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Circulation on the Run

Sep 28, 2020

This week’s episode includes author Finnian Mc Causland and Associate Editor Justin Ezekowitz as they discuss angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction.


Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Dr Greg Hundley: And I'm Greg Hundley Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr Carolyn Lam: Greg, we're going to be talking about RNEs and renal outcomes in HFpEF. Oh, you got to hold me back this is going to be such an interesting discussion. But maybe let's grab our coffees. Are you ready to talk about some of the papers in today's issue?
Dr Greg Hundley: You bet.
Dr Carolyn Lam: Well the first paper I have really represents a novel gene therapy approach to atrial fibrillation. So doctors led by Dr Arora from Northwestern University Feinberg School of Medicine and colleagues used a novel gene therapy approach in a canine rapid atrial pacing model of atrial fibrillation to demonstrate that NADPH oxidase-2 or NOX2 generated oxidative injury by causing upregulation of a constitutively active form of acetylcholine-dependent potassium current, or IKH is an important mechanism underlying electrical remodeling in the fibrillating atrium.

Dr Greg Hundley: Wow, Carolyn, very interesting. Tell us a little bit more about this gene therapy approach.

Dr Carolyn Lam: They performed targeted expression of anti-NOX2 short hairpin RNA in the intact atria of the dogs, and then subjected those animals to rapid atrial pacing for a period of several weeks to months. The novel atrial gene therapy approach prevented the development of electrical remodeling and sustained atrial fibrillation thus demonstrating for the first time a clearer causative role for NOX2 generated oxidative injury in the creation, as well as the maintenance of electrical remodeling in atrial fibrillation. Furthermore, they demonstrate that a likely cellular and molecular mechanism by which oxidative injury created a vulnerable substrate for atrial fibrillation, the results of this study yield therefore valuable mechanistic insights into the pathogenesis of atrial fibrillation and have important therapeutic implications for this clinical management.

Dr Greg Hundley: Very nice, Carolyn. We need more therapies for AFib. Boy, that's so informative. Well, the next paper that I have sort of merges the world of electrophysiology with the world of imaging and it comes to us from Dr Michela Casella from Centro Cardiologico Monzino. Among 162 consecutive patients, this study evaluated the combined utility of electroanatomic voltage mapping coupled with cardiovascular magnetic resonance imaging to guide endomyocardial biopsies.

Dr Carolyn Lam: Oh, so interesting. A combined noninvasive and invasive electrical guide to perform cardiac biopsies, wow. So what did they find Greg?

Dr Greg Hundley: So they found that the sensitivity of pooled electroanatomic voltage mapping and cardiovascular magnetic resonance was as high as 95%. EVM and CMR together conferred an endomyocardial biopsy positive predictive value of 89%. Endomyocardial biopsy analysis allowed to reach a new diagnosis different from the suspected diagnosis in 39% of patients, complication rates were low, mostly vascular access related, with no patients requiring urgent management. Most impressive for this manuscript are the illustrative figures that are provided. It's really a great article for those performing biopsies, doing imaging, or the EP procedures that guide the biopsy process.

Dr Carolyn Lam: Really nice, Greg, thanks. Now for the last paper, have you ever thought about atherosclerosis as an autoimmune disease?

Dr Greg Hundley: Well, I wonder, we're learning so much about our immune systems these days, perhaps.

Dr Carolyn Lam: Indeed, throughout the inflammatory response that accompanies atherosclerosis auto-reactive CD4 positive T helper cells do accumulate in the atherosclerotic plaque. Apolipoprotein B-100 or Apo B is the core protein of LDL really serves as the auto antigen that drives the generation of pathogenic T helper one cells with pro inflammatory cytokine secretion. Yet there may also exist Apo B specific CD4 positive T cells with an athero protective regulatory T cell phenotype in healthy individuals. And that relationship between the protective Apo B reactive T regulatory cells and the pathogenic T helper one cells really has remained unknown until today's paper.
And this is from Dr Ley from the La Jolla Institute for Immunology and colleagues is really the first report to characterize CD4 positive T cells recognizing Apo B in the mouse with a combination of a novel MHC II tetramer and single cell transcriptomics immuno receptor sequencing and functional evaluation, and their results demonstrated an unexpected mixed phenotype of Apo B reactive auto-immune T cells in atherosclerosis and suggest an initially protective auto immune response against Apo B with a progressive derangement in clinical disease. These findings really identify Apo B auto-reactive T regulatory cells as a novel cellular target in atherosclerosis.

