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Circulation on the Run


Jan 31, 2023

Please join Guest Host Maryjane Farr, authors Sarah Franklin and Stavros G. Drakos, as well as Associate Editor Hesham Sadek as they discuss the article "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support."

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 cohosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo.

Dr. Carolyn Lam:

Peder, today's featured paper is very, very important in the heart failure world. It is such a deep dive into the transcriptomic and proteomic profile that specifies heart failure and the potential of myocardial recovery with mechanical unloading and circulatory support.

Dr. Peder Myhre:

Can't wait for that feature discussion today, Carolyn.

Dr. Carolyn Lam:

But you have to wait because I insist on telling you about yet another really important paper, of course in my favorite subject, heart failure with preserved ejection fraction or HFpEF. Now you know that exercise intolerance is a defining characteristic of HFpEF and a marked rise in pulmonary capillary wedge pressure during exertion is pethepneumonic for HFpEF and it's thought to be a key cause of the exercise intolerance. Now if that is true, acutely lowering the wedge pressure should improve exercise capacity, right? Well, don't assume this because to test this hypothesis, authors led by corresponding author Dr. Ben Levine from UT Southwestern evaluated peak exercise capacity with and without nitroglycerin, which was used to acutely lower pulmonary capillary wedge pressure during exercise in patients with HFpEF.

Dr. Peder Myhre:

Oh, that's so cool. What an amazing research question and Carolyn, you're the best to summarize this. Please tell us what did they find?

Dr. Carolyn Lam:

Well, they studied 30 patients with HFpEF and get this. They underwent two bouts of upright seated cycle exercise dosed with sublingual nitroglycerin or a placebo every 15 minutes in a single blind randomized crossover design. So really well done. Wedge pressure, VO2 and cardiac output were assessed at rest with 20 watts exercise and at peak exercise during both the placebo and nitroglycerin conditions and the principle finding of the study (singing) acutely lowering pulmonary capillary wedge pressure during upright exercise with nitroglycerin in HFpEF did not improve peak exercise performance. So peak VO2 was practically identical with a 1% difference despite a 17% drop in peak wedge pressure. Peak cardiac output and peak peripheral oxygen extraction were unchanged, again, despite the drop in peak wedge pressure suggesting that oxygen delivery and utilization were unaffected. Exercise performance variables including peak wattage, peak ventilation and peak RER were unchanged, suggesting that again, reductions in peak wedge were insufficient to improve exercise tolerance.

All these results suggest acute reductions in wedge pressure are insufficient to improve exercise capacity and provide convincing evidence that a high wedge during exercise by itself is an epiphenomenon perhaps rather than a primary limiting factor for exercise performance in patients with HFpEF. Now of course this is incredibly interesting contrary to hypothesis and so please read the paper. The discussion is very rich.

Dr. Peder Myhre:

Oh wow, Carolyn. That is such a great paper. I can't wait to pick it up and read it from start to finish and now Carolyn, we're going to look into research within cardiovascular disease from COVID-19 and we have learned so much and so quickly about COVID-19 and its effects on the heart and we have really come a long way from the first case reports reported in the beginning of the pandemic and this paper, which comes to us from corresponding author Professor JP Greenwood, really adds important knowledge to this field. The COVID heart study was a prospective longitudinal multi-center observational cohort study of patients hospitalized with COVID-19 and at elevated serum troponin levels across 25 hospitals in the UK and these investigators aim to characterize myocardial injury, its association and sequela in convalescent patients following hospitalization with COVID-19 utilizing appropriately matched contemporary controls.

Dr. Carolyn Lam:

Ooh, important stuff. So what did they find?

