Circulation March 3, 2026 Issue

Welcome listeners and now we're into the month of March and this is Circulation on the Run and I'm one of your co-hosts, Dr. Greg Hunley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. And I'm Doctor Sharin Durudgar, Associate Professor at University of Arizona College of Medicine Phoenix. You know, over the past what four years.

We've really had a lot of emphasis on myocarditis, and this week's feature discussion involves an exploration into the natural history of patients with histologically proven Acute eosinophilic. Myocarditis. You know, we don't hear a lot about that, but a fascinating natural history discussion in our feature today.

Before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And this week, perhaps I go first. That sounds good, Greg. Well Shirin, this first paper comes to us from Australia. And Shirin, sinus bradycardia is a well-recognized physiological adaptation in endurance athletes.

primarily attributed to sinus node remodeling and or increased vagal modulation. Now, Although genetic influences on resting heart rate have been observed, The genetic contribution to athletic bradycardia has really not been elucidated. And so Sharin, this team, in association with corresponding author, Professor Andre Lagerche from Saint Vincent's Institute of Medical Research.

phenotyped current and former elite endurance athletes in the PROHART cohort study using multimodal cardiac imaging cardiopulmonary exercise testing and halter monitoring. And then Sharin, genetic susceptibility to bradycardia was assessed using a validated heart rate associated polygenic risk score. And so this score, when the score was lower, that was associated with a lower heart rate. And so this team evaluated this score in elite endurance athletes compared to healthy non-athletic control.

And Sharin clinical and genetic features of bradycartic endurance athletes with a minimum heart rate of less than or equal to 40 beats per minute on a halter monitor were compared with non-bradycartic athletes. And then also, Sharin, a healthy cohort of nonathletes from the Espree study were used for genetic comparison. So we really have sort of three groups here, Sharin. We have braidocardic endurance athletes, non-bradycartic endurance athletes, and then also the non-athletes.

Okay, what a nice setup. So Greg, a study that sought to identify the ideology of very low heart rates experienced by elite endurance athletes. And how many endurance athletes did they enroll and what did they find? Right, Shrin. So the study included four hundred and sixty five endurance athletes, and their average age was twenty-three years, and seventy-five percent of them were men.

Now, a hundred and seventy five or thirty eight percent of this cohort had a minimum heart rate on the halter of less than forty beats per minute, of whom Seven, and that's two percent of the total, had a heart rate of less than 30 beats per minute. Schrin pauses greater than two seconds on this Holter monitor were observed in one hundred and fifteen or twenty five percent of the athletes, of whom twelve, so that's three percent of the total, had pauses for greater than three seconds.

And Sharin Mobit's type one, second degree A V block, was observed in fifteen of the athletes. Now, bradycartic athletes, they were found to be younger, fitter and exhibited greater athletic cardiac remodeling than the non bradycardic athlete. And Sharin, the mean heart rate polygenic risk score was significantly lower in all the athletes compared to, remember that third group of non-athletes.

and in the bradycartic athletes compared to the non-bradycartic athletes. And the p-values for those comparisons were really significant, less than 0.001 for the comparison with the non-athletes. and point zero zero six for the bradycardic versus the non-bradycartic athletes. Now, Sharin, after adjusting for age, sex, fitness, and indexed right atrial volume, Heart rate polygenic risk score was independently associated with a lower minimum heart rate.

and an increase in the odds ratio of arresting bradycardia by two fold. And then finally, Sharin, neither bradycardia nor pauses were associated with increased risk of adverse outcomes over the subsequent five and a half years. Wow, a nicely informative study. And what can we conclude from the study, Greg?

Right, Sharin. So first, a resting brachycardia of less than 40 beats per minute, and then pauses of two to three seconds, well, they're present in a significant proportion of endurance athletes, and they're well tolerated. Second, Sharin, this team's data suggests that both fitness and genetic variation contribute to sinus node function in these endurance athletes. And then finally, and you know what, Sharene, somewhat intriguingly, the heart rate associated polygenic risk score.

differed between athletes and nonathletes, raising the question as to whether genetics play an important role in some of the lower heart rates experienced by athletes versus non athletes. So very interesting study.

