Circulation November 25, 2025 Issue

Welcome listeners to this week's issue of Circulation on the Run. And in the United States, you are getting close to Thanksgiving, I think. And Shirin? You are here with us today, and I am Dr. Petter Meiery from University of Oslo in Norway. And I'm Shirin Darutgar from University of Arizona College of Medicine, Phoenix. Yes, happy Thanksgiving, everyone. We are very close to Thanksgiving right now.

But before we start celebrating, I think we're gonna review some science and we have some great papers in this issue. Even a feature discussion looking into a novel biomarker-based score for predicting stroke in patients with atrial fibrillation. So that's the ABCAF. risk score and the great discussion from a randomized control study coming up after we look into the mailbag to see what else is there. And Sharon, perhaps I'll go first this week. Yeah, that sounds great, Petter. I'm excited.

Thanks. So this first paper is about coronary artery anomalies, which is a group of congenital conditions characterized by the abnormal origin, course, and or termination of coronary arteries.

and with each variant occurring in less than 1% of the general population, so quite rare. So among these coronary anomalies... anomalous aortic origin of coronary arteries, and I'm going to abbreviate that AAOCA, are of particular interest due to their association with sudden cardiac death in young athletes. However, the clinical significance and outcome predictors of AAOCA in adults remain unclear. Until we had this data from an Italian tertiary referral center.

analyzing more than 17,000 coronary CTAs performed over 20 years. And this initiative was led by Dr. Francesco Gentile from Cardiology Department Pise University Hospital. Wow, Peter, what an effort to systematically look for the patients with anomalous aortic origin of coronary arteries. How many did they find? And what was the presence of these anomalies associated with? Yeah, Sharon.

Out of the more than 17,000 CCTAs, they found 173 patients with AAOCAs and the mean age among these was 62 years and 34% were females. and chest pain was the most common indication for the coronary CTA. Now, Sharon, the obstructive coronary artery disease was present in 36 of these patients, so that's 21%. And myocardial ischemia was detected in 60% of those who underwent functional imaging testing. Now, within follow-up, they saw that only 10 of the patients, so that's 6%, underwent...

repair of this anomaly, with the majority of patients treated conservatively. And after a median 37-month follow-up, mortality and mace, were similar between patients who had these AAOCAs and controls, with p-values at 0.32 and 0.39 respectively. And only obstructive coronary artery disease remained as a predictor of higher event rates during follow-up. Whereas the subtype...

of AAOCA or ischemia were not predictive of event rates. So, Shirin and listeners, in conclusion, the overall prevalence of AAOCA's was 1%. and surgical repair was performed in only a small subset of these patients, while medical therapy effectively reduced symptoms and ischemia in most cases. So clinical presentation and adverse event rate were comparable between patients with AAOCAs and match controls. So quite reassuring results, Sharon. Wow. Yes, thanks, Petr.

That was a fascinating look at coronary anomalies in adults. So, better sticking with structural and functional complexity in the heart, our next paper dives into something a bit More molecular, but just as important for understanding disease. And that is alternative splicing of RNA in the human heart.

better alternative splicing we know is the process by which a single gene can produce multiple versions of a protein called isoforms and that allows the cells to fine-tune their function And alternative splicing therefore plays a critical role in normal heart development and in cardiac disease by shaping protein coding sequences, functional domains, and even...

cell-cell interactions. Yet, veteran listeners, despite its importance, we still lack a complete map of the full-length isoforms in the human adult left ventricle. So, this is really digging into the hidden layers of gene regulation, Sharon, at least it sounds like, right? Right. Absolutely, Peter. So this team led by Dr. Rui Gao at Northwestern used long read single nucleus RNA sequencing.

to see the full length isoforms in different cardiac cell types. Now in healthy hearts, about 30% of cell type specific genes make multiple isoforms. And that gives each cell type its own toolkit. And even genes shared across cells use different isoforms to fine tune their function. All right. That's incredible. But what happens in heart failure? So if they're in heart failure, isoform usage shifts a lot, especially in cardiac myocytes, but also in fibroblasts and endothelial cells.

