Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: December, 2018
Dec 31, 2018

Dr Carolyn Lam:                                Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg.

Dr Gregory Hundley:                       Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors.

Dr Carolyn Lam:                                Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start?

Dr Gregory Hundley:                       Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings.

Dr Carolyn Lam:                                Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?


Dr Gregory Hundley:                       Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results.

Dr Carolyn Lam:                                Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.

                                                                However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan.

Dr Gregory Hundley:                       Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin?

Dr Carolyn Lam:                                Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.

                                                                So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.


Dr Gregory Hundley:                       That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?

                                                                And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.

                                                                So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels.

Dr Carolyn Lam:                                 Hm. So, how can this be addressed then? How can we raise that H2S?

Dr Gregory Hundley:                       That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low.

Dr Carolyn Lam:                                Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.

                                                                Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events.

Dr Gregory Hundley:                       So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment?

Dr Carolyn Lam:                                That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.

                                                                And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.

                                                                So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?

                                                                Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.

                                                                So, Ciantel, can you just perhaps start by telling us what you found.

Dr Ciantel Blyler:                               So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.

                                                                And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group.

Dr Gregory Hundley:                       Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles?

Dr Ciantel Blyler:                               So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there.

Dr Greg Hundley:                             Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men?

Dr Florian Rader:                              So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study.

Dr Greg Hundley:                             And do you think that there was more compliance in this pharmacist-led group?

Dr Florian Rader:                              One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed.

Dr Greg Hundley:                             It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?


Dr Ciantel Blyler:                               Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program.

Dr Greg Hundley:                             And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South.

Dr Ciantel Blyler:                               I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.

                                                                With respect to the area of the country again, I think it translates.

Dr Carolyn Lam:                                I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share?

Dr Wanpen Vongpatanasin:         I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination.

Dr Greg Hundley:                             Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall.

Dr Florian Rader:                              Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.

                                                                And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves.

Dr Greg Hundley:                             Wanpen, do you have anything to add about Ron? I think he was your mentor as well.

Dr Wanpen Vongpatanasin:         Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine.

Dr Carolyn Lam:                                What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!

                                                                Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.

                                                                This program is copyright American Heart Association 2019.


Dec 24, 2018

Dr Amit Khera:                  Welcome to Circulation on the Run, your weekly summary and backstage pass to the journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas. And I have the privilege of standing in for Dr Carolyn Lam, your usual weekly podcast host. Today we have a special treat. It is our semiannual fellows and training FIT podcast. And the additional part of this treat is we have three very special FITs today. These are our assistant editors for social media for Circulation. And really I want to introduce you just a moment, but I want to thank these three for their hard work and efforts. It really is them that helped bring our social media to life. And importantly for us, we really have a commitment to enhancing fellow education involving fellows in our editorial process and really making sure that the journal is appealing to fellows in training. So we really rely on these three to help us understand what best resonates and what is most helpful for fellows in training. So without further ado, Jainy Savla from UT Southwestern. Welcome Jainy.

Jainy Savla:                         Thanks for having me on the podcast today.

Dr Amit Khera:                  And we have Daniel Ambinder from Johns Hopkins University. Hi Dan.

Daniel Ambinder:             Hey Amit. Thanks for having me on the podcast today.

Dr Amit Khera:                  Absolutely. And finally we have Jeff Hsu from UCLA. Hi Jeff.

Jeff Hsu:                               Hi Amit and hi everyone. Very glad to be here.

Dr Amit Khera:                  Well, Jainy, I'm going to start with you. You've been with us on the social media side the longest. I think it's maybe almost a year or a bit more that you've been working on these efforts. And again, very much appreciate all of your hard work and insight. Tell us a bit about yourself.

Jainy Savla:                         So I'm currently a research fellow at UT Southwestern. So I completed my general cardiology training and I've been doing some extra research training in one of our basic science labs there.

Dr Amit Khera:                  So not surprisingly with your background, do you select an article? So we've asked them each to select one article as they've been working through the social media side and see all of our articles come through. Each to select one that they found was interesting and perhaps summarize for us what it included and what appealed to them. So Jainy, tell us a little bit about the article you chose and why you chose it.

Jainy Savla:                         So, I chose one of the articles that was published in April of 2018 from the Molkentin team lab. And this is a basic science article that focused on which types of cells contribute to heart regeneration. They hadn't thought that there was cardiac progenitor cell that could contribute to the development of new cardiomyocytes. And more recent data has shown that maybe that's not quite the case. So what this study did was used a lot of fancy lineage tracing models to try to figure out which types of cells we're actually contributing to the development of new cardiomyocytes. So importantly, what came from this was that one of their models, they were able to delete two transcription factors that are necessary for cardiomyocytes to develop from these progenitor cells. But they found that when they did that, they even got a higher number of cardiomyocytes that formed. And then what they were able to show in this paper was that actually comes from fusion of leukocytes to cardiomyocytes. And then interestingly, they found a role for one of these transcription factors and the development of endothelial cells. So that was kind of a new, not known function of one of these genes that was previously thought to be just contributory to cardiac development.

