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: January, 2020
Jan 27, 2020

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

Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement.

I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology.

They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France.

Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find?

Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig.

I want to tell you about another paper before I let you tell you about yours, okay?

Dr Greg Hundley: Sounds great, Carolyn.

Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think?

Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world?

Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump.

They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs.

Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that?

Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support.

Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state.

As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation.

Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find?

Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells.

Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation.

Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered?

Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation.

Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease.

Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting.

Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure.

What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article?

Dr Carolyn Lam: You bet.

Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both.

Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript?

Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done.

These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it.

Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project.

Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients.

Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study.

Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years.

Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could?

Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed.

The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations.

The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did well balanced between the two groups suggesting that the mortality effects that we observed was not related to this kind of unbalance related to something else that was not captured by analysis.

Dr Amit Khera: Yeah, I think that was quite an important observation you mentioned. The first that these two groups are generally well-balanced to begin with, even before with all the matching parameters and then certainly the falsification endpoint helped to add validity to the findings.

Dharam, I'm going to turn it over to you. Maybe you can show this from an associate editor's perspective. What are some of the observations you found interesting about this study and what are some of the considerations we had in some of the discussions about it?

Dr Dharam Kumbhani: I'll just remind our listeners that this was also a late breaker at AHA last year in 2019, so this is really a very important finding. As Eric briefly pointed out, there haven't really been head to head comparisons between, the two dominant valves in the market even though TAVR has pretty much become the dominant strategy for treatment of aortic stenosis.

At the end of the day, it's an observational analysis. We have to take the findings with that in mind. At a minimum, it's first a lot of debate and discussion about the need to have randomized trials and our belief that, perhaps, TAVR is a class effect may not always be true. I think that hypothesis would certainly need to be tested and that's what this paper really sparks as far as discussion going forward.

Dr Amit Khera: Maybe I'll ask both of you. One of the challenges of any type of observational research is time period. First there was a hint towards even maybe a greater effect in the more recent time period than the distant time period. Also, there's always commonly changes in technology, especially interventional field where a study comes out and it's already obsolete because there's some new technology. There are some newer generations of valves that have come out. Do you think that it would affect these findings in any way? Maybe we'll start with you, Eric.

Dr Eric Van Belle: That's always an issue. Again, because it's a very rapidly evolving field and if you want to have strong data, you need to have really long-term follow-up. You need to have mortality data. There is some kind of contradiction between both that the field is evolving very quickly but then to have solid data, you need to have some time.

What we could say, indeed, as a study period was 2013 and 2015, but the device that we are using at that time were already really well matured and also the devices that were used at that time was usually the ones that were used for the comparison with the surgical techniques. Again, these devices are not so much obsolete since they were accepted and used again, when you need this one device study to compare with surgery.

Of course these devices have still had some evolution and change, and it is for the good of the patient, but again, as mentioned there, I'm seeing what is very, very important is that this finding is, in my view, intriguing enough to say, okay, even if it's difficult to conduct this kind of randomized study, it has to be done now because we need to really know. Let's say 80% of the patients could indeed be treated with any of the two device in this large margin of patients. Do we have to choose one or the other one to start with? This has already been well answered in a larger randomized trial.

Dr Amit Khera: Dharam, maybe I'll ask you, do you think this large randomized trial, are you optimistic that that would happen? Certainly it sounds like it's something that would be very helpful for the field. What are your thoughts on whether that's actually going to occur?

Dr Dharam Kumbhani: I know that there are some head to head trials ongoing. I don't know if they will have the sample size to really drill down, as far as hard endpoints, mortality, for example. I think the field clearly needs it. The question is, who's going to sponsor a trial like that? There's probably not much incentive for industry to sponsor something like that. Really it would fall down to whether there's a way for government agencies to partner with industry or other ways to run this. I do agree with Eric that that's really very important and hopefully we'll see that in the field going forward.

I did want to comment on the next iteration of devices as far as what we may see now. The mortality signal, I know we've talked about it. It's an observation study. It's hard to know if there's confounding, and even with all the sophisticated statistical analyses that the team did, there's always a possibility that somehow there was sicker patients that received self-expanding valves.

