May 23, 2022
This week, please join author Sanjiv Shah, Editorialist Evangelos Michelakis, and Associate Editor Justin Ezekowitz as they discuss the article "Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure" and Editorial "Atrial Shunt Devices in Patients with Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns."
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, Associate Editor, Director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, I love today's featured article. It's all about heart failure with mildly reduced and preserved ejection fraction, talking about device therapy and the response to therapeutic atrial shunt device. Now, this is a very interesting discussion of how specifically selecting patients based on latent pulmonary vascular disease may hold some answers, but we're going to keep everyone hanging here. You've got to, got to listen to the discussion. But first, we'd like to tell you about some of the papers in today's issue. And I think Greg, you've got one to start us with, right?
Dr. Greg Hundley:
Absolutely. Carolyn, thank you so much. Well, this first paper comes from Dr. Eliot Peyster from the University of Pennsylvania. And Carolyn, the aim of this study was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies, to develop a precision medicine tool for predicting cardiac allograft vasculopathy, years before overt clinical presentation.
Dr. Carolyn Lam:
Ooh, interesting. Again, precision tools. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So there was a clinical predictive model that achieved modest performance on the independent test set, with area under the receiver operating curve of 0.7. But interestingly, a histopath- predictive model for predicting cardiac allograft rejection achieved good performance, with an area under the receiver operating curve of 0.8. Most importantly, however, a model, incorporating both clinical and histopathologic features, achieved excellent predictive performance, with an area under the receiver operating curve of 0.93.
Dr. Greg Hundley:
So in summary, Carolyn, these authors found that prediction of future cardiac allograft vasculopathy development is greatly improved by incorporation of computationally extracted histologic features. Their results suggest morphologic details, contained within regularly obtained biopsy tissue, have the potential to enhance precision and personalization of treatment plans for post heart transplant patients.
Dr. Carolyn Lam:
Aw, that's cool. Makes so much sense, but yet so novel. Thanks.
Dr. Carolyn Lam:
Well, for the paper I want to talk about, we are going to talk about dapagliflozin. Now we know the SGLT-2 inhibitor, dapagliflozin, improved heart failure and kidney outcomes in patients with Type two diabetes with or at high risk for cardiovascular disease, in the DECLARE–TIMI 58 trial. In the current paper, authors, led by Dr. Wiviott from the TIMI study group, aimed to analyze the efficacy and safety of dapagliflozin stratified, according to baseline systolic blood pressure.
Dr. Greg Hundley:
Ah, so an interesting question, since SGLT-2 inhibitors are known to reduce blood pressure. And given the concerns regarding the safety of SGLT-2 inhibitors, in patients with low to normal systolic blood pressure. So Carolyn, what did they find?
Dr. Carolyn Lam:
Nicely put Greg. So in patients with type two diabetes with, or at high risk of, atherosclerotic cardiovascular disease, dapagliflozin reduced the risk for heart failure hospitalizations and renal outcomes, regardless of baseline systolic blood pressure, with no difference in benefit for reduction in heart failure or renal outcomes, among patients with blood pressure from the normal range, all the way to severe hypertension. Moreover, there appeared to be no difference in adverse events of volume depletion, acute kidney injury, or amputations, across the levels of baseline blood pressure. So these results indicate that dapagliflozin provides important cardiorenal benefits in patients with Type two diabetes at high risk, the independent of baseline blood pressure.
Dr. Greg Hundley:
Oh, very nice, Carolyn. Well, my next paper comes to us from the world of preclinical science, and it's from professor Jeffrey Towbin and colleagues, at Le Bonheur Children's Hospital. So Carolyn, as we know, arrhythmogenic cardiomyopathy is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 has been reported to be the most common disease causing gene when mutation is positive. Now in the early concealed phase, the arrhythmogenic cardiomyopathy heart is at high risk of sudden cardiac death before cardiac remodeling occurs, due to mis-targeted ion channels and altered calcium handling. However, the results of pathogenic plakophilin-2 variants on myocyte contraction in arrhythmogenic cardiomyopathy pathogenesis, really remains unknown. So Carolyn, these authors studied the outcomes of a human truncating variant of plakophilin-2 on myocyte contraction, using a novel knock-in mouse model, as well as evaluation of human subjects.
Dr. Carolyn Lam:
Oh, interesting. So what were the results from this plakophilin-2 knock-in mouse model?
