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Circulation on the Run


Feb 8, 2021

This week features Two Feature Discussions. In our first discussion, author Thomas Metkus and Guest Editor Allan Jaffe discuss the article "Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome." Then in our second discussion, author Naveed Sattar and Guest Editor Ileana Piña discuss the article "Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

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

Dr. Greg Hundley:

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

Dr. Carolyn Lam:

Guess what? Double feature again, this episode with the first talking about empagliflozin and its effect on left ventricular volumes in patients with type two diabetes, pre-diabetes, and HFrEF, and this is the sugar DM heart failure study.

Dr. Greg Hundley:

Carolyn, the second of our double feature Tuesday is a paper that involves myocardial injury in severe COVID-19 compared to non-COVID acute ARDS. Well, let's grab a cup of coffee and Carolyn this week, I'm going to jump into my first paper, which comes to us from Dr. Are Kalstad from the University of Oslo at the Oslo University Hospital. Carolyn, this study tested the hypothesis that the daily addition of 1.8 grams of N-3 PUFA to standard of care, secondary prophylaxis in elderly patients who have survived a acute MI would reduce the risk of subsequent cardiovascular events during two years of follow-up.

Dr. Carolyn Lam:

Interesting, Greg and a clinically important question. So what did they find?

Dr. Greg Hundley:

Yes, Carolyn. They enrolled 1,027 subjects who were randomized in this investigator initiated, multi-center randomized clinical trial of adding that 1.8 grams of n-3 PUFA, 930 milligrams of EPA, and 660 milligrams of DHA versus placebo, which was a corn oil supplement, daily to the standard of care in 70 to 82 year old patients with recent, so within two to eight weeks, acute myocardial infarction. The authors found that they could not detect reduction in clinical events in these elderly patients with the recent acute EMI treated with the 1.8 grams of n-3 PUFAs daily for two years. So, a negative study, Carolyn.

Dr. Carolyn Lam:

Surely, we'll add to that debate that's just so interesting surrounding the PUFAs. But let's go onto another paper I want to tell you about, it provides novel insights into the complex crosstalk between the cardiac endothelial cells and cardiomyocytes during cardiac repair after myocardial infarction. This paper is from Dr. Taleb and colleagues from Park Inserm in France. Their study suggested a deleterious role for endothelial indoleamine 2,30-dioxygenase-1, which I'm now going to abbreviate as IDO, which is an enzyme involved in tryptophan catabolism. They found that the specific deletion of IDO in endothelial cells enhanced cardiomyocytes survival and contractility leading to cardiac function improvement. The IDO dependent effects were mediated by endothelial cell production of kynurenine. The study in essence found that therapeutic strategies targeting cardiac IDO could, in fact, constitute an innovative approach to curb cardiac dysfunction following MI. This was followed by an editorial by Drs. Ma and Wang from Thomas Jefferson University.

Dr. Greg Hundley:

Very nice, Carolyn. Great studies again from the world of basic science. Well, my next paper comes to us from Professor Gerasimos Filippatos from the University of Athens Hospital. Carolyn, this was a sub-study of the FIDELO-DKD trial that evaluated the effect of the nonsteroidal selective mineralocorticoid receptor antagonists finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type two diabetes with optimized renin angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. Here the authors report the effect of the finerenone on individual cardiovascular outcomes and in patients with and without a history of atherosclerotic cardiovascular disease.

Dr. Carolyn Lam:

This is a much anticipated paper. Very excited for you to describe the findings, Greg.

Dr. Greg Hundley:

Thanks, Carolyn. Among patients with chronic kidney disease and type two diabetes, finerenone reduced the incidents of the composite cardiovascular outcome, that included time to cardiovascular death, myocardial infarction stroke, or hospitalization for heart failure. Additionally, there was no evidence of differences in treatment effect based on pre-existing cardiovascular disease status.

Dr. Carolyn Lam:

Emerging therapies. Isn't that awesome? Well, some other papers in this issue, there's a White Paper (Frontiers) about the therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing PCI, a North American perspective, 2021 update by Dr. Angiolillo. There's a Research Letter on the gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function, and these are observations from VERTIS-CV trial by Dr. Cherney. There's also a sub-study analysis from Explorer HCM, and that is entitled “Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy.” This is by Dr. Saberi. There's another Research Letter on COVID-19 myocardial pathology evaluation in athletes with by CMR and that's by Dr. Clark.