Dr Amit Khera:                  It's really a fascinating article when you think about it. Most of the science we publish are people bringing to light new discoveries and certainly there was a component of that here. But in many ways, it was kind of a different article where there had been this a prevailing thought about these c kit positive cells and here they're actually had gone through, refuted what people had thought was happening with these in this de novo cardiomyocyte formation. So you'll see that very often where people's articles or work is headed out to sort of maybe refute or set right what's happening in the literature in the field. Can you comment on that as to that type of article and how that appealed to you in this study?

Jainy Savla:                         That is interesting because previously it has meant that these cells can be used as a therapeutic option in human patients. But some of them were recent data showed that perhaps the new cardiomyocytes weren't actually coming from these cells, but it was hard to say. So the nice part about this paper was really they used a lot of important lineage tracing models to really show where these cells are coming from. And it helped clarify some of the, I guess, more confusing science that had been in the field since there were a few papers that showed these cells were contributary and then a few papers that have shown that maybe they weren't. So I think that's really helpful, particularly when you're talking about things that could be potentially used as therapeutic agents in human. And also the interesting thing is that while these cells themselves may not be useful to perhaps harvest and give to someone, you could potentially alter these cells and then they produce cells that fuse with cardiomyocytes. Or could you use this a different way? So I thought that was also interesting about this article.

Dr Amit Khera:                  Great points in it. It does remind us again that in our enthusiasm for rushing things to clinical practices in some things in this field, the importance of rigorous basic science to really understand the molecular underpinnings. And as you mentioned, there's some new insights here that could be used for clinical therapeutic purposes in the future. So definitely an interesting article and glad you enjoyed it and brought it to our attention. I'm going to ask you a bit of a different question. You again have been working with this in the social media side for longer. You've seen this now for some time about the different articles that come through. I know you and I've had several conversations about our different platforms, Twitter or Facebook, and how they're different and how we engage with them and how we engage with the audience. Can you tell us a little bit just reflecting now on your time and working with social media from a journal perspective, kind of what you've learned? What are some interesting observations over this year?

Jainy Savla:                         Definitely one interesting observation is just that their general usage of these social media platforms has increased significantly since I've started doing this. And you can see this with when we get articles that are accepted, how many authors have Twitter handles that they'd like to be tagged in some of these posts. And that's just gone up significantly since I've started doing this. And that also changes sort of what the comments we get on some of the posts and the back and forth discussions that we're seeing on these platforms. And then the second thing I found really interesting over time is that the way people use Facebook is really different from the way people use Twitter. And you can follow the discussions that people have linked to our posts a little bit better on Facebook. And then on Twitter, there's also a lot of similar discussions about these posts. But they kind of manifest in different ways and it's really interesting to see how that plays out.

Dr Amit Khera:                  I think those are fantastic points. And from a fellow's perspective, how do you think fellows are engaging with social media now compared to maybe, I don't know, when you started your training a few years back. What have you seen in a positive light?

Jainy Savla:                         I mean in general, there are more fellows on Twitter now than when I was a first-year fellow. Even myself, I've got my Twitter account when I was in fellowship. I didn't have one prior to that. I mean it's interesting because people are able to showcase their work a little bit better I think with these types of handles whereas before maybe you wouldn't know that even one of your own co fellows had published something. So it's kind of nice to see people use that kind of as a networking tool in some ways or to showcase some of their own work, which is something that when I was a first year and I didn't have a Twitter handle and there weren't as many fellows on Twitter, I didn't really notice some of the work that's being done by some of my colleagues at my level.

Dr Amit Khera:                  Those are great points and I'll stoplight some of the things you just said talking about it being a way for fellows to really showcase their work, to help with networking and in some ways, it's sort of the great equalizer. So I think it's really a valuable platform specifically for fellows. Well thank you Jainy. I'm going to move on to Daniel and hear a little bit from Daniel. Tell us a bit about yourself.

Daniel Ambinder:             I'm currently a second year cardiology fellow at John's Hopkins Hospital and I plan on doing interventional and structural cardiology in the future.

Dr Amit Khera:                  Great and certainly a lively and growing field and so many exciting things happening. Well, it's interesting you chose an article today that is more of a clinical article and obviously quite different than the last one we heard, but equally as interesting. Tell us a little about the article you've chose and why you chose it.

Daniel Ambinder:             I was very excited about this article that was published in Circulation back in July 2018. So, it's by Dr Borlaug and Reddy on how to diagnose HFpEF and what they did was they took patients with clinical dyspnea and they used invasive human dynamics to kind of assess whether or not they had HFpEF. And by doing so they were able to generate a list of clinical and eco based guidance to help us kind of identify patients with heart failure with preserved ejection fraction. So they came up with this amazing little table which was featured in Circulation and on Circulation twitter, where they have a chart that basically goes through several clinical variables including weight and hypertensiveness, atrial fibrillation, pulmonary hypertension, being elderly. And filling pressure is based on echo cardiographic information. And by that they were able to generate a score and give you a probability of if your patient has HFpEF or not.

                                                And the reason why I really enjoyed reading this article and also posting this article was because going through internal medicine and not being so fundamentally aware of echo and kind of what goes into understanding left ventricular filling pressures, it was challenging to make a diagnosis of heart failure with preserved ejection fraction. Do you just basically say, "My patient has lower extremity swelling but normal EF? They have heart failure with preserved ejection fraction and [inaudible 00:09:32] on the [inaudible 00:09:33]. And so I thought that this would be really helpful to the medical community at large. And in fact, shortly after we posted it, I saw that our cardiology console fellow is actually utilizing this exact table to help one of the medicine teams manage a patient with lower extremity swelling and come to the diagnosis of heart failure with preserved ejection fraction. So that is why I chose this article for today.