Dr. Greg Hundley:
Right, Carolyn. So serial echocardiography, a plakophilin-2 heterozygous mice revealed progressive failure of the right ventricle, but not the left ventricle, in animals older than three months of age. Now next, adrenergic stimulation enhanced the susceptibility of plakophilin-2 heterozygous hearts to tachyarrhythmia and sudden cardiac death. Contractility assessment of isolated myocytes demonstrated progressively reduced plakophilin-2 heterozygous RV cardiomyocyte function, consistent with right ventricular failure, measured by echocardiography.
Dr. Greg Hundley:
And the next, Western blotting of plakophilin-2 right ventricular homogenates revealed a 40% decrease in actin. In contrast, plakophilin-2 heterozygous left ventricular myocytes had normal contraction and actin expression.
Dr. Greg Hundley:
And finally, Carolyn, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in the right ventricles of end stage arrhythmogenic cardiomyopathy patients. So in conclusion, Carolyn, during the early concealed phase of arrhythmogenic cardiomyopathy, reduced actin expression drives loss of RV myocyte contraction, and that contributes to progressive RV dysfunction.
Dr. Carolyn Lam:
Wow. Thanks, Greg. Well, also in today's issue, there's an exchange of letters among Drs. Whitman, Ibrahim, and Løfgren, regarding physics at the heart of the matter, referring to the article, “Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation.”
Dr. Greg Hundley:
Right Carolyn. And also in the mail bag, there's an On My Mind piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing Winter Olympics, The Spotlight On Cardiac Metabolism.”
Dr. Greg Hundley:
Well, how about we get onto that feature article, and learn a little bit more about atrial shunts, and how they may be helpful in heart failure with preserved ejection fraction?
Dr. Carolyn Lam:
Ooh, can't wait.
Dr. Greg Hundley:
Well, listeners, we have a very interesting feature discussion today related to hemodynamics pertaining to interatrial shunt devices, in those with and without pulmonary hypertension. And we have, gosh, a repertoire of speakers today. We have Dr. Sanjiv Shah, from Northwestern University in Chicago, Dr. Evangelos Michelakis, from Edmonton Alberta, and our own associate editor, Dr. Justin Ezekowitz, also from Edmonton Alberta.
Dr. Greg Hundley:
Well, Sanjiv, we're going to start with you. Describe for us, some of the background pertaining to your study, and what was the hypothesis that you wanted to address?
Dr. Sanjiv Shah:
Great. Thanks, Greg. Thanks for having me today. Well, the background of our study is that, it was a subgroup analysis, or a secondary analysis, of the REDUCE LAP-HF II trial. Now this trial has been in the making for over 12 years, almost 13 years. It started out as an idea that was David Celermajer. David is a pediatric cardiologist in Australia, who had this idea that, in mitral stenosis patients, it's well known that, if there's a concomitant secundum ASD, a congenital secundum ASD, in these patients with mitral stenosis do better. They have a way to unload the left atrium, and distribute that blood to the systemic veins and the right atrium, the right side of the heart. And so could this be helpful in quote, diastolic, heart failure or HFpEF?
Dr. Sanjiv Shah:
And so, I started working with him about 12 years ago. This started out as a concept. It was studied in animal models, and then in humans, in open label studies, and then, in a first randomized controlled trial. Where we showed, that an intraatrial shunt device, an iatrogenic ASD, so to speak, put in humans with heart failure with risk preserved EF, results in a lowering of exercise pulmonary capillary wedge pressure. And so based on that data, we designed a pivotal trial, a Phase III trial, the largest trial of its kind, of heart failure with preserved and mildly reduced ejection fraction, to see if interatrial shunt device would improve outcomes. And we published that trial earlier this year in the Lancet. Unfortunately, it was a totally neutral trial. And when you have a neutral trial in any condition, but as we see often in HFpEF, the question is, was it neutral overall? Or was there a subgroup that benefited? And what we found in that trial was that, there were three predefined subgroups that came out that seemed like there was a difference.
Dr. Sanjiv Shah:
First, there was a sex difference. Women did better. Men did worse with the device. Then, there was right atrial volume. Those with bigger right atrial volumes did worse. If you had a smaller right atrial volume, you did better. But the most significant interaction and subgroup was exercise pulmonary artery systolic pressure.
Dr. Sanjiv Shah:
If the pulmonary artery systolic pressure was greater than 70 at 20 Watts of exercise, so just with a little bit of exercise, those patients did worse. And if PA pressure stayed low, the patients did better. And so we sought to further explore this to say, "Okay, what's exactly going on?" In a post hoc analysis, what's going on with the pulmonary vasculature during exercise, and how does that differentiate how patients potentially respond to the device? And that's what we hope to figure out.