The signal for paravalvular regurgitation is not just in this study. We've observed it in many other studies and for other self-expanding platforms as well. Both the SCOPE trial and the St. Jude trial last year, both came around the same time. They were self-expanding platforms and both of them showed a higher paravalvular regurgitation rate compared to the balloon expandable rate. That may be a real thing, and I don't know if that is an inherent design flaw in the self-expanding platform or if there are ways that that could be mitigated going forward. Again, I think the trials, for it to be meaningful, it would be obviously important to collect and have short term and imaging markers. Really, what the field needs is long-term evaluation of these two strategies.

Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric Van Belle l from Lille University Hospital. Thank you both for joining today.

Dr Greg Hundley: This program is copyright, the American Heart Association 2020.


Jan 20, 2020

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

Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia.

Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it?

Dr. Greg Hundley: Absolutely.

Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds.

Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects.

Dr. Greg Hundley: Tell me, how does this help me as a clinician?

Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction.

Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route.

Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route.

Dr. Carolyn Lam: So what were the results, Greg?

Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration.

Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous.

Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch.

Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today.

Dr. Greg Hundley: Is that right? And what did the authors find?

Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation.

Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction.

Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts.

Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH.

Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications?

Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure.

Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia.

Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article?

Dr. Carolyn Lam: You bet.

Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us.

Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you.

Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work.

Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction.

Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition.

Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC.

Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients.

Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study.

Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients.

Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized.

Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important.

Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with.

Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes.

Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward.

Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes.

Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation.

Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically.

Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your population was more judicious testing.

Dr. Amit Khera: The second point that you brought up was the event rates, type I versus type II MI. I guess this does remind us again that patients with type II have almost comparable cardiovascular deaths and MI rates as type I, so certainly a higher risk group. As you pointed out, there's many comorbidities there and this gets to your point about treatments. I guess the question is now the event rates are higher, these are higher risk group or what to do about it I think is one of the vexing problems. As you pointed out, there's, there's not a lot of secondary prevention treatments, but what should those treatments be and where do we go from here in terms of these type II MI?

Dr. Andrew Chapman: That's the million dollar question I suppose and something that we've explored in another recent circulation review under the [00:17:07] lead author is what we do for these patients. When we've looked at different strategies, it seems the most reasonable initial approach is determining, does my patient with type II MI or myocardial injury actually have a cardiac problem?

Dr. Andrew Chapman: Now I don't think we have the evidence to support routine and baited testing in this population yet and indeed that might expose patients to harm and that's one of the tensions with this diagnosis.

Dr. Andrew Chapman: For example, consider the patient with gastrointestinal hemorrhage and could it have gone forward for an angiogram. Giving them heparin might not be the best thing to do in their acute illness. However, whether or not these patients would benefit from noninvasive tests such as a CT scan to delineate the coronary anatomy and identify those that might benefit from an iron platelet agent or a statin or indeed an echocardiogram to determine which patients have left ventricular impairment and could benefit from the many number of treatments we have now for LV impairment and that would be my initial thinking is that we need to firstly risk profile these patients.

Dr. Andrew Chapman: What is their pretest probability or likelihood of coronary artery disease? It's not intermediate or high. Let's have a think about investigating their coronary arteries. In the first instance, I think a noninvasive test is going to be most appropriate for the majority of people, but we need a personalized approach. It may be that someone's just had a very brief run of an arrhythmia and that's resulted in a disproportionate level of ischemia and a very high cardiac troponin.

Dr. Andrew Chapman: Your index of suspicion for that patient having coronary disease is going to be significantly higher. So a personalized approach, I think, is where we're heading. And there are trials which are coming in this area. So yeah, two trial is being led by Derek Chu of Melbourne in Australia and they're evaluating the use of CT or invasive angiography to identify coronary disease and target treatment to see if that can improve outcomes.

Dr. Andrew Chapman: And certainly here in Scotland, we're hoping to evaluate the use of a personalized approach to target treatment in patients with type II MI and again, try and improve cardiovascular outcomes. So things are coming.

Dr. Amit Khera: Well, I appreciate that and I think as you pointed out, as we wait for these additional data and additional studies, sort of a thoughtful. algorithmic approach would be helpful and we certainly will make sure the readers and listeners look out for that paper that you mentioned in circulation.

Dr. Amit Khera: I should also point out that your paper here is an excellent editorial by David Morrow, which has a nice figure and illustration of your central findings. So we appreciate that. As we wrap up here, maybe you can tell us what are the main take homes? What should they take away from this study?