Dr. Peder Myhre:

So these authors included in total 519 patients comprising 342 patients with COVID-19 and an elevated troponin, 64 patients with COVID-19 and a normal troponin and 113 age and comorbidity matched controls without COVID-19 and the frequency of any heart abnormality defined as left or right ventricular impairment, scar or pericardial disease was two full greater in patients with COVID positive and troponin positive, so 61% compared to the control groups and that is 36% for COVID positive and troponin negative and 31% for COVID negative and comorbidity positive and the myocardial injury pattern was different for these patients with COVID and an elevated troponin more likely than controls to have infarction and micro infarction. But there was no difference in non-ischemic scar and using the late MRI criteria, the prevalence of probable recent myocarditis was almost 7% for those with COVID and elevated troponin compared to only 2% for the controls without COVID-19 and myocardial scar is but not prior COVID-19 infection or troponin was an independent predictor of MACE.

So Carolyn, these authors discussed their findings in light of previously reported studies and these authors identified a lower prevalence of probable recent myocarditis than previously described and a higher proportion of myocardial infarction and this newly described pattern of micro infarction following COVID-19 and Carolyn, there is a brilliant editorial really summarizing this by Dr. Stuber and Baggish entitled "Acute Myocardial Injury in the COVID Heart Study Emphasizing Scars While Reassuring Scarce." I really recommend everyone to pick this up and read the editorial as well.

Dr. Carolyn Lam:

Very clever title. Thank you. For the last original paper in today's issue, it focuses on the crosstalk between sterile metabolism and inflammatory pathways, which have been demonstrated to significantly impact the development of atherosclerosis. Authors today are featuring and focusing on 25 hydroxy cholesterol, which is produced as an oxidation product of cholesterol and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. So these authors with co-corresponding authors, Dr. Suárez and Fernández-Hernando from Yale University School of Medicine, they showed beautifully that first, 25 hydroxy cholesterol accumulates in human coronary atherosclerosis. Next, that 25 hydroxy cholesterol produced by macrophages accelerated atherosclerosis progression and promoted plaque instability by promoting the inflammatory response in macrophages and also via paracrine actions on smooth muscle cell migratory responses.

Dr. Peder Myhre:

Wow, that is so interesting, Carolyn. What are the therapeutic implications of these findings?

Dr. Carolyn Lam:

Yes, I'm glad you asked because it was summarizing a lot of work in those findings with the very important implications that inhibition of 25 hydroxy cholesterol production might therefore delay atherosclerosis progression and promote plaque stability. So this study actually opens a door to explore the role of 25 hydroxy cholesterol as a target to control inflammation and plaque stability in human atherosclerosis.

Dr. Peder Myhre:

Oh, that is so important. Thank you so much and there is more in this issue as well, Carolyn. We have another issue of Circulation Global Rounds and this time we're going to France in a paper written by Dr. Danchin and Bouleti. We also have an exchange of letters by Dr. Yang and Dr. Schultze regarding the article, "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation" and an ECG Challenge by Drs. Manickavasagam, Dar and Jacob entitled "Syncope After Transcatheter Aortic Valve Implantation: Pace or Not."

Dr. Carolyn Lam:

Interesting. There's a Frontiers paper also by Dr. Dimopoulos on “Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus,” a Research Letter by Dr. Kimenai on the impact of patient selection on performance of an early rule out pathway for myocardial infarction from research to the real world. Nice. Well let's carry on to that feature discussion on heart failure, transcriptomics and proteomic, shall we?

Dr. Peder Myhre:

Can't wait.

Dr. Maryjane Farr:

Welcome everybody to Circulation on the Run. We are so pleased to be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from the University of Utah. My name is Maryjane Farr and I am the heart failure section chief at UT Southwestern and Digital Strategies editor for circulation. Myself and Hesham Sadek will be talking with them about their new paper and circulation called "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients with Potential of Myocardial Recovery Upon Mechanical Unloading and Circulatory Support." Just briefly, Dr. Stavros Drakos is the director of cardiovascular research for the division of cardiology at Utah and co-director of the Heart Failure Mechanical Circulatory Support and Heart Transplant Program. Dr. Sarah Franklin is associate professor of medicine at the University of Utah whose lab has a specific expertise in the applications of proteomics to heart disease. Welcome, Stavros and Sarah.

Dr. Sarah Franklin:

Thank you.

Dr. Stavros Drakos:

Thank you. Thank you for having us.