Dr Amit Khera:                  That's a great article and I thought you summarized it very well. And it is a field. HFpEF you'd see a lot of articles in Circulation on this topic. We have many people that are interested from an editor’s level but also from a society level. This is a huge problem, but we know very, very little. And I'm sure you know that as well and this was a wonderful tool. Just shows you're sort of the beauty and simplicity. Although if you read it, the message were pretty rigorous and they had a lot of great work that they did to develop it. But I love that the H2 HFpEF, how they basically came up with it h for heavy and the f from fibrillation. So I thought that was incredibly creative and a very simplistic but useful score. So, you said your, tell us about yourself. Have you used the H2 of the HFpEF score yet?

Daniel Ambinder:             Absolutely. I use it in clinic on a daily basis. And I actually pull up the Tweet in my office and show the patients why I think that they have heart failure preserved ejection fraction, especially since many of my patients start to get really nervous when you start talking about heart failure. But then they don't understand that they have a normal functioning heart. They can't really put those two together. And so going through this chart and going through the etiology, or at least what we know about heart failure with preserved ejection fraction, turns out to be quite helpful.

Dr Amit Khera:                  And the basis of this study goes back to hemodynamics. This obviously is a cohort where they had done invasive hemodynamics to essentially diagnosed HFpEF based on pressure. So as you, as someone who's going interventional and structural where we are really seeing kind of the rebirth or refocus on hemodynamics again, tell me a little bit like what you're learning in terms of hemodynamics and how you think that importance in today's practice of cardiovascular medicine.

Daniel Ambinder:             One of my passions is spending as much time as I possibly can in the cardiac ICU. And we're fortunate to meet many different patients that come in with very different kinds of cardiogenic shock for other hemodynamic compromise from other types of shock. And I have found it extremely helpful to think about either using a virtual Swan or by actually getting the measurements with a PA catheter to kind of identify where the break in the system is to hopefully provide our patients with the ability to turn them around in a fast manner before they develop metabolic compromise from prolonged hypoperfusion.

Dr Amit Khera:                  Great summary of how you're using hemodynamics and the training. And I'm going to pivot. The last question for you is when we first met I think several months back and we're communicating about your interest in social media, one thing that was really interesting and fascinating was the great work you're doing on Twitter on your own account where you essentially, if I think you told me this right, you sit on your iPhone and basically in this matter of a very few minutes would construct cases and teaching points on Twitter. So tell me a little bit about that, about using Twitter for medical education and learning cardiology and cases. And I know you're passionate about that. So tell us a little bit more about that.

Daniel Ambinder:             Back in May, last year, I had been in my first year of cardiology fellowship. And I was really kind of obsessed with grabbing as much imaging and cases as I could to construct them into teaching stories to share these important stories that I encounter with other people. And so also share the aha moments that I have when I'm learning from my mentors about a new clinical condition or even a clinical condition that I've encountered many times. We never thought about any unique way. And so I was putting these all together and developing somewhat of a library of cases. But I would share them with the residents that I was working with at the time. And then Dr Erin Michos was one of my mentors at Hopkins. She's an echocardiographer and she kind of exposed me to the Twitter community where you're really able to just start reaching out to different people and share the same insights that I had saved on my drive on my computer. And so I started constructing these cases, putting that together and developing them and then associating them with like a few bullet pointed tidbits of pearls that I can put on Twitter. And I quickly realized what an amazing community Twitter have to offer in terms of cardiology and in terms of the medical education community at large.

                                                At first, I realized you can't put out content and not expect to participate in a conversation. It has to be two ways. You have to really engage with others and others will engage with you. And then just a couple months later, it's really grown that you can post a case, post the teaching pearl and in about 24 hours it can be viewed thousands and thousands of times, really internationally. And generates just so much great conversation. So it's been really a tremendous way to communicate with the world, especially within the cardiovascular world.

Dr Amit Khera:                  Well thanks. I think there's so much learning that can happen and I think the work you're doing with cases and with others. And I know when I've gone on Twitter, even in just two minutes you can see really fascinating things and learn a lot. So keep up the good work and appreciate your efforts there. I'm going to switch gears and finally finished with Jeff Hsu from UCLA. Jeff, tell us a bit about yourself.

Jeff Hsu:                               I'm a fellow at UCLA. So I actually finished my general cardiology fellowship pretty recently and now I'm a research fellow in the STAR program here. I'm also enrolled in the PhD program at UCLA in the Department of Physiology and planning to defend in the next few months. So right now, very stressed out about that. Starting in July, I'll be starting advanced fellowship in advanced heart failure and transplant here at UCLA.

                                                Well excellent and best of luck to you in your PhD defense. Now you also chose a very interesting article that again, all of yours are a bit different. So tell us a little about the article you chose and why you chose it.

