Show notes
This week's episode features authors David Kasss and Kavita Sharma as they join Greg to discuss their article "Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction." 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: And I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: I am so excited about today's feature paper. It talks about my favorite topic, heart failure with preserved ejection fraction, or HFpEF, this time giving us really novel myocardial gene expression signatures in human HFpEF. Can't wait to go to that, but I also can't wait to share about some of the really cool papers in today's issue. Dr. Carolyn Lam: Now, we know that mitral valve-in-valve and valve-in-ring are alternatives to surgical reoperation in patients with recurrent mitral valve failure after a previous surgical valve repair or replacement. But, what are the outcomes after transcatheter mitral valve-in-valve or valve-in-ring procedures? And what is the clinical significance of post-procedure residual mitral stenosis or regurgitation? Well, we're going to find out in today's paper. Dr. Dvir from Hebrew University in Israel and authors examine the midterm outcomes in the Valve-in-Valve International Data registry, which is a multicenter collaboration and rolling cases performed between March, 2006 and 2020, in 90 centers worldwide. Dr. Greg Hundley: Wow, Carolyn. So what did they find? Dr. Carolyn Lam: Well, a total of 1079 patients were included with a median follow-up of 492 days. 4-year Kaplan-Meier survival rate was 62.5% in the valve-in-valve, versus 49.5% in valve-in-ring procedures. Significant residual mitral stenosis occurred in 8.2% of the valve-in-valve, and 12% of the valve-in-ring patients. Significant residual mitral regurgitation was more common in valve-in-ring patients. The correlates for residue mitral stenosis were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual mitral regurgitation was a valve-in-ring procedure. Significant residual mitral stenosis and residual mitral regurgitation were both independently associated with repeat mitral valve replacement. Dr. Carolyn Lam: So, significant residual mitral stenosis and/or mitral regurgitation were not infrequent after mitral valve-in-valve and valve-in-ring procedures, and we're both associated a need for repeat valve replacement, so strategies to improve post-procedural hemodynamics in mitral valve-in-valve and valve-in-ring should certainly be further explored. Dr. Greg Hundley: Very nice, Carolyn. Well, my first paper, it really involves results from the American Heart Association COVID-19 Cardiovascular Disease registry, and it comes from our own associate editor, Dr. Justin Grodin from UT Southwestern Medical Center. So Carolyn, obesity may contribute to adverse outcomes in coronavirus disease, or COVID-19. However, studies of large, broadly-generalizable patient populations are still lacking in the effect of body mass index, or BMI, on COVID-19 outcomes, particularly in younger, adults remains uncertain. Dr. Carolyn Lam: Yeah. It is an important question. And so, what did they find? Dr. Greg Hundley: Well, Carolyn, obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if they're young. So individuals less than age 50 years. Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals, regardless of age. Dr. Carolyn Lam: Wow. An important public health message. Well, my next paper is a basic science one from doctors, Rayner and Karunakaran from University of Ottawa Heart Institute in Canada. For the first time, they investigated the role of RIP kinase 1, a coordinator of NF-kappa B inflammation and cell death, in atherosclerosis. Dr. Carolyn Lam: They found that RIP kinase 1 expression was highly expressed in early atherosclerotic lesions in humans and mice. In vitro, both basal and TNF alpha stimulated NF-kappa B activity, and resultant inflammatory gene expression was reduced in macrophages and endothelial cells when RIP kinase 1 was silenced. In vivo therapeutic administration of RIP kinase 1 antisense oligonucleotide markedly reduced atherosclerotic lesion size and macrophage content. Dr. Carolyn Lam: Together, these findings suggest that RIP kinase 1 drives inflammation in early atherosclerosis, and targeting RIP kinase 1 therefore provides a novel preventive strategy to treat atherosclerosis. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. Kristin Stanford from The Ohio State University. So, Carolyn, brown adipose tissue is an important tissue for thermogenesis, making it a potential target to decrease the risk of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified brown adipose tissue as an endocrine organ. Dr. Greg Hundley: While brown adipose tissue has been implicated to be protective in cardiovascular disease to this point, there are no studies that identify a direct role for brown adipose tissue to mediate cardiac function. This study was performed to address this issue. Dr. Carolyn Lam: So what did they find? Dr. Greg Hundley: Okay, Carolyn. The authors found that transplantation of brown adipose tissue improves cardiac function via the release of the lipokine 12,13di-HOME. Sustained overexpression of 12,13di-HOME using tissue nanotransfection negated the delirious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13di-HOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13di-HOME increase mitochondrial respiration. So, Carolyn, these results identify an endocrine effect of brown fat to enhance cardiac function. Dr. Carolyn Lam: So interesting. Well, there are other very interesting types of papers in today's issue. There's an exchange of letters between Drs. Gui and Nahrendorf regarding the article Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes. Dr. Carolyn Lam: In cardiology news, Tracy Hampton highlights articles from Nature Biomedical Engineering on AI-based eye movements for cardiovascular risk prediction, from Science on the metabolic profiling of the failing and non-failing heart, and from Science Translational Medicine on the heart healing effects of extracellular vesicles. Dr. Carolyn Lam: There's an On My Mind paper by Dr. Pelliccia on gaps in evidence for risk stratification for sudden cardiac death in hypertrophic cardiomyopathy, as well as a Research Letter by Dr. Brown on the association of inducible myocardial ischemia with long-term mortality and benefit from coronary artery bypass graft surgery in ischemic cardiomyopathy, which is a 10-year follow-up of the STICH trial. Dr. Greg Hundley: Nice, Carolyn. Well, my articles: Professor Himbert has an In-Depth article on the current indications for transcatheter mitral valve replacement using transcatheter aortic valves, valve-in-valve, valve-in-ring, and valve in mitral annulus calcification. There's a Research Letter from Dr. Martin (Than) regarding the single troponin rule-out of myocardial infarction. And finally, Professor Isser has an ECG challenge involving chest pain with ST-segment elevation in a young woman with a broken heart. Dr. Greg Hundley: Well, now how about we proceed to that feature discussion? Dr. Carolyn Lam: Yay. Let's go, Greg. Dr. Greg Hundley: Well, listeners, we want to bring you to our feature discussion today, and we have with us Dr. David Kass and Dr. Kavita Sharma both from Johns Hopkins University in Baltimore, Maryland. David, could you tell us a little bit about the background related to this study and what hypothesis did you want to test? Dr. David Kass: Sure, Greg. My pleasure to be here. We have long had an interest in the syndrome we know as heart failure with preserved ejection fraction, going back, really, decades, and the difficulty in assessing what's really wrong with the heart in this syndrome has been that we get so little information from the tissue itself, that most of the studies that have been done have been done at the macro level and physiology level and epidemiology level. Dr. David Kass: But at Johns Hopkins, Kavita Sharma, who now heads up our heart failure transplant group, had established a clinic, a HFpEF clinic, one of the very few in the United States, and the availability of both the patients through the clinic, and then as part of this, right heart catheterizations associated with endomyocardial biopsies being obtained, was really a very extraordinary opportunity to examine tissue at a molecular level, essentially for the first time. There's been no other data set quite like this one. Dr. David Kass: So, we had already established both a patient population, very, very well-phenotyped, very much symptomatic, and we had a tissue bank. And as part of a consortium, a network consortium grant that was sponsored by the American Heart Association, called the Go Red for Women Network, we had a project that basically was focused on trying to better understand HFpEF. Dr. David Kass: The impetus was really, no one knew anything about what's going on in the heart at the molecular level. Really. There had not been transcriptomic analysis ever done before, and there were plenty of questions that we thought this might be able to answer. Among them, how really different are these hearts from patients who have, what we'll call, garden-variety heart failure, heart failure with a low ejection fraction? That's seemingly not so controversial now, but actually there's still controversy as to exactly what's wrong with these hearts, and so we thought we would be able to tease that out. Dr. David Kass: Then it's also been, I think, widely discussed that this is a very heterogeneous disease or syndrome, really, that has a lot of different factors, comorbidities, that are associated with it. So question two was really, how cohesive is the molecular signature that you might see in the myocardium? Is it going to be hopelessly heterogeneous as well, in which case, what does that say about our possibility to develop drug therapies when the underlying biology may be very, very heterogeneous? And if not so heterogeneous, question followup would be, what signatures