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Circulation on the Run: August 8, 2023

  • Carolyn S.P. Lam, MBBS, PhD orcid
  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20230807.753501

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. Peder Myhre:

And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today, Carolyn, there is a super interesting feature paper within the field of cardio-oncology where we are going to talk about immune checkpoint inhibitor myocarditis. And these authors measured several cardio-muscular biomarkers, including troponin I, troponin T, and CK, and really evaluated the trajectories of these, in patients with immune checkpoint inhibitor myocarditis. Isn't that exciting?

Dr. Carolyn Lam:

Wow. And right up your alley. Super cool. But, I think we should first start with the summaries of today's issue. Shall we?

Dr. Peder Myhre:

Yes. Do you mind if I go first?

Dr. Carolyn Lam:

Please.

Dr. Peder Myhre:

So the first paper is about the streptococcus species in the gut, linked to coronary atherosclerosis. And Carolyn, as you know, the microbial community of the gastrointestinal tract, also known as the gut microbiota, is hypothesized to affect the progression of atherosclerosis through three potential mechanisms. Recent evidence support that oral species are commonly transmitted to the gut, indicating that the gut and oral microbiota are connected, rather than being two separate microbial communities. And in this paper, from the population-based Swedish cardiopulmonary bioImage study, SCAPIS, which comes to us from corresponding author, Tove Fall et al, from Uppsala University, aimed to identify associations between the gut microbiome, the abundance of corresponding bacterial species in the oral cavity, and computer tomography based measures of coronary atherosclerosis, and to explore relevant clinical correlates.

Dr. Carolyn Lam:

Oh, so interesting. And what did they find?

Dr. Peder Myhre:

Yeah, very interesting. So they enrolled 8,973 participants age 50 to 65 without overt atherosclerotic disease. Coronary artery calcification was detected in 40%, and 5% had at least one stenosis with more than 50% occlusion. And in total, 64 bacterial species were associated with coronary artery calcification, independent of cardiovascular risk factors. With the strongest association observed for Streptococcus anginosus and S oralis. And associations were largely similar across CCTA-based measurements.

And out of these 64 species, 19, including the streptococci, and other species commonly found in the oral cavity, were associated with high sensitivity C-reactive protein plasma concentrations. And another 16 proteins were associated with neutrophil counts.

Carolyn, in conclusion, this study provides evidence of an association for gut microbiota composition, characterized by increased abundance of S streptococcus species, and other species commonly found in the oral cavity, with coronary atherosclerosis and systemic inflammation markers.

Dr. Carolyn Lam:

Very nice. Thank you, Peder. Now, the paper I'm about to tell you about really is the first report that suggests that atrial fibrillation could be an autoimmune disease. Now we know that about 3% of individuals, atrial fibrillation develops as a primary disorder without an identifiable trigger. We call it idiopathic, or lone AF.

In line with the emerging field of autoantibody related cardiac arrhythmias, these authors, led by Dr. Li from University of Zurich in Switzerland, really aimed to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF. So what they did is, they used peptide microarray to screen patient samples for autoantibodies, comparing 37 patients with unexplained AF to 37 age and matched controls. So what they found, was a common autoantibody response against inwardly rectifying potassium channel. So I'll abbreviate. Kir 3.4 protein was detected in patients with AF, and even before the development of clinically apparent AF. Now, because this inwardly rectifying potassium channel, Kir 3.4 protein, is a component of the ionic channel underlying the atrial specific acetylcholine activated potassium current, it would represent quite an attractive pathophysiologic candidate to explain lone AF.

Dr. Peder Myhre:

Oh, that is so impressive, and really pioneer work. So I'm curious, Carolyn, what did authors do next?

Dr. Carolyn Lam:

Yeah, so they proved this. So using human induced pluripotent stem cell derived cardiomyocytes with an atrial phenotype, the author showed in vitro that these anti-Kir 3.4 autoantibodies could activate this acetylcholine activated inwardly rectifying potassium current, and shorten atrial action potential duration. Pushing the demonstration further, they used an in vivo dedicated autoimmunized mouse model. They were able to demonstrate that anti-Kir 3.4 autoimmunity shortened atrial effective refractory periods, thereby, leading to an almost threefold increase in AF induction by atrial burst pacing.

So putting it all together, the authors really support a causal link between anti-Kir 3.4 autoantibodies and AF. And thus, suggests that the management of this autoimmunity could represent a new therapeutic target in these patients. This is discussed in a beautiful editorial by Dr. Algalarrondo from Hospital Bichat, and Dr. Extramiana, also from Paris in France. And their editorial is really, really interestingly entitled, Autoimmune AF or AF-induced Autoimmunity: A New AF Begets AF Pathway.