Dr. Andrew Chapman: What we've shown is that high sensitivity troponin are useful and we've shown that they increase recognition of patients who have myocardial jury or type II myocardial infarction, where in the past this may not have been found and we've shown quite clearly that these are prognostic. Not only predicting non-cardiovascular disease, but also going on to identify patients at increased risk of myocardial infarction, cardiovascular death.

Dr. Andrew Chapman: So I think moving forward, clinicians using these tests and identifying these patients should be considering investigations to identify coronary or structural heart disease. And until we have that high quality randomized controlled trial data, we need to be pragmatic and we need to evaluate secondary prevention on an individual patient basis, be that an antiplatelet agent or be that a statin as the primary ones. This may even go on to include an ACE inhibitor or a beta blocker if there's LV impairment, but our aim ultimately has to be to try and reduce the cardiovascular event rates in this population who, to date, have been under investigated and undertreated.

Dr. Amit Khera: That summarizes it quite well. And I want to thank Dr. Andrew Chapman for his excellent discussion today and that's why we do these backstage passes to get an inside look as to what the authors were thinking and some behind the scenes on their papers.

Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for circulation, and thank you for joining us on this circulation on the run podcast.

Dr. Greg Hundley: This program is copyright, the American heart association 2020.

Jan 13, 2020

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond, who is in the second of his two-week stint without his dear friend, Dr Carolyn Lam who will be returning in a week or two. Our feature article this week is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and the Georgia Institute for Global Health, and University of New South Wales. And we'll review the effects of dapagliflozin on quality of life and other metrics in patients with heart failure and reduced ejection fraction. But first, let's have a look at the other articles in this issue and just like last week we've got four other original manuscripts. The first two are sort of clinically related and that very first article comes from Dr Ben Levine from University of Texas Southwestern and he serves as the corresponding author and he's examining future predictors of the development of heart failure and preserved ejection fraction or HFpEF.

His team tested the hypothesis as to whether patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF. The team recruited 46 patients with LVH. The LV septum was greater than 11 millimeters and elevated cardiac biomarkers, so the NTproBNP was greater than 40 or the cardiac troponin T was greater than 0.6. And they were recruited along with 61 age and sex-matched cohort of healthy controls. To define LV pressure volume relationships, right heart catheterization and 3D echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. They found that the left ventricle was less distensible in the LVH patients relative to the controls, that is they had a smaller volume for the same filling pressure. When preload was expressed as transmural filling pressure or wedge pressure minus right atrial pressure left ventricular myocardial stiffness was nearly 30% greater in the LVH group compared to the controls.

The author's note that although LV myocardial stiffness of LVH patients was greater than that of the healthy controls at this relatively early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.

Well, the second paper comes from Professor John McMurry of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in the United Kingdom. And the paper is somewhat similar to our feature article because it emanates from the DAPA Heart Failure dataset that we will hear about later. So in this paper, the authors examined the effects of Dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly in the prior trial. A clinical trial that as we know, demonstrated that a reduced risk of mortality and heart failure hospitalizations occurred in patients with HFrEF.

So in this current study, a total of 4,744 patients that were 22 to 94 years of age were randomized. 636 were less than 55 years of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74, and finally 1,149 were greater than 75 years of age. Consistent benefits were observed for the components of the primary outcome of all-cause mortality and symptoms across all the age groups. Although the adverse events and the study drug discontinuation increased with age, neither was significantly more common with Dapagliflozin across any of the age groups. There was no significant imbalance and tolerability or safety events between Dapagliflozin and placebo, even in the very old population group. So we'll have more to discuss later in the feature discussion with a second paper that really looks also at the DAPA-HF study.

The next original article comes from our world of Basic Science and it reports that the deficiency of circulating monocytes ameliorates the progression of myxomatous valve degeneration in the Marfan syndrome. And this paper comes from Dr Katherine Yutzey from Cincinnati Children's Medical Center. Well, first is some background, leukocytes comprised primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in myxomatous mitral valve degeneration is not known. So the authors found in this study that Marfan syndrome mice recapitulated the histopathologic features of myxomatous valve disease by two months of age, including mitral valve thickening, increased leaflet cellularity and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation.

