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This week is a Double Feature Circulation on the Run. Please join author Patrick Serruys, editorialist Shamir Mehta, and Associate Editor Emmanouil Brilakis as they discuss their article "Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study" and editorial "Achieving complete revascularization for multi-vessel coronary artery disease." Then, please join author G. Michael Felker, and Associate Editor Mark Link as they discuss the Research Letter "Implantable-Cardioverter-Defibrillator Eligibility after Initiation of Sacubitril/valsartan in Chronic Heart Failure: Insights from PROVE-HF."
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:
So guess what, Greg, we have another double feature this week. First, we need to talk about completeness of revascularization in patients with three-vessel disease or left main coronary artery disease. Always a question, and this time we've got insights from the SYNTAX Extended Survival Study. And then, the next feature talks about implantable cardioverter defibrillator eligibility after initiation of sacubitril/valsartan in heart failure, and these are insights from PROVE-HF. But before we get to that, I suggest, as I pick up my coffee, could you tell us what some of the papers you've spotted?
Dr. Greg Hundley:
Thanks so much, Carolyn. Sure. So I'm going to start from the world of preclinical science, and the paper comes to us from Dr. Vadim Fedorov from The Ohio State University Wexner Medical Center. Carolyn, up to 50% of the adult human sinoatrial node is composed of dense connective tissue, and cardiac diseases, including heart failure might further increase fibrosis within the sinoatrial node pacemaker complex, leading to impaired automaticity and conduction of electrical activity to the atrium. However, unlike the role of cardiac fibroblasts in pathological fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inheritantly fibrotic sinoatrial node environment.
Dr. Carolyn Lam:
That's true. So what did these authors do?
Dr. Greg Hundley:
Right, Carolyn. So these authors found that increased sinoatrial node-specific fibrosis, with presence of myofibroblasts and CILP-1, and periostin-positive interstitial fibrosis only in heart failure versus non-heart failure human hearts. And comprehensive proteo-transcriptomic profiles of sinoatrial node fibroblasts identified up-regulation of genes and proteins promoting stiffer sinoatrial node extracellular matrix in heart failure hearts.
Dr. Greg Hundley:
And next, fibroblast specific profiles generated by the team's proteo-transcriptomic analyses of the human sinoatrial node provided a comprehensive framework for future studies to investigate the role of sinoatrial node-specific fibrosis in cardiac rhythm regulation and arrhythmias. So really very interesting preclinical science, Carolyn.
Dr. Carolyn Lam:
Yeah. Makes me think of arrhythmias and heart failure very differently, too. Thanks Greg. Well, for my next paper, we know that dietary high salt is bad for us. It's associated with mortality and morbidity. Serum sodium can accumulate at sites of inflammation and affect the function of both innate and adaptive immune cells. But how do changes in extracellular sodium actually affect mononuclear phagocytes?
Dr. Greg Hundley:
Ah. Carolyn, this is really an interesting question, but how would you even set this up or go about investigating this?
Dr. Carolyn Lam:
Ah, good question, Greg, and these investigators are really smart. So first, let me tell you about the co-corresponding authors, Dr. Kempa from Berlin Institute of Medical Systems Biology at Max Delbrück Center for Molecular Medicine in the Helmholtz Association, and Dr. Müller from the Experimental and Clinical Research Center in Berlin, Germany. Now, guess what they did? They used sea horse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays to characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under high salt, in vitro.
Dr. Carolyn Lam:
And what they found was a disturbance of mitochondrial respiration as the initial step by which high salt mechanistically influenced immune cell function. While these functional changes may help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory cardiovascular disease. A further potential implication is that mitochondrial functional analysis in monocytes and other immune cells upon a high-salt challenge, could serve as a test for salt sensitivity of immune cells in future.
Dr. Greg Hundley:
Oh wow, Carolyn. We don't often think about salt sensitivity in immune cells. Really informative research. Well, my next paper comes to us from the world of clinical science, and it's from Professor Derek Chew, from the school of medicine, at Flinders University, the Department of Cardiovascular Medicine at Flinders Medical Center.