                                                When I chose this article, I was really excited by a few weeks ago. It was published in the December 4th issue of Circulation called Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells. So this came out of the lab of Joe Wu at Stanford and the co first authors is Ning Ma, Joe Zhang and Ilanit Itzhaki. But I think the beauty of this article is that it really addressed this frustrating clinical scenario in question that we often encounter nowadays in this era of genome sequencing. And now that we're sequencing a lot more people, since the cost of sequencing has come down a lot, we were finding a lot of these mutations that we don't know what to do with, so I think Dr Wu's lab really try to address this question using the disease model with the cardiomyopathy. So, leveraging Dr Wu's expertise in using human induced pluripotent stem cells or iPSCs, they found a patient who is actually healthy but apparently had this mutation in this gene called MYL3 or myosin light chain 3. And so this patient had a variance of uncertain significance in this gene.

                                                Now, notably, this patient, again had no clinical phenotype, was very healthy and the patient's family members over three generations were all healthy too. But had this mutation that based on in silico analyses was thought to be likely pathogenic. So using cells from this patient that they reprogrammed into cardiomyocyte, they tested various properties of these cells from the same patient to see whether or not they thought this mutation is actually a pathogenic mutation. So again, using these reprogrammed cardiomyocytes, they tested a variety of things including gene expression, sarcomere structure, and cell contractility, action potentials, and the handling of calcium. And they saw that even with this mutation, there were no abnormal findings in vitro in their system.

                                                Now just to prove that their cell culture system and this in vitro model of testing the pathogenicity of certain mutations actually works, they actually took cells from a patient who did have the clinical phenotype as a result of a known mutation that causes hypertrophic cardiomyopathy. And found that when testing those cells in vitro, they did demonstrate abnormal phenotypes in all the parameters I mentioned before. So I thought this is really exciting. I thought this is a great way to address, potentially answer whether or not we think these variants of uncertain significance that we often encounter are indeed pathogenic because we are often just left in this situation where we don't know what to do with this information. But this potentially at least is a proof of concept for this protocol where we can finally take advantage of the ability to take cells from our patient and actually test them in the lab to see whether or not either various treatments work or whether or not these mutations that actually will results in pathology down the line. So I thought overall this was a great paper that was a great summary of how we can take the bedside to the bench actually. And I'm just really looking forward to the future where we can maybe then bring it back to the bedside.

Dr Amit Khera:                  Well thanks. I think that's an excellent choice and a great summary. And this article really hit all of the kind of timely and cutting-edge topics in the era genomic medicine and precision medicine have really kind of individualized treatments. And when we get stuck, these VUSes, these are a nightmare. And also this is sort of proof of concept for extending this to other treatments and other ways to test drugs and therapies. I've heard Joe, we talk about this before and use the word disease in the dishes. He did I think in the article itself and it's exactly that. I mean the potential here is profound. I'll pivot this into the next question for you. For our roles, one thing we do is we interact a lot with media and I interact a lot with them to help translate, I guess, the articles that we have to things that would be able to be digestible for media and for lay individuals. It was interesting because it's hard for us to do that with basic science and most of the time we have some difficulty in translating that. But this one translated pretty well and I think we had done some various press releases and things because it really showed the potential of modern medicine and kind of the excitement of it.

                                                But that gets to the question I have for you, something we have discussed as well, your interest in basic science and some of the challenges of taking basic science articles and digesting them down to a couple hundred-word tweet. Even as beautiful as all the pictures are, and in this article I think there's six figures, but each panel is 10 pictures or 10 figures by themselves. And how do we digest basic science articles down to make them really appeal to people on social media and help people understand that may not be in the fields or in basic science that are clinicians, if you will. I know you've thought about that a little bit. Tell me a little bit about your thoughts on that.

Jeff Hsu:                               Jainy, Dan and I have this challenge on a weekly basis, figuring out how to summarize great articles such as this one into a short tweet. And I think that is a big challenge particularly for basic science articles on social media to make it appeal to a broader audience because the audience you're seeing on Twitter and Facebook, again, they're not just basic scientists. If you want to catch people's attention, you need to find a way to really understand the big picture of the question you're answering in your basic science research. So I think that is a challenge. You're challenged to make your science appealing to a broader audience. But I think again, that's one of the advantages of social media is that you can appeal to a larger audience and have a wide range of people engage with your research and understand your research. So it is something that we work on is to try to pick out the figure that best represents the science that was done in these basic science articles.

                                                It can be quite challenging because a lot of times one picture won't do it justice. So it's tough to distill a full article in one picture. It is helpful when some articles do have a summary, a graphic or figure where they typically reserve their last figure for either a cartoon or some type of schematic that really explains either the mechanism or pathway that they explored in their article. So what we've found is that these articles that do have some of these illustrations or summary figures, they seem to engage a larger audience on Twitter and social media. So personally I find it more appealing when I do see these summary figures. So if there is one recommendation, I would have the basic science researchers, especially trainees is in this age of social media, try to come up with an illustration or summary figure for your research. I think it helps you figure out what is truly important with the research that you've done and helps you communicate this research to a broader audience. And I've seen a lot of people take advantage of a graphic designers to really help them illustrate their research. And I found that to be very effective in articles I've read on social media.

Dr Amit Khera:                  Thanks Jeff. That's a great point and great suggestion. And certainly these days the most effective communicators are those they can translate their complex science into easily digestible bites and can think of ways to portray them in ways that sort of summarize, like you said, be it summary figures or otherwise. And it's a challenge and also talent. And you all are certainly perfecting that. Well, I think we've had an excellent conversation. I have to tell you, I'm so excited to get the chance to spotlight you all. You do excellent work each day. Every week you're working hard and coming up with great ideas and suggestions and we really value having your input as fellows and training and as a colleague.