Dr. Greg Hundley:

Very nice, Carolyn. I have an exchange of letters from Dr. Alkhalil and Kuzemczak, as well as Dr. Navarese regarding the article, “Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: A Network Meta-Analysis of 52,816 Patients From 12 Randomized Trials.” Next, there's another exchange of letters from Dr. Kastrati and Ferracane regarding the article, “Comparative Efficacy and Safety of the Same Oral P2Y12 Inhibitors in Acute Coronary Syndromes.” Dr. Karabinos has a nice ECG challenge. It's a bizarre down sloping ST segment elevation challenge. Finally, Carolyn, there's a Perspective piece from Dr. Okorodudu entitled, “Exposure to Cardiology as a Strategy to Increase Black Men Involvement in Medicine.” Well, Carolyn, how about we get on to those two feature discussions?

Dr. Carolyn Lam:

Oh, yes. Exciting. Let's go.

Dr. Greg Hundley:

Well, listeners, we are here for our first feature discussion today on this February 9th. We have with us Dr. Tom Metkus from Johns Hopkins and Dr. Allan Jaffe from Rochester. Tom, can you tell us what was the background that really framed this study and what hypothesis did you want to address?

Dr. Thomas Metkus:

This study really arose out of a time and a place in the COVID pandemic. If you can all turn your clocks back to late last spring, we were all enmeshed in the clinical care of many patients with COVID here in the United States, depending on your geography, and also reading an increasing number of reports from other centers that had been enmeshed in the pandemic for some time about myocardial injury, elevated troponin, different aspects of cardiac disease in patients with COVID-19. My background is as a cardiac intensivist, dual boarded in cardiology and critical care, and so this was of particular interest to me, specifically so in that my clinical practice at the time was in a COVID ICU. I spent much of the day every day taking care of these patients, so conceptualizing what myocardial injury meant, what's the pathogenesis, and what does it mean, was an open-ended question at the time. There are certainly many reasons to think that COVID-19 is particularly cardiotoxic. There's obviously the pro-thrombogenic nature of the illness. There's the inflammatory nature of the illness.

Dr. Thomas Metkus:

Yet, we also found that clinically, there was certainly many patients with COVID-19 who acted like they had myocardial injury from ARDS and pneumonia and we had investigated this in some prior studies prior to the pandemic. Really, the aim of the study was to clarify to the extent that we could and contribute to the growing body of knowledge about what is the prevalence and prognostic significance of myocardial injury in COVID-19. We felt that we had a unique lens on this because we also had a cohort of patients with generic ARDS who had cardiac biomarkers assessed, gave us a nice opportunity to do that.

Dr. Thomas Metkus:

Our hypothesis, that was really based on our clinical gestalt at the time from being in the ICU every day with COVID-19 patients, was that there are assuredly COVID-19 patients who have unique features of myocardial injury, myocarditis or malignant arrhythmias, or requiring mechanical support. But perhaps more, or at least a majority have myocardial injury that looks and acts an awful lot like it would in a sepsis patient, in an ARDS patient. We hypothesized that myocardial injury in COVID-19 would be more similar than different to the generic ARDS population. As such, we drew a population of patients with COVID-19 from our health system here across several hospitals, and did a bit of a comparison with our historical cohort of ARDS patients.

Dr. Greg Hundley:

Great description, Tom. Tell us a little more about that study population. You said there was going to be a comparison. What were some of the outcomes that you wanted to evaluate?

Dr. Thomas Metkus:

Right. This question alludes to an important point as we try to delve and do inference around the COVID literature in general, which is to say the pandemic is heterogeneous across geography and across time. In looking at this study, or indeed any study, and understanding of the study population where these ambulatory patients or intubated patients or patients on the ward, for example, as well as any comparison group are these sepsis patients, pneumonia patients, influenza patients, it's just imperative to do inference and to place the study in context. This study, we sought to look at only intubated patients, and that was partially driven by clinical interest, partially driven by the ability then to provide a comparison to our ARDS cohort. So, intubated patients with COVID-19.

