention considering ways in which we can reduce disparities by reaching people where they are. So that brings me to you Kazi. So your study uses the same population, but addresses a slightly different question that I think is very relevant to our audience as we seek to try to promote cardiovascular health equity. So tell us a little bit about what you did in the same population and what you found. Dr. Dhruv Kazi: I want to also start out by acknowledging that the study is anchored in the vision and genius of the late Dr. Ron Victor, who ran the barbershop based blood pressure controlled studies in Dallas, and then in Los Angeles. And kind of motivated by his pragmatic optimism, this idea that we have a problem where others high rates of uncontrolled blood pressure in black men, but it is a problem that can be addressed through a novel intervention that will then have to be contextualized. He was open-eyed about the need for contextualization that even though there's a large 20 millimeter mercury reduction in blood pressure, any intervention, when we go beyond Los Angeles would have to be contextualized for geography and for payer. Would treating blood pressure in Dallas, or San Francisco, or Detroit, or Atlanta would look different from both the economics and the practical aspects of delivering this care in Los Angeles?   Dr. Dhruv Kazi: So we set out to ask the question that if we were to make these barbershop based pharmacists led blood pressure control programs more widely available across the country in urban areas, metropolitan areas, and were able to enroll black men with uncontrolled blood pressure into these programs, what would the clinical impact be and what would the economic constraints be for these programs to be sustainable? We estimated that about 950,000 black men could be enrolled in a program of this nature. So that's about a third of black men with uncontrolled hypertension and that doing so on an annual basis would reduce about 8,600 or 8,600 major adverse cardiovascular events. That's about including 1800 MIs and 5,500 strokes. So quite a large number of events, but 40% of events in enrolled populations. And we then set out to ask, "Well, that's great. If we could deploy these programs at scale, there's the potential for substantial clinical impact, what would the economic constraints have to be for this program to be sustainable?" Dr. Dhruv Kazi: So if we imagine that this were not a delivery program but rather a pill, and you were willing to pay $100,000 to reduce per quality adjusted life here for blood pressure control medication, how much would we be willing to pay for this barbershop based program? And we found that approximately it would have to be delivered at a cost of $1,400 per patient per year. Now, $1,400 per patient per year is a substantial amount of money when you scale it up across the entire eligible population, but at the same time would require innovation and delivery that goes beyond pharmacists driving from one barbershop to another. So what we hope is that our work will stimulate this conversation around how can we take this intervention that is highly effective, that is potentially scalable and adapted in a way that we can afford to deliver it nationwide without losing effectiveness that we saw in the Los Angeles trial? Dr. Mercedes Carnethon: Thank you so much Dr. Kazi. And this just generates a lot of discussion as we really think about how we can bring interventions to people and how we can have an impact. So Kirsten, I'm so pleased that you were also able to join us as one of the senior authors, senior members of these research teams, because we really value your perspectives as well about where do the findings from this study situate us in the field. How do we move forward to achieve our goals of achieving equity and particularly among black patients and black adults in this country who we know have experienced significantly higher rates of hypertension and hypertension related disorders, we have a significant need here. So tell us how do we use this important information in order to make a difference? Dr. Kirsten Bibbins-Domingo: Thank you so much for having us and congratulations on this really important issue. Dr. Kirsten Bibbins-Domingo: I think what we see here in why these papers and this work is important is that it is really trying to take the important science that we're producing, trying to aim that addressing disparities and put it in the context that we could ideally rapidly translate it to actually help and address this issue. And with hypertension, we have both the urgency of declining rates of blood pressure control in the US as well as the persistent disparities that we see. So we have this effective intervention marrying a care provided by clinical pharmacists with community-based venues and partnership with black barbershops that is highly effective. The detailed studies led by Brandon really suggest that even in LA, pharmacists driving around this is a cost-effective intervention and that if we were to scale it, it could actually reach a lot of black men in the US and even though $1400 per person per year is a lot of money, it's actually not out of context of other things that we do that are high priority for our healthcare systems. Dr. Kirsten Bibbins-Domingo: So what we hope is that these two papers together help us to start to bring more people to the table to how we can translate now an effective trial, a trial that can effectively scale in a cost-effective way to thinking about what we could actually do. So how might this look? We think this is something that we hope health systems start to engage in. When they see disparities in the care for their members, for their patients, how could they think more creatively? Dr. Kirsten Bibbins-Domingo: How could payers, how could Medicaid for example, think about incentivizing different ways of delivering hypertension care? How could we think in other contexts about departments of public health or cities that really want to have a population-based approach to improving cardiovascular health? And money isn't everything, but is an important thing that many of these entities are thinking about and understanding both that this is a cost-effective intervention and that the amount per person to actually achieve this important role in cardiovascular health is not out of scale for other things that we prioritize in terms of health I think is important and that's what we hope people will take away from these important studies. Dr. Mercedes Carnethon: Wow, I really appreciate the time and attention that your team put into designing these really high impact research studies that achieve what our goal is, is to really think about ways in which we can address and eliminate disparities. I've really loved hearing about this work, and I hope that a broad audience receives it and really thinks about some of what we talked about before, which are the multiple different parties and disciplines that are required to come to the table for us to effectively address disparities. So thank you so much for spending time with us at our Circulation on the Run podcast, Dr. Kirsten Bibbins-Domingo from University of California at San Francisco, Dr. Brandon Bellows from Columbia University College of Physicians and Surgeons and Dr. Kazi from Beth Israel Deaconess Medical Center. So thank you so much for spending time with us today. Dr. Dhruv Kazi: Thank you for having us. Dr. Brandon Bellows: Thank you. It's been a pleasure. Dr. Mercedes Carnethon: And finally, I'd like to end by thanking our listeners for spending time with us today. We hope that you enjoyed the podcast, and we hope that you will enjoy the issue even more. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation June 8, 2021 Issue

    Play Episode Listen Later Jun 7, 2021 24:39