                                                Thank you for joining us today on our FIT podcast. Amit Khera standing in for Carolyn Lam. We look forward to seeing you for our next edition of Circulation on the Run. This program is copyright American Heart Association 2018.


Dec 17, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.

                                                In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.

                                                In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.

                                                Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.

                                                To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.

                                                The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.

                                                What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.

                                                The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.

                                                As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.

                                                The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.

                                                And that brings us to the end of our summaries. Now for this week's feature discussion.

                                                Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials.

Dr Gabriel Steg:                Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat.

Dr Carolyn Lam:                So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis.

Dr Subodh Verma:           Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.

                                                So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.

                                                So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.

                                                I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.

                                                So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?

                                                So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.

                                                And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen.

Dr Carolyn Lam:                Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore?

Dr Gabriel Steg:                Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component.

Dr Subodh Verma:           True.

Dr Gabriel Steg:                And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis.

Dr Subodh Verma:           Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to.

Dr Carolyn Lam:                Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next?

Dr Subodh Verma:           I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint.

Dr Subodh Verma:           So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ...

Dr Carolyn Lam:                Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective?

Dr Gabriel Steg:                Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes.

Dr Subodh Verma:           Me, too.

Dr Gabriel Steg:                Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes.

Dr Subodh Verma:           Right.

Dr Carolyn Lam:                And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here.

Dr Subodh Verma:           And it's being noticed. There's no doubt about it.

Dr Carolyn Lam:                I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast.

Dr Subodh Verma:           I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well.

Dr Carolyn Lam:                Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.


Dec 10, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. What are the long-term effects of oxygen therapy in patients with suspected acute myocardial infarction? Well, to find out, stay tuned for our discussion of our feature paper this week, coming right up after these summaries.

                                                The first two original papers demonstrate that, similar to neonatal mice, one day old and two-day old neonatal pigs are capable of mounting a cardiac regenerative response following myocardial infarction, which is characterized by restoration of contractile function, cardiomyocyte replenishment, and minimal fibrosis. Now, interestingly, this regenerative capacity is lost after the first two days of life.

                                                The first paper is from co-corresponding authors, Drs Yeh and Cook from National Heart Research Institute of Singapore and National Heart Center, Singapore, and the second from co-corresponding, authors Drs Zhang and Zhu from the University of Alabama at Birmingham.

                                                These authors report collectively that proliferation of preexisting cardiomyocytes appear to be the primary source of cardiomyocyte replenishment in neonatal pigs with markers of cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis elevated following injury in the one day and two-day old hearts, but not at later time points.

                                                Furthermore, cardiomyocyte DNA synthesis was increased following neonatal pig myocardial infarction. Cardiomyocyte proliferation significantly decreased after this two-day window, which was associated with a marked reduction in telomerase activity.

                                                Heart failure with preserved ejection fraction may look different in the young compared to that in the elderly. First author, Dr Jasper Tromp, corresponding author, myself, Carolyn Lam from the National Heart Center, Singapore and Duke National University of Singapore, and our colleagues from the Asian Heart Failure Registry studied more than 1,200 patients with HEF PEF from 11 Asian regions and found that 37% of our Asian HEF PEF population was under 65 years of age. Younger age was associated with male preponderance, a higher prevalence of obesity, and less renal impairment, atrial fibrillation, and hypertension. Left ventricular filling pressures and the prevalence of left ventricular hypertrophy was similar in the very young of less than 55 years and elderly HEF PEF of more than 75 years of age.

                                                Compared to age matched controls from the community without heart failure, the very young HEF PEF patients had a three-fold higher death rate and twice the prevalence of left ventricular hypertrophy. Thus, young and very young patients with HEF PEF display similar adverse cardiac remodeling as their older counterparts, but very poor outcomes compared to controls without heart failure.

                                                Obesity may be a major driver of HEF PEF in a high proportion of HEF PEF in the young and very young.

                                                How important is hospitalization for heart failure as a complication of diabetes? In the next paper from first and corresponding author, Dr McAllister from University of Glasgow, the authors examined the incidents and case fatality of heart failure hospitalizations in the entire population age 30 years and older resident in Scotland during 2004 to 2013.

                                                Over the 10-year period of study, among 3.25 million people, the coot incidence rates of heart failure hospitalization were 2.4 per thousand-person years for those without diabetes, 12.4 for those with type two diabetes, and 5.6 for those with type one diabetes. Heart failure incidents had fallen over time for people with and without diabetes, but remained around two times higher in people with diabetes than those without diabetes. Heart failure case fatality was higher in people with type one diabetes. Duration of diabetes and glycated hemoglobin was associated with increased risk of heart failure in type one and type two diabetes. Thus, clinicians should be aware of the importance of heart failure and diabetes, especially in type one diabetes where this is under appreciated.