Dr Greg Hundley: Very nice Carolyn, boy that was a beautiful summary. I've got in the mail bag just a couple of things to talk about before you get to the discussion of some research letters. There's an ECG challenge from Dr Gunaseelan involving a young patient with chest pain. And then Theresa Wang has a very nice case series involving pulmonary hypertension, entitled Pressures at an All Time High.

Dr Carolyn Lam: There's also an On My Mind piece by Dr Perman on overcoming fears to save lives. So COVID-19 and the threat to bystanders CPR in out-of-hospital cardiac arrest. There's a research letter by Dr Myhre on cardiovascular hospitalizations, influenza activity, and COVID-19 measures, another by Dr Gurbel on the first inhuman experience with inhaled acetylsalicylic acid for immediate platelet inhibition, the comparison with chewed and swallowed acetylsalicylic acid. A final research letter by Dr Zurek rounds us up regarding neuregulin one inducing cardiac hypertrophy and impaired cardiac performance in post myocardial infarction rats, very surprising because we thought this was protected. So there you have it for this issue, Greg, shall we go on to our future discussion?

Dr Greg Hundley: Absolutely.

Dr Carolyn Lam: In patients with heart failure, chronic kidney disease is really common and associated with a higher risk of renal events than in patients without chronic kidney disease. In fact, these renal events are really increasing in prominence in the heart failure literature. And so I'm really welcoming the discussion of today's feature paper, which looks at the renal effects of angiotensin neprilysin inhibition in patients with heart failure with preserved ejection fraction in the PARAGON trial. I'm so pleased to have with us the first and corresponding author of this paper, Dr Finnian Mc Causland from Brigham and Women's hospital, as well as our associate editor Dr Justin Ezekowitz from University of Alberta. Finnian, congratulations on this beautiful paper. Could you please tell us a little bit about the overview? What motivated it, what you found?

Dr Finnian Mc Causland: It's long been a passion of mine to look at this interaction or intersection between cardiology and renal events. And if the truth be told, I had a moment in my life where I thought about being a cardiologist but I was swayed in other directions during my training in Ireland. Well, I've always been very much interested in this intersection, like I said, and so I've had the opportunity to work very closely with Scott Solomon and others at the Brigham who lead many of the heart failure trials that you are all aware of much more than I have been.
And this particular subset of patients with heart failure with preserved ejection fraction is a very unique population that were studied in the PARAGON-HF trial. And we thought it was a unique opportunity to look at some of the pre-specified secondary end points, which were the renal outcomes in terms of trying to figure out what the effect of this was compared to valsartan therapy in this patient population. So I think looking at this intersection between heart failure and preserved ejection fraction and the deterioration of kidney function was the primary driver to look at this in the PARAGON heart failure trial, and to really
look at the comparison between sacubitril-valsartan with valsartan in this patient population.

Dr Carolyn Lam: Indeed, thanks so much Finnian, and here's a confession too. I really liked nephrology during my training. (laughs) I thought it was really cool and with all the interventions, and so I really admire the many things you think about, especially in these patients, who've got multisystem disease, but okay. Moving on with PARAGON, I know that the secondary outcomes were reported and it was really a striking effect on the renal events. And so glad that you're shedding more light in it. Could you tell us what this paper added?