    This week's podcast features author Nicholas Mills and Guest Editor Allan Jaffe as they discuss the article "High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial." (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052380) 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 and VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to examine cardiac troponin, high-sensitive cardiac troponin, and its association with myocardial infarction. But first, before we get to that, how about we grab a cup of coffee and start in and review some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would love that. The first paper brings up the problem of stroke, remaining a devastating complication of transcatheter aortic valve replacement or TAVR. Now, this stroke risk has persisted despite refinements and the technique and increased operator experience, while cerebral embolic protection devices have been developed to mitigate this risk data regarding their impact on stroke and other outcomes after TAVR are limited. Dr. Carolyn Lam: Dr. David Cohen from Cardiovascular Research Foundation in New York and colleagues performed an observational study using data from the STS-ACC TVT registry, including more than 123,000 patients from almost 600 sites who underwent elective or urgent transfemoral TAVR between January 2018 and December 2019. Dr. Greg Hundley: Wow, Carolyn, this sounds like a really good use of the registry. What were the results? Dr. Carolyn Lam: Indeed, in this nationally representative observational study, the authors did not find an association between embolic protection device use for TAVR and in-hospital stroke in their primary instrumental variable analysis. And that's a technique designed to support causal inference from observational data with site-level preference for embolic protection device use within the same quarter of the procedure as the instrument. Dr. Carolyn Lam: However, they found a modestly lower risk of in-hospital stroke in their secondary propensity weighted analysis. These findings provide a strong basis for large-scale randomized control trials to really test whether embolic protection devices provide meaningful clinical benefit for patients undergoing TAVR. And this is discussed in a nice accompanying editorial by Dr. Tam and with Wijeysundera from University of Toronto. Dr. Greg Hundley: Very nice Carolyn. Well, my first paper comes to us from Professor Hua Zhang from Shanghai Children's Medical Center. Cyanotic congenital heart disease is a complex pathophysiological condition involving systemic chronic hypoxia and some cyanotic congenital heart disease patients are chronically hypoxic throughout their lives which heightens their risk of heart failure as they age. Dr. Greg Hundley: Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-Alpha. And Carolyn, this study aims to determine the effect of chronic hypoxia on cardiac metabolism and function in cyanotic congenital heart disease patients and its association with age. The authors investigated the role of hypoxia-inducible factor 1-Alpha in this process, and the potential therapeutic targets for this were explored. Dr. Carolyn Lam: What did they find Greg? Dr. Greg Hundley: In cyanotic congenital heart disease patients maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout mice, chronic hypoxia failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF1-Alpha and was responsible for cardiac metabolic maladaptation in animals exposed to chronic hypoxia. Dr. Greg Hundley: Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal chronic hypoxia animals. And so, Carolyn, perhaps future studies could test whether pioglitazone administration during puberty might improve cardiac function in cyanotic congenital heart disease patients. And this article is nicely accompanied by an editorial from Professor Ghofrani. Dr. Carolyn Lam: That's really interesting. For the next paper we're going from cyanotic congenital heart disease to plain old hypertension asking the question, What is the association of blood pressure classification using the 2017 ACC/AHA blood pressure guideline with risk of heart failure and atrial fibrillation? Well, this question was addressed by Dr. Kaneko and colleagues from University of Tokyo who performed analysis using a nationwide health claims database collected in the JMDC claims database between 2005 and 2018. Now note, this was more than 2 million patients followed for a mean of more than a thousand days in whom more than 28,000 incident heart failure, and more than 7,700 incident atrial fibrillation events occurred. Dr. Greg Hundley: Carolyn, this is a really large cohort a lot of events. What did they find here? Dr. Carolyn Lam: Among adults not taking anti-hypertensive medications and with no prevalent history of cardiovascular disease, stage one and stage two hypertension, according to the 2017 ACC/AHA blood pressure guidelines was associated with a higher incidence of heart failure and atrial fibrillation. The population attributable fractions for heart failure associated with stage 1 and stage 2 hypertension were 23.2% and 51.2% respectively. The population attributable fractions for atrial fibrillation associated with stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The categorization based on 2017, ATC/AHA blood pressure guidelines may improve risk stratification for identifying adults at high risk for heart failure and atrial fibrillation. Dr. Greg Hundley: Wow Carolyn. Really useful data and something I love about our journal, a transition from a large cohort study on hypertension, and now we're going to delve into the world of preclinical science and talk about myocardial hypertrophy. Carolyn, exercise can induce physiological myocardial hypertrophy and former athletes can live five to six years longer than non-athletic control suggesting a benefit after regression of physiological myocardial hypertrophy. Dr. Greg Hundley: Accordingly, these authors led by Professor Yulin Liao from Nanfang Hospital and Southern Medical University hypothesized that anti-hypertrophic memory exists after physiologic myocardial hypertrophy has regressed increasing myocardial resistance to subsequent pathological hypertrophic stress. In this study, C57BL, six mice were submitted to 21 days of swimming training to develop physiological myocardial hypertrophy. Then after termination of the swimming events and exercise, the physiological myocardial hypertrophy regressed within a week. And these physiological myocardial hypertrophy regression mice termed the exercise preconditioning group or HP, and then sedentary mice as a control group underwent transverse aortic constriction, or a sham operation and were observed for four weeks. Dr. Greg Hundley: Finally, in these two groups, cardiac remodeling and function were evaluated using echocardiography invasive left ventricular hemodynamic measurements and histological analysis. Dr. Carolyn Lam: Wow. Exercise induced and I hypertrophic memory in the heart. That is so cool. Greg, could you summarize what they found? Dr. Greg Hundley: Yeah. And how about that exercise stimulus? The mice were swimming. Carolyn, these authors found that exercise-induced physiological myocardial hypertrophy can produce cardioprotective effect. And this cardioprotective effect continues to exist after the physiological myocardial hypertrophy subsides. And it's termed a phenomenon exercise hypertrophy preconditioning. Dr. Greg Hundley: Now, mechanistically, the investigators found that exercise hypertrophy preconditioning up regulates the expression of the long noncoding RNA Mhrt779 by increasing the three methylation of histone 3 at the A4 promoter of Mhrt779. Dr. Greg Hundley: Carolyn, also cardiac overexpression are knocked down of Mhrt779 respectively enhanced or weakened the anti hypertrophy effect of exercise hypertrophy preconditioning. The clinical implications of this research are that these results will likely stimulate further research into the mechanisms of exercise hypertrophy preconditioning, and Mhrt779 may be a potential therapeutic target for myocardial heart hypertrophy and heart failure in clinical practice. Dr. Carolyn Lam: Wow. Thanks so much, Greg. That was an incredible summary. Dr. Carolyn Lam: Let me tell you what else is in today's issue. There's an exchange of letters amongst doctors Mehmood Donkor, and Westermann regarding the article “Left Ventricular Unloading is Associated with Lower Mortality in Cardiogenic Shock Patients Treated with Venal Arterial Extracorporeal Membrane Oxygenation.” There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman with Palpitations. Is It a Poison or Is It a Reality?” Dr. Carolyn Lam: In Cardiology News by Tracy Hampton, she describes new research, revealing mechanisms behind exercise-induced heart damage, new details behind muscle injury repair, and new insights on plasma membrane rupture during cell death. Very interesting. A new section there. There's a Perspective piece by Dr. Passman on “'Pill in the Pocket?' Anticoagulation for Atrial Fibrillation. Is That Fiction, Fact, or Foolish?” Dr. Greg Hundley: Great, Carolyn. Well also in the mailbag, there's a Frontiers and medicine piece from Professor Rohatgi entitled “HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.” And then finally, Carolyn, a Research Letter from Professor Felker, entitled Probabilistic Re-adjudication of Heart Failure Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn, what a great group of articles summarized. How about now we proceed to that feature discussion? Dr. Carolyn Lam: Let's go Greg. Dr. Greg Hundley: Well, listeners. We are now to our featured discussion today and we have with us one of our associate editors who has submitted a paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have a guest editor. Sometimes he's been a feature author, but now he's serving as a guest editor, Dr. Alan Jaffe from Rochester, Minnesota. Welcome gentlemen. Dr. Greg Hundley: Well, Nick, could you start us off first and describe for us the hypothesis that you wanted to test, and then maybe also provide a little bit of context or background around the study that you and your team have just performed. Dr. Nicholas Mills: Thanks, Greg. I've been working for about a decade trying to understand how we can