Very, very interesting, Greg. Thank you. So that study is a great reminder that not all dramatic cardiac findings are dangerous, but Our next paper shifts to a setting where cardiac injury is very real, and that is chemotherapy related cardiotoxicity. Oh wow. Just now pivoting into the world of cardio oncology, Sharin. So that's very much in the forefront of many of us in clinical practice. So what angle does this study take?

So right, Greg, this study in association with the corresponding author, doctor Yan Bo Fan at the Ohio State University Wexner Medical Center. Looks at patients receiving doxorubicin and asks a simple but important question. Can protecting the endothelium help protect the heart? you know, just a a nice paper sort of examining another form of injury and not necessarily direct injury on the cardiomyocite.

Exactly, Greg. So this study is very interesting. It identified a transcription factor called transcription factor EB. which is a master regulator of autophagy and lysosome biogenesis as a protector of endothelial cells against damage. So the investigators show that when endothelial cells are healthier, Cardiac outcomes after doxorubicin are better and there is less cardiac dysfunction, less fibrosis, and improved survival in preclinical models.

And Greg, when endothelial protection was lost, cardiotoxicity worsened. you know, this may help us really reframe Sharin how Perhaps we think about some of the doxerubicin mediated cardiovascular injury in patients treated for cancer. It does, Greg. So here the takeaway for clinicians is that vascular injury is a key contributor to chemotherapy related cardiotoxicity.

And monitoring and protecting vascular health could help identify patients at higher risk and potentially reduce long-term cardiac complications in cancer survivors. Greg, this is a timely paper, especially as more patients are living longer after cancer therapy. Very nice.

So Greg, building on that theme, how understanding key cellular contributors can guide therapy, our next Study shifts from protecting the heart in chemotherapy to actively recovering the failing heart. You know, Sharin, you're always so creative in these transitions. So moving from prevention to now cardiac repair. Thank you, Greg. So exactly this study, led by corresponding author.

Professor Leslie Leinwand at the University of Colorado Boulder Biofrontiers Institute looked at patients with advanced heart failure receiving left ventricular assist device therapy. So Greg, while LVATs support circulation, only a small subset of patients experience reverse remodeling where the heart actually shrinks back towards normal size and function improved. So Greg, understanding what distinguishes responders from non responders is a major clinical question, as you know.

Oh, absolutely, Sharan. And so what did these authors find? Greg. They studied heart tissue from patients before and after LVAT support and found that RNA splicing of the CAMK2D gene, that's a gene encoding CAMK2 delta. was a key factor in recovery. And patients who improved had Cam K2D splice variants. that supported proper heart function while in non-responders, abnormal splicing and phosphorylation of the protein caused CamK2 delta to stay in the cytoplasm.

And that disrupted calcium handling and limited cardiac recovery. Oh wow. So Sharin, from your perspective, does this give us a molecular signature of recovery? Absolutely, Greg. So clinically, this suggests Cam K2D splicing could serve as a biomarker to predict who will respond to LVAT therapy and this points towards Therapeutic strategies that modulate CAMK2D or CAMK2 delta protein localization or activity to promote recovery in nonresponders. This is very exciting work.

you know, just beautifully described Sharin Your synopses for us all are just fantastic. And this is a nice example of translating molecular insights into potential patient specific interventions. Absolutely wonderful.

Well, how about Sharin? We jump into the mailbag this week and there are a lot of letters here. And the first is an exchange of letters from Professor Zhang and Chen regarding the prior article entitled Partnership Model. Of regionalized care for congenital heart disease in resource-limited settings results from the Assist project. And then next you're in there's a nice perspective piece from Professor Leaper entitled Micro and Nanoplastics A New Perspective in Cardiovascular Prevention.

There's a research letter from Professor Fu entitled Abundance of Naturally Occurring Mononuclear Diploid Cardiomyocytes and How They Associate with Cardiac Regeneration. And then also, Sharin, there's another exchange of letters to the editor from Professors Lee and Schumacher regarding the article Refining Fontan Transplant Risk Stratification, Integrating Hemodynamics and Psychosocial Factors.

And then lastly, Sharin, there's another exchange of letters to the editor from Professor Zhao and Develd regarding the article Critical Analysis of the Praetorian XL Trial Findings. Well How about we take our cup of coffee now and jump to that feature discussion? Exciting. Let's do it.