Dr. Sanjiv Shah:
We hypothesize, that if exercise pulmonary vasculature resistance is lower, then the shunt can actually work, and blood can flow from the left to the right, into the lungs, and the right heart doesn't get too overloaded. And we know, that the normal response of the pulmonary vasculature is to vasodilate with exercise. And so, if patients had retained that response, the ability to do that, that they may benefit. And so, we sought to figure that out with this subgroup analysis.
Dr. Greg Hundley:
Sanjiv, it sounds like a really elegant, well thought out hypothesis. So what was your study design? And describe your study population.
Dr. Sanjiv Shah:
Yeah. This was a randomized controlled trial. And so this was 626 patients enrolled at 89 centers across the world. And it was really, heart failure with mildly reduced, so an EF of greater than 40, or preserved EF, and 93% of them had HFpEF. And what was unique about this trial is that we, this is the first trial really, that confirmed that these patients actually had heart failure, with mildly reduced or preserved ejection fraction. Most trials say, well, you have to have an elevated BNP, and you have to have some sign of structural heart disease, and maybe, a history of heart failure hospitalization. In this trial, every single patient had to undergo rigorous noninvasive echocardiography. And then, on top of that, they had to undergo exercise invasive hemodynamic testing. And people thought that it wasn't possible for 626 patients, but we did it. And every single patient had had an exercise pulmonary capillary wedge pressure greater than, or equal to, 25. And so this really was HFpEF. So it's a randomized trial.
Dr. Sanjiv Shah:
And then, beyond that, we did a subgroup analysis. So we looked on various subgroups, focusing on exercise PVR, and we really looked to see the effect on three outcomes. Number one, a hierarchical endpoint, a combination of cardiovascular death, ischemic nonfatal stroke, recurrent heart failure hospitalizations, and the KCCQ. And then the other two outcomes were just the individual recurrent heart failure hospitalizations, and the KCCQ. We looked at all of these, and tried to figure out if there are certain subgroups that benefit.
Dr. Greg Hundley:
Great detail. So Sanjiv, what did you find?
Dr. Sanjiv Shah:
Well, we found that, there's this group of patients, that during exercise, the pulmonary vascular resistance at peak exercise stays above 1.74 Wood units. Now that seems like an arbitrary number, but in fact, in older individuals that are healthy, when you exercise them, the PVR upper limit, the exercise PVR upper limit, is about 1.8. So we're right about the upper limit of where the PVR should be. And if it was above that, the patients actually did worse with the shunt device. They had a lot more heart failure hospitalizations. Their KCCQ got worse, didn't benefit. And if they were below that threshold, meaning they were, sort of compliant pulmonary vasculature, and it stayed compliant, or they vasodilated effectively with exercise, then they benefited from the device. And what we call this concept of exercise-induced pulmonary vasoconstriction, or inability to vasodilate, is latent pulmonary vascular disease.
Dr. Sanjiv Shah:
And so, if you have that latent pulmonary vascular disease, your win ratio is 0.6. That means you do worse. And if you don't have this pulmonary, this latent pulmonary vascular disease, your win ratio is 1.31. And that means, you do better with the device. And we saw very similar findings with the KCCQ. We saw similar findings with the recurrent heart failure hospitalizations.
Dr. Sanjiv Shah:
And the final thing is, we found that, we looked at various other subgroups, and it turned out that if there was no latent pulmonary vascular disease and no history of pacemaker, which we found was kind of associated with sex and right atrial volume, those patients, for about 50% of the group, actually did the best. And that was what we called, the responder subgroup.
Dr. Greg Hundley:
Thank you, Sanjiv. Well, listeners, we're going to turn now to our associate editor, Justin Ezekowitz. And Justin, you have many papers come across your desk. What attracted you to this particular manuscript?
Dr. Justin Ezekowitz:
So Greg, this paper kind of stood out for a number of different reasons, as I sent you. You're to be congratulated for a variety of reasons. But the number one is, pursuing the data from a neutral trial overall, to understand who might benefit and who might be harmed from a pretty novel device and way to treat patients in such a scale, that's not being done like this before. So it stands out by just the magnitude of number of right heart catheterizations, number of patients enrolled, number of procedures done. And all of those things really lead to us to be able to understand the area much better than I think we can in a human population.