Dr. Greg Hundley:
Carolyn, this paper reports results from a multicenter prospective, patient-level, randomized comparison of care informed by unmasked zero to one-hour, high-sensitivity troponin-T protocol, reported as less than five nanograms per liter versus standard-practice, masked high-sensitivity, cardiac troponin T-testing, reported at a value of less than 29 nanograms per liter, assessed at zero to three hours, and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. And the primary endpoint was timed to all-cause death or myocardial infarction.
Dr. Carolyn Lam:
Interesting experiment there. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So, while the use of the zero to one-hour, high-sensitivity, cardiac troponin T-protocol expedited discharge of patients presenting to the emergency department, with a low-event rate at 30 days, an increase in death or myocardial infarction was observed at one year in those with unmasked, high-sensitivity, cardiac troponin T-concentrations. Next, among those with intermediate cardiac troponin concentrations, where care was informed by zero to one-hour unmasked, high-sensitivity, cardiac troponin T-protocols, increases in revascularization and reductions in noninvasive cardiac investigation were observed.
Dr. Greg Hundley:
So these changes in practice that result from the use of rapid-discharge protocols, may be potentially associated with an increase in all-cause death or MI, by 12 months among those low-level troponin elevations. So in summary, Carolyn, this research found that unmasked, high-sensitivity, cardiac troponin T-reporting, deployed within a zero to one hour protocol, did not reduce ischemic events over a 12-month followup, and changes in practice associated with the implementation of this protocol may be associated with an increase in death in MI among those with newly-identified troponin elevations.
Dr. Carolyn Lam:
Wow, that's very, very interesting and clinically important. Thanks, Greg. Well, let's do a little bit of a tour around what else is available in this week's issue, shall we? I want to talk about a Special Report that I was so privileged to contribute to and was led by Dr. Gemma Figtree. And it's a Call to Action for new global approaches to cardiovascular disease drug solutions. There's also a Research Letter by Dr. Solomon on the prognostic value of natriuretic peptides and cardiac troponins in COVID-19.
Dr. Greg Hundley:
Great, Carolyn. So I'm going to tell you about an exchange of letters between Professors Correia and Chaitman regarding a prior published article, entitled "Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons." Also, there's a very nice Case Series from Professor Shapira entitled, "In the Heart of the Ancient Silk Road: Fever of Unknown Origin, Right Ventricular Mass, and Systemic Vasculitis. And then, finally, Dr. de Boer has a very nice On My Mind piece From Studying Heart Disease and Cancer Simultaneously to Reverse Cardio Oncology.
Dr. Carolyn Lam:
So interesting. Well, let's get onto our double feature, Greg.
Dr. Greg Hundley:
Absolutely. Well, listeners, we are here for our first feature discussion today and we have with us really, an very interesting panel. First, Dr. Patrick Serruys from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster University in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute. Welcome gentlemen. Patrick, we're going to start with you. Could you describe for us the hypothesis that you wanted to test.
Dr. Patrick Serruys:
Yeah. The hypothesis was that if the surgeon and the interventional cardiologist doesn't achieve a complete revascularization, there will be a penalty. The penalty is we look at the all-cause mortality because that's really a unbiased assessment.
Dr. Greg Hundley:
And then, tell us the design of your study for us.
Dr. Patrick Serruys:
So SYNTAXES, which is the extension of the SYNTAX study up to 10 years, had 1,800 patient, and then basically, we took a threshold of eight. If you have a residual SYNTAX for more than eight, you have an incomplete revascularization. We stratify for less than four, four to eight, and above eight. And clearly, the group above eight has a bad outcome, not only with PCI, but also with surgery. The score is a little bit more difficult to establish in surgery, because you don't have an angiography immediately after the procedure.