Welcome listeners to our feature discussion on this March 3rd. And we are going to probe into the world of eosinophilic myocarditis. And we have with us today the first author of this paper, Dr. Enrico Amorati from Neguardia Hospital in Milano, Italy, and also one of our associate editors, Dr. Justin Azikowitz. from University of Alberta in Edmonton, Canada. Welcome to you both, gentlemen. Well Enrico, we will start with you first.

Can you describe for us some of the background information that went into the preparation of your study? And what was the hypothesis that you wanted to address? Yes, the general idea is that we know that most of myocarditis are lymphocytic myocarditis. Just a minority of them, let's say 15% around, are isonophilic. That means that together with the lymphocytic cells, there are also isonophilic cells that are infiltrating the myocardium.

So we do not have in uh Data to define the prognosis of these patients substantially so we have just case reports a small series So it was important to understand the outcome of this patient. What was the clinical presentation? In particular, what are the associated systemic disorders that can be part of the clinical presentation? And very nice. And so with this particular study, could you describe for us your study design and then who did you include in your study population?

Yeah. We focus on patients with uh histological demonstration. So histological proven isonophilic myocarditis. So it was not just based on peripheral isonophilia. plus a left ventricular systolic dysfunction or uh a suspected myocarditis, but uh all these patients have uh proven histological isonophilic myocarditis. And as they are rare cases, we created a large network involving fifty three hospitals around the world.

And finally, we got 156 patients from 43 hospitals that provided us at least one patient that was suitable for this registry. And we focused. On patient with an acute presentation. That means within one month from the onset of cardiac symptoms. So we ruled out those patients with chronic forms that can be seen, for instance, in Africa. where there are chronic forms of esunophilic cardiomyopathy.

Very nice. And could you give us an idea of the age range of the patients that were included in the study and how many men versus how many women? So the median age is 48 years and the interquartile range is between 34 and 56 years. And there was a male predominance in the As we see in other forms of of myocarditis. Like lymphocytic, and the prevalence was 67% of male. While the pediatric population was rare, only two cases were pediatric, that means below or equal to 16 years of age.

And how long did you follow these patients for? And then describe for us your study results. So the follow-up of of these patients is highly variable due to the collection of of cases from several hospitals. So we focus on in-hospital outcome and estimated the outcome at one and three years. So we focus on this data on the related to the outcome. And what were your study results? So the first main result was that the peripheral isonophilia was present in only uh 57.4% of patients.

And this is remarkable because uh you think that all isonophilic myocarditis can have uh peripheral isonophilia. While for this reason, performing an endomyocardial biopsy is a key part of the diagnostic pathway in this patient. The second relevant result is that In around a forty five percent of cases The zoonophilic myocarditis is an idiopathic or isolated form, while in the remaining form there are an associated condition that can explain why there is an zoonophilic myocarditis.

And the most common associated form was a form of vasculitis, that is the esunophilic granulomatosis with polyangiitis, that was found in 22% of patients. and this is characteristic by the presence of asthma. So a patient with asthma can be a good suggestion to steer your diagnosis toward a potential osinophilic myocarditis. Then we have, as a second most common form, the hypersensitivity form that was found in 14% of patients. And these are the patients with a sort of allergy.

And in most of cases, these patients have a recent history of assumption of penicillin. So common antibiotics and what is amazing in this population that is that peripheral isonophilia is rarely found compared with the other cases. So it's very important to reach this diagnosis. And it is important to understand the rate of mortality because it's high. So we have an in hospital death or need for heart transplant of fourteen point seven percent.

And about uh 43.6% of those receive a temporary mechanical circular supports, and 93% receive immunosuppressive treatment. And we looked at the overall estimated survival fee of our transplant that was 19% at one year and 23% at three years. That means that still there is a risk of mortality and heart transplant after discharge. So this is another important point. Finally, we identified that immunosuppression was a predictor.

Of better outcome in the long term. So, in the absence of clinical trial, it is important to have registry that support the use of immunosuppressive medicines. Very nice.