Concurrently, disease mitral valves of the Marfan syndrome mice exhibited a marked increase of infiltrating and resident macrophages along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited Marfan syndrome pigs as well as human subjects exhibited increased monocytes and macrophages detected by immunofluorescence. So remarkably deficiency of monocytes was protected against mitral valve disease progression resulting in a significant reduction of macrophages, had minimal leaflet thickening and preserved mitral valve integrity. So the authors identify for the first time in this interesting study from the world of basic science that monocytes are a viable candidate for targeted therapy in myxomatous valve degeneration.

The second basic science original article in this issue is entitled "Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis" and the corresponding there is Pradeep Natarajan from the Mass. General is background clonal hematopoiesis of indeterminate potential or CHIP is a term that refers to clonal expansion of hematopoietic STEM cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice CHIP accelerates atherosclerosis and increases IL-6 and IL-1 beta expression raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease risk.

So in this study, the authors observed some really exciting results. They analyzed over 34,000 samples from the UK Biobank and identified 1,079 individuals with CHIP, including 432 with large clones an LV fraction greater than 10%. During a 6.9-year median follow-up CHIP presence was associated with increased incidents, cardiovascular disease event risk with greater risk from large CHIP clones. IL6R attenuated cardiovascular event risk among participants with large CHIP clones but not in individuals without CHIP. This really exciting research results suggest that CHIP is associated with increased risk of incident cardiovascular disease. And among carriers of large CHIP clones, genetically reduced IL-6 signaling abdicated this risk. Really exciting results in an emerging area of science.

So what else is in the issue? Well, in our in depth review feature, Professor Stephan Rosencrantz from the University of Cologne Heart Center reviews the systemic consequences of pulmonary hypertension with right side heart failure. And then an On My Mind piece, our own associate editor, Dr Vlad Zaha coupled with doctors Walter Myers and Javid Moslehi from Vanderbilt discuss the impact of evolving immunotherapies for cancer and their impact on the cardiovascular system. In our mailbag, Dr Xiayan Shen from the Medical Classification Center of the Singapore Armed Forces discusses in a research letter the prevalence of Brugada Syndrome in a large Singaporean young male population. In letters to the editor, Dr Muddassir Mehmood from University of Tennessee Medical Center in one letter and Dr Goodarz Danaei from Boston in a response letter discuss the importance of diet relative to the development of HFpEF and how heart failure may be coded in by the World Health Organization when assessing global cardiovascular outcomes.

Bridget Kuhn in our cardiology news feature reports on preliminary results from the International Childhood Cardiovascular Cohort or i3C Consortium that was presented at the 2019 European Society of cardiology Congress. The i3C Consortium used data on 40,000 patients who participated in seven major longitudinal cohort studies that evaluated childhood cardiovascular risk factors from repeated measures during childhood and adolescence. And finally, our own Molly Klemarczyk at Circulation gathered and combined a very nice serial update that highlights important articles from our circulation family of journals, including electrophysiology, imaging, heart failure, and others.

Well, listeners, that's a summary of what's in the journal. But let's now proceed to our feature discussion to learn more about the rapidly emerging field of SGLT2 inhibition.

Well listeners, we are very excited for this feature discussion we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada. And we're going to be discussing the paper related to the effects of Dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction. They're going to be presenting results from the DAPA Heart Failure trial. Well Mikhail, I was wondering could you orient us a little bit to the DAPA heart failure trial. And then what was the hypothesis that you were trying to address in the current study?

Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome trial trying to answer two critical questions about the effects of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction. We knew from prior trials, outcome trials in patients with diabetes SGLT2 agents can effectively prevent heart failure inpatients, overwhelming majority of which did not have heart failure and baseline. But what we didn't know was whether these agents can also be used as therapies for patients with established heart failure, and specifically heart failure with reduced ejection fraction. And they reduce death or worsening heart failure in the patient population. And the second question was whether that effect, if in fact this medications can significantly improve outcomes in patients with heart failure reduced ejection fraction. Can they do that even in patients who do not have type 2 diabetes? Because, in a diabetes trial it appears that that heart failure protective effect may be completely independent on the hemoglobin AONC.

