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Circulation on the Run


Mar 15, 2021

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 and director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature involves interleukin-6 and a phenome-wide association study. So we have a lot to look forward to, but before we do that, how about we grab a cup of coffee and jump into the other articles in this issue? I could start first because I've got to tell you about some results from the ODYSSEY outcomes trial. And Carolyn, this comes to us from Professor Gregory Schwartz at the University of Colorado School of Medicine. Well, Carolyn, this study pertains to LDL lowering. As you know, recent international guidelines have lowered the recommended target levels of LDL cholesterol for patients at very high risk for major cardiovascular events or MACE.

Dr. Greg Hundley:

However, uncertainty persists as to whether additional benefit results from achieving LDL-c levels below some of these conventional targets. Now inferences from prior analyses are limited because patients who achieve lower versus higher LDL-c on lipid lowering therapy differ in other characteristics prognostic for MACE, and because few achieved very, very low LDL-c levels. So to overcome these limitations, these authors performed a propensity score matching analysis of the ODYSSEY outcomes trial, which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving intensive or maximum tolerated statin treatment.

Dr. Carolyn Lam:

Sensible question, and what did they find?

Dr. Greg Hundley:

Well, Carolyn, the main finding of the study was that after accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-c levels less than 25 milligrams per deciliter did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-c levels of say 25 to 50 milligrams per deciliter. So, Carolyn, the take-home message is that recent international guidelines have lowered LDL-c goals for patients at very high risk for MACE to levels less than 55 milligrams per deciliter, and in some cases, maybe less than 40 milligrams per deciliter. However, any potential benefit of achieving LDL-c levels significantly below these goals to those very low, less than 25 really remains uncertain.

Dr. Carolyn Lam:

Very interesting. Thanks Greg. Well, my paper is about the HOST-REDUCE-POLYTECH-ACS trial. Got your attention? All right. I'll tell you what it is. It's an investigator-initiated, randomized, open-label, adjudicator-blinded, multicenter, non-inferiority trial, which compared the efficacy and safety of durable polymer versus biodegradable polymer, drug-eluting stents. And these investigators led by Kyung Woo Park from Seoul National University Hospital looked at 3,413 patients with acute coronary syndrome. At 12 months, the primary endpoint of patient oriented composite outcome, which was a composite of all-cause death, nonfatal myocardial infarction, and any repeat revascularization, occurred in 5.2% of the durable polymer group and 6.4% of the biodegradable polymer group. And so that met the non-inferiority P value of less than 0.01. the key secondary end points of device oriented composite outcome, which is a composite of cardiac death, target vessel MI, or target lesion revascularization occurred less frequency in the durable polymer versus biodegradable polymer groups, and this was mostly due to a reduction in target lesion revascularization. The spontaneous nonfatal MI and stent thrombosis rates were very low with no significant difference between the groups.

Dr. Greg Hundley:

Well, Carolyn, you know one of my favorite questions, so what's the take-home message here?

Dr. Carolyn Lam:

In patients with acute coronary syndrome receiving PCI durable polymer drug-eluting stents were non-inferior to biodegradable polymer drug alluding sense with regards to patient-oriented composite outcome at 12 months. I think that's the significant take-home message, and it's accompanied by an editorial where all this is discussed, and this editorial is by Doctors Byrne and Hanratty from Dublin.

Dr. Greg Hundley:

Very nice, Carolyn. Well, Carolyn, I am going to turn to the world of basic science and discuss phospho-lamin phosphorylation and how that may regulate vascular tone, blood pressure, and hypertension in both mice and men. And it comes to us from Dr. Michael Shattuck from King's College, London. So Carolyn, it's long been recognized that smooth muscle Na,K-ATPase modulates vascular tone and blood pressure. However, the role of its accessory protein phospho-lamin has not been characterized. So Carolyn, the aim of this study was to test the hypothesis that phospho-lamin phosphorylation regulates vascular tone in vitro, and this mechanism plays an important role in the modulation of vascular function and blood pressure in experimental models, both in vivo and in man.