Dr. Patrick Serruys:
And then as I said, if you do a complete revascularization by PCI, and that's basically a residual SYNTAX score of zero, then you have an outcome which is comparable to the surgical outcome. What is interesting, if you have above eight, you have to think twice and maybe refer that patient to surgery. It's difficult to anticipate, but of course, bifurcation, total chronic occlusion, small vessel, is the three major reason to have a residual SYNTAX score.
Dr. Greg Hundley:
Very good. So Shamir, could you help us put these results in context with other studies that have been performed in this sphere of research?
Dr. Shamir Mehta:
Yeah, sure. I would be happy to. So the SYNTAX study was unique in that they were able to look at the degree of revascularization, and the key finding that PCI was comparable to CABG surgery in terms of outcomes, when complete revascularization was able to be achieved, is a very intriguing finding. In cases where PCI was not able to achieve complete revascularization, it was clear superiority of CABG surgery. And so the question is in this study, this comparison, which is a non-randomized comparison, whether or not there's any type of external validity for these findings.
Dr. Shamir Mehta:
And, in fact there is. It's a timely publication, because recently we had the 4,000-patient multinational COMPLETE trial, which looked at the issue of complete revascularization versus incomplete revascularization in patients with STEMI, and found that complete revascularization with multi-vessel PCI, in appropriately-chosen patients, reduced hard clinical outcomes, including the composite of cardiac mortality and/or current myocardial infarction. And it reduces it quite substantially, by about 26%, and it's a highly-significant benefit.
Dr. Shamir Mehta:
I think the caveats to this finding are important, though. Because in the COMPLETE trial, patients were not eligible for recruitment, unless the interventional cardiologists felt that all of the lesions were amenable to PCI. So complete revascularization had to be achieved in the trial. And in fact, over 90% of patients in the trial were able to achieve complete revascularization. So that's absolutely key, and that brings up the importance of having a heart team in evaluating these patients.
Dr. Shamir Mehta:
The second point is that the SYNTAX score, Patrick had referred to was relatively low in the trial, it was only 4.6. Meaning that the lesions that were attempted were relatively straightforward, meaning that there was a high probability of achieving complete revascularization. So again, I think we're starting to see from the randomized trials and from the observational studies, the types of patients that may be suitable for PCI versus suitable for CABG surgery.
Dr. Greg Hundley:
Very nice. Well, Manos, Shamir, what an outstanding description in helping us put this paper in context with other research in this space. Manos, I know you see a number of papers come across your desk. Also, for you, what attracted you to this particular study?
Dr. Emmanouil (Manos) Brilakis:
Yeah, thank you, Greg. And again, congratulations to Patrick for a phenomenal study. I think the main strength of this analysis is the clinical relevance. I think everyone is still debating this question, is complete revascularization the goal in every patient? And all of the data, as mentioned already, have several limitations. Nevertheless, they move us a little bit closer to understanding better on whom complete revascularization should be used.
Dr. Emmanouil (Manos) Brilakis:
So the clinical relevance is one key. I think this paper does set the stage well for a randomized trial. End of the day, we are still not hundred percent sure if COMPLETE is the best for everyone, because COMPLETE counts as a risk, and the risk is going to be higher in those patients who have more complex anatomy. But that study will give us the definitive answer about which is the best way to go for each individual base.
Dr. Greg Hundley:
Very nice, Manos. So that's a great segue. So I'll turn to both Shamir and Patrick, and ask them also, as well, what do you think is the next study to be performed in this particular space? Shamir, you first and then we'll finish with Patrick.
Dr. Shamir Mehta:
Well, I think the concept of complete revascularization has now essentially been proven in multiple trials. And don't forget, if you go back several decades, really the first proof was in the context of CABG surgery. So really, this should be the goal in patients with multi-vessel disease. The next large randomized trial that is going to be starting very soon is the COMPLETE 2 trial where we are actually looking at the lesions physiologically to see whether or not we need to revascularize lesions that are physiologically significant versus anatomically severe.