Dr. Peder Myhre:

That is really interesting, and I recommend everyone to pick this paper up. So provocative and very, very nice. So Carolyn, we also have a few other papers in this issue. We have Cardiology News, by our own Tracy Hampton. And first, she covers a study published in Nature Medicine, which links to artificial sweetener erythritol to cardiovascular disease events.

Next, she covers, Oral Mevalonolactone May Help Treat Statin Myopathy, published in proceedings of the National Academy of Sciences.

And finally, she's covering two accompanying manuscripts published in Nature Medicine, where two research groups independently used approaches involving CRISPR-Cas9-based editing to prevent hypertrophic cardiomyopathy in mice.

Dr. Carolyn Lam:

So cool. And a tongue twister. Thank you, Peder. There's also a Perspective piece by Dr. Yeh, “Bringing the Credibility Revolution to Observational Research in Cardiology.” And a Research Letter by Dr. Kallikourdis entitled, “Long COVID-19: Cardiac Complications are Associated with Autoimmunity to Cardiac Self-Antigens Sufficient to Cause Cardiac Dysfunction.” Wow, what an issue. But now, let's go on to this super interesting feature discussion, shall we?

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Well, welcome listeners to this feature discussion on August 8th. And we have with us Dr. Joe-Elie Salem from Paris, France. And also, our guest editor, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome, gentlemen.

Well listeners, today we're going to focus on a paper that's related to immune checkpoint inhibitor myocarditis. And Joe-Elie, let's start with you. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address?

Dr. Joe-Elie Salem:

So as you well know now, immune checkpoint inhibitor myocarditis is an emerging disease with more and more cases coming in. And initially, we described and we kind of discovered, we're all facing a very explosive, massive life-threatening cases. And with more time, we discovered more and more that the spectrum of the disease was a bit wider, and some smoldering cases might happen, other asymptomatic. And that we needed biomarkers to help us to stratify kind of which cases were the most severe, and which one are not going to be that severe, and to help us in the prognostication.

So as many cardiologists know, troponin was an obvious thing to try, and to see if level of troponin, which is probably reflecting the cardiac damage, or cardiovascular damage, would be associated to this. So when we started our program in France, and in collaboration with a very good collaborator, Lorenz Lehman, that also has been critical to this work, we say that we're going to build up a prospective cohort of our patient, and monitor their troponin to see if it's related to MACE.

And when you go for troponin, I'm not a troponin guy for sure, and I discover it's way more complex basically, with a different rounds of editing that it should, it looked, seems to be initially. You have troponin T, you have troponin I, not just one, many kits hypersensitive or contemporary. So it's a whole word, actually.

So we used the one we had in our hospital, each one of us. Some were similar to troponin T kit, which is basically a Roche one, one single vendor, and troponin I, many possibilities. So we use the one that we were using in clinic. So this is how it started, to see and seek for biomarkers potentially associated to MACE, troponin being a major hypothesis. Plus, CK we tried also, because in this disease it's particularly, it's very particular to this disease, as compared to other diseases or myocarditis in general, is that the involvement of peripheral muscle is key and critical. And I don't call it really any more myocarditis, but more myotoxicity. So the CK level is also potentially what would be potentially, it was hypothesis, associated to MACE disease. So this is how it went.

Dr. Greg Hundley:

Very nice. And thanks so much, Joe-elie. So sounds like we are going to be evaluating patients that perhaps had previously been treated for cancer, and had received the newer class of drug, the immune checkpoint inhibitors. And so, maybe describe for us that your study population, and also, your study design.

Dr. Joe-Elie Salem:

So basically, we were collecting, prospectively, consecutively, all cases seen with a suspicion of ICI myocarditis in France, in Paris, in my hospital, Pitié-Salpétrière, and in Lorenz Lehman Hospital in Heidelburg. Both groups we have included prospectively each one around 30 patient consecutively. And we were sampling troponin and CK, using in the standard of care, in the normal follow-up of those patients that we were prospectively seeing, and looking for a year or so. Sometimes, patient had to go back to their hometown, because we are a big referral center from all over France, and the same for Heidelberg in Germany. So sometimes, we had to deal with patient going back to their city, like 300 kilometer away, and use the troponin kits that was available there.