Dr. Maryjane Farr:

This paper is exciting for clinicians. It's exciting for translational scientists. Hesham, why don't you start digging into this paper and tell us one or then the other of you tell us what this paper is about, what's the background and let's get into the science. Let's go there and then we'll pull back and look at some of the big picture stuff. Hesham.

Hesham Sadek:

Well, thank you. So I've been fascinated by the field of cardiac recovery for some time now and obviously Stavros is as an expert and one of the leaders of that field and what struck me about this is that we are starting to see some distinct molecular signature of patients that can experience recovery as opposed to patients undergoing the same procedures with the same profile that do not manifest evidence of myocardial recovery and specifically, the study was conducted very rigorously and the signature was very clear in that they saw primarily interest for someone like me who's interested in cardiac regeneration, a signature of cell cycle in the patients that experience recovery as well as ECM signature which could suggest reverse remodeling and also there's some evidence that ECM might impact cardiomyocyte and myocardial regeneration. So my interest in this for selfish reasons is primarily that this supports the hypothesis that perhaps there is a molecular signature of regeneration that occurs in patients that experience myocardial recovery with LVAD.

Dr. Maryjane Farr:

So Stavros, let's start with you. Give us the reason why to do this study. You mentioned some of the background. It'd be great to sort of talk for a moment about re-stage heart failure and then how it brought you to this study.

Dr. Stavros Drakos:

Thank you, Jane. So again, thank you for the opportunity to talk about the findings and the implications of this study. I like the way you are asking us to look a little bit at what led to this study and as you mentioned, the re-stage is a multi-center study that was performed in six US sites which showed in a reproducible fashion now given that we had single center studies from all over the world suggesting that, advanced heart failure is not an irreversible process that has to lead to end stage, an irreversible disease and what a re-stage demonstrated was that there is a subset of patients which if you select them based on clinical characteristics that we derived from other studies that were performed previously, you can achieve reverse remodeling, essentially a bad heart looking much better by every clinical, functional, structural characteristic in up to 50% of the selected patients. That's what re-stage showed.

So having this finding now in a multicenter study, what made this study very timely was to be able to understand what drives this remarkable response. What are some of the mechanisms, as Hesham said, that we can if uncover take advantage of and expand this paradigm and enhance it and achieve reverse remodeling and recovery of even more patients and even go earlier in the disease process. So that's kind of how I would link the clinical findings that preceded this study with the motivation to perform the study and the implications of these findings for the ongoing translational and basic science research.

Hesham Sadek:

I'd like to ask a question here. So Stavros, do you think it's too early to sort of redefine the term reverse remodeling in this context to include perhaps some evidence of regeneration? Is there evidence of regeneration in this field or that's too premature to say?

Dr. Stavros Drakos:

I think the data are directing us towards the direction you just mentioned. I think that we can begin talking about it and planting the seed. We do have other evidence from work that you and others have performed indicating that this indeed is one of the mechanisms that drives this phenomenon and I think that the findings, especially in the cell cycle that we identified add to and contribute even more to that body of work that you and others have done. At this point, I will turn it to Sarah who can talk a little bit more about the findings related to the cell cycle that we identified in our study and I think that these may complete the answer to you, Hesham.

Dr. Sarah Franklin:

Yeah, I would love to comment. I think it's a really interesting phenomenon and really in these patient samples we were trying to understand molecularly what the difference is between individuals that respond positively to therapy and individuals that receive the same exact therapy and do not respond positively. So these are termed responders and non-responders and in our analysis we combined two platforms where we could molecularly interrogate what's different in these two tissues and try to see what is differentiating these populations. So what's consistent and reproducible different in responders and non-responders on a molecular level and in both the transcriptomic data and the phospho proteomic data, we saw clear patterns with cell cycle regulation and extracellular matrix or focal adhesion molecules and the interesting thing about cell cycle is cardiomyocytes have typically been thought to exit the cell cycle not long after birth and we see some interesting phenomenon either in humans or mice where we can have nuclei that have either multiple sets of chromosomes or multiple nuclei and there's some differences that have been observed in the nucleus with regards to disease, so hypertrophy, heart failure.