These changes contribute to disease-specific cell states. Now they found that genes with more isoform diversity show bigger functional changes. And these patterns can even help identify heart failure cell subpopulations. So this study gives us a new view of the heart at the molecular level. showing that RNA splicing is a key player in disease. And what's really great is that the team has made all this data available online for anyone to explore.

Wow, Sharon, that's really fascinating. Thanks. And we're gonna move on to a paper that is in the cross section between preclinical and clinical research show. We're going to talk about the mechanisms of peri- and myocarditis following COVID-19 vaccination. So, Sharon, the COVID-19 pandemic caused by severe acute respiratory syndrome, coronavirus 2.

or SARS-CoV-2, has led to the first approval of an mRNA vaccine. And we're all very aware of this term now in humans. And by producing full-length SARS-CoV-2 spike protein, they induce protective antiviral immunity. Now acute myo or myopericarditis development post vaccination has repeatedly been reported. However, the pathogenesis of this complication remains elusive. Wow. Okay, Peter. This is one of the remaining questions after the COVID-19 pandemic.

Very important. And how do they assess this? Yeah, sure. And so this team led by Dr. Morelli Berg from William Harvey Research Institute in London, UK, performed several experiments. So they did in-depth phenotyping of peripheral blood T cells in a cohort of patients who developed myo- or pericarditis post-MRI vaccination. and patients hospitalized for severe COVID-19 and even healthy subjects with no cardiac side effect of post mRNA vaccine.

and also shared invalidation studies were carried out using an experimental model of cardiac inflammation in which a shared epitope elicits functional responses in patients and mice. in which it induces myo or pericarditis. So, Petr, did they find a mechanism for cardiac injury following COVID-19 vaccination? Yeah, so...

T-cells from patients who developed myopericarditis after mRNA COVID vaccine recognized vaccine-encoded spike epitopes, homologous to those of cardiac self-proteins. Quite interesting. Socherin, one of these epitopes mimicking an amino acid sequence from cardiomyocyte expressed potassium channels induced myopericarditis in mice.

and when functional responses were analyzed post mRNA vaccination myopericarditis patients but not COVID-19 patients displayed an expanded pattern of cytokine production similar to that observed in myopericarditis mice and in autoimmune myocarditis.

Ann Sheeran, crucially, T-cell autoimmunity segregates to cardiotropic C-met expressing T-cells and is prevented by inhibiting this C-met, suggesting that heart... homing imprinting and sharing that is the process by which the immune system imprints or teaches a cell permitted by the unique mRNA vaccination bio distribution is required.

for myopericarditis development. So Sharon, to sum all of this up, myopericarditis development post-mRNA vaccines is mediated by distinct immune components including molecular mimicry, T-cell receptor affinity, and importantly, homing imprinting, which I just explained. Wow, thanks Petr. That answers a lot of our questions. What an elegant study. Dissecting the immune mechanisms behind post-vaccine myoherocarditis. Okay, so we also have several other exciting pieces in this week's issue.

First, there's a letter to the editor by Yiran Chen on the article titled Dose Response of Incidental Physical Activity Against Cardiovascular Events and Mortality. And for those who love an ECG challenge, Dr. Kenneth Ellenbogen has another engaging one titled Measure Twice, Cut Once. That's sure to get you thinking.

Yeah, I look forward to reading that one. And also, Sharon, there is a research letter by Dr. Fukuyama entitled Proteomic Signatures Involved in Cardiac Recovery After Mechanical Unloading. And I look forward to reading that one. So, Sharon, that's a wrap for the summaries. And now we're going to delve into the feature with Professor Oldgren and even our own handling editor, Torbjörn Omlund.

to discuss AF risk scores to prevent strokes. Are you ready? I'm ready. Let's go. Well, thank you so much, Petter and Shirin. And listeners, now we are transitioning to our feature discussion today on November 25th. And I am one of your co-hosts, Dr. Greg Hundley. Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia. And we have with us today Dr. Jonas Olgrien from Uppsala University in Uppsala, Sweden.

And our own associate editor, Dr. Torborn Omlund from University of Oslo in Oslo, Norway. And today's paper listeners comes to us from the world of atrial fibrillation. And we're going to be discussing risk scores and how we might apply that to the management of patients with atrial fibrillation. And so to get started, Jonas...