Dr. Greg Hundley:

Very good. So sounds like a two center study, a longitudinal cohort, where we're going to be following those patients over time. And you enrolled 60. Roughly 30 at the two sites, one in France and one in Germany. And then you mentioned you were going to follow patients for cardiovascular events. What type of events did you ascertain?

Dr. Joe-Elie Salem:

Like in myocarditis in general, we do know that two main cause of deaths could be initially like heart failure or cardiac arrhythmias and sudden deaths. So we were seeking for it very carefully. And we have also to admit that very, very early on, I realized in my first very first patient, before even starting this cohort, that the respiratory muscle involvement was key. And some of my patients were dying of it, even if they had normally have the NP normal. So we were also drawing a very particular attention to the ventilation need, mostly to, basically in this disease, to respiratory muscle failure as well, not just only heart failure. So the three main toxicities we were seeking for, calling a myotoxicity, not really MACE as cardiologist standardly used, it's, cardiac arrhythmia is very severe heart failure, and respiratory muscle failure leading to ventilation. Those three main items we're looking for. And of course, tests that's linked to this

Dr. Greg Hundley:

Very nice. So sort of a mild toxicity grouping of cardiovascular events, and following serial measures of troponin I, troponin T, and creatine kinase. So Joe-elie, describe for us, what were your results?

Dr. Joe-Elie Salem:

So the main result, it's troponin T at least can, is associated to the MACE, at least in this study. And what I can say, as most people may know, that we're also leading an international REDCap database, collecting cases throughout the world, with almost 1000 case right now. And I'm just like, just before talking to you, we were finalizing some of the results we're looking. And it's again replicating it, this database very, very interestingly. So troponin T is probably a good biomarker, and may help us to stratify the risks in those patient. And it's important, because not all myocarditis need treatment, aggressive treatment at least. Which is like steroids plus many second-line immunosuppressant, potentially. And we don't want to give immunosuppressants to people who do not need it. Because they have a grade one very mild controlled myocarditis, and troponin T, at least in this work, and probably very soon replicated afterwards, is very helpful. So this is one take.

The second take is, the heterogeneity with troponin I was a bit complicating massively the interpretation of this result of the troponin I output, because of the heterogeneity present. And it was less evident to follow patient with this. Plus, probably as well, even though this paper was not done to carefully study one specific kit very nicely, it seems that there is some discrepancies that appear two weeks to three weeks after the presentation with troponin I becoming negative. We don't know why yet. And troponin T is staying positive. We don't really know neither the real significance of it. But what we can say is, at the time of some MACE, some of the events, troponin T was always positive. And troponin I, in almost 20, 25% of the patient, some troponin I were negative. Even if the disease, at least from a cardio muscular point of view, seemed to be still active. And we were not able to understand why.

We tried the hypothesis of antibodies against troponin I, because this has been shown in other diseases, and our results are not suggesting that this interaction is massive, or very important to explain this. But what we have, what seems to be the most potentially reason for that, is that cardiac troponin T is also expressed in the peripheral muscle. So this is something being known, and more and more identified in many disease, but here, it's particularly relevant, because the whole muscles are destroyed somehow.

So cardiac troponin T and not cardiac troponin I is expressed in peripheral muscle, and probably we're capturing with the troponin T some of the overall burden and regeneration processes, when the disease is very active and very massively destroying the muscles.

So our data suggest very strongly that troponin T and I are not providing the same information in this specific disease. More research is needed to determine exactly what is what. But troponin T is very useful for prognostication, differences in troponin T and I, and some explanation we try to provide by studying the expression of cardiac troponin T in peripheral muscle that we're identifying very massively in this disease as well.

Dr. Greg Hundley:

Very nice Joe-elie. And just for our listeners, a couple points of clarification for your very interesting results. Number one, was it a particular value of troponin at one point in time, or was it a trend in these values, that was indicative of a future event? And then second question, what was the breakdown of the types of events that occur? Because I know some, you've got some respiratory failure, some you have some death, some you have heart failure, some you have arrhythmia. What was the breakdown of those events?

Dr. Joe-Elie Salem:

So the breakdown was a bit like the three events occurred, and you have to acknowledge that the full package, when the patient come with a very severe form, they're like, so full, and the whole three events are there actually at the end of the day. Heart failure occur when you have a bunch of BTs or AV blocks, and it's very often associated to respiratory muscle failure. And when you have patient milder with none of those symptoms, and some may be more peripheral and less cardiac, some may be more cardiac and less peripheral. I would say it's hard to give number 100% on this. We have a number of our own cohort in this paper, but when you go more broadly and more... And for example, in my center, now we have seen 100 patient, not any more 30. And so, I do know what I'm seeing.