                                                What are epigenetic mechanisms contributing to ischemia reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang, co-corresponding authors, Dr Xu from Nanjing Medical University, Dr Sun from Fudan University, and Dr Ge from Fudan University, and their colleagues evaluated the potential role of megakaryocytic leukemia one, or MKL 1, as a bridge linking epigenetic activation of NAD pH oxidases, or NOX, to reactive oxygen species production and cardiac ischemia reperfusion injury in mice. They found that genetic deletion of pharmaceutical inhibition of MKL 1 attenuated cardiac ischemia reperfusion injury in mice. MKL 1 levels were elevated in macrophages, but not in cardiomyocytes in vivo, following cardiac ischemia reperfusion injury.

                                                MKL 1 recruited the histone acetyltransferase, MOF, to activate NOX transcription in macrophages. Pharmaceutical inhibition of MOF attenuated cardiac ischemia reperfusion injury in mice, and pharmaceutical inhibition of NOX one or four attenuated cardiac ischemia reperfusion injury as well.

                                                These findings provide a novel link between MKL 1-mediated epigenetic regulation of gene expression in macrophages and ischemic heart disease. This opens the door to small molecule compounds targeting the MKL 1 MOF NOX access as a novel therapeutic strategy against ischemic heart disease.

                                                Is the time from last hospitalization for heart failure to placement of a primary prevention ICD associated with patient outcomes? First and corresponding author Dr Ambrosy from the Permanente Medical Group in San Francisco performed a post hoc analysis of Medicare beneficiaries enrolled in the national Cardiovascular Data Registries implantable cardioverter defibrillator, or ICD registry, all with a known diagnosis of heart failure and an ejection fraction of less than 35%, undergoing a new ICD placement for primary prevention.

                                                They found that older patients, currently or recently hospitalized for heart failure, undergoing initial ICD placement for primary prevention, experienced a higher rate of periprocedural complications and were at increased risk of death compared to those receiving an ICD without recent heart failure hospitalization. Additional prospective real world pragmatic comparative effectiveness studies should be conducted to define the optimal timing of ICD placement.

                                                The final original paper presents result of the VERDICT trial, a large scale randomized controlled trial evaluating the value of very early invasive strategy conducted within 12 hours of diagnosis on long term clinical outcomes in patients with non-SD elevation acute coronary syndrome. First and corresponding author Dr Kofoed from University of Copenhagen and colleagues studied 2,147 patients who were randomized and found that an invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcomes, compared to an invasive strategy conducted within two to three days.

                                                However, in the pre-specified subgroup of patients with a GRACE risk score of more than 140, a very early invasive treatment strategy did appear to improve outcomes, compared to a standard invasive treatment strategy. And that wraps it up for our summaries. Now, for our feature discussion.

                                                For our feature discussion today, we are talking about oxygen therapy for patients with suspected acute myocardial infarction. Something that seems so benign, something we've taken for granted, and yet now we now question since the Detox AMI trial. Well, for today's feature paper, we have a follow-up of this trial, and I'm so pleased to have actually our associate editor, but also author of this paper, Dr Stefan James from Uppsala Clinical Research Center, and the guest editor for this paper, Dr David Morrow, who's from Brigham Women's Hospital and Harvard Medical School. So, thank you both for being here.

                                                Stefan, could I just ask you to start by taking us back. How was Detox AMI first conceived? What made you even question oxygen therapy? And then, perhaps then, tell us about what this new paper adds.

Dr Stefan James:              I think that's so interesting because I think we all learned in medical school that for myocardial infarction, you should always deliver oxygen. That's sort of the first choice. And the other sort of first choice that we learned was morphine. Some of the other important things that we learned was to give not only oxygen but morphine, and nitroglycerin, and perhaps aspirin. And by those four, only aspirin is really the agent that has been proven beneficial to patients.

                                                But we thought for many years actually about this oxygen hypothesis, or we were interested in trying to understand, is it really helpful to give patients oxygen? Or are we in fact harming patients? Because there is, as you may know, there is a metanalysis performed long ago with small trials on the fibrinolysis era that showed actually a threefold increased risk of dying in those patients who had received oxygen in randomized various small trials, and their animal experience actually suggesting that oxygen is also hazardous. You don't think about that so often, but it's really an agent that constricts arteries, and so as the arteries close by a clot in myocardial infarction, there is no way the oxygen that you breathe in your nose can reach the suffering myocardium. It actually contracts the arteries, and may make the infarct larger than it would be otherwise.

Dr Carolyn Lam:                I love that explanation. Alright, so what did you find in the current analysis of longer term results?

Dr Stefan James:              So, we performed this, the main oxygen trial that we call Detox. We built it upon our national registries, and so we decided to include not only MI patients, but patients who were suspected of MI, in order to be able to enroll patients before the diagnosis was clear. We didn't want to wait for troponins, so we enrolled patients in the ambulances, in the emergency departments, in the cath labs, or in the wards, patients who had suspected myocardial infarction.

                                                Most of them, eventually, did have myocardial infarction, but a proportion did not have myocardial infarction. They had other diseases that resembles MI and have breathing problems. And we selected the cut point of 90%. We said if they are below 90%, they're hypoxic, and it would be unethical to withdraw oxygen, if you were hypoxic. So, we sort of arbitrarily selected the cut point of 90%. And then, we randomized patients to receive oxygen or do not receive oxygen.