Perhaps describe for us the background information that has gone into the preparation of your study, and what was the hypothesis that you wanted to address? Thank you, Greg. It's really a pleasure to discuss this study. So it's well known that patients with atrial fibrillation are at risk for stroke, death, and other complications. And we have shown that biomarker-based risk scores provide better quantitative estimates.

of stroke and bleeding risk in patients with AF. And these scores have been repeatedly validated by us and other independent groups in patients with AF. and on oral anticoagulant treatment or without oral anticoagulant treatment. So that's the basis for the biomarker-based risk scores. And then guidelines recommend a multifactorial approach to risk reduction and to treatment selection in patients with AF.

So our hypothesis was that a biomarker-based ABCAF risk or guided multidimensional treatment strategy may improve clinical outcomes as compared to usual guidelines-based care in patients with atrial fibrillation. Very nice. And can you describe for us then, Jonas, your study population and then also your study design?

So we aim for a broad population of adult patients with the diagnosis of atrial fibrillation, newly or previously diagnosed with or without current oral anticoagulant treatment. Of course, we had some exclusion criteria. contraindication to any oral anticoagulant, indication for OAC treatment beyond atrial fibrillation, for instance mechanical heart valve prosthesis, or currently on a treatment with a direct oral anticoagulant.

not eligible or candidate to change to another DOAC. To do this study we realized that we need a high number of patients so we really designed it as a very pragmatic randomized clinical study.

a multi-center study performed in sweden and the idea to do it in sweden is that we have clinical quality reduces disease specific reduces for instance for atrial fibrillation So we used the Swedish atrial fibrillation clinical quality register for facilitated enrollment, of course after written consent from each individual patient.

Baseline characteristics important for AF patients are in a way collected in the registry, so we can use them for a clinical study. So after randomization, blood samples were obtained for routine analysis. and also for biobanking in both study arms, both the active ABCAF arm and the control arm. In the active ABCAF arm, additional blood samples were sent for direct analysis of the specific biomarkers.

in the ABCAF risk score. That is high sensitivity troponin, NT-proBNP, a newer marker called GDF15, but also hemoglobin. And within two working days, The investigator was informed of each individual's ABC AF risk scores for stroke and bleeding, which was also used as a decision support to tailor treatment recommendations, including preference of

type of direct oral anticoagulant. In the control arm, patient management was entirely at the discretion of the investigator and the primary outcome was a composite of stroke or death. and we had secondary outcomes including stroke separately, death separately, and major bleeding events and the triple composite. Of note, we had no physical visits.

All outcome data were retrieved from mandatory national registers covering all hospitalizations in Sweden. So irrespective of where we recruited the patients, we can follow them anywhere in Sweden. Very nice. Maybe just a couple more points of clarification for our listeners. Jonas, could you describe for us what was the age of the participants in the study? And then number two.

How many participants had, for example, paroxysmal atrial fibrillation versus permanent atrial fibrillation? And then lastly... On the A, B, C, A, F score, how does that differ from, say, CHADS-VASc-2 score or has-blood scores? So, thank you. That's great questions, Greg. So, let me start with the ABC AF risk score. The beauty, in my opinion, with the ABC AF risk score is that we use...

age as a continuous variable instead of categorization. And the A stands for age, B stands for biomarkers, which I mentioned before, and those are also continuous variables. and see its clinical history of stroke or bleeding respectively. By that we can have better precision with this risk score. We aimed for 6,500 patients in this study and it was an event-driven study so we needed 1,191 events.

Recruitment was unfortunately terminated prematurely on 12th of May 2023 based on a recommendation from the Data Monitoring Committee due to safety concerns in a subgroup of patients with CHASVASC 3 or higher. At that time, we had recruited 3,933 patients in 39 centers in Sweden. Median age, as you asked, was 74 years. We aimed for higher ages. One-third were females. And to our surprise, 51% of the patients had paroxysmal atrial fibrillation, which was higher than expected.