So the molecules that we've identified, we saw a large difference in proteins involved in cell cycle regulation. Now the interesting thing is not all of those molecules are increasing or decreasing. We see a combination of molecules that are increasing or decreasing. But I think the other thing that's interesting is that these molecules, even though we are seeing changes in expression or changes in phosphorylation, exactly how that contributes to either cell cycle or cell cycle reentry or just nuclear function and transcription of proteins or genes or DNA regions is still what we need to continue to study. So exactly how these changes in proteins or transcripts related to the cell cycle, how they are exactly contributing to the physiological improvements that we're seeing is something that still needs to be investigated but is really important that that is a highlight of this study and as Stavros mentioned of previous work.

Dr. Maryjane Farr:

Stavros, tell us the design of the study.

Dr. Stavros Drakos:

Okay. So this study was performed in 93 patients that were prospectively enrolled in the Utah transplant affiliated hospitals here in Salt Lake City between the University of Utah, Intermountain Medical Center and the VA and these people came from all over the mountain west, the surrounding states of Utah and through our VA, through the state, from all over the west and south, from Alaska and Hawaii to Texas and we think it's a very representative population of our country's patient population and then we followed prospectively these people with serial echocardiograms so we can tell who will respond as Sarah said before, which essentially means which hearts are going to get better by echocardiographic criteria functionally and structurally, the dimensions of the heart shrinking and the ejection fraction improving to more than 40% and the dimension shrinking to normal range and then we compare these people, the subset of patients that have responded to the majority of patients actually that they have not responded. As we know these are advanced end stage patients and there is only a subset of those that they will favor respondents.

As we said earlier, these subset can increase if you go selectively and pick these patients based on baseline characteristics. So then we analyze the tissue we got from these people when the LVAD went in, which is the core of the apex of the heart and compare that to the tissue we receive when the patients got transplanted and we got the whole heart. So in the meantime, as we just discussed, we phenotyped these people so we knew who were responders and non-responders and then we went back in the lab and tried to marry two basic processes, analyzing the transcriptome and the proteome and by doing that we were able to see some overlapping changes between the transcriptome and the proteome and we felt that by doing this overlapping analysis, we will increase the likelihood that what we are seeing, exponential mechanistic drivers will be the real mechanism and not just associations that you can frequently find when you do studies in humans and that's kind of a rough, brief summary of the design. Sarah, would you add something to that?

Dr. Sarah Franklin:

No, I think that's a great overview of it. I think what excites me about it is that this was first clinically observed that these patients were recovering and so I think the exciting part is the hypothesis was that there was some molecular underpinnings that could molecularly define these patients that were responding or not responding and so with that hypothesis we then carried out these analyses hoping that we would see a difference and we're very excited. It's very successful in that we found very clear, molecular differences that are reproducible between these patient populations.

Dr. Maryjane Farr:

So obviously there's lots of implications. Let me start with one very simple clinical one and that is, so based on some of the differences in the signatures and pathways that you saw for the next patient who needs LVAD therapy and you're trying to predict in some way whether they may be a responder or a non-responder, could you look at a biopsy sample and try to make some sort of prediction based on some of your findings so that they can choose a VAD over a transplant? That's a very clinical question and then I guess the second question is would it have to be a left ventricular myocardial sample? So are the differences? What do you think about that question? Or it's just too much too, far beyond? This is obviously a mechanistic study. But I'm just asking.

Dr. Stavros Drakos:

No, that's a great question and I'll start and Sarah can add later. So obviously it will be great if we can have a practical way to predict before the intervention who are the people that they will respond and that's one of the motivations for this study. It was not just to find the mechanism so we can make this phenomenon better and enhance it and find the mechanism, create new therapies. It was also the practical approach that you suggested, Jane, and I think that yes, this adds to the clinical predictors that we have already identified from other studies and yes, we could theoretically take the tissue and do this analysis. Is this the most practical thing we can say to the patient to biopsy the heart, right? It would've been better to be able to identify a biomarker in the plaque and we've done that. We started in other studies, identifying what's going on in the tissue and then going targeted in the blood and that's how we identified two cytokines and a two cytokines model, interferon gamma and TNF alpha being predictive as circulating biome.