get the value from high-sensitivity cardiac troponin in our clinical practice. We've tried a number of different approaches to implement them for the benefit of patient care that I'm particularly proud of this trial. What we'd recognized that I think with the rollout of these assays across Europe and more recently in America is that they're excellent tests, but they do generate some diagnostic uncertainty in clinical practice. Dr. Nicholas Mills: But as we've got used to using them, we've learned that actually their major strength is that the confidence that they bring in ruling out myocardial infarction rather than ruling it in. And they allow us to make really early decisions often with a single test at the point of arrival, where we can say with absolute confidence that a patient does not have acute coronary syndrome and it's unlikely to have a problem in the next 30 days or one year based on just how low that high sense of high-sensitivity cardiac troponin result is. And I've been a strong advocate for using these tests in that way for some time. But the limitation has been that much of the work in this field has been observational. And so the patients were actually managed accordingly because of uncertain pathways. And there's always been some uncertainty as just how effective they are when in clinical practice, whether using these approaches are safe. And so we designed the Historic Trial to address that definitively in our hospitals in Scotland. Dr. Greg Hundley: Very nice Nick. So what was the study population and what was the design for this Dr. Nicholas Mills: Thanks Greg. So we use an interesting study design set wage cluster, randomized controlled trial, where rather than randomizing individual patients and randomized hospitals in Scotland, in order to do a trial like this, you need very detailed infrastructure because we wanted to enroll every consecutive patient, attending our emergency departments with symptoms, suspicions of acute cardiac syndrome. We embed it so into our care path, which allows our clinicians to enroll patients for us. We were keen to enroll all consecutive patients because we wants to be confident that our findings were truly generalizable at any included patients with complex comorbidities presenting that of ours who were sick unwell, which is often not the case; they've been observational studies. We randomized hospitals and follow up patients with acute coronary syndrome up for a year in order to determine whether the implementation of already changed clinical care and that was safe and did not lead to recurrent and in the future. Dr. Greg Hundley: Very nice. So Nick, in this randomization of hospitals, how many total patients did you encounter and then what were your study results? Dr. Nicholas Mills: So we enrolled 31,492 consecutive patients. I've crossed all seven hospitals implementing our early relapse pathway, reduced length of stay overall in the hospital. By just over three hours, we increased the proportion of patients who are directly discharged home from the emergency department by more than 50%. So that overall 71% of patients attending hospital with possible acute coronary syndrome were able to be discharged from the emergency department rather than being admitted unnecessarily for further investigations. But the critical result was, was that major change in the care pathway safe. We had a non-inferiority design. We had a very small number of safety outcomes at 30 days, and it was difficult to prove non-inferiority, but the event rate favored the implementation there. Dr. Nicholas Mills: They will have pathway with the 0.4% of patients we attend within 30 days of heart attack or dying from heart disease for our implementing it and 0.3% in and crucially, we followed everyone up for a year and were able to demonstrate that the safety outcome was not increased in those that we are able to that pathway one year with absolute confidence. And furthermore, there was no difference in re attendance or an all-cause mortality. We the two different arms of the trial. So we concluded that the early relapse pathway was effective and safe, and that using this approach we'd have major benefits from patients who can avoid unnecessary for healthcare providers in terms of reducing actual cost limitations. Dr. Greg Hundley: Fantastic. Well listeners, we're now going to turn to our guest editor, Dr. Alan Jaffe, and Alan, could you help us put into perspective these new data regarding high sensitivity, proponent, and also comment what attracted you to this article so much so that you feel it's needs to be published and circulated worldwide in the literature? Dr. Allan Jaffe: One of the important areas in the field of biomarkers is the movement just finally occurring. And Nick has been the forefront of this, of starting to do randomized trials. Observational data is just that it's observational. The patients are not created based on the information that is by the biomarkers. Patients can be missed if you're missing a sample, you exclude those patients. In addition, most observational trials, try and get informed consent. And by getting informed consent often miss the sickest patients. So what's desperately needed by the field. And which is just now starting with two or three ongoing randomized trials is just that a randomized trial where the investigators are forced to use the data, to manage the patient. And by using the step wedge design that Nick and his group has used in other trials as well, they guarantee that they don't miss patients either. Dr. Allan Jaffe: So that it's comprehensive and takes all into account. This is terribly important to then validate things like in this instance, the rule-out pathway. And I think these data do substantially confirm the fact that a single sample rule-out strategy using the cutoff value that Nick had previously established as optimizing the percentage of the population that can be included works well. It is unfortunate that the way in which they design their trial mist and design their non-inferiority outcome for safety was such that they ended up not finding significance to that. But I agree with Dr. Mills in the sense that the outcome adverse effects were so low, that despite that I think there's very important and reasonable data that this strategy is also safe. Dr. Greg Hundley: Very good. Well, Nick, thinking forward, what do you feel is the next study that needs to really be performed in this area? Dr. Nicholas Mills: I completely agree with everything Alan said. I think there's lots of really interesting approaches to find a group diagnosis, risk stratification of this really common condition. We need trials that demonstrate these approaches actually influence care and outcomes. For me, the challenge remains how to really harness these great tests to route the ruler of my cognitive function. I run about ads of patients with elevated cardiac troponin added due to an underlying condition that is an acute coronary syndrome. And we're starting to think about ways in which we can individualize our decision-making a little bit moving to walk away from binary thresholds, because values are influenced by age, by sex, by comorbidities like renal disease and preexisting heart failure about heart disease. Dr. Nicholas Mills: And by incorporating some of these patient factors into the interpretation of cardiac troponin. I think we can give clinicians better guidance on who to treat early with antiplatelet therapies and who needs invasive investigation than just simply saying that the troponin concentration is all positive or negative. And it's our challenge, I think, is how to harness that information, make it workable in clinical practice, and then demonstrate that by doing so we actually target effective therapies better, and that it makes a difference for patient care. So this is where we're working on at the moment. And I hope that in due course, we'll be able to do randomized trials in this space and that will move things forward again. Dr. Greg Hundley: Alan, do you have anything you'd like to add to that? Dr. Allan Jaffe: Yes. I think we're in a new era. We are finally starting to see there are now two or three randomized trials. It is time that the biomarker diagnostic studies graduate to a higher level of evidence, meaning randomized controlled trials. Nick is leading the way in that regard and I suspect and hope that subsequent trials, although observational trials may help inform which ones we should do, but that subsequent trials will continue to be randomized and generate the more robust data that randomized trials are capable of generating. Dr. Greg Hundley: Well, thank you both. And Nick, thank you for bringing us this research and also Alan, for evaluating it and providing this commentary today. It's quite exciting to have really this new information produced from a randomized trial, which evaluated the utility of a low high sensitivity treponema value in patients presenting to hospitals with chest pain syndromes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.  