might be there in subgroups that we could identify, and with subgroup analysis then, help us target in a more personal medicine fashion, ultimately, a therapeutic for the syndrome? Dr. Greg Hundley: Very nice. So, David, how did you assemble a study population, and what was your study design? Dr. David Kass: In this sense, this was very much an ongoing effort by Dr. Sharma and what was the HFpEF clinic team. Back, probably about 4 years ago, maybe even more, she had started to become interested in this and had amassed a clinic population while she was a resident, and then as a senior resident became more and more interested in this and this became her fellowship project when she was a cardiology fellow at Hopkins. Dr. David Kass: And by the time I became more involved with this, basically she had it in operation with study nurses and seeing patients. It was very clinically-oriented. There was some sort of more, I would say, population-level data being collected and studies being done, but nothing like quite what we did here. But that was there. Dr. David Kass: So, in terms of a study design, this was almost more a biobank. At this point, there was a cadre of patients she had been following. She had been following this group for some time. Basically, in a freezer we had endomyocardial biopsies under an IRB-approved protocol that had been obtained, and in part we were sort of waiting to get enough tissue together so we had a large enough data population and enough sample, and then really thinking through what might we be able to look at in these pieces, knowing full well that very little had been done. So almost anything we came up with, and we've been doing quite a few other things now as well, was going to be new, so I suppose the simplest study design of all. Dr. Greg Hundley: So, what did you find? Dr. David Kass: Well, going through those initial questions. Question number one, is there a unique molecular signature? We're looking at using what's called RNA-Seq, which is the newest generation of RNA gene expression analysis, in these myocardial biopsies. The answer was, yes, actually. There was a very unique signature. And this was all done using what we call agnostic bioinformatics approaches, where you just give the data, you give all the genes that are different between HFpEF and a control group, we had a control group, donor hearts. You look at basically the HFrEF group, the people with low ejection fraction, versus control. What are those differentially expressed genes? And of course you have your control. Dr. David Kass: So there are three groups and you get a series of little dots in what's called principal component analysis, and it was very clear, right from the beginning, that these groups separated, and this was just purely a statistical approach to say, are they different? Dr. David Kass: And then we asked further, are they still different even if we adjust for what are the common comorbidities and the things that differentiated, often, HFpEF from other forms of heart failure, specifically age, sex, having a large body mass index, having diabetes, these were all things that were more prevalent and more severe in the HFpEF group. So we adjusted for these things, again, sort of statistically, and redid this, and it's still absolutely separated. So question one, are they different at the transcript level? Yep. They're different. Dr. David Kass: And then, question two is basically, despite the heterogeneity, if you start digging into the genes, what kinds of genes are being differentially regulated? Is there a signature that becomes cohesive and consistent among the patients within the HFpEF group? The answer to that was, yes. And this too was very interesting because we also did an adjustment for the comorbidities, and what we found were the genes that were upregulated in HFpEF, that actually turned out mostly to be down-regulated in the other form of heart failure. Genes specifically associated with the manufacturing of ATP by mitochondria, the ATP synthase genes, those genes were significantly upregulated in HFpEF, but once you adjusted for body mass index, a lot of those pathways disappeared. So, the class of genes that were up regulated was in fact related to comorbidities. Dr. David Kass: Then we did the opposite. We looked at those genes that are down-regulated, and found that a large group of genes that were quite different, that are not on the tip of most people's tongues for what goes on in heart failure, mostly associated with protein processing, trafficking, autophagy, the process of protein recycling, endoplasmic reticular stress, which was something that the journal senior editor, Joe Hill, had talked about and published about earlier in the year in a mouse paper where he first came up with this idea that ER stress might be important. Well, looks like it's important in these humans. So, we found some unique signatures. Dr. David Kass: And then the l…
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