Not the least, a very high proportion of patients were on oral anticoagulant treatment before anonymization, much higher than expected when we designed the study. And Jonas, now your study results. So...

we stopped the trial then because of the recommendation from the dmc and then we followed the patients for 12 months more after that so after a median 2.6 years uh follow-up We had results that were presented at the EEC Congress in Madrid and simultaneously published in Circulation. And of course, to our disappointment, the individual tailored multidimensional treatment strategy was not associated with any.

improvements in any of the clinical outcomes and the primary outcome the composite of stroke and death occurred only in 323 events in total with a hazard ratio of 1.19 but the confidence rather wide confidence interval and not significantly different compared to between the ABCAF and the control arm. The changes in treatments which we hoped for and by the design were

Rather modest, except for the type of DOAC where the investigator really followed our advices. So in summary, neutral results. And perhaps somewhat surprising. Janas, well, thank you so much. And now, listeners, we're going to turn to our associate editor, Dr. Chorborn Omlin, who really has international expertise on the use of biomarkers.

and how we apply them in patients with cardiovascular disease. And Torborn, you have many articles come across your desk. What attracted you to this particular article? And then... How do we put its results really in the context of other studies for managing patients with atrial fibrillation? Thank you, Greg, for those great questions.

So first of all, there were several reasons that I felt that this was a manuscript that should be published in circulation. I have followed the work by Dr. Holgren and colleagues. And there are studies which provided the rationale for this study for many years back to 2016, I believe, when Dr. Olgren and colleagues first reported the performance of the ABC-AF score for ATRIO.

fibrillation in circulation. And then secondly, a prospective evaluation of the clinical utility of risk scores to guide treatment decisions and improve clinical outcomes in large-scale randomized trials. It's quite rare, and the results of this specific trial, I think, were highly anticipated. Third, as you alluded to, I found the results of the trial surprising and important.

And I also believe that this article would interest circulation readership and would enhance their understanding of why the refined assessment of stroke and bleeding risk with APCAF scores. did not translate into clinical benefit. And finally, when I received the manuscript, I was aware of the results of the trial would be presented at the hotline session at the ESE meeting in Madrid.

And I thought that the simultaneous publication in circulation would likely increase the visibility and also underscore the importance of this impressive piece of work. So concerning your second question, I think the important point is that even though the biomarkers provided a more precise and accurate estimate of risk,

it didn't translate into a clinical benefit, which is interesting and also, in a way, provoking. And I am very interested in hearing Dr. Holgren's interpretation of those results. Very nice. Well, thank you so much, Torborn. And Jonas, we're now turning back to you. What do we do next? What do you see as the next study to be performed in this sphere of research? Thank you for your...

questions. And thank you, Torbjörn, for your comments. So, I mean, it's a disappointing result. It's perhaps not that surprising when we look at the baseline characteristics of the patients. So they were extremely well treated already when entering the study. So almost 93% of the patients were on oral anticoagulants. When we designed the study, 60% of patients in Sweden received proper anticoagulation treatment. So our treatment recommendations were not effective enough.

to make a difference we we know from and and that's shown in the publication that the risk prediction is really good as expected by the abcf risk scores but the contrast with the active treatment recommendations and the standard treatment according to guidelines was too small. Torben alluded to, I think that the utility of all types of risk stratification and precision medicine tools need to be prospectively tested.

before implementation in clinical practice because there are many other studies showing that risk-based treatment does not always or perhaps even seldom translate into better outcomes and Torborn, any closing thoughts? No, I think this is a very important and valuable study. And it's also sort of a reminder to people conducting clinical trials that, you know, we need to go to this important step of testing.

novel clinical decision supports in clinical trials. And as Jonas pointed out, if use of the tool does not translate into a meaningful difference in therapeutic management. it's not likely to result in a clinical benefit to patients. Very nice. Well, listeners, we want to thank Dr. Jonas Ulgrian from Uppsala University in Uppsala, Sweden. and our own associate editor, Dr. Chornborn Omlin from University of Oslo in Oslo, Norway.

for bringing this study highlighting that the individually tailored multidimensional treatment strategy based on ABC-AF risk scores did not improve clinical outcomes as compared with usual guideline-based care in patients with atrial fibrillation. And the results, as both have illustrated to us today, emphasize the need for prospective testing of the utility of risk stratification and precision medicine tools in different clinical settings before implementation of routine care. Well.

On behalf of Petr, Shirin, 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 2025. 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 haajournals.org.