    Circulation June 1, 2021 Issue

    Play Episode Listen Later Jun 1, 2021 26:01

    In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed. 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, Dr. Carolyn Lam: Greg, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up. Dr. Carolyn Lam: But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world? Dr. Greg Hundley: Well, Carolyn, I would think that, actually, they might be linked. Dr. Carolyn Lam: That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents. Dr. Greg Hundley: Wow, Carolyn. So what did they find here? Dr. Carolyn Lam: Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction. Dr. Carolyn Lam: Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world. Dr. Greg Hundley: Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES. Dr. Greg Hundley: And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat. Dr. Carolyn Lam: All right, Greg. So the DTS compared to the SES, what did they find? Dr. Greg Hundley: Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups. Dr. Greg Hundley: Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents. Dr. Carolyn Lam: Okay, another interesting study. And so, how did they do that? What did they find? Dr. Greg Hundley: Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months. Dr. Greg Hundley: And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher. Dr. Greg Hundley: So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium. Dr. Greg Hundley: And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus. Dr. Greg Hundley: In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher. Dr. Greg Hundley: And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved. Dr. Greg Hundley: And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers. Dr. Carolyn Lam: Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, very interesting. So what did they find here? Dr. Carolyn Lam: Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself. Dr. Carolyn Lam: There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before. Dr. Carolyn Lam: I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta. Dr. Carolyn Lam: So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means. Dr. Peter Light: Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells. Dr. Peter Light: So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel. Dr. Peter Light: So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all. Dr. Peter Light: And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes. Dr. Peter Light: We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine. Dr. Peter Light: And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death. Dr. Carolyn Lam: Thomas, could you put this in context for us? Dr. Thomas Eschenhagen: Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?   Dr. Thomas Eschenhagen: And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine. Dr. Thomas Eschenhagen: And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare. Dr. Thomas Eschenhagen: But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried. Dr. Peter Light: Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not. Dr. Carolyn Lam: Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found? Dr. Jesper Jensen: Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients. Dr. Jesper Jensen: So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits. Dr. Jesper Jensen: However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients. Dr. Jesper Jensen: So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks. Dr. Jesper Jensen: And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes. Dr. Jesper Jensen: We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population. Dr. Carolyn Lam: Tell us what you found after 12 weeks. Dr. Jesper Jensen: Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo. Dr. Jesper Jensen: And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan. Dr. Carolyn Lam: Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh? Dr. Justin Ezekowitz: Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients. Dr. Justin Ezekowitz: Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life. Dr. Justin Ezekowitz: So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road? Dr. Jesper Jensen: Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss. Dr. Justin Ezekowitz: So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy. Dr. Jesper Jensen: Yeah, that could be a way to put it. I would agree upon that. Dr. Justin Ezekowitz: So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn. Dr. Carolyn Lam: Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first. Dr. Jesper Jensen: So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more. Dr. Carolyn Lam: Thank you. And Peter, could you very quickly tell us what are next steps, in your view? Dr. Peter Light: Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging. Dr. Peter Light: Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that. Dr. Peter Light: And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now. Dr. Carolyn Lam: You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation May 25, 2021 Issue

    Play Episode Listen Later May 24, 2021 20:20

    Please join editorialist Padma Kaul and Associate Editor Karol Watson as they discuss the original research article "Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study" and the editorial "Pregnancy as Oracle: What it Augurs for Women's Health." 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. Dr. Carolyn Lam: Oh Greg, today's feature paper is really important. It's about preterm delivery and the long-term risk of stroke in women. A very, very important cardiovascular risk factor that we don't talk about. This is important data from the national cohort and co-sibling study. So hang on, look out for it. But first, how would you take us through some of your spotted original papers? Dr. Greg Hundley: So Carolyn, my first paper comes to us from Dr. Guido Claessen from University Hospitals in Leuven. Exertional intolerance, Carolyn, is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension, and traditionally, the etiology has been attributed to central factors, including ventilation, perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. So pulmonary endarterectomy and balloon pulmonary angioplasty provides substantial improvement of functional status and hemodynamics. However, despite normalization of these pulmonary hemodynamics, exercise capacity often does not return to age-predicted values. So by systemically evaluating the oxygen pathway, these authors aim to elucidate the causes of functional limitations of chronic thromboembolic pulmonary hypertension patients before and after these pulmonary vascular interventional procedures. Dr. Carolyn Lam: So very interesting. Tell us more, what did they find, Greg? Dr. Greg Hundley: Yeah, well Carolyn, they utilize cardiovascular magnetic resonance, as you know, one of my big interests, but guess what? They also did it with exercise and simultaneous invasive hemodynamic monitoring. The authors in doing so, sought to quantify the steps of the oxygen transport cascade from the mouth to the mitochondria in patients with this pulmonary hypertension. So they had 20 subjects with pulmonary hypertension and they compared those to 10 healthy individuals. Furthermore Carolyn, the authors evaluated the effect of pulmonary vascular intervention procedures, both endarterectomy or balloon angioplasty, on the individual components of the cascade in 10 of those 20 individuals. Dr. Greg Hundley: So what did they find? They found that in this chronic thromboembolic pulmonary hypertension condition, these patients, they have significant impairments of all steps in the oxygen utilization cascade, resulting in markedly impaired exercise capacity, the thick equation uncoupled. And pulmonary vascular interventions increased, peak VO2, by partly correcting the oxygen delivery, but having no impact on abnormalities in peripheral oxygen extraction. Dr. Greg Hundley: So Carolyn, this suggests that the current interventions only partially address patient's limitations and that additional therapies may improve functional capacity, such as improvement in skeletal muscle function and metabolism. So maybe one of your faves, cardiac rehab, perhaps could work on some of those peripheral factors in these patients. So, really interesting, very well accomplished study. Dr. Carolyn Lam: Nice, elegant and clinically impactful. Very nice. Well, the next paper is the same. We know that prenatal detection has benefits for infants with hypoplastic left heart syndrome and transposition of the great arteries. Well, this next paper describes the largest multicenter study to evaluate whether social economic quartile, public insurance, race or ethnicity, rural residence and distance from the residence are associated with the prenatal detection of critical congenital heart diseases in North America. This study is from Dr. Krishnan from Children's National Medical Center in Washington, DC and colleagues. Basically, what they found was that lower socioeconomic position, Hispanic ethnicity, and rural residence were all associated with decrease prenatal detection rates of hypoplastic left