Dr. Justin Ezekowitz:
Where this sits with other devices that are very similar, is hard to really know, if all devices are going to be the same or different, but your population is quite unique is if they're not all end stage, but they're sick enough to get into your trials. So there's this population we treat actively. And I wondered if you could touch on that continuous nature. And so for readers, there's this beautiful figure, which shows a continuous nature of exercise PVR. And I wonder if you could touch on that. Is this mid group, the group that we should target for our future therapies like this, or this needs further study?
Dr. Sanjiv Shah:
Well, I think it needs further study. I think the listeners should be aware that this is a post hoc analysis. We did pre-specify exercise PA pressure. This is one trial. But it makes a lot of sense, pathophysiologically. What we're doing here is we're shunting this excessive LA, overloaded LA, shunting the blood from the LA to the RA and into the pulmonary vasculature. Well, if that pulmonary vasculature can't accept that increased flow, the patient's not going to do well. And how can we simulate that? Well, we can simulate it with exercise. As the patient's pedaling on the bike, on the cath lab table, there's increasing blood flow to the pulmonary vasculature, and we're seeing what happens with the pulmonary vasculature. Does it vasodilate, does it not? And so, I think that's why we were excited about this finding.
Dr. Sanjiv Shah:
I do think that, there are at least seven other companies making shunt devices, interatrial shunt devices or therapies. And I do think, they need to pay attention to this and really look at this. Not all trials are doing exercise and basic hemodynamics, that needs to be done, I think. So it'll be really interesting to see.
Dr. Sanjiv Shah:
Now, one thing I will say is that, and I've written about this, this is a really interesting trial. Because the BNPs were lower, and so you would think, okay, these are patients that are less sick. And yet, their heart failure hospitalization rate was at least one and a half times higher than pharma Phase III trials. KCCQ was way lower, like 30 points lower. So there are these patients out there that are really sick, and they're the ones that I think, are where their life, their sort of quality of life, their outcomes, are being driven by the HFpEF. And that's what we found in this trial.
Dr. Greg Hundley:
Very nice. Well, listeners, let's turn now to our editorialist, Dr. Evangelos Michelakis. And Evangelos, two questions. How do we put the results of this substudy, really in the context of the main trial? And then secondly, do you have any, with your expertise in endothelial function, and understanding the mechanisms of pulmonary hypertension, can you describe what you think might be operative as a mechanism here, and why Sanjiv observed these positive results in some patients?
Dr. Evangelos Michelakis:
Thank you. So the first point is that, I have to also repeat, that it was a remarkable achievement to do all this right heart catheterization on a treadmill in the cath lab. It's a very complex procedure. And it is, they have to be congratulated, the authors, for actually doing this. There is no question that, like Sanjiv said, ongoing trials for future trials will need to include the hemodynamics in the trials, before and after the procedure.
Dr. Evangelos Michelakis:
So another important thing is that, the authors brought up this, they called it latent pulmonary hypertension, we could call it latent pulmonary hypertension, or probably, early pulmonary hypertension, as an entity. Now that entity, it's newer in the heart failure field. It's not that old in the PIH, the pulmonary interior hypertension field, since it used to be in the guidelines for this disease, that exercise pulmonary hypertension was a diagnostic criterion for that. Because the idea is that, exercise pulmonary hypertension reflects early pulmonary hypertension. So you needed to intervene with therapies early.
Dr. Evangelos Michelakis:
Now, I'm not sure that this is a fact. But it is very likely that these patients, in Sanjiv's trial, that had the early, that had the sort of enhanced response with exercise, did have at least, endothelial dysfunction in the pulmonary arteries. Not only because this population has a number of endothelial risk factors, diabetes, smoking, you name it. But also, there are newer problems like SNPs polymorphism mutations, that will recognize more into the pulmonary arterial hypertension field, to be more unique to the pulmonary circulation.
Dr. Evangelos Michelakis:
But the reason I say that is that, the reason that you dilate with exercise, is mostly because of your pulmonary arterial endothelial cells, secreting vasodilatory factors. And also, allowing previously closed capillaries to open up with increased flow. However, the problem is that, if you have pulmonary arterial endothelial cells in vitro, and you expose them to high flow, like in this case, you can actually change their identity. Turn them into cells that are not endothelial cells anymore, are proliferative pro-inflammatory, and they can actually cause structural pulmonary circulation damage.
Dr. Evangelos Michelakis:
Also, there are animal models and people working in PAH and ASD, where they've shown that, if you have, if you're given endothelial toxin in animals, and then, you do an aortocaval shunt, then you get really severe pulmonary hypertension with structural disease, that is not even reversible if you remove the shunt.