                                                We considered to do double blind, but in order to do a double blind, you need to provide air on a mask. And air is not available in ambulances or in the emergency department. We cannot put a mask without anything in it because then it will feel more difficult to breathe. So, we had actually oxygen versus nothing, and we enrolled all patients coming to the cath labs, and emergency departments, and ambulances in Sweden. And thanks to the infrastructure that we have built on the national registries, we were able to enroll these to conduct this large trial, larger than any other trial, 6,600 patients.

                                                In the main study, we found no benefit, and fortunately, no harm of providing oxygen for our primary end point, which was all caused death. But we realized that we were little bit underpowered actually to really clearly rule out that there was any benefit on the primary endpoints. And so, we said, we probably need a longer follow-up, and we probably also need other important measures such as heart failure. Because we thought that oxygen may, if it works, it may reduce the infarct size and may result in a lower risk of heart failure in the long-term. We don't believe that we will reduce the risk of re-MI because we're not interfering with atherosclerosis or plaque ruptures, but we may interfere with the development of heart failure.

                                                So, in this particular paper, we said, longer follow up in order for patients to possibly develop heart failure and increase their risk of heart failure hospitalizations. So, in this paper, we used as a primary endpoint of this analysis, death or hospitalization for heart failure, post MI. And with this way of calculating events, we are more sure that we are not underpowered for this evaluation.

Dr Carolyn Lam:                Right. And the results?

Dr Stefan James:              The results were completely neutral. There was no benefit at all in any sub group. It doesn't matter if you were ST elevation MI, or no ST elevation MI, or no MI, or high risk prior MI, prior heart failure, respiratory disease, there is no benefits and no harm, which is good. And those results are supported by our findings on troponin levels. So, we checked troponins repeatedly. I shouldn't say top troponin, but the highest measured, we did not find any difference between the two groups in Troponin elevations. And we did not find any difference in LVEF and in Echo performed during the initial hospitalization.

                                                So, I think both of those results support the primary endpoint of death and repeat hospitalization for heart failure.

Dr Carolyn Lam:                So David, you've thought a lot about this, and also framed it so nicely when we were just talking a little bit earlier. What do you think is the real significance of this paper on so many levels?

Dr David Morrow:            Yeah, I think there are many levels. I think it's such important work because it takes something that we are still doing in many hospitals every day for patients and is difficult to study because it's become part of standard of care, as Dr James pointed out, and so the authors are to be congratulated for being able to study this intervention. And I think in additionally because it is a therapy that's not associated with high cost, has been part of our care for so long, it's not one where there is the support for a large type of randomized trials. So, the ability to perform this with relatively low costs by nesting it in a registry is important, not only for this particular test, but also as a model for future research of so many interventions that we make right now where they started in a time where our threshold for a need for data was much less.

Dr Carolyn Lam:                Yeah. Indeed. That's wonderfully put. I am also really struck. It's the importance of the message, but also especially about how you do a pragmatic registry-based randomized trial. The ability of Sweden to do this, it's just rock the world, right? Because we really need solutions like that for our clinical trial world, which has to be sustainable somehow. Could you maybe take us behind the scenes a little bit? I mean you did already in your description. I didn't realize there were so many considerations when you're planning this, but how easy or difficult is it to do a trial like this?

Dr Stefan James:              We call the entity RRCT. We call it registry based randomized trial, but being aware that there is no strict definition of what is a registry based randomized trial. So, sometimes for some simple interventions like strategies, we can use only the registry for collection of baseline variables, procedure variables, and also outcomes. The registry can really do everything. The only thing we need to add is a randomization, so then we just program into the registry, which is used live in front of the patients.

                                                So, when I enter a patient in the registry, the personal identification number collects me to the population registry that supports directly back to me name and gender of the patient, and then I enter all the baseline characteristics anyway in the registry. And then, there is a question that comes up that screens my patients. So, the system proposes to me to randomize patients who are eligible because I programmed the inclusion/exclusion criteria. So, it proposes to every doctor in the country, this is a patient that is eligible potentially for this trial and just click randomize, and that's the trial. Everything is completed by that. No extra tests, no visits, no follow up, no telephone calls.

                                                That's the basic, very simple format that can only be used for a strategy, like a device or a strategy. But many of the questions we have in medicine are really regarding strategies. How long should you treat? How often do you need to come back? Sort of strategies. Then, when we've tried to expand this to pharmaceutical agents, and oxygen was the first pharmaceutical agent that we wanted to try. You may not consider oxygen as a pharmaceutical agent, but it is in fact. But it's not manufactured by any companies, and we are still, in this trial, wanted to keep all-cause mortality as the primary end point because that's very reliable. That's indisputable, and in our country it's absolutely 100% correct. If they registered dead, they are dead. There's no question.

                                                The next level we did in the validate was a true pharmaceutical agent manufactured by a company, [byobatterin seprin 00:18:31]. A little bit more complex because you need to be careful about making sure that the patients are receiving the pharmaceutical agent in the right manner, in the right time point. We need to be a little bit careful about collection of side effects, and complications, and so on, but it also worked very well in that trial. If they validated, we did actually adjudicate events because in the primary end point we had it where it was more complex primary endpoint, including myocardial infarction. If you include myocardial infarction or bleeding events, that needs to be defined in a certain way according to protocol. You need to adjudicate. If you really need to rely on the outcome assessment.