heart syndrome and transposition of the great arteries. Dr. Greg Hundley: Wow Carolyn, so social determinants of health, interesting. So how do we, as clinicians, apply these results? Dr. Carolyn Lam: Well, clinicians can use the findings of the study to focus efforts on improving overall prenatal detection rates for congenital heart disease. They can specifically improve health equity in prenatal detection and timing of prenatal detection by improving linkages between tertiary care centers and these populations and regions that were identified in this study. Dr. Greg Hundley: Very nice Carolyn. Well, I'm going to turn to the world of aortic aneurysms and this next paper comes to us from Dr. Maria Mittelbrun from Centro de Biología Molecular Severo Ochoa. Carolyn, it involves Marfan syndrome, which you know, is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene, encoding a large glycoprotein in the extracellular called fibrillin one. The major complication, again as you know, of this connective disorder is the risk to develop thoracic aortic aneurysms. To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are surgery. So here, the authors studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm dilation, and mitochondrial boosting strategies as a potential treatment to manage these aneurysms. Dr. Carolyn Lam: Wow, that's really fascinating. So what did they find? Dr. Greg Hundley: So Carolyn, just like in circulation, these wonderful translational basic science studies, the research here by these authors was performed in both mice and in patient samples from Marfans patients. So mitochondrial function of vascular smooth muscle cells was found to be controlled by the extracellular matrix and drive the development of aortic aneurysm in the Marfan syndrome. Interestingly, restoring mitochondrial metabolism with the NAD precursors nicotinamide riboside rapidly reversed aortic aneurysm in the fibrillin positive mice. Thus Carolyn, the clinical implications are that by potentially targeting vascular metabolism, a new available therapeutic strategy for managing aortic aneurysms associated with these genetic disorders, such as Marfan syndrome, may become available. Really interesting new development in the world of managing aortic aneurysm dilation in patients with Marfan syndrome. Dr. Carolyn Lam: Oh my goodness, that would be paradigm shifting. Wow, hope that's going to be pursued further. Well, this next one is from the preclinical world and this study really uncovered a metabolic transcriptional axis that explains how dividing cells coordinate metabolism with gene regulation in pulmonary arterial hypertension. So this is from Dr. Rabinovitch and colleagues from Stanford University School of Medicine who applied RNA sequencing to pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension with and without a BMPR2 mutation compared to control pulmonary artery smooth muscle cells, basically to uncover genes required for their heightened proliferation and glycolytic metabolism. The assessment of differentially expressed genes establish metabolism as a major pathway. The most highly up-regulated metabolic gene was aldehyde dehydrogenase family 1 member 3, an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular smooth muscle cells, but now demonstrated in pulmonary arterial hypertension. Isn't that cool? Dr. Carolyn Lam: The findings were basically like this, an increase in this particular aldehyde dehydrogenase family 1 member 3, underlined the heightened proliferation and glycolysis of pulmonary artery smooth muscle cells in patients with both idiopathic and hereditary pulmonary artery hypertension, while promoting survival of their endothelial cells under stress. The authors further uncovered the way this molecule interacted with genetic factors in doing so and then finally demonstrated that transgenic mice with the deletion in smooth muscle cells did not develop chronic hypoxia-induced pulmonary hypertension. Dr. Greg Hundley: Wow Carolyn, really new, inventive material from the world of basic science. So what's the take-home message? Dr. Carolyn Lam: So these findings really suggest that selectively disrupting the pivotal role of aldehyde dehydrogenase family 1 member 3 in pulmonary artery hypertension smooth muscle cells, note that was smooth muscle cells, not the endothelial cells, may be a important therapeutic consideration in patients. Dr. Greg Hundley: Very nice. Dr. Carolyn Lam: So Greg, let me tell you about some other articles in today's issue. There's an exchange of letters between Drs. Pengo and Kario 00:10:36 regarding the article Nighttime Blood Pressure Phenotype And Cardiovascular Prognosis, A Practitioner-based Nationwide JAMP Study. Dr. Greg Hundley: Great Carolyn, well also in the mail bag, we have a perspective piece from Professor Chang entitled Trial By Wildfire, The Need To Expand The Framework Of Environmental Determinants Of Cardiovascular Health From Climate Change To Planetary Health. Also, there's a primer from Professor Miano entitled The Fate And State Of Smooth Muscle Cells And Atherosclerosis. Then lastly, we have another article from the world of basic science, a research letter from Dr. Ieda entitled Overexpression Of GATA4, MEF2C and TBX5 Generates Induced Cardiomyocytes Via Direct Reprogramming And Rare Fusion In The Heart. Well, Carolyn, how about we get to the world of preterm delivery and onto that feature article? Dr. Carolyn Lam: I'm there already, let's go. Dr. Greg Hundley: Well, listeners. Now we are turning to our feature discussion and we're so excited today to have with us our editorialist for this article, Dr. Padma Kaul and our own associate editor, Dr. Karol Watson and we'll be discussing today, a paper related to preterm delivery and long-term risk of stroke in women. Padma, I'd like to start with you. Describe for us a little bit, the context for this study, and then what were the authors' study population and study design? Dr. Padma Kaul: So Greg, this is a study, which is a retrospective cohort study from Sweden and they looked at women who had given birth over a pretty long period of time, from 1973 to 2015. In over two million women, they looked at the association between preterm birth and the long-term development of stroke in the mothers. It's a really interesting study. What they did find is that preterm birth was associated with a higher hazard ratio for stroke, over 48 million person years of follow-up. The authors also did an interesting co-sibling analysis to supplement what the overall primary analysis. This was by looking at a subset of women who had at least one sibling in the cohort. The point of that was to assure that the association between preterm birth and stroke risk remained, even after you account for familial or genetic environmental factors. They do find that it was demonstrated even in the subset. Dr. Greg Hundley: Very nice, just a couple quick clarifying points. Were these ischemic strokes, were they hemorrhagic strokes? And then give me a little bit of definition. How did they define preterm? Dr. Padma Kaul: So preterm was in less than 37 weeks of gestation, and they looked at both hemorrhagic as well as ischemic strokes in the women. So they did an overall stroke endpoint as well as looked at whether these two types of strokes, whether the relationship stayed. Dr. Greg Hundley: And was there any particular age at which these strokes occurred? Dr. Padma Kaul: That's an excellent point. As I told you, that the time period of the study is pretty long. So they did stratify the follow-up period into 10 year segments, and they found that higher risk in the early part of the 10 and the 10 to 20 time periods. It stayed in the latter periods as well, but it was more so associated with a higher hazard in the early time periods, the 10 and the 20. Dr. Greg Hundley: Thank you so much, Padma. Well now listeners, we're going to turn to our associate editor, Dr. Karol Watson from UCLA. Karol, I know working on the editorial board at Circulation, you see many papers come across your desk. What attracted you to this particular manuscript? And how would you put the results from this study in the context of other studies that have really evaluated women's health in this situation? Dr. Karol Watson: That's a fabulous question. I think really so many great manuscripts come in and there are important features of many of them, but this one caught my eye for a couple of reasons. It was so incredibly well done. This is a huge, huge cohort of over two million women and it's from Sweden, where they keep really exquisite records, so we had so much data on this population. So we really got to know all about these soliton deliveries in Sweden, over a 40 year period. So the great cohort that was really well characterized, the really long follow-up. I love the co-sibling analysis that they talked about, they really did control for so many things, shared familial factors, shared genetic factors, covariates. So they just did a fabulous study. Dr. Karol Watson: So, in the whole realm of women's health, we are understanding that pregnancy is a great window into a woman's vascular future. So we now know so many things, we know that