Dr. Carolyn Lam:

Okay. So what did they find?

Dr. Greg Hundley:

Carolyn, these authors found that in aging wild type mice, phospho-lamin was hypo-phosphorylated, and this correlated with the development of aging induced essential hypertension. In human subjects, they identified a non-synonymous coding variant, a single nucleotide polymorphism RS-61753924, which causes the substitution of R-70 C and phospho-lamin. The R-70 C mutation prevented phospho-lamin phosphorylation at searing 68. This variance rare Alleo was associated with increased blood pressure in middle-aged men. So Carolyn, taking together these translational animal and human studies demonstrate the importance of phospho-lamin phosphorylation in the regulation of vascular tone and blood pressure and suggest a novel mechanism for aging-induced essential hypertension.

Dr. Carolyn Lam:

Interesting. And I suppose opening the door to translationally preventing this hypertension. Very interesting. Well from the next paper we switch to cardiac troponins, and you know these are the cornerstone of diagnosing acute myocardial infarction. But have you ever wondered, what is the duration of ischemia necessary to induce a measurable release of the cardiac troponins, or the very early release kinetics of cardiac troponins following an ischemic event? Well, this study is the first to report the early release kinetics of cardiac troponin concentrations, following different durations of experimental coronary balloon occlusion in humans.

Dr. Greg Hundley:

Ah, Carolyn. So how did they do this?

Dr. Carolyn Lam:

So 34 patients with N geographically normal coronary arteries were randomized into four groups with different durations of induced myocardial ischemia from zero to 30, 60, 90 seconds. Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected prior to balloon inflation and every 15 minutes for the first three hours and every 30 minutes for the next three hours. Cool, huh?

Dr. Greg Hundley:

Yeah. So did any of the patients suffer complications?

Dr. Carolyn Lam:

So the first thing to report is none of the patients had any complications, but what they found, and this was from authors, Dr. Iverson from Copenhagen, Denmark and colleagues. This is what they found increased cardiac troponin concentrations were detected by all three high sensitivity assays, be they high sensitivity troponin T by the Roche assay, high sensitivity troponin I by the Siemens essay, or high sensitivity troponin I by the Abbot essay. All assays detected a cardiac troponin increase after only 30 seconds of ischemia. High sensitivity troponin I by Siemens rose faster and reached a higher peak. Copeptin levels did not significantly change. So these interesting findings are accompanied by an editorial by Christopher deFilippi and Nicholas Mills discussing how the findings challenged some of our assumptions and may help shape future care pathways and the classification of ACS.

Dr. Greg Hundley:

Carolyn, so more in the evolution of high sensitivity troponins. Well, I'm going to shift to my last article of the day, and it focuses on eccentric remodeling and ischemic cardiomyopathy, and comes to us from Professor Konstantinos Drosatos at the Lewis Katz School of Medicine at Temple University. So Carolyn, these authors have shown that cardiomyocyte Krüppel-like factor or (KLF)-5 regulates cardiac fatty acid oxidation, and as heart failure has been associated with altered fatty acid oxidation, they now investigated the role of cardiomyocyte (KLF)-5 in lipid metabolism and the pathophysiology of ischemic heart failure.

Dr. Carolyn Lam:

Wow, Greg. What did they show?

Dr. Greg Hundley:

Well, Carolyn, they found that (KLF)-5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of (KLF)-5 in mice with myocardial infarction prevents ceramide accumulation, alleviates eccentric remodeling, and increases left ventricular ejection fraction. Thus, the authors suggest that (KLF)-5 may emerge as a novel therapeutic target for the treatment of ischemic heart failure. Well, Carolyn, we've got some other articles in the issue, and I'm just going to tell you quickly about an in-depth article entitled, “Cardiovascular Disease and Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options” that come to us From Dr. Marx, and then I'm going to turn it over to you.