In this study we identify changes that can also inform future studies of biomarkers in the blood. But if we had a way to easily get the tissue and analyze the genes, yes, we could have done that as a predictor as well. The practical issue is that asking a patient for a biopsy just to predict the response to therapy may be something that most patients and most clinicians will consider way too advanced and complicated, right?that's why more work should and could be done to identify circulating biomarkers or other modalities that can help us interrogate what's going on in the heart related with these findings. But not that we cannot also do what you said. It's just more complicated. I don't know if Sarah would like to add to this.

Dr. Sarah Franklin:

I'd love to. I think that's a great overview. I think the only thing that I would add is that there are a number of conditions whether in the heart or otherwise in the body that you can use a single biomarker and it can be very predictive of conditions. Heart failure is so complex that often individual biomarkers are not sufficient enough to cover an entire population and all the nuances that can go into heart failure symptoms or syndromes and I think the exciting part about this study is it is one of the largest cohorts of patients that have been examined in this manner, which is exciting, but also that we have a multi-factor panel that is made up of multiple biomarkers that with the number of individuals that we examined is completely predictive of all of these patients.

So these biomarkers are consistent and reproducible across all of these patients between responders and non-responders regardless of some of the nuances in the heart failure that they have and so it's very exciting because it's possible that a multifactorial panel could be much more applicable and last the test of time more so than an individual biomarker. I think the one other thing that is exciting like Stavros mentioned is that we did initially identify these in the left ventricle and it will be really exciting to see how far these biomarkers can be used if they can be used in potentially other aspects of the heart or blood, which obviously is less invasive and so that's not something that we've applied this panel to yet, but I think is a really wonderful extension of now saying, can we also identify some of these biomarkers in the blood which would be less invasive even if it's a fraction of them. That would still be wonderful.

Dr. Maryjane Farr:

I have so many clinical questions. But Hesham, what questions do you have?

Hesham Sadek:

Yeah, so the elephant in the room here obviously is that the variable is that these patients have an unloaded heart and there is evidence that unloading can reverse some of the changes that occur after birth with increasing ventricular load and initiate cascade of molecular events that may allow myocytes to proliferate. So this begs the question, is there a difference in how these ventricles of patients that recover versus those that do not recover see load? Are we able to measure load appropriately and is there a difference in load between these patients and if so, can this be improved or detection or measuring unloading or the degree of unloading clinically, can this be improved?

Dr. Stavros Drakos:

No, that's a great question and it provides the opportunity to talk about some of the things we can do on the clinical arena to further enhance this phenomenon. Yes, there are ways that we can use to tailor the mechanical unloading that we can provide in order to enhance this phenomenon. One way, and that's a study that we are proposing, is to use sensors, pressure sensors that can guide the way you function the machines, the devices, right? The way you remove part of the load and these sensors, some of them are clinically approved like cardioments and then without doing invasive procedures you can follow chronically how these patients are being unloaded and how the heart is responding to this unloading. We know that a lot of LVAD patients, despite doing clinically well, we know this from snapshot evaluations in right-heart cath studies, they are not optimally unloaded. They are feeling pressures left and right are not always optimized and so by doing this kind of prospective assessment of the mechanical unloading, you can tailor what you offer and the hypothesis generated is that by doing that you may be able to recover even more people.

You can do this as we said, with approved sensors like cardioments or with other sensors that they are under investigation. You can also do more invasive stuff like PV loops. Of course these will require cathing these patients, which is a little bit more complicated. But it will provide more accurate assessment and it will also interrogate how the heart is improving and provide to you in-depth investigation and in-depth insights on also how the recovery process and the reverse remodeling process is being, I would say, digested by the heart and translated to functional response instead of just looking at it with an echocardiogram or the findings of a right-heart cath and these are studies that others have performed and have published and we know that they can give you a real good look into the systolic and diastolic function of the heart and how this is changing and improving down the road. So yes, that's the short answer. We can do that and we can tailor the unloading and potentially that's the hypothesis, maximize the effect that we saw here.