And so DAPA-HF was specifically designed to test those two hypotheses. It enrolled about 4,800 patients with heart failure and reduced ejection fraction about 45% of which had types 2 diabetes. And there's a majority of us, 55% did not. And the main trial results that were published prior to risk analysis showed that in fact dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death and worsening heart failure. It was a 26% relative risk reduction and the effects were identical in patients with or without type two diabetes. So both of those hypothesis were proven to be correct. It was effective therapies for established heart failure and reduced ejection fraction, and it was equally effective regardless of diabetes status. Now what we did in this study is really trying to understand the effects not just on cardiovascular deaths and hospitalization for heart failure, but on health status, which is symptoms, physical limitations, and quality of life.

He knows that heart failure is a debilitating disease, causes high burden of symptoms, and physical limitations, has adverse impact on quality of lives. We know that two key goals of managing heart failure are to; one, reduce deaths and hospitalizations for heart failure and two to reduce the burden of symptoms and physical limitations and improve the quality of life. So, that was really the focus of this specific analysis that we're talking about today.

Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12, maybe help us understand what that test is and then tell us a little bit about your methods and your study population. Did you use the whole study population?

Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy Questionnaire and we actually in the study we use KCCQ-23 which is the full Kansas City Cardiomyopathy Questionnaire, consists of 23 items. And it a disease-specific tools for evaluating health status and heart failure.

So it essentially assesses four key domains, which are the symptom burden, physical implementations, quality of life, and social limitations. In this particular study is a primary endpoint as a primary part of the KCCQ as KCCQ total symptom score, which is a domain that focuses on symptoms. And the idea behind KCCQ is that you have a debilitating disease, which is heart failure. That disease has impact on the patient by causing symptoms, the symptoms then translate to physical limitations. And the combination of the symptom burden physical limitations has an impact on quality of life and social limitation. So that's why are this four different domains assessing these four components of the adverse effects of the heart failure compared to health status. And just very briefly, to mention that KCCQ has been proven to be responsive to clinical change. It's highly for data predictive of death and hospitalizations from heart failure. It has been extensively validated both of them hearts failure was reduced enters and the ejection fraction.

And so we essentially focused, or the primary focus of the paper was really to evaluate the effect of dapagliflozin versus placebo on a Kansas City Cardiomyopathy Questionnaire or KCCQ level symptom score. But we also looked at other domains as well. We looked at the clinical summary score, which includes both symptoms and physical limitations and we looked at the overall summary score, which includes all of the four domains that I mentioned before.

Dr Greg Hundley: What did you find?

Dr Mikhail Kosiborod: The patients treated with dapagliflozin had a greater improvement in health status as assessed by a KCCQ total symptom score or for that matter KCCQ clinical summary overall summary score as compared to patients treated with placebo. So if you look at the mean effect, there is some improvement in the patients taking placebo. That's what we call a placebo effect. And it's very commonly seen in clinical trials. We assessed health status, but there was a greater improvement with dapagliflozin as compared with the placebo, it was statistically significant even in four months. But as the effects were further amplified to eight months and this differences were, I would say favorable when you kind of compare the effect of Dapagliflozin versus other established heart failure therapies when you look at the effects on health status.

What I think was even more important than analysis from a clinician standpoint, and then they think it's actually much more meaningful clinically is what we call a responder analysis. And that's where we look as the proportion of patients that have a clinically meaningful improvement with one type of therapy versus other in this case Dapagliflozin versus placebo.

So it's been previously established that at five-point difference or a five-point change rising KCCQ is what's considered to be clinically meaningful or minimal clinically meaningful difference. So a 5.2 grade deterioration KCCQ means it's a clinically important deterioration. And a five-point or greater improvement is a clinically important improvement. And then we also looked at the proportion of patients with moderate and large improvements in health status as well defined as STEM point of grade of two, or two point a great improvement. And essentially what we found was that significantly fewer patients treated with dapagliflozin and as compared with placebo had a clinical importance deterioration. And significantly greater proportion of patients treated with dapagliflozin has small, moderate, large improvements in health status. And the numbers needed to treat to see those differences, as the small moderate large improvements was very favorable ranging typically between 12 and 18 and over eight-months-treatment period.

Dr Greg Hundley: Outstanding. So both clinically relevant as well as statistically significant findings. Now we're going to bring in Justin, our associate editor. Justin, help us put these results into the just our perspective in looking at SGLT2 inhibitors, particularly for treatment for heart failure.