Dr. Carolyn Lam:

Yes, we've got an exchange of letters between Doctors Grace and Mital regarding the article, “A Validated Model for A Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.” There's an ECG challenge by Dr. Peng on an irregular complex tachycardia. And there's this very interesting on-my-mind paper by Dr. Skolnik simply entitled, Gratitude. And I just have to tell you a bit about it, and I'm quoting from it now, “…having two surgeries for a large aortic aneurysm and aortic regurgitation, I am also left with an overwhelming sense of gratitude for living in the age in which I'm living. While some focus on what is wrong in the world, at least for today, my focus is on what is right.” Now, please read that paper. It's just such a beautiful piece. And, finally, there's a perspective piece by Dr. Sandhu entitled, “The Affordability of Guideline-Directed Medical Therapy, Cost Sharing, and How Cost Sharing is a Critical Barrier to Therapy Adoption.” Well, looks like it's a wrap. Greg, let's get on to our feature discussion, shall we?

Dr. Greg Hundley:

You bet. Well, listeners, we are now coming to our feature discussion today, and we're very fortunate to have with us today, Dr. Martin Dichgans and Dr. Marios Georgakis both from Munich, Germany. And we also have Dr. Svati Shah from Duke University, one of our associate editors. Welcome to you all. And I'll start with you Martin, could you explain to us a little bit of the background behind this study and what was the hypothesis that you wanted to test?

Dr. Martin Dichgans:

Yes, of course. We are interested in stroke, and more broadly, in cardiovascular disease, and inflammatory cytokines and inflammatory mechanisms in general play a major role in cardiovascular disease and particularly in arthrosclerosis, which connects a cardiac disease and stroke and also multiple other disorders. So that was our starting point. And we previously noted the importance of specific inflammatory cytokines in stroke, which is all primary area of research. We then quickly became aware of the central position of IL-6, which is downstream of IL-1β in the inflammatory cascade, and recognized not only that there's a lot of data on IL-6 in cardiovascular disease already, but that IL-6 actually is implicated in multiple inflammatory conditions, including autoimmune diseases, vascular, as I mentioned, and also metabolic disorders. And we noted that IL-6 receptor inhibition is already in use in some of these disorders, particularly in the treatment of autoimmune diseases, but not yet in use in cardiovascular disease.

Dr. Martin Dichgans:

So we asked ourselves whether there would be any repurposing potential, and also whether there would be an opportunity to explore the safety profile in its full width using genetic data because, and this I didn't mention, we have a background in genetics, a large interest in genetics, and you might have noticed that previously there has been a wealth of genetic data coming out, both on stroke, but also on cardiovascular disease in general. So also including other phenotypes, like for instance, and it has now become possible via a methodology called Mendelian randomization to utilize these genetic data and explore causal relationships between exposures such as IL-6 levels or specific cytokines and outcomes such as ordinary-after disease or stroke, and even go one further and explore the therapeutic potential, and also the full width phenotypes that could be relevant in such a scenario. So what we did is we took advantage of large scale genetic data from the UK biobank and data on specific outcomes available in the UK biobank to dive into the questions we were interested in.

Dr. Greg Hundley:

Martin, that was a wonderful explanation. So could you describe, what was the aim of your study?

Dr. Martin Dichgans:

In brief, the aim was to use large scale genetic data to explore the repurposing potential and safety profile of IL-6 receptor inhibition in the general population.

Dr. Greg Hundley:

Very nice. Describe your study design.

Dr. Martin Dichgans:

So the study population was the UK biobank, which is a population-based sample of, in this case, 340,000 unrelated individuals. And what we did is we performed the phenome-wide association study. So we looked across all available phenotypes that are systematically encoded in the UK biobank, and which included both clinical outcomes and biomarkers, in this case about 1,400 clinical outcomes and 360 or 70 biomarkers and endophenotype of human disease in this biobank. And again, explored relationships between IL-6 receptor inhibition and the effect on these outcomes.

Dr. Greg Hundley:

Very nice. Well, Marios, let's turn to you. Could you describe the results? What did you find?