preterm delivery is amongst those pregnancy outcomes that we have to look for. So we have to look for pregnancy-induced hypertension, gestational diabetes, but also preterm delivery and pregnancy loss. So all of these things are telling us that a woman's vascular system is under stress and we have to do things to make sure they have good outcomes, because we know they're at greater risk. Dr. Greg Hundley: Very nice. So as leading experts in the era, Padma first to you, and then I'll come back to Karol. Padma, tell us, what do you think is the next area of research that needs to be explored in this topic area? Dr. Padma Kaul: I think that this is an observational study. So one of the things we have to recognize is how do we add to the evidence that this study has provided us? That I think, is to see if in other cohorts, similar pregnancy birth cohorts with longitudinal data, whether we observe the same patterns that we ever observed in Sweden. Sweden is actually quite unique in terms of the makeup of the population and these are historical trends. We do know that the characteristics of the mothers who are giving birth are changing over time. Women are delaying childbirth, they are getting heavier, they may have preexisting conditions. So I think to keep monitoring the health of the mothers and pregnancy factors is what is needed to move the field forward. Dr. Greg Hundley: Very nice, and Karol? Karol, would you like to add anything? Dr. Karol Watson: Yeah, I agree completely with what Padma says. The beauty of the Swedish cohort is how well characterized it is, but one of the limitations is it's a fairly homogenous cohort. So I would love to see similar data in other racial or ethnic groups. We'd also like to see, again, as Padma said, this is observational cohort study, so we don't know truly the causal validy here, although this is a really good study to identify this trend. I would love to think of ways why this might be, we really don't have a good handle on the pathobiology. We can surmise some things endothelial dysfunction, et cetera, but we just don't know for sure. The other thing I'd like to think of is ways we might address mitigating risk. If this truly is a risk factor, how are we going to help these women have better vascular outcomes. But again, a great study to start all these questions. Dr. Greg Hundley: Well, thank you Karol and Padma and listeners. We certainly want to thank both Drs. Kaul and Watson for their time today and also the author group under the direction of Dr. Casey Crump for submitting this article to us at Circulation reporting on this large cohort of women from Sweden, identifying a preterm delivery and long-term risk of both ischemic and hemorrhagic stroke. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

    Circulation May 18, 2021 Issue

    Play Episode Listen Later May 17, 2021 26:49

    This week, please join author Uwe Tietge and Associate Editor Anand Rohatgi as they discuss the article "High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events" (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808) 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, we've got a very interesting feature this week. It involves another paper in the line of the story of HDL, and looking at HDL and future cardiovascular events. But before we get to that, how about we grab a cup of coffee and jump in and review the other articles and the issue? And Carolyn, this week, maybe I'll go first. Dr. Carolyn Lam: Go, I've got my coffee. Dr. Greg Hundley: Very good. So Carolyn, this paper comes to us from Dr. Huso Hakala, from the University of Turku at Turku University Hospital, and the study pertains to cognition and cardiovascular disease. So Carolyn, as you know, cardiovascular risk factors such as high blood pressure, adverse serum lipids, and elevated body mass index, and midlife may harm cognitive performance. So importantly, perhaps the presence of cardiovascular risk factors since childhood, Carolyn, may impact cognition later in life. So these authors studied the associations of the cardiovascular risk factors from childhood to midlife, their accumulation and midlife cognitive performance. They gathered their data beginning in 1980 from a population-based cohort of 3,596 children who are aged three to 18 years that were repeatedly followed up for 31 years, and they assess blood pressure, serum lipids, body mass index, all in the follow-ups. Dr. Carolyn Lam: Wow. So accumulating risk, I suppose, Greg. So what did they find? Dr. Greg Hundley: Great. Carolyn, glad you asked. So consistently high systolic blood pressure or serum total cholesterol associated with worse midlife episodic memory and associated learning, compared to situations when blood pressure or cholesterol values were low. Obesity since childhood associated with worse visual processing and sustained attention compared to individuals or children that had normal weight. And an inverse trend association was observed for the cardiovascular risk factor accumulation with episodic memory and associated learning with visual processing and sustained attention and with reaction and movement time. So the take home Carolyn, is that, maybe we should be launching preventative strategies against some of these cardiovascular risk factors beginning in childhood, because perhaps they could benefit primordial promotion of cognitive health for those later in adulthood, maybe like you and me. Dr. Carolyn Lam: Oh, wow. Thinking back on my blood pressure, cholesterol and weight, I suppose, since childhood, yikes. Well, the next paper Greg is an important analysis from DAPA-HF. Now as a reminder in the DAPA-HF trial, the sodium glucose co-transporter two inhibitor dapagliflozin was shown to reduce the risk of cardiovascular death and a first episode of worsening heart failure, in patients with heart failure with reduced ejection fraction or HFpEF. In the current paper from Drs. Jhund and colleagues from University of Glasgow, they described the efficacy of dapagliflozin on the predefined secondary end point of total heart failure hospitalizations. That's the first and recurrent heart failure hospitalization and cardiovascular death. And this is so important because we know that patients with HFrEF are known to experience multiple episodes of heart failure during the course of the disease. Dr. Greg Hundley: So Carolyn, what did they find? Dr. Carolyn Lam: Well, they did this analysis by two methods in the first, which was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for the effect dapagliflozin on recurrent heart failure, hospitalizations or cardiovascular death was 0.75. Dr. Carolyn Lam: And the second method, a joint frailty model, the rate ratio for total heart failure hospitalizations was 0.71 while for cardiovascular death, the hazard ratio was 0.81. The factors associated with more hospitalizations were, being a men, having a higher heart rate, NT-proBNP, New York Heart Association class type 2 diabetes, and a longer duration of heart failure with less hospitalization in those with higher systolic blood pressure and higher ejection fraction. So in summary, dapagliflozin in reduced the risk of total heart failure, hospitalizations and cardiovascular death. In fact, if you compare it to the time to first analysis, you can see that, that actually underestimated the benefit of dapagliflozin in HFpEF. Dr. Greg Hundley: Very nice Carolyn, well, my next paper comes to us from the world of basic science. And so Carolyn, neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocytes cell cycle exit and loss of the capacity for cardiac regeneration. Now the mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Dr. Carolyn Lam: Okay, Greg. So what did this current paper find? Dr. Greg Hundley: Right, Carolyn, so Dr. Ahmed Mahmoud from University of Wisconsin-Madison, they found that malonate, a competitive inhibitor of succinate dehydrogenase, promotes adult cardiomyocyte proliferation, revascularization of the infarct zone and myocardial regeneration following infarction. They also found that SDH inhibition by malonate is consistent with a metabolic shift from oxidative phosphorylation to glucose metabolism in the adult heart. So Carolyn, the clinical implications include the observation that transient inhibition of SDH may represent an important metabolic target to promote adult heart regeneration, following myocardial infarction. Dr. Carolyn Lam: Cool. Thanks Greg. Well, I've got another basic science paper. Let me try to tell you about la ribonucleoprotein domain family member seven. And I'm going to call that LARP7. Again, it's la ribonucleoprotein domain family members seven. Now LARP7 is a master regulator that governs the DNA damage response. The authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao Tong University and colleagues aim to study its role in heart failure, pathogenesis by assessing LARP7 expression in human heart failure and in non-human primate and mouse heart failure models. Dr. Greg Hundley: Great, Carolyn. So what did they find? Dr. Carolyn Lam: LARP7 was essential for mitochondrial biogenesis energy production and cardiac function by modulating silent mating type information