Dr Finnian Mc Causland: Yeah, so here we really got into I suppose the depths of the renal composite outcome and just to remind everybody that was a composite of a 50% or greater decline in eGFR, the development of end stage renal disease, or death from renal causes, so this was the composite outcome that was examined. We really evaluated this in a lot more detailed breaking our composite down into its individual components, as well as looking at it in totality. And I think the big take away point was that we found there was an almost 50% reduction in this primary renal composite outcome for patients on sacubitril-valsartan compared with valsartan.

Dr Carolyn Lam: And what about the components and the sort of further analyses?

Dr Finnian Mc Causland: Yeah, so getting into the, I suppose the details in a little bit more granularity, the major driver of those events will be 50% or greater decline in eGFR. And that's where the majority of these events really came from over the follow-up of PARAGON. And so this was assessed that various study business throughout the course of the few years that the patients followed up with PARAGON. And I think if we look at this slope and this was clarified in terms of the overall slope analyses of the eGFR. And we thought this relatively early separation in favor of sacubitril-valsartan so that there was less decline in eGFR over time compared with valsartan. So I think this was a supportive finding from the slope analysis that really got to this 50% threshold and that many people have examined in greater detail than they had the cardiovascular literature. So it takes a fair degree of kidney function decline to really reach that threshold of 50%. And so I think this was a very repulsed finding supported by the slope analyses.

Dr Carolyn Lam: Yeah, and to the audience that's listening, you have to grab hold of figure three of this paper, and that shows the eGFR slopes, which is something that's I think really important in current heart failure literature, the concept of the eGFR decline. So really nice work. Congratulations again, Finnian. Justin, could you put these findings in context for us?

Dr Justin Ezekowitz: Finnian once again, congratulations on getting this analysis. Pretty complex area to try to analyze and analyze properly, given that there's an expansive renal literature out there about looking at eGFR and how you look at it. So I think there's a couple of questions that come to mind when we think about the PARAGON trial overall. When we think about the protection of the kidneys over three, four, five years, my sense was from your analysis and perhaps you could expand on it is there seems to be very few events in those people with pretty preserved eGFR, but a greater number of events in those less than 60 mils per minute, and I'm wondering if you think that there's more of a unique place for medications such as sacubitril-valsartan and that cohort and if so is it really, that's where all the action is, but there's no real difference? Or do you think there's an interaction there that we should explore?

Dr Finnian Mc Causland: Thinking back to the entry criteria for PARAGON-HF, one had to have an eGFR more than 30 mils per minute at baseline. And you had to go through this kind of complex running period where you didn't have elevations of creatinine or potassium that went inside the pre-specified ranges. So after you took that element of what many people would consider hemodynamic changes, acute hemodynamic changes out of it, you were left with participants who entered the double blind randomized period. And there, I think that's where again, we started to kind of see most of the end points in terms of follow-up, which again were mostly the eGFR decline. If you go to table two of the paper, you'll see the composite, the components of the renal composite broken out into those with eGFRs of less than 60 or 60 or greater at baseline.
And even in both groups, I think you'll find that again they were both driven by the 50% decline, but you only really saw the end stage renal disease events or very few deaths from renal causes in those with eGFR of less than 60 mils per minute of baseline. And I think really what that speaks to is that these are the patients with quote unquote, chronic kidney disease at baseline are the ones who have that detrimenting kidney function to begin with. And so we're more likely to progress as we know than those with more preserved kidney function. And so if you followed patients both for really good kidney function over time, it's going to take a long time before they get that really severe decline due to the compensating mechanisms that the kidney has to preserve eGFR in the face of decline. So I think once you get into the more advanced disease, you really start to see the deterioration where there's very little renal functional reserve to cope with any additional damage or hemodynamic changes.
So to me, it wasn't particularly surprising that that's where the action was. To answer your second point of should we be focusing therapy here? If you look at the median eGFR in the PARAGON heart failure study was around 63 mils per minute. So about half of these patients I suppose could be classified as having impaired kidney function. If you look at it by CKD criteria it's eGFR of less than 60. And so I think there's a huge opportunity there to really think about this population in terms of trying to look for interventional studies and potentially protect patients as we've seen with this molecule, and but also with others such as SGLT-2 inhibitors, what I'm really intrigued about is if this was persistent at eGFRs below 30, because of course, one of the most devastating icons for patients with kidney disease that we deal with is the development of end stage renal disease and those who go on to hemodialysis.
So if there was some mechanism to prevent those even higher risk patients from progressing, I think that would be a huge opportunity for further research in this area.