Dr. Thomas Metkus:

The comparison group is from a study of acute respiratory distress syndrome patients. Primary lung injury patients that were drawn in turn from NHLBI sponsored areas, network clinical trials. That was a study that was a secondary analysis that we did where we checked troponin levels in everybody. A true cross sectional assessment. That's important in that there's a selection bias, isn't there, when you just look at patients who had troponin drawn in the context of clinical care? So, I think for this study in particular, it's important to note that the comparison group of ARDS patients was truly cross-sectional and that it was a population defined who had biomarkers assessed in the entirety; whereas our COVID-19 population was intubated patients who had troponin checked at the point of clinical care.

Dr. Thomas Metkus:

Now, to address some of the potential biases that are inherent in that assessment of exposure, we purposefully looked at only patients who had troponin assessed within 24 hours of intubation, really to sync up time zero in a sense. It's also important to note the time course of the pandemic. These patients were all in the late spring and very early summer. This was really before steroids, before the recovery trial, before steroids became standard of care. And really, health systems wonder a fair bit of duress at that time and indeed, as many of the listeners will know, the outcomes for hospitalized patients have improved since then for many reasons. But it's only to point out that this study was a place in geography and a place in time, and there are certainly implications about that that I'm sure we'll focus on subsequently.

Dr. Greg Hundley:

How many subjects did you enroll and what were your study results?

Dr. Thomas Metkus:

Our COVID-19 patient population here in the Johns Hopkins Hospital included 243 patients. All of them were intubated with COVID-19, so severe disease. Of those, we reported that just over half had clinical troponin levels greater than the upper limit of normal. We assessed the main clinical factors associated with elevated troponin in that patient population, which are largely similar to other reports and they include chronic kidney disease, lactate levels of the marker of malperfusion, ferritin fibrinogen levels as markers of systemic inflammation. We showed as have others that there's a graded increase in mortality with increasing amounts of myocardial injury. Then, probably what I would found the most interesting component of the study is that when we did covariate adjustment for features of critical illness, renal failure, lactate, how severe your hypoxemia was, vasopressor use, age, and sex. Age, sex, and multi-organ dysfunction in a sense.

Dr. Thomas Metkus:

The association of troponin with mortality attenuated quite significantly. That's similar to what we found in a general ARDS population and consistent with a paradigm of myocardial injury in the non-cardiac critically ill. I think the final finding that we would emphasize is that after you adjust for those mediating factors, the incidence of myocardial injury in COVID-19 was at least comparable to that in the general area's population. It gives an idea to place myocardial injury in context, in my view, as a function of critical illness in most COVID-19 patients. Surely, not all. There are patients with unique syndromes, but in many or most.

Dr. Greg Hundley:

Well, Alan, let's turn to you. Help us put these results that Tom has described for us really in the context of what we're learning about the heart and in patients with COVID-19.

Dr. Allan Jaffe:

Well, let me start by saying that as a cardiologist, too, at the Mayo Clinic in Rochester, Minnesota, we've studied previously patients with acute respiratory failure. In point of fact, although most of you are not quite as old and may not remember, when we first started seeing ARDS patients, many of the same issues that are here today for COVID, came up. For example, and people may not remember this, we actually did a randomized trial of anti-platelet therapy in patients with ARDS because we were convinced that thrombosis was ubiquitous and was a frequent contributor to the illness that we saw. So that if one thinks about it in another sense and says, "If you'll correct for modern day technology that gives us some additional insights, how different really is COVID ARDS from standard ARDS." I think what this paper has substantiated is that there are lots and lots of similarities that exist. I think that's important because it keeps us from chasing around and looking for some additional issues for us to try and take care of or treat additionally.

Dr. Allan Jaffe:

That said, I think the way to conceptualize it is some of the troponin elevations are because patients who have chronic heart disease get COVID and they may have those elevations right at admission. There's an acute component having to do with critical illness that is nicely described in this manuscript. Then, there are those unique clinical features, whether you think it's myocarditis, I'm not sure how common myocarditis, type 2 MI, ischemia, a variety of things, and maybe a new type of myocarditis that we're finding with some very peculiar cells that we see in interstitium with or without increases in troponin. But I think it puts it into the bucket of saying, treat these patients conventionally and look for the other complications. I think that's a terribly important message that I was attracted to when I read this paper. So, thank you, Tom.