regulation to homolog-1, which is cert one, cert one homeostasis and activity. Now, reduction in LARP7 and diseased hearts due to activation of ataxia-telangiectasia mutated protein pathway contributed to the heart failure pathogenesis and conversely restoring LARP7 in the injured heart conferred myocardial protection. So in some, these results identified that this LARP pathway is a target or rather is a potential target for therapeutic intervention in heart failure. Dr. Greg Hundley: Great, Carolyn. One of the things I love about our journal is really the translational basic science that really could have future implications for how we manage patients with cardiovascular disease. So I, to follow, have another basic science article, and it comes to us from Dr. Florian Weinberger from the University Medical Center in Hamburg-Eppendorf. So Carolyn, human engineered heart tissue transplantation represents a potential regenerative strategy for our heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices and determination of the effective dose. So these authors performed studies in which cardiomyocytes were differentiated from three different human induced pluripotent STEM cell lines, including one reprogrammed under these GMP conditions. Protocols for human induced pluripotent STEM cell expansion, cardiomyocyte differentiation and engineered heart tissue generation were adapted to substances available in good manufacturing process quality. Engineered heart tissue geometry was modified and repair efficacy was evaluated at three doses in a cryo-injury Guinea pig model, human scale patches were epicardialy transplanted onto healthy hearts in pigs to assess the technical feasibility of this entire process. Dr. Carolyn Lam: Wow. And what did they find? Dr. Greg Hundley: Right, Carolyn? I mean, this is just so exciting, the practicality of how you implement some of these new strategies that we work on in the lab. So Carolyn, they found that human engineered heart tissue patch transplantation resulted in a partial re-muscularization of the injured heart and improved left ventricular function in a dose dependent manner in a Guinea pig injury model and human scale patches were successfully transplanted in pigs in a proof of principle study. So an exciting new front for engineered cardiac tissue transplantation. I mean, this is a really exciting article. Dr. Carolyn Lam: Wow, well, indeed. Thanks, Greg. Well, other than those wonderful papers in today's issue, we have an exchange of letters between Drs. Morgan and Lopes regarding initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure of left ventricular dysfunction and that's insights from the ischemia trial. Tracy Hampton does her wonderful review from the literature and it covers new research published in nature medicine, which indicates the impact of a Mediterranean diet on cardio-metabolic disease risks, which may be affected by an individual's gut microbes and goes all the way to network correcting therapeutic candidate for heart valve disease, which was published in science and even a newly discovered genetic arrhythmia syndrome, which was described in science translational medicine. That's a perspective piece by Dr. Kuwabara on the Japanese national plan for promotion of measures against cerebral vascular and cardiovascular disease. Dr. Greg Hundley: Great, Carolyn. Well, you've heard of mission accomplished. Well, Dr. Brooke has an On My Mind piece entitled mission unaccomplished, the optimal hyper, any hypertensive therapy. And then finally, Dr. Glembotski has a Research Letter entitled optimizing AAV9 for studies of cardiac chamber specific gene regulation. Well, Carolyn, what a great issue and integrating all the wonderful world of basic science in a translational fashion. Now, how about we get on and move toward our feature discussion? Dr. Carolyn Lam: Yep. HDL, here we come. Dr. Greg Hundley: Well, listeners, we are onto our feature discussion today and we're very excited to have with us today, professor Uwe Tietge from Stockholm, Sweden, and our own associate editor Anand Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could you describe for us the hypothesis that you wanted to test and tell us a little bit about your study design? Dr. Uwe Tietge Okay. So thank you very much for inviting me and for having the opportunity to discuss this article with you today. So we've been for a long time interested in HDL function, and we have developed an HDL anti-inflammatory see, and we have tested it in some cross-sectional studies. And we have seen in this cross-sectional work, for example, in the acute mi or diabetes, are associated with significant reductions in HDL anti-inflammatory function. So we felt that the next important step would be to study this prospectively in the general population. So this is why we made use of the prevent cohort, which is a prospective general population study with white participants from Groningen, which is a city in the North of the Netherlands. Prevent stands for prevention of menial and stage disease, and prevent has a total number of participants of 8,592. Dr. Uwe Tietge So we first excluded all that had already experienced mi intrusion. And then we took all subjects, was the first cardiovascular disease events during follow up and matched controls for sex, age, smoking, and importantly also for HDL cholesterol levels. And we felt that such a design would allow us to truly identify changes in HDL function, independent of HDL cholesterol levels. So then finally we ended up with 340 match case control pairs. Dr. Greg Hundley: Uwe, sounds like a very interesting hypothesis. So what was your methodology and how did you perform your analysis? And then also describe for us, what did you find? Dr. Uwe Tietge The key method that we used was our essay determining the atrial anti-inflammatory capacity and the main outcome measured was incident cardiovascular disease. And in our case, that was deaths from cardiovascular disease, hospitalization from mi, PDCA, ischemic heart disease, or CABG. We did not have stroke in our study. So with respect to HDL function, we isolate HDL by means of PEG precipitation. And this is an established method that is widely used in larger cohort studies. We then take a primary industry that cells, humans, and we pre incubate them for 30 minutes with the individual engineer preparations. Then the agents removed and TNF alpha is added for another five hours. And after these five hours, we isolate RNA and determine BK1 and mRNA levels by quantitative real time PCR. Then we calculate the results relative to the [inaudible 00:16:09] or without the edit HDL. So when the empties data, we use statistical analysis to determine the perspective association in, based on HDL anti-inflammatory function and the outcome measure incident CVD. Dr. Uwe Tietge So to summarize the main findings of the study. So first of all, the anti inflammatory activity of HDL baselines intrusion in this study was significantly higher in controls than in cases. Next, the HDL anti-inflammatory activity was not correlated with any other CBD related biomarkers. Importantly also know it was HDL cholesterol at 8.1, but also not, for example, with triglycerides, or isolated CRP, and also not with [inaudible 00:16:58] capacity, which is another function metric of HDL. Dr. Uwe Tietge The further finding was that in conditional logistic regression analysis, we found that baseline HDL anti-inflammatory activity was significantly associated with future CV events, even in a fully adjusted model. Then finally, when we were adding this function of HDL to the premium, this form, or when we were replacing anti-inflammatory capacity in the score that improved risk prediction and interestingly adding cholesterol reflux and other HDL function, as said before, resulted in a further improvement. Dr. Uwe Tietge So the general conclusion was that of the HDL functional measures in the case of our actual study, this is the HDL anti-inflammatory activity has the potential to provide clinic information independent of conventional use biomark. Dr. Greg Hundley: Very nice who made. So we always think of HDL is the good cholesterol. And sounds like you're describing a whole nother process by which HDL could be beneficial. Well, Anand turning to you now. I know you see many papers come across your desk. What drew your attention to this particular manuscript and how does this new HDL anti-inflammatory capacity or activity impact the remaining science that we have that focuses on other beneficial effects of HDL? Dr. Anand Rohatgi: Thank you, Greg. And I would like to first start by thanking Dr. Tika to submitting his article to circulation and thinking about us for his studies. I will say when this came across my desk, I became extremely excited as HDL function is an area that is near and dear to my heart as well. And Dr. Tika is an international expert in this area. So we are quite excited. The reason why this really picked our attention at circulation is that this was really the first and large demonstration that this novel marker on anti-inflammatory capacity was linked to the incidents of cardiovascular events, so that it wasn't just the