Dr. Evangelos Michelakis:
So from this trial, the conclusion that patients with pulmonary hypertension should not get the device, is very clear. And probably, the ones with exercise pulmonary hypertension. My theoretical concern is, for those that don't have exercise pulmonary hypertension, or those that do have it, could they get worse after a number of years, and have structural pulmonary vascular disease? And unfortunately, we didn't have a follow up right heart catheterization to prove that, whether this is right or wrong. Which is a thing, is the most important thing to do in the future. So mimic the protocol for this trial from now on, but also add a follow up right heart catheterization, perhaps not just in a year, but longer. In other words, enough time to allow the structural pulmonary remodeling get established, but also, affect the right ventricle, these things don't. So maybe in a few years. It's a very demanding thing for these protocols, but I think, that's what needs to be done before we say this device can actually be beneficial for those patients, or for some patients, or not hurt others.
Dr. Greg Hundley:
Very nice. And so, a great segue, Evangelos, into what we think the next studies may need to be performed in this particular sphere of research.
Dr. Greg Hundley:
So Sanjiv, in just 30 seconds, could you share your thoughts first, and then we'll circulate back to Justin, and then finish up with Evangelos. Sanjiv?
Dr. Sanjiv Shah:
Yeah. I think the key thing is, to do a confirmatory trial. And that's what we're aiming for, is to do a confirmatory randomized sham-controlled trial, but focus in on these patients with an exercise peak PVR of less than 1.75, around there. And I think, that'll help answer the question. The Qp/Qs we get with this device is 1.2 to 1.3. So I don't think it's a high flow. And we actually have open label studies, where we've gone out to three years, with repeat invasive hemodynamic testing, echocardiograms, and we've had patients who've been implanted for seven years. We're not seeing, at least at that point, any sort of worsening of pulmonary vascular disease, or RV function, or anything like that. And so, it remains to be seen.
Dr. Sanjiv Shah:
The last thing I'll say, which I think is provocative, in the field of HFpEF, all pulmonary vasodilator drugs have failed. And though, we only measure pulmonary vascular resistance at rest. And what we saw in this trial, is that some patients have a high PVR and it comes down. Some people have a PVR that stays low, and is low and stays low. Some people have a low PVR and it goes up. You know? So I think what we need to think about in the field of PH‐HFpEF, is more exercise genotyping, to determine what's the dynamic exercise PVR? And maybe, those with exercise elevation of pulmonary vascular resistance are the ones that respond to pulmonary vasodilators. So that's another thing that I think we can think about taking away from this trial.
Dr. Greg Hundley:
Thank you, Sanjiv. Justin.
Dr. Justin Ezekowitz:
Yeah. So my thoughts are mimicking Sanjiv's. But one of the things that we desperately need is, ways in which we can noninvasively assess the exercise PVR, so that we can think about the large scale interventions that might come down the road, if interventions such as this work well. Because the noninvasive scans will really help us look at broader populations. Those are, that don't make it into trials, and those that aren't traditionally in our studies of HFpEF. So I think, that's another area where we can really grow the field, and then, grow our knowledge.
Dr. Greg Hundley:
Very nice. And Evangelos.
Dr. Evangelos Michelakis:
So, yes. Of course, like everybody said, we need trials that will have a follow up right heart catheterization, at least address, if not both, like the investigators did. But because the big question is, are these patients having an earlier stage pulmonary hypertension or not? These patients that the authors called, latent pulmonary hypertension, we need to phenotype more their endothelial cells, or their disease. And in the absence of biopsies, the only way we could do that, is perhaps, with molecular imaging, or at least, in some small populations. Or with analyzing pulmonary arterial endothelial cells in the blood, and their molecular phenotype, to see if they are a distinct group, which I suspect they may be. So further genotyping of this exercise induced pulmonary hypertension in this population, will be important as well.
Dr. Greg Hundley:
Thank you. Well, listeners, we've had a great discussion today, from Dr. Sanjiv Shah, from Northwestern University in Chicago, our editorialist, Dr. Evangelos Michelakis, from Edmonton, Alberta, and our own associate editor, Dr. Justin Ezekowitz from Edmonton, who brought us this study, demonstrating that in patients with heart failure and preserved ejection fraction, or heart failure and mildly reduced ejection fraction, the presence of pulmonary vascular disease, uncovered by invasive hemodynamic exercise testing, identifies patients who may worsen with atrial shunt therapy. Whereas, those without pulmonary vascular disease may, at least in the short term, benefit. And of course, as Evangelos has pointed out, the long term findings really warrant further study.
Dr. Greg Hundley:
Well listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. 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.