Dr. Shamir Mehta:
This is an important question because what it does is it has the potential to reduce the number of lesions that we perform PCI in, by about 50%. We are also looking at plaque composition in that trial with optical coherence tomography. A very, very large number of patients will be receiving that. So that will be trying to target PCI to the actual pathophysiology of the disease, by targeting unstable plaques to perform PCI on. I think this is the whole next era of coronary intervention, where we are now beginning to target our therapies to the actual pathophysiology of the disease, which is a very, very exciting idea.
Dr. Greg Hundley:
And Patrick, do you have anything to add?
Dr. Patrick Serruys:
Yeah. I think, that obviously, you have to convert the anatomical SYNTAX Score in a functional SYNTAX Score. You could do that with the pressure wire and hyperemia of diastolic resting gradient. You can also do that by QFR or FFR CT. So we are going in that direction since a few years. The second point is that we have been working on machine learning that, at some point, the segmentation of the coronary segment, the assessment of the narrowing is done. And then, the next step that we are doing right now to is to convert that to the multi-slice CT scan.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Patrick Serruys, from National University-Ireland, Galway, Dr. Shamir Mehta from McMaster university in Ontario, and our own associate editor, Dr. Manos Brilakis, from Minneapolis Heart Institute, really bringing to us this paper that, in patients with complex coronary artery disease, incomplete revascularization can be common after PCI. And the degree of incompleteness can be associated with 10-year mortality. And therefore, if it's unlikely that complete or nearly complete revascularization can be achieved with PCI in patient with three-vessel disease, maybe we should be considering coronary artery bypass grafting.
Dr. Greg Hundley:
Well, again, let's get on now to that second feature discussion. Well, listeners, we are now here for our second feature discussion today, and we have with us Dr. Michael Felker from Duke University, and our own associate editor, Dr. Mark Link, from UT Southwestern. Welcome, gentlemen. And Mike, we'll start with you. Tell us a little bit about the background pertaining to your study and what hypothesis did you want to address?
Dr. G. Michael Felker:
Great. Thanks, Greg. So I think everybody's very familiar with the concept of favorable ventricular remodeling in patients with heart failure, that we know is something that happens when we treat our patients with guideline-directed medical therapy, like beta blockers, ACE inhibitors, MRAs. Interestingly, with the introduction of sacubitril/valsartan and the landmark PARADIGM trial, we had a drug where we had clearly a major outcome benefit, but we actually had very little understanding about whether that was mediated by remodeling.
Dr. G. Michael Felker:
And those questions led us to design the PROVE trial, which was a single-arm trial of 794 patients, looking at whether or not patients with heart failure and reduced ejection fraction who met the FDA label for sacubitril/valsartan, the initiation of that therapy will be associated with favorable changes in ventricular structure and function, as well as favorable changes in natriuretic peptide. The current paper's really trying to put those results in a clinical context around some of the things that we make clinical decisions about, in taking care of heart failure patients in this case, whether and when patients qualify for a primary prevention ICD.
Dr. Greg Hundley:
Fantastic, Mike. And so you've told us a little bit about the study design, and did you have exactly the same number of patients, or what was the study population for this sort of substudy, if you will?
Dr. G. Michael Felker:
Yeah. So in PROVE, we enrolled people who had chronic heart failure in the EF, less than 40%, because that's the FDA label for sacubitril/valsartan. In this analysis, because we were interested in patients who qualified for ICD therapy, we limited our analysis to those who an EF plus or equal to 35%. Because, as you all know, the guideline for primary prevention ICD is people who have a EF less or equal to 35% after at least three months of optimized heart failure therapy.
Dr. G. Michael Felker:
And so, one of our questions was in some patients start on sacubitril/valsartan, what happens to their ventricle and how many patients might favorably remodel? This is, obviously, a question that comes up a lot clinically as more and more we're switching people from ACE inhibitors, or ARBs, to sacubitril/valsartan in line with the recommendation that's 1A from the AHA guidelines.