You don't see, if your question behind, is like cardiac troponin T is... Sorry. Cardiac troponin I is negative only when it's just respiratory muscle failure and not ventricular tachycardia or cardiac failure. It's not what we're seeing. In some patients that just go a month after they're out from the hospital, cardiac troponin T is up, very up. But they considered in the initial hospital because cardiac troponin I decreased and was negative, so in their wisdom, they discarded, discharged the patient. He comes to our hospital two weeks later with a complete AV block, with a negative troponin I, while it was positive before, and the cardiac troponin T is still very up, above the threshold we have identified.

So there is no clear correlation right now. I have not put this back together yet. And the number we had were too small to play around this, we didn't want to go there with this small cohort we have initially published in Circulation. There is no evident trend right now for me to say that cardiac troponin I and T, or its discrepancy is more showing one specific type of cardiac event to date, it's not yet clear.

And as of the cutoffs, in this paper we identify 32, in times upper reference limit for troponin T. So one used here was the upper reference limit of 14. And with this threshold, we have been able to identify... Our aim was to identify a low risk population, because we're overwhelmed by patient coming with a suspicion of troponin T, increase 2, 3, 4 times the normal. We don't really know this patient, our cancer patient. We don't have baseline troponin, and we're like, we don't know what to do with them. So we wanted to know which one we don't have to keep forever in the hospital, to just do all the exam we have to do. So what we do now, and we have applied basically in those patient, is to monitor troponin six hours later, and eventually, 12 hours later. And if troponin is not increasing too much, like doubling or tripling, and is not above this threshold of 32, we can sometimes withdraw the patients that can discharge, and monitor very carefully in outside setting after verifying there is no symptoms.

And those who have those, the threshold of 32, doesn't mean that all of them will go and do a MACE. It just means that those patient need to be monitored at least. And this threshold, we have keep being using it of 32, right now it's over 60, 70 plus patient after this paper, our 31st,and 70 plus afterwards. And I have to say that, I don't have the data yet neither, published or even computed. But when we do monitor for a few hours later, and the threshold is below 32, we haven't been like having MACE or very bad events, a very serious event, even with discharge patient with those kind of cutoffs.

So of course, it has to be prospectively validated in multiple center, and with the same kit, a troponin T. But in our experience, what we have seen in those 30 in my center, and same thing for Lorenz Lehman, 30 from his side, is kind of being the threshold we're using now very in clinic, we're using in our own clinic, to really stratify our patient.

Dr. Greg Hundley:

Very nice. And then, last very quick question, can you describe for us how many men, how many women? What was the age? And then the cancer types, as I understand, folks with small cell lung cancer, melanoma, renal cell carcinoma, hepato-carcinoma, were basically the majority, correct? So how many men, how many women, and what was the average age of your patients?

Dr. Joe-Elie Salem:

So basically, here we described the very first use of immune checkpoint inhibitors, as you stated very correctly. The first indication were melanoma, lung cancer, and some kind of kidney afterwards. So those patient are the one mainly representing our cohort, and those patient are more prevalent in male than in female. So our cohort is kind of two third, one third, I don't have the exact number right now. But it's a two third male, one third female. And it's kind of an elderly population, 70 plus population.

Dr. Greg Hundley:

Very nice. So an average age of 70 years. Well listeners, we're going to turn to one of our experts, Dr. Allan Jaffe. And Allan, I know you have many papers come across your desk. What attracted you to this particular manuscript? And then, how do we put these results in the context of other studies pertaining to identification of future adverse events in patients with immune checkpoint inhibitor myocarditis?

Dr. Allan Jaffe:

Well Dr. Greg, there is a need in the field that was clear, to make and allow the diagnosis of immune checkpoint inhibitor or myocarditis to be made with a greater degree of facility, and particularly, to define prognostic indications. And there's very little literature that helps define that. So this paper had an advantage right from the beginning, of moving into an area that was a relatively data free zone. And in trying, I must compliment the authors in being very responsive to the reviewers, and helping eventually to define what I think are very important points now, that can be made from this manuscript. And I would summarize them as follows.

Number one, although they had a heterogeneity of heart cardiac troponin I assays, the vast majority of their patients had a diagnosis made by biopsy. And it's quite clear, that there were at least some patients, maybe not all, who had positive biopsies, and didn't give one a cardiac troponin I signal. That's important. The etiology of why that occurs is not totally clear. It may have to do with the fragments of troponin it elaborated, which is a discussion for a different day. They looked to see if this was due to anti-troponin I antibodies, and didn't find that.