Dr. Greg Hundley:

Very good. Well, Tom, what do you see as the next study really to be performed in this space? I'll ask you first and then come back and gather some of Allan's thoughts.

Dr. Thomas Metkus:

Absolutely. I love that framing about kind of COVID in the heart, which is to say that there are some things that are direct pathogenic related to COVID and there are some things that are secondary, and then there are some things related to patients with underlying heart disease coming to care. I think the next set of studies that can help us disentangle this are related to that paradigm in that more multimodal phenotyping, biomarker phenotyping, but also echo phenotyping and MRI phenotyping, we're starting to see those come down the pike to say, here's the biomarker evidence of myocardial injury, but what does that mean, functionally? What does that mean from an imaging perspective? The second important facet for the next series of studies will be the long-term follow-up. We know from the general critical care literature, that there is indeed a powerful and important entity of the post critical illness syndrome, and in COVID that's come to be called long COVID or the long hauling. We've known that even patients with general critical illness get that and to the extent that the heart plays a role in that, it implies one needs to follow these patients prospectively.

Dr. Thomas Metkus:

I think the other implication of this work for the next set of studies is that there are many biases that can be brought to bear when reviewing the pandemic literature and assuredly an editorial team sees the entire spectrum of them, but they would include, as I alluded to, careful selection of patients assuring meaningful classifications of exposure at a uniform time assuring adequate comparison groups. That's really going to be the key to doing good inference. Then, the final thing I'll add is that the next set of studies should and will integrate clinical research and clinical epidemiology with causal inference principles with using what we're learning from the basic science community, to have conceptual models about how has COVID affecting the heart at the cellular level, et cetera, et cetera, et cetera. In a sense, that community of researchers that you see coming together in this pandemic is why doing this work is very rewarding and I think meaningful. I think those are all features of the next set of studies that should include indeed epidemiologic analysis, randomized trials, and basic science analysis.

Dr. Greg Hundley:

Allan, do you have anything to add?

Dr. Allan Jaffe:

Well, I want to endorse the idea that one of the problems in this field is that patients present at different times with different clinical syndromes, because some of them have been at home, some of them have been hospitalized, some of them are recognized de novo late. One of the things that's necessary as a consistent repetitive approach so that we get consistent data, not only on each COVID patient sequentially, but also on the control group that is important. The other point I'll emphasize that Tom mentioned is that individuals who have elevated troponins who are critically ill with ARDS and most likely with COVID as well, have some sort of underlying cardiovascular disease. Often once those patients leave the hospital there, the troponin is out of sight and out of mind. COVID is reminding us by showing us the panoply of additional clinical syndromes that exist post-hospitalization. That as with ARDS, I would argue, that's a mistake. These patients need to have follow-up with cardiology to investigate what that underlying cardiovascular component is.

Dr. Greg Hundley:

Great. Well listeners, we want to thank Dr. Tom Metkus from Johns Hopkins om Johns Hopkins and Dr. Allan Jaffe from the Mayo Clinic in Rochester, Minnesota for bringing us this study regarding intubated patients with COVID-19, indicating that the myocardial injury shares many similarities to that experienced by patients with ARDS. Now listeners, we will turn to our second feature discussion on this February 9th.

Dr. Greg Hundley:

Well, listeners, welcome to our second feature discussion today. We have with us, Dr. Naveed Sattar from Glasgow, Scotland, and our guest editor, Dr. Ileana Pina from Detroit Medical Center. Welcome to you both. Naveed, we'll start with you. Could you describe some of the background that helped you formulate this study and what hypothesis did you want to address?

Dr. Naveed Sattar:

Yeah, thanks Greg. When I was watching the empirical outcomes study, I almost fell off my seat when I saw the results in heart failure, hospitalization. I actually, I sent a text to John McMurray who wasn't actually at the meeting and I sit next door to John McMurray who's obviously preeminent heart failure. I worked also with many of the fantastic heart failure colleagues, Mark Pietri, Cardic Joon and colleagues. At that time I felt, well, actually it wouldn't it be lovely, I was aware of MRI studies they've done on other drugs in heart failure and I thought, well, if this drug effects improves heart failure, well potentially, although we didn't have it amply reduced at the time or have heart failure, they've come subsequently. Perhaps it changes, lead to cardiac remodeling.