Dr. Greg Hundley:
Fantastic. ell, we're all listeners waiting to hear your results, Mike. This is very exciting. So what did you find?
Dr. G. Michael Felker:
I think our results were quite interesting. I mean, for one thing, the patients that were enrolled PROVE were incredibly well-treated at baseline, and they had had heart failure for quite some time, and a average median time of over six years. So this is not patients who are just recently diagnosed. A lot of these are people that you might think, clinically, we're unlikely to go on and have much favorable ventricular modeling, but that's not what we found. We actually found that after the initiation of sacubitril/valsartan, after six months, on average, we had a five point increase in injection faction.
Dr. G. Michael Felker:
And by 12 months, on average, that was almost 10 points. So quite a bit of favorable remodeling, even in these patients you might think were less likely to do that. And we put that in the context of ICD decision-making. By six months, 32% of the patients who would initially have been eligible based on the guidelines for primary prevention ICD, no longer met those criteria because their EF had risen to greater than 35, and by 12 months, it was up to 62% of those patients. So as we're thinking about decision-making around ICDs, I think these data have some pretty obvious direct clinical relevance to decisions we now make in the care of our patients.
Dr. Greg Hundley:
Really interesting. So Mark, I know you get several papers coming across your desk, and as associate editor, boy, I think I can see why this paper was attractive to you. Tell us a little bit, how do we put these results from this study into the context of how we decide whether a patient should receive an ICD?
Dr. Mark Link:
Yeah. The current guidelines are to wait three months after guideline-directed medical therapy, and then repeat the ECHO and see if they still qualify. I think what this study shows us is that patients can continue to improve after three months, and that improvement is somewhat continuous, actually. Because at six months, the improvement in EF was five percent, and at 12 months, it was 10%. So I think that's what this shows, the context is, if you have a patient who has a low EF and they are improving, but still haven't quite made it to 35, let's say when they went from 25 to 30 in three months, I'd probably hold off and wait another three months and repeat the ECHO again.
Dr. Greg Hundley:
Excellent. Well, Mike, Mark, I'm going to ask you question. And we'll start with you Mike, and then go to Mark. What study would you perform next in this space? Mike, you first.
Dr. G. Michael Felker:
So, I think it's important to recognize some of the limitations of any study you do, including this one. So this was not a randomized trial. PROVE was a single-arm trial, there wasn't a control group. And the question about the ICD per se was not pre-specified. It was really a post-hoc analysis. So as is often the case, I think these are intriguing and highly-suggestive results, but I think there's clearly an opportunity to confirm them in perspective studies designed to answer this specific question.
Dr. G. Michael Felker:
So you could imagine a trial where patients who are starting on sacubitril/valsartan who don't have ICDs, get randomized to waiting three months or waiting six months, or 12 months or whatever the interval would be. So I think these are intriguing, and that there definitely opportunities to develop confirmatory results.
Dr. Greg Hundley:
Excellent. Mark, do you have anything to add to that?
Dr. Mark Link:
I think the big thing we would really like to know are predictors, predictors of response and predictors of non-response. And that would take a larger trial perspective, and that would be very, very valuable. Because if you could have a predictor of a non-responder, they would get an ICD earlier, and predictors of responders, you might wait a while.
Dr. Greg Hundley:
Very nice. Well, listeners, we get rate studies here in circulation, and you'll find this one as a research letter, highlighting that in the substudy of the PROVE heart failure study, that in patients with an EF less than or equal to 35%, the introduction of sacubitril/valsartan improved EF to greater than 35%, at 62% of subjects at 12 months. Really an interesting finding, and perhaps further randomized clinical trials as suggested by both Mike and Mark here, are maybe warranted in the future.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to A, thank Dr. Mike Felker and also our associate editor, Mark Link, and wish you, as listeners, 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, 2021. 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, visit ahajournals.org.