Dr Justin Ezekowitz: This is an exciting class of medications and we're eagerly awaiting these results because we saw the DAPA-HF Overall results. The majority of us treat patients with a pretty symptomatic disease and as such this quality of life is quite an important change. There's ongoing trials we're eagerly awaiting which are also going to be using other medications in the same class, but I think one question that remained was, are these simply improving symptoms by one meaning, so the total symptom score? Or the overall quality of life? And I think you nicely, elegantly portrayed that in the figures and you have. The one other part maybe Mikhail, you could expand upon, which is when you think about DAPA-HF, and the quality of life gains and across all the three different ways of looking at quality of life, where do you see this in terms of its relationship to other things that we know improve quality of life? Where we send patients, for example, CRT or put them on an RNE. Where does this fit on top of those types of changes?

Dr Mikhail Kosiborod: Thanks Justin. I think it's a really important question because it says think critical from a clinical standpoint to put it in the context of other therapies that had been previously shown to improve health status, which means again, reduced symptoms, improve physical and patient quality of life. And there are a number of perhaps the types of therapies on heart failure and LVCF that have been evaluated particularly on side this one there also have been studies with exercise training in heart failure or and the ones that you brought up, which is cardiac resynchronization therapy in patients with heart failure reduced ejection fraction and left bundle branch block. And as that perhaps, if you kind of think about it. What are some of the most effective treatments to improve the health status? That is ones that we typically would consider as such, which is CRT in patients with half RAF and a left bundle branch block.

And in fact, if you look at the mean effects dapagliflozin compares very favorably even with highly effective therapies such as TRT. Relatively few studies have previously reported to this responder in analysis. But if you look at Digoxin comparing those to dapagliflozin, one of the recent ones that I can think of is [inaudible 00:20:23], again dapagliflozin compares very favorably when you look at this types of responder analysis where again you look at proportion of patients, it was a clinically meaningful change.

So I think the beautiful thing about putting the study in the context of further studies looking at health status and also in the original main results that were published from a DAPA-HF early this year is that it's really kind of a full house if you will. So as the agent reduced deaths, reduced hospitalizations and made patients feel better and all of that, with very favorable safety profile. So, if you kind of think about risk benefit analysis and you look at numbers need to treat both for clinical outcomes such as CVS and hospitalizations for heart failure for example, where health status, it looks really impactful from a clinical standpoint.

Dr Greg Hundley: So relevance to other therapeutic interventions for heart failure is what this whole class of agents seems to be showing? So briefly, what do you see is the next important study in the field?

Dr Mikhail Kosiborod: I will waffle on this question a little bit and say there was more than one, but my views are there kind of two key components to this. One is that there are additional trials going on and heart failure with reduced ejection fraction with other agents. And so seeing what happens with those other agents in the class in a similar patient population and whether is this a class effect or not? Now the diabetes trials would suggest that these may well be class effects but I think it's nice to have validation of that. I would say that is one real important questions that hopefully we will have additional answers to in the coming year or so.

And the second and perhaps I would argue even more important question is whether these agents can also be effective in improving outcomes in patients with heart failure and preserved ejection fraction. That's a patient population that has also very high debilitating burden of symptoms that has poor prognosis and for which unlike them, half rubs, there are very few, if any medications that have been proven to be disease-modifying and actually have shown outcomes and benefit. So I would say those in my mind, are the two critical developments that we'll be seeing. And the good news is, there are the trials going on with more than one agent in a class and half to half as well. Great.

Dr Greg Hundley: And Justin?

Dr Justin Ezekowitz: Yeah, I think that there's been an explosion of therapies and Mikhail is bang on with this is the one class where we're excited about. I think the other groups of medications include Omecamtiv Mecarbil we'll know in a year or two. We'll hear more details in the spring and then there's a few other medications that Mikhail mentioned. I think this is a real good message though, that both HFrEF and HFpEF, it's the rise of medications again. Because we were on a device track for a while, but I think the medications have such more potent effect on the underlying structure and function that it's great to see that there's been such a development and explosion of medications that may obviate the need for implanted devices or advanced therapies, so we're very excited about that.

Dr Greg Hundley: Outstanding. Well, listeners, we've had the opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada, and learn more about SGLT2 inhibition and its importance in improving clinically symptomatology both in those with diabetes and heart failure, but also those with heart failure alone.

On behalf of Carolyn and myself, we wish you a great week and we look forward to running and having a coffee chat next week. Take care of. This program is copyright the American Heart Association, 2020