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Circulation on the Run

Sep 3, 2019

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events?

Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that.

Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis.

Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis?

Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.

                                                Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.

                                                Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.

                                                They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh?

Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.

                                                So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation.

Dr Carolyn Lam:                 Nice. A lot of work. So what did they show?

Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.

                                                Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction.

Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one.

Dr Greg Hundley:             Tell us a little bit about notch signaling.

Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.

                                                So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.

                                                So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation.

Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications.

Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found.

Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.

                                                So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work.

Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion.

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that.

Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time.

Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right?

Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance.

Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me?

Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example.

Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings.

Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference.

Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts?

Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.

                                                But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk.

Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically?

Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.

                                                And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well.

Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that?

Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice.

Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct?

Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test.

Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually.

Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course.

Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.

                                                And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march.

Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs?

Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies.

Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week.

Dr Carolyn Lam:                 This program is copyright American Heart Association 2019.