Dr. Naveed Sattar:

So we've designed the randomized placebo control trial of empirical fluorescent versus placebo and 105 patients who had heart failure with ejection fraction below 40%. We wanted big 4th ventricles as Professor McBuddy would tell me, we have lots of debates about these things to really give us adequate power follow-up for at least 36 weeks to see if we can see improvements in left ventricular installment volume or global longitudinal strain, which were our primary outcomes.

Dr. Greg Hundley:

Very nice. Great overview of the study design. Who did you enroll? I know patients with an ejection fraction less than 40%, but equal numbers of men and women, was this ischemic heart disease?

Dr. Naveed Sattar:

I think the majority of patients were male about two-thirds average age, 68, pretty much like the empirical reduced to that by half population. About 80% here had type two diabetes, about 20% had pre-diabetes. The other characteristics, the majority had class 2, NYHA Class IV heart failure, minority Class III. About a third were already on arnes. Also, the background theoretically was fantastically well.

Dr. Naveed Sattar:

The other critical thing we really did, we excluded people with atrial fibrillation because that really affects the quality of the MRI. Our group and it's a brilliant journey to be, I'm not a heart failure expert, but working with all these colleagues, they have brilliant experience in this. They know the mistakes to avoid, and one of them is, do not include people with atrial fibrillation because your MRIs will just not be readily interpretable. Also, it needs to be big enough. It needs to have big enough volumes to begin with to be able to see a change. It needs to be long enough to potentially see the remodeling. All that experience of John, Mark and Pandeep were put together in a really tight protocol. When the results came, I almost, again, fell off my seat because well, it worked. I guess, you're going to ask me about the results and what we find.

Dr. Greg Hundley:

Absolutely. Tell us about those results. We're waiting to hear.

Dr. Naveed Sattar:

Two primary outcomes were really what we saw was a reduction in the left ventricular and systolic volume index and by six mils per meter squared, and the diastolic volume index by 8.2 mils per meter squared. We didn't see a change in global longitudinal strain. We did not see changes in KCCQ or six minute walk test, but actually the reality is we now know the size of this chart is underpowered to see changes in six minute walk tests or KCCQ, in lieu of another trial that has some changes in that, but we didn't see them and I think our study was done ... I can tell you, Greg, the amount of work that went in this study, the quality control that people should look at the supplement when it comes out, the degree of attention to imaging protocols and quality control was, I think in my experience, unparalleled.

Dr. Naveed Sattar:

The team really pulled out all the stops to get this, but so the reductions in the volumes, that's probably the key thing. We think that this may reflect the reverse cardiac remodeling and that we think then fits in what you see with other drugs that benefit patients with heart failure. Because the bigger the volumes, the more people tend to die with heart failure or get readmitted. If you shrink the ventricles, that probably their contractility improves. What the actual mechanism is, I don't know, but I'm sure Ileana probably come in there in terms of discussing potential pathways. The final thing I should say is just for the internal validity or external validity, NT-proBNP did come down, suggesting less left ventricle wall stress. Schematic also went up. All the things that we've seen in the big trials was there so I think we've done a really strong, robust trial.

Dr. Greg Hundley:

Thank you, Naveed. Well, Ileana, as a guest editor, what attracted you to this paper? Then, how do you put the results from this study in the context with some of the other publications related to SGLT 2 inhibition in patients with heart failure?

Dr. Ileana Piña:

I think all of you know, that we, the heart failure community is pretty excited about these drugs and what they're doing. I also nearly fell off my chair when I saw the first EMPA-REG and I saw those curves splitting. Then, I further did that when the DAPA data came out and you see these curves split up almost immediately. What was attractive about this paper is that we really don't know how this happens. We think we do, but we really don't. We don't think necessarily that it's the glucose excretion, because that maybe happens in diabetics, but not necessarily in the non-diabetics. Yet the drugs seem to work in both. But remodeling is such a fascinating concept. I personally happen to love the concept of reverse remodeling. It's something that we in the heart failure community really believes that if we can reversely remodel the ventricle, then outcomes will get better.