Dr. Marios Georgakis:

Yes. Hello from my side as well. So, as Martin mentioned, we explored associations between genetically down-regulated IL-6 signaling and 1,400 clinical outcomes, as well as with 360 biomarkers in another, I would say hypothesis reapproach. So, following corrections from output testing, we found significant associations with genetically down-regulated IL-6 signaling activity with 16 clinical outcomes and 17 biomarkers. As we had shown in the past, genetically down-regulated IL-6 signaling activity was associated with several cardiovascular phenotypes, specifically atherosclerotic phenotypes, primarily including coronary artery disease manifestations, but also for example, abdominal aortic. Interestingly though, we also found a significant association with a lower risk of type two diabetes, as well as with a lower glycated hemoglobin, another finding that was consistent not only in the UK biobank, but also in two cohorts that we use for validation. So in the past, there have only been data from small observational studies and small case series in patients with rheumatoid arthritis supporting these findings, but to date, no data from large clinical trials.

Dr. Marios Georgakis:

Furthermore, we find significant associations between genetically down-regulated IL-6 signaling and higher total cholesterol, but also higher HDL cholesterol levels, but no association with LDL cholesterol. This further supports associations of IL-6 signaling downregulation with, let's say more favorable argument among the profile. Now, why is this important? This is a very interesting finding because previous clinical trials had suggested that IL_6 receptor inhibitors might lead to increases in total cholesterol levels, which would, of course, be an undesired side effect for people who'd ever envisioned using IL-6 receptor inhibitors in the context of lowering cardiovascular risk.

Dr. Marios Georgakis:

Here, however, we show, and our results support, that this increases primarily the results of the effects of IL-6 signaling bar down-regulation on HDL and not LDL levels. On the negative side, and finally, we found significant associations between genetically down-regulated IL-6 signaling and the number of potential side effects, particularly strong associations with bacterial infections, such as cellulitis and urinary tract infections, which is probably also related to the identifed association with the lower risk of neutropenia. So while these are well-described side effects of IL-6 signaling and condition in the context previous clinical trials, this, we believe, disagreement with our findings adds additional confidence to, let's say, the validity phenome-wide association state.

Dr. Greg Hundley:

Very nice Marios. Really appreciate this exciting work. And now we want to turn to our associate editor, Doctor Svati Shah. And Svati, you have many papers come across your desk, what attracted you to this paper? And then how do you put the results that these men have presented into context with other papers in this area of investigation?

Dr. Svati Shah:

Yeah. Great question, Greg, and thanks for having me. I thought this paper was really important, but I want to start at a broader level, and that's why it's attracted my attention is, I think genetics can not sort of inherently appeal to the broad Circulation reader. It can feel somewhat esoteric. We do these genome-wide association studies, these whole-exome association studies, and we find new genes and we're really excited about them as people who live in the genetic epidemiology realm. But when we think about the broader circulation readership and the broader cardiology readership, how does this really relate to how I take care of patients, and what might be important for me in my cardiovascular realm? And I think this paper really highlights the power of human genetics and how we really understand things that have clinical utility.

Dr. Svati Shah:

And let me just expand on that really briefly. And that is, in the human genetics realm, we can look at what we call human knockouts. We're not actually doing gene editing in humans, but looking at people who have loss of function variants. They're emulating a drug for example. And we also have PheWAS, which is a phenome-wide association study, where we say, "We're just going to look at lots of different clinical things and biomarkers and try to understand things that are associated." And then finally we have Mendelian randomization, which allows us at a very statistical level to really assess causality. We know there are things that are correlated with each other, but we don't necessarily know that they're causal, and this is a statistical way for us to potentially assess causality. I say that very carefully because it's a statistical way to do that.