Hesham Sadek:

So this begs the question, maybe two questions here. One, is there evidence that patients who recover not from this study only but from other studies, is there evidence that patients who recover are more unloaded than patients that do not recover and the second question is: is it time to standardize assessment of mechanical load in patients with LVAD, especially those that will undergo or would be considered for recovery?

Dr. Stavros Drakos:

Yes. So that's a great opportunity to share with our audience what we know and what we don't know in this field in relation to your question about whether we know what is the optimum degree of unloading and the answer I think is that we need to know and understand more. What do I mean by that? There's this idea that the heart as every other organ after being unloaded and not working for some time may it lazy, may get atrophic and may need some rehab like the skeletal muscle when we put it in the cast and get atrophic and we need to rehab it when we remove the cast. So you can imagine that the LVAD and the unloading that provides, which in many cases may take over a significant part of the function of the heart may need gradual reloading as a second phase after the first phase of unloading and that's something that we've done. We have an ongoing study on this and also others have published that it may be beneficial.

Of course, it needs to be validated and investigated further and to discuss about the degree of unloading in the first phase and what is the optimum degree of unloading, I would say even there, there is room for us to understand better what's going on and I think that we can investigate with ongoing studies right now whether full unloading versus partial unloading and measure the pressures using these sensors can translate to better changes functionally and structurally. I think that's something that is very doable and it would be very beneficial. What was the second part of your question, Hesham?

Hesham Sadek:

I was asking whether it's time to start standardizing some measure of unloading if these patients are planned for recovery?

Dr. Stavros Drakos:

Yes, and that's what we are doing. In all of these people, we report from the get-go what is their recovery score based on the intermixed ICARS derived score and when we have patients that they have high likelihood of recovery, we monitor them very closely and clinically what we do is just looking at the echo and whenever we do a right heart cath for clinical reasons. But in a prospective research study we could do more than just looking at the echo and occasional right heart cath and using the sensors we just discussed previously, you can tailor the unloading and begin prospectively unloading them in a more I would say well monitored wave. Yes.

Hesham Sadek:

So this is unloading or device specific parameters. Now are there patient specific parameters with regards to type of heart failure? So we talked initially about whether there's an element of regeneration specifically when it comes to cell cycle. But many patients with non-ischemic cardiomyopathy for example, don't have large scars and don't have lot of myocytes as the underlying cause of cardiomyopathy. Would you foresee that there is different mechanisms, for example, in these patients that don't have myocyte loss, that perhaps maybe it's not cardio myocyte proliferation and not regeneration?

Dr. Stavros Drakos:

Yes. So I think that the differential responses we get based on the heart failure theology warrant further investigation. Sarah and I have discussed that and actually we are following on our findings with larger number of patients so we can tease out these and I'll let Sarah talk a little bit more about it in a minute. But to answer the clinical part of this question, we don't know yet whether different parts of heart failure should be prescribed different modes of unloading. But the way you described it of course invites the hypothesis that of course different substrates, different injuries of the heart, as you said, it's a completely different failing heart if you have a big scar there versus a patient who has a mode of heart failure, another type of injury and would this be treated better and more effectively in terms of reverse remodeling by applying a different mode of unloading? That's things that we need to investigate further. But Sarah, would you like to comment on the potential on the effect of the different heart failure theologies on some of the findings we saw?

Dr. Sarah Franklin:

Yeah, definitely. So I think it's a really interesting question and in this analysis we included ischemic and non-ischemic samples in the patient populations and really we're just stratifying them based on responders and non-responders. When we start layering additional levels onto that, then we're effectively kind of reducing the potential numbers. So if we have 25 responders and we start breaking that down into ischemic and non-ischemic to see if there's another layer of biomarkers there, we actually did that we did not include it in this study. It's something that we're working on to add that. But we do reduce the number overall of patients in those two populations. So it would be fine to share that we were seeing stratification between ischemic and non-ischemic. But we did not feel like the numbers might be high enough within the responder and non-responder categories that warrant including that in this manuscript. So it's very intriguing that just responders and non-responders alone stratify as well as they do.