                                                We're not trying to take this type of study to the next level, to use it for typical oral pharmaceutical agents. Our largest trial now running is the spirit HFPF lactone versus no treatment in patients with HFPF. And again, this is a pharmaceutical agent that is a very inexpensive. There's no company that would sponsor such a trial, but we think it's a really important question. There's so many patients that suffer from HFPF, and in order to do that trial, it has to be simple and inexpensive.

                                                So, that's running. We hope to be successful. There are, of course, many challenges. Like any other trial, it's difficult to write a protocol. You have to be very dedicated and detailed for any trial. So backstage, this is not easier than any other trial, but for the investigator, it is much easier. That's the reason we have succeeded to reach out to every hospital in the country, and every physician seeing these patients are investigators. And many of them have never done any trials before. They have no experience with research, but still they should be able to randomize and do the trials because it seems to be so easy for them and for the patients. That's the whole idea.

Dr Carolyn Lam:                Yeah. I'm just enamored by the whole concept, and of course, a lot of people I think are wishing that we could institute that in all countries as well. Trust me, a lot of conversation has occurred about that in Singapore, for example, where population based capture is possible. But, as you said, it's not that easy. It's got to be well thought out. Protocols still have to well thought out. Investigators still need to be trained, and so on.

Dr Stefan James:              We want the investigators to feel that it's easy, that it's attractive to participate. Not for money, just because it's so easy and so interesting to be part of such an experiment.

Dr David Morrow:            I think testing some of those therapies that are commonplace that they're used to, and our nature of practice is this is the perfect type of setting than more complicated interventions where you may need to train the investigators more in order how to implement to them, and apply the therapy correctly. That's the new trend, is ... I think the key issue is that in order to reliably test things where mortality is not the acceptable outcome that you could power adequately for, it's really the endpoint collection in the safety collection, and because of the robust medical record systems you have, you're able to do that. And we're so far from being able to do that reliably in the United States right now that it's not possible to do that. Unless we have specific well-constructed registries, which we do in some areas. I think we're learning, and hopefully we'll get there, but we're far behind [crosstalk 00:21:55].

Dr Stefan James:              [crosstalk 00:21:55] Yeah, but even-

Dr David Morrow:            [crosstalk 00:21:57] Nationals-

Dr Stefan James:              Even if you're not able to do a registry based, I think we all should consider in all trials to do it as easy as possible and really try to ask ourselves, what is the most important reason we're doing this trial? Sometimes we need to collect a lot of extra information because we need to understand the mechanisms or the side effects. If that's the case, I don't think at this trial methodology is not suitable. You shouldn't perform it that way. It needs to be the more traditional, more conservative, more expensive and burdensome way, but for many therapies, a more simple approach, more pragmatic approach is preferable.

Dr Carolyn Lam:                Well, thanks again for diving into that because it gives us a real, to me at least, even greater appreciation for this paper when you understand the amount of work that's gone into it. But may I just end by saying, what do you think is the take home message for clinicians now? David, for example, you started by saying everyone's still doing it? I fully agree.

Dr David Morrow:            Yeah. I think it's a very simple message, and that we know that oxygen is not effective in patients who have an oxygen saturation above 90%. And there's really no rationale to use it.

Dr Carolyn Lam:                Perfect. Has this been put in practice in Sweden already?

Dr Stefan James:              It has been. One of the virtues of running these registries is that we can also check the adherence to the results, so we can check that this is not used anymore.

Dr David Morrow:            And since the investigators are your entire country, they all learned actually from participation in these trials.

Dr Stefan James:              Exactly. Exactly.

Dr David Morrow:            There's more of an investment in it already.

Dr Carolyn Lam:                That's amazing. So, thank you again for sharing. Thank you for publishing this in circulation and for helping us to do that.

                                                You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright the American Heart Association in 2018.


Dec 3, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.

                                                The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.

                                                Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.

                                                Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.

                                                Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.

                                                Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.

                                                Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.

                                                Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.

                                                Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.

                                                The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.

                                                First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.

                                                Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.

                                                The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.

                                                They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.

                                                Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.

                                                The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.

                                                Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.

                                                Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.

                                                Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.

                                                These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.

                                                How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.

                                                They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.

                                                And that brings us to the end of our summaries this week. Now, for our feature discussion.

                                                Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.

                                                So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.

                                                I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.

                                                Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found?

Dr Martine Gilard:            Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.

                                                It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.

                                                But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.

                                                As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message.

Dr Carolyn Lam:                Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement?

Dr Anita Asgar:                  I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.

                                                One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two?

Dr Martine Gilard:            It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.

                                                So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention.

Dr Anita Asgar:                  So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration?

Dr Martine Gilard:            We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that.

Dr Carolyn Lam:                Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper?

Dr Dharam Kumbhani:   Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.

                                                And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there?

Dr Martine Gilard:            Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.

                                                However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.

                                                But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.

                                                So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk.

Dr Dharam Kumbhani:   So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France?

Dr Martine Gilard:            Yes, exactly.

Dr Carolyn Lam:                How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now?

Dr Anita Asgar:                  For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR.

Dr Carolyn Lam:                Oh, wow.

Dr Anita Asgar:                  Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.

                                                I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view.

Dr Carolyn Lam:                I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper?

Dr Dharam Kumbhani:   Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.

                                                If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France.

Dr Carolyn Lam:                Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association, 2018.