Dr. Svati Shah:

And what's really cool about this paper is they combine PheWAS and Mendelian randomization, but with a very clinically important aspect. What are the potential good side effects, the on-target things that we want to try to address with these potential drugs, like tocilizumab, and what are potential side effects of these potential drugs. And in this case, because they combined PheWAS, they're able to look across all kinds of things. So the things that we already know about, they're not looking at a drug per se, but they're emulating a drug by looking at these genetic variants to say, "Okay. Well, we're going to look across all these different clinical factors." So it's not only things that have been evaluated in these clinical trials, but even just beyond that. And then the Mendelian randomization piece allows them to be able to say, again, statistically, are these causal. So if you antagonize these receptors, does it 'cause' these downstream effects. So, that's what was really cool to me about this paper. Is it really highlights the potential for human genetics in a very short term translational clinical potential.

Dr. Greg Hundley:

What a wonderful explanation for our listeners here. Well, let me ask each of you, Martin, Marios, and then Svati, what do you see as the next research endeavor in this space? Martin, you first.

Dr. Martin Dichgans:

And I completely agree with Svati that we have to utilize genetics in order to improve our means of treating patients, and I think that's obviously our aim here. And what this study shows, and let me just briefly also confirm what you said, we were intrigued by how the genetic data reflect what we see, for instance, in clinical trials. Just to expand a little bit on that aspect, the seven genetic instruments, which consisted of seven snips, single nucleotide polymorphism, when we looked at the effects of genetic lowering in this context on upstream and downstream, known upstream and downstream biomarkers of IL-6 signaling, this really very much matched what we know from clinical trials with tocilizumab so with pharmacologically lowering IL-6 signaling. Again, giving us confidence that it's informative and we will see with genetics what we are going to expect in the future in clinical trials.

Dr. Martin Dichgans:

So now getting to your point here and providing an answer, what we see as the next step, we should, for instance, combine the genetic data we have here with genetic data on other approaches to see whether, and maybe Marios can be more specific about this, whether by combining two different approaches, for instance, LDL lowering and targeting residual inflammatory risk, whether we could in future clinical trial provide additional benefits to high-risk patients with a cardiovascular disease. And I think that will be a very important area. Also, I think we should extend this approach to other inflammatory cytokines that have come up in Mendelian randomization analysis to explore their potential in future clinical trials.

Dr. Greg Hundley:

Marios?

Dr. Marios Georgakis:

Yeah. So just to add a little bit on Martin's summary, I would say here that now that we have established the efficacy of anti-inflammatory approaches in lowering cardiovascular risk, both with clinical trials, but also with showing genetic and clinical evidence, I think that the next step is first to identify the proper clinical scenario where anti-inflammatory approaches targeting IL-6 signaling would be used for reducing cardiovascular risk in order to design the proper clinical trials. And secondly, as Martin mentioned, to explore whether targeting IL-6 signaling would, one, pass additive benefits on Kruppel available approaches such as lipid-lowering approaches, and second, to see whether the risk-benefit balance of anti-inflammatory targeting IL-6 signaling would be acceptable in the clinical setting.

Dr. Greg Hundley:

And Svati.

Dr. Svati Shah:

Yeah. It's hard to follow up on those comments. I'll say, since I am very interested in diabetes and insulin resistance, the cholesterol story is fantastic, but I think the fact that they see effects on, again, statistical lowering of hemoglobin A1C and type two diabetes is fascinating to me. I would take it even a little step further. I think we need clinical trials. These data are very suggestive. It sort of flips the story almost. We've seen, even in some of the clinical trials of these drugs, that there are beneficial metabolic effects with regards to glucose, although some of the data are contradictory. So flipping it and saying, we know that inflammation is complex and we know that IL-6 has pro and anti-inflammatory roles in inflammation, and we know that diabetes with regards to inflammation is very complex, but maybe these drugs potentially are useful in type one and type two diabetes. So I think we need carefully designed clinical trials, potentially, to understand the role of blocking inflammation, and in particular IL-6 signaling, in patients who have diabetes.

Dr. Greg Hundley:

Excellent. Well, listeners, we want to thank Dr. Martin Dichgans, and Dr. Marios Jojakas, and our own associate editor, Dr. Svati Shah for bringing us this study incorporating phenome-wide association and Mendelian randomization to identify a relationship between down-regulated IL-6 signaling with subsequent clinical cardiovascular outcomes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021.