Well, thank you so much, Enrico. And listeners, next we're gonna turn to our associate editor at circulation, Dr. Justin Azikowitz. And Justin, I know you participate in many discussions of articles as they come in and are evaluated by the editorial board. Can you summarize for us the enthusiasm related to this particular article? And then as an expert in heart failure, and also someone that manages patients that are

May have myocarditis. What do you see are the important features that we should be thinking about moving forward with this particular disease process? Yeah, thanks, Greg, and congratulations Enrico to you and your very large team that it took to put to this effort together. So that's the first part is this was really exciting because it's a lot of patience with the

a rare diagnosis or an unusual diagnosis that we often only see case reports, you know, small case series, but this really overwhelms that literature by showing with a oh, you know, the right amount of patients where you can really dig into some of the features that you've identified. Plus having the additional things such as biopsy and in some cases also cardiac MRI findings, so really sets the stage for much larger studies going forward and and a much deeper dive into the disease state.

Now what was really also exciting about this was the distribution of this was from a number of different continents, different hospitals, different age ranges, but really did start to hone down on a couple of features you've highlighted, which are we cannot rely on peripheral EOC naphilia. That was a really stark contrast to what we've been trained in our early medical training. So that's number one lesson to really unpack why that is.

The other part was When we see a lot of other cases of myocarditis, with especially with influenza and other types of viral illnesses, we have to have a very high uh rate of s or index of suspicion to understand is this is synophilic. uh myocarditis because of their underlying conditions. And you raised a few of them, H E S

and a few of the other other conditions that can be associated with it. What was also I think we were trying to unpack and try to understand about the details of this, the rate of serious poor outcomes, mortality, transplantation was also quite difficult.

When I flip this on its head is these individuals are quite sick when they show up to the hospital. So wearing my heart failure hat is, you know, how do we treat these patients going forward? Knowing that these risk factors still predominate with their underlying diseases.

They're go through those three different phases of the esophagic microditis from the inflammatory phase, which is most of these patients that when they show up through the thrombotic phase, through the fibrotic stay phase. And I was trying to understand You know, if I saw a patient tomorrow in my clinic

What would I be doing differently now that I know this? And I I think I'd have a very high concern that these patients may deteriorate further given their risk for heart transplation and death. So Enrico, I I wondered if if you how it's changed your thoughts on this entire disease state from myocarditis to eosinophilic myocarditis. And do you do you think differently now after this publication and assembling these hundred and fifty plus patients?

Yes. I I was surprised to see that the proportion of uh isonophilia was not so high. And we explore better this point to rule out uh and with subanalysis, for instance, in patient with a previous administration of steroids that could be a potential confounder. But still this is uh this is the case. So when you have peripheral zoonophilia, you can suggest based on our results a specific form of uh isonophilic myocarditis. Most of them are associated with uh eGPA.

Or with hyper-esenophilic syndromes. So you have already an nth based on the presence of isonophilia. To me it's not enough. to confirm the diagnosis just relying on peripheral eosomophilia. So it's important to better characterize the overall phenotype of these patients performing a biopsy. If you perform a biopsy before steroids, it's better if it's possible because you are not going to cover the presence.

uh my attention moved to the potential treatments because we saw that most of these patients are treated with steroids, but in particular in the long run, there are potentially specific treatments. like uh anti-interlocking five agent. So this could be the potential game changer in those patients with isonophilic myocarditis associated with a condition that can further an increase in peripheral isonophilia or tissue isonophilia. So in the next step should be, should be a potential trial.

Where you add an anti-interloquin-5 agent to see if you can improve the outcome or decrease the total amount of steroids in the long run of these patients. This is the perspective of my. Beautiful description. And Justin, thanks so much for that question. And Enrico, that guidance. of how we should consider this diagnosis and then also the future looks uh regarding therapeutic interventions that may be implemented and studied moving forward.

We want to thank doctor Enrico Amerati from Naguardia Hospital in Milano, Italy, and our own Associate Editor, Doctor Justin Ziekowitz from the University of Alberta in Edmonton, Canada, For bringing us this study that highlighting that acute eosinophilic myocarditis can often present without Peripheralyphilia.

and that the in-hospital and midterm mortality or need for heart transplantation were very high, and reminding us that endomyocardial biopsy is often required to reach the final diagnosis.

Well, on behalf of Petter and Sharin 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 2026. The opinions expressed by speakers in this podcast are their own and not.