range and people who already had disease, but at baseline, in people who are otherwise healthy, it could predict those who would go on to be at higher risk of atherosclerotic events. So in this case, what we saw was a truly unique and novel cardiovascular marker. Dr. Anand Rohatgi: It was a significant translational study working in effort on the part of Dr. Tika and his research team to be able to do this, and so many participants, this is not an easy undertaking. So to be able to do this and show the results that they were able to show is really remarkable, which is really why it elevated to our interest at circulation. A couple of things in terms of the implications in science are that when they recorded this study, they intriguinly we found that there were really no other stablished risk factors, cholesterol levels, or other markers that are associated with this novel anti-inflammatory capacity, it really wasn't associated with high sensitivity CRP, a global marker of inflammation. And it wasn't associated with the only other HDL function that had been shown to be linked to cardiovascular events, cholesterol influx. Dr. Anand Rohatgi: So really what we have here is a truly novel marker that stands on its own. And it's not confounded by the usual things of obesity or other cardiovascular risk factors, and is clearly imparting different information than a global marker, like CRP. I'll extend that these observations to one or two concepts, when it comes to inflammation, there are a couple of things to think about. One is the timing of the inflammatory cascade. A lot of markers are studied at the time where people are in an acute disease state and pro-inflammatory already, and so that can actually have an effect itself on the markers. In this case, by self-report, the participants did not have any acute illness. And so the relationship we see here between anti-inflammatory capacity and cardiovascular events is presumably in the context of a healthy, low inflammatory state. So I think that's important. The other thing that's important, I think for our audience to know is that the inflammation can have tissue specific effects. Dr. Anand Rohatgi: So when you think of global markers like CRP or interleukin 6, those are flagged systemic levels of inflammation in your body, and they are also predictive. But when it comes to atherosclerosis, we think about specific tissue types, the endothelium, macrophages, dipocytes. And in this case, what this marker represents is specific activity at the level of the endothelium, which is a key player in the atherosclerotic process. So it really gives us new and novel insights into that process. And it highlights the potential to find maybe therapeutic targets that can be more precise in targeting the atherosclerotic process and improving outcomes. So those were some of the main things that we saw that were exciting. Dr. Greg Hundley: Very nice. Uwe, as an international expert. What do you see as the next study that needs to be performed that will perhaps use this new market? Dr. Uwe Tietge I think what we need here first would be validation in another cohort and ideally a cohort that involves different ethnicities because our participants were predominantly white. So in terms of generalization, I think this is the next step that we would need. In terms of making this essay applicable to clinical settings in the daily routine, so to speak, we need to simplify it. And this is another issue that we are currently working on, trying to have an easier essay that gives us quicker readouts and ideally, maybe not using primary industry, but something that is better standardizable. And I mean, when you think about next steps, then also identification of a certain biomarker, comes to mind. So something that would reflect the dimension, the activity component of the age that reflects its functioning. And can be used in daily routine and is applicable. It lies to take all the types of essays. Dr. Greg Hundley: Very good. Anand, do you have anything to add to that? Dr. Anand Rohatgi: Well, I agree completely. I think when you always see a novel marker, you want replication and validation, and I think extending this to other nonwhite cohorts is important. The prevent cohort with 70% men, and also add average out there were probably higher than contemporary populations, at least in the United States. So it'd be nice to see an extension of these observations and cohorts that reflect that diversity. Interestingly, cholesterol wheat blocks the other HDL functions that's been associated with events is not linked through vascular events, it's mostly linked to coronary events. So it would be really interesting to find out how the anti-inflammatory capacity relates to events related to other vascular beds outside of the coronary tree. And then I guess a question that I had for professor Tika is, do you think there might be certain groups of people either by disease or demographic that this might be more powerful formative? Or do you think you would have the same kind of information across the board? Dr. Uwe Tietge Yeah, that's a relevant question of course. When we divided our population by participant level characteristics, we saw that there are sex differences. So the predictive capacity seems to be a bit better in females are significantly better than females, which is in male. And also in participants with lower BMI, with ahigher BMI. And the third parameter was in participants with was lower for this one was higher this month. So yes, I expect that some parameters can play a role here and it would be very wise to explore these connections. Dr. Greg Hundley: Very good. Well listeners, what an excellent discussion. And we want to thank Dr. Uwe Tika and his team from Stockholm, Sweden, and also our associate editor, Dr. Anand Rohatgi for bringing to us this new research regarding this marker of anti-inflammatory capacity involving HDL, that demonstrates an inverse association with cardiovascular events. Dr. Greg Hundley: On behalf of both Carolyn and myself. We want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association, for more visit ahajournals.org.  

    Circulation May 11, 2021 Issue

    Play Episode Listen Later May 10, 2021 31:55

    This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up. Dr. Carolyn Lam: First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance. Dr. Carolyn Lam: What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen. Dr. Greg Hundley: Really interesting, Carolyn. Clinically, what are the implications today as we see these patients? Dr. Carolyn Lam: Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg? Dr. Greg Hundley: Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury. Dr. Carolyn Lam: Oh, wow. Interesting, Greg. what did they find? Dr. Greg Hundley: Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits. Dr. Carolyn Lam: Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic. Dr. Greg Hundley: Wow, Carolyn, really interesting. Can you summarize it for us? Dr. Carolyn Lam: Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy. Dr. Carolyn Lam: Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood. Dr. Carolyn Lam: Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find? Dr. Greg Hundley: Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production. Dr. Carolyn Lam: Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles? Dr. Carolyn Lam: Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation? Dr. Carolyn Lam: Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found? Dr. Alexander Benz: Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies. Dr. Alexander Benz: Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable. Dr. Alexander Benz: Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy. Dr. Carolyn Lam: Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation? Dr. Lars Wallentin: I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients. Dr. Lars Wallentin: This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments. Dr. Carolyn Lam: Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex? Dr. Alexander Benz: Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from. Dr. Carolyn Lam: Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable? Dr. Lars Wallentin: Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples. Dr. Carolyn Lam: Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish? Dr. Alexander Benz: Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this. Dr. Lars Wallentin: Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course. Dr. Carolyn Lam: Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion. Dr. Carolyn Lam: Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found? Dr. Timothy McKinsey: Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension. Dr. Carolyn Lam: You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found? Dr. Timothy McKinsey: Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction. Dr. Timothy McKinsey: We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction. Dr. Carolyn Lam: Very nice. If you could just give us a one-line on how will you find this hidden fibrosis? Dr. Timothy McKinsey: We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at ext