Dr Justin Ezekowitz: Thanks for that very complete and thorough answer Finnian, and that actually maybe leads to putting this in context for the majority of people who will read Circulation and the audience will most likely be cardiovascular specialists and understand a lot of what you said, but could you put this in context with other studies that really are nearby to this trial, such as CREDENCE where the eGFR slope might be slightly different, or even the UK HARP-III trial where the same molecule was used, but in a different population, I wonder if you could give us some context for these findings.

Dr Finnian Mc Causland: Sure, yeah. I mean, I think the UK HARP-III trial maybe is the first one to discuss since this was a comparison of sacubitril-valsartan versus irbesartan. This was a study performed in the United Kingdom and they recruited patients with chronic kidney disease, a small proportion of those patients had heart failure, but this was not any of the pre-specified entry criteria for this study. And their primary outcome was the change in measured glomerular filtration rate after 12 months. And really they found that there was no significant difference at the 12 month mark between sacubitril-valsartan versus irbesartan. And so we were asked a similar question when we presented this study in abstract form at the American Society of Nephrology meeting in Washington last year. And I think a lot of the differences potentially relate to the difference in entry criteria for the patients. But also one might argue that 12 months of follow-up may not have been enough to see these differences in eGFR slope, which tend to occur, I suppose, rather later in the course of progressive kidney disease and heart failure.
And so that may be part of the reason that we didn't see the differences with UK HARP-III. In terms of CREDENCE, obviously it's a different molecule. And if you look at our main eGFR decline over time in PARAGON-HF, it was around 0.7 mils per minute, per 1.7, three meters squared per year. And so this compares with the about 1.5 mils per minute in CREDENCE, remember CREDENCE recruited patients with chronic kidney disease. PARAGON-HF recruited patients with heart failure and preserved ejection fraction. So differences in terms of the inclusion criteria right off the bat. I think other big differences where the CREDENCE compared, and it kind of flows in versus placebo, there was an active comparator in PARAGON-HF in terms of it was sacubitril-valsartan versus valsartan. So we saw differences in eGFR slope, despite an active comparator, I think was also quite telling and that there appears to be some additional renal benefit in the additional sacubitril versus blast inhibition alone.
And so I think the mechanisms is a whole other area, right? For research, I don't think we're entirely clear of the underlying mechanisms of this potential renal benefit, but I think we're pretty excited in the kidney community. Where now we have several molecules that may have potential to slow kidney functional decline, SGLT-2 inhibitors being one class potentially sacubitril-valsartan in another, and the top line results from their number are just out as well. And so there's ongoing trials that are looking at kidney function outcomes there. So we're getting pretty excited and we're not quite as jealous of the cardiology community as we used to be.

Dr Carolyn Lam: I couldn't think of a better way to summarize those findings and to put it into context of other very hopeful medications for the cardio renal outcomes. Thank you so much Finnian for joining us today and for publishing such a great paper with us at Circulation. And thank you, Justin, for your perspectives.

Dr Justin Ezekowitz: Thanks Carolyn, and Finnian congrats to your team as well. This has been a terrific paper to be able to handle and read and look at figure three, and it tells a lot of the story of what you saw.

Dr Finnian Mc Causland: Thank you very much again for the opportunity and a big shout out to everybody that worked in PARAGON-HF and especially to the support from Scott Solomon and John McMurray for getting me involved. It's a pleasure to be part of this.

Dr Carolyn Lam: Thank you so much from Greg and I for joining us today, tune in again, next week.

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