And troponin I went down with the treatment of myocarditis fairly rapidly. In contrast, troponin T stayed elevated. And the question is, why is it more sensitive, that in part, the reason it's more sensitive is it is less specific, as was pointed out. And this was an important concept. We've known for some time from the work of others, that cardiac troponin T can be re-expressed in skeletal muscle. And RNA expression profiling in some of these patients allowed documentation, in fact, that that was occurring in these patients.

So one of the reasons troponin T may have been more prognostic, is because it continued to monitor the process, even once cardiac troponin I had become normal. And maybe that means, that the involvement of the heart was less, but the process that went on in the muscle per se, was still terribly ongoing. And that's an important message for clinicians. Because the fact that troponin I normalizes and the heart may have been improved, doesn't necessarily tell us that the underlying pathophysiology of this syndrome, which almost invariably involves both myocarditis and myositis, is still ongoing. And I think that's an important message for clinicians, whether they use cardiac troponin I and CK to eventually monitor for the myositis, or they use troponin T, that this is a disease where the prognostic effect, to use the author's terms, is on the cardio muscular impact of the disease process.

Dr. Greg Hundley:

Very nice. Well Joe-elie, let's turn back to you. What do you see is the next study that maybe your group will entertain to perform in this sphere of research?

Dr. Joe-Elie Salem:

So what we're trying to do right now, but it's very complicated I have to say, is going back to all the contributor of the international REDCap we have put together, to ask them for which specific kits they have used. But I can tell you that a lot of people are not troponin people, and doesn't just know what's going on with the kits. So we're around 1000 patients right now, so it's a big number. We're going to see if we're able to replicate our findings with troponin T, and eventually troponin I, and look at the interaction, and predict cardio myotoxic event in those patient, 1000. So this is a first step. We have given a big stab at it right now, and I have the preliminary result. But, I mean, it's very hard to get the kits, troponin I kits again.

The second one, would be to go for a prospective trial, where you're going to pick 2, 3, 4 kits. I don't know which one we want to try. With the troponin T kit of course, and two, or three, or four, troponin I kit, to see if it's the same invariably trends that you observed, that were exactly well discussed by Dr. Jaffe, with the troponin I decreasing super rapidly. And it's even faster for CK. This is really impressive. CK as soon as you give one drop of steroids, goes down and normalize in 48 hours, even if the patient is completely dying in the ward, CK go down. So you cannot use it at all, at all, at all, for the evolution of the patient. It helps you first diagnosis, but not for the evolution.

So going for a prospective trial, look for the different troponin I kits. See if it's inconsistently, invariably the same thing that you're observing or not, to try to understand why we have this.

And lastly, and just something we're trying to do again, is also to dissect the different types, more peripheral muscle or more cardiac, and see if we're, it's more one type or the other, or some ratio. But those are the effort we're doing right now. And I don't know for, of course, other people are interested in this, and may try other biomarkers, but for now, this is what we have been doing, or planning to do.

Dr. Greg Hundley:

Very nice. And Allan, your thoughts?

Dr. Allan Jaffe:

Well, I think there's a lot that still we don't know. First of all, we don't know the relationship of these phenomenon to the type of tumor we're treating, or to the specific checkpoint inhibitor. And they may be different, even though they have a common mechanism of inhibiting PD-L1. So we need to sort that out.

We also need to make it clear to those people who are treating this syndrome, that the evolution of the disease process often can be ongoing, despite a negative cardiac signal, such as a normal cardiac troponin I. That may not mean that the heart is still involved. It may simply mean the process is there and fulminating, although we don't even know that with 100% certainty. So there's a lot that needs to be done in particularly, and I would argue, that this is where imaging would have a terribly critical role in clarifying many of these phenomena.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Joe-elie Salem from Paris, France, and also Dr. Allan Jaffe from Rochester, Minnesota, for bringing this results of the study in cancer patients that have experienced immune checkpoint inhibitor myocarditis, and finding that cardiac troponin T was associated with MACE, and was sensitive for the diagnosis and surveillance of immune checkpoint inhibitor myocarditis.

And also, listeners, finding that there were potential differences in the diagnostic and prognostic performance between cardiac troponin T and troponin I. And that may be related to a function of these assays, and deserves further evaluation in future studies pertaining to immune checkpoint inhibitor myocarditis.

Well, on behalf of Carolyn, Peder, 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 2023. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

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