 

Dr. Ileana Piña:

We really link them. Your proBNPs were elevated but not huge. This wasn't a very sick debilitated population. This was primarily Class II. Pretty well-medicated in background, you didn't necessarily give the doses clearly, but pretty well with percentages of RAS inhibition and everything else. Now you see that the volumes are coming down and you say, "Wow, is that what's it doing?" If it happens that quickly, because remember, we've got to explain why the curves of heart failure, hospitalizations split up almost immediately. You did show in your time of follow-up that these changes occurred during that follow-up. I am actually not at all surprised that you didn't see anything in the KCCQ because we know that first of all, the patients weren't that sick to start with so it's hard to see improvement when you don't have a lot of sickness and a six- minute walk. This group, for a six-minute walk, is going to have a very wide standard deviation. A six-minute walk doesn't really distinguish the people who are doing well. To me, it's more for the sicker.

Dr. Ileana Piña:

The fact that neither of these things change doesn't bother me at all. But I think that the next step before Greg asked me, is what's the outcome. In other words, can you tie that reverse remodeling directly to an outcome, be it mortality, which is getting argued out there, whether all the drugs are the same? Or just even the heart failure hospitalization, which I think is a very important outcome in this population. You did it well, you did it carefully, you can tell the data's very clean. You did do a little bit better with the women, so I can't scold you for that as I usually do, because you've had about 30 some percent women, which is very similar to what the big EMPEROR trial has had. I'm always fighting to get more women in the trial.

Dr. Ileana Piña:

At some point you may want to examine the reverse remodeling by gender, by sex, actually and see, even though you have a small number, you have 105 patients, you may not have enough data. But I think in the future, because we do believe that women remodel differently and reversely remodeled differently. That would be very interesting to see if there's any differences.

Dr. Greg Hundley:

Thank you, Ileana. Naveed, do you have anything to add? Ileana's really laid out on a nice course to follow forward. Do you have anything to add to her comments?

Dr. Naveed Sattar:

No, I completely agree with all of them. I think the key thing is nice that this came out straight after EMEPEROR-reduced and a year after that, for heart failure with the team that, John and colleagues were led out. I was involved in the EMPEROR-reduced so that the mechanism helps. I think clinicians buy into this concept. It does what they think drugs do to improve heart failure outcomes. I think that helps and it might help prescribing, get people the confidence that these drugs do work in a mechanism that works.

Dr. Naveed Sattar:

The only thing that I think we would love to have done is if doing the MRIs even sooner, how quickly do these actual volumes change? We think it's reverse remodeling, but maybe we need another trial doing MRIs at one month, three months just to see how quickly these volumes do actually change. Because I still think that's a bit of doubt. But having said all that, I've loved this journey working with my fantastic Hatfield colleagues, a brilliant team in Glasgow. We're now thinking about the next trial. Let's see where we get to in terms of algorithms and trials, but the diabetes, heart failure, kidney disease fraternity coming together is fantastic. I'd loved being part of that journey. So great.

Dr. Ileana Piña:

There's another interesting observation in your data was a hematocrit. It's really tiny, but the signal is there, which to me has also been fascinating. We see a lot of anemia in this population. A benefit in the hematocrit, I think, is really important. The fact that you did this with MRI, I don't think this is a good echo study, to do this with echo. I think you need the reliability and the precision of an MRI.

 

Dr. Naveed Sattar:

Yeah, I agree. We have other data coming up, Ileana, in terms of renal blood flow, because you've mentioned that as well at the same time, which we haven't yet analyzed. There's a lot more data which needs a good Biobank and pick some of these mechanisms. So, yeah, fantastic.

Dr. Greg Hundley:

Well listeners, this has been an excellent discussion and we want to thank Dr. Naveed Sattar from Glasgow and our guest editor, Dr. Ileana Pina from Detroit Medical Center, bringing us these results regarding the administration of empagliflozin and favorable changes in left ventricular volumes in patients with heart failure and a reduced ejection fraction.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2021.