They separate based on these biomarkers and it looks like it will also be possible in the future for us to even separate these samples further based on similar or additional biomarkers based on more specific factors in the etiology. So I think that will be another really exciting next step for future research.

Hesham Sadek:

My final question would be maybe a little bit broader than LVAD population, but definitely informed by this study. The term non-ischemic cardiomyopathy, do you think it's too broad and too vague for us to use in this setting because this encompasses many different types of cardiomyopathy that really are not nuanced enough by this definition.

Dr. Stavros Drakos:

Well, Jane was smiling while you were asking this question because we all as heart failure clinicians need to accept that it was not a good idea to name all of these different diseases non-ischemic cardiomyopathy when we did it or when this happened many moons ago. As you said, Hesham, and I couldn't agree more, these are completely different diseases. We need to understand them better and I think that the way we treat nowadays, chronic heart failure, many years down the road when people will look back, they will consider it a little bit, I would say, surprising that we were treating all of these the same way.

We need more studies like the one we just did, that they will have enough numbers and that's when the issue becomes that you need enough numbers to be able to tell the differences between all of these non-ischemic cardiomyopathy types, theologies and if you go upstream, motivated and inspired by findings like this, we hope that we will be able to identify how to go and do a root cause analysis and treat these diseases, not down, down, downstream the same way, but going upstream, finding what really went wrong and treating them earlier in the molecular or other pathophysiological mechanism pathway that led to the heart failure and so yes, it was a bad idea to do that. But of course sometimes we do things because we don't understand it better, right? As one of our keynote speakers here in the recovery symposium said a few years ago, Jay Khan, the founder of Heart Failure Strata of America, some things look complicated until you understand them. Then when you understand them, they look simple.

So here we don't really understand non-ischemic cardiomyopathy and how all these theologies lead there and I think studies like these can help us really inform the field better. But we will need, as Sarah said, more numbers.

Dr. Maryjane Farr:

So that was a great conversation. I wanted to just raise one last thing and that is what's so interesting about this cohort relative to re-stage heart failure is these were older patients and for re-stage heart failure, I think the average age was 35. So you would imagine there might have been one etiology for cardiomyopathy, uncontrolled hypertension or peripartum. But for cohorts in their fifties, there's probably an accumulation of different insults over many years time and so I thought that was particularly interesting from the point of view of that you were probably dealing with, again, a mixed bag of pressure overload, volume overload, maybe a genetic underpinning, whatever the life trajectory of some of these patients were and then lastly, the decision to try to go to recovery rather than to transplant, which would be the real world experience of why this wet pathway than the other. These are people truly in their fifties where they may have one or two surgeries in their lifetime left and so it's the relevant population that you're studying and so I'll leave it at that. That's a comment rather than a question, I think.

But I think for heart failure clinicians, this is why the bench to bedside piece is so relevant to understanding this because it actually does change clinical practice, even if the mechanistic pathways may take still many more years to truly understand. It helps understand what's possible from an accrued clinical decision-making level.

Dr. Sarah Franklin:

Jane, if I might just comment on that, I actually think that's one of the most exciting parts about this dataset is that, as you mentioned, these patients have complex diseases. They are older. But yet we are still able to see consistent and reproducible differences between the patient populations that respond and don't respond and to me that suggests that at the end of the day there are consistent differences or reproducible or consistent molecular changes in cardiac tissue and in response to stress and I think that that gives us hope that we could potentially not only predict who would respond or not respond, but that as we get better at understanding the differences, that there could be potential therapeutic targets or therapies that would still be beneficial regardless of the complexity of the heart failure.

Dr. Maryjane Farr:

Okay. So Sarah, Stavros, thank you so much for spending time with Hesham and myself and look forward to EUCORS--I'm allowed to say that.

Dr. Stavros Drakos:

Of course.

Dr. Maryjane Farr:

Thanks so much. Bye.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.