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Circulation on the Run


Sep 5, 2022

This week, please join author Keith Channon as he discusses the article "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex."

Dr. Carolyn Lam:

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

Dr. Greg Hundley:

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

Dr. Carolyn Lam:

Oh, Greg, today's feature paper, something that's really been discussed a lot in the press and in lay public as well, the risk of myocarditis following sequential doses of the COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Everyone's going to want to tune into that one. But before we get there, shall we go through some of the key papers in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. How about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

So Carolyn, this first manuscript involves the world of machine learning and ECG interpretation. And as you know, novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy detection; however, it's low prevalence, 0.5%, and resemblance to common diseases really present challenges. So Carolyn, these authors, led by Dr. Rahul Deo from Brigham and Women's Hospital, sought to develop machine learning models to detect hypertrophic cardiomyopathy and differentiate it from other cardiac conditions using EKGs and echocardiograms with a robust generalizability across multiple cohorts.

So Carolyn, what did they do? They used single-institution hypertrophic cardiomyopathy EKG models that were then trained and validated on data from three academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of hypertrophic cardiomyopathy from aortic stenosis, long-standing hypertension, and cardiac amyloidosis. And then finally, automated detection was compared to manual interpretation by three cardiologists on a data set with a realistic hypertrophic cardiomyopathy prevalence.

Dr. Carolyn Lam:

Wow, incredible. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So the authors identified 74,476 EKGs for 56,129 patients and 8,392 echocardiograms for 6,825 patients across the four academic medical centers. Now, while ECG models trained on data from each institution displayed excellent discrimination of hypertrophic cardiomyopathy on internal test data, the generalizability was limited, most notably for a model trained in Japan and then subsequently tested in the United States. Now, however, when trained in a federated manner, discrimination of hypertrophic cardiomyopathy was excellent across all institutions, including for phenotypic subgroups. The models further discriminated hypertrophic cardiomyopathy from hypertension, aortic stenosis, and cardiac amyloid. Analysis of ECG and echocardiography paired data from 11,823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists.

So Carolyn, in conclusion, federated learning improved the generalizability of models that use EKGs and echocardiograms to detect and differentiate hypertrophic cardiomyopathy from other causes of left ventricular hypertrophy compared to training within a single institution. It will be really interesting to see the future applicability of these methods.

Dr. Carolyn Lam:

Oh, I'm such a fan of this work. Awesome. Thank you, Greg. My paper, it's a preclinical paper that uncovers a novel mechanism through which GATA4 mutations can lead to heart disease.

Dr. Greg Hundley:

All right, Carolyn, no quiz this time, I'm just coming right out. I'm reversing the question on the teacher. Tell me, what is GATA4?

Dr. Carolyn Lam:

I'm glad you asked, Greg. GATA4 is a zinc finger-containing DNA binding transcription factor essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Now, in today's paper, authors led by Dr. Srivastava from Gladstone Institutes in San Francisco, California, showed that GATA4 regulated cell-type-specific splicing through direct interaction with RNA and the spliceosome in human-induced pluripotent stem cell-derived cardiac progenitors.

An unbiased search for GATA4 interacting proteins in these human iPS cells revealed interaction with many members of the spliceosome complex. GATA4 also bound to pre-messenger RNAs in a sequence-specific manner that resulted in generation of alternatively spliced isoforms in human iPS cells. Many of these GATA4-dependent isoforms had distinct functional properties illustrating the importance of the splicing regulation to cardiac function.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the world of preclinical science. So what's the take home message here?

Dr. Carolyn Lam:

So these results essentially uncover a previously unrecognized function for GATA4 in regulating alternative splicing through direct RNA interaction. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, thus suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Dr. Greg Hundley:

Very nice, Carolyn, wow. Well, my next paper comes to us from back in the world of clinical science and it's from Professor Bertrand Cariou from L'institut du Thorax in Inserm UMR1087. So Carolyn, only a few genes causally related to plasma LDL-C levels have been identified so far, and only one, ANGPTL3, has been causally related to combined hypocholesterolemia. In this study, the authors aim to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in four generations of a French family and used next generation sequencing and identified a novel dominant rare variant in the LIPC gene encoding for hepatic lipase, which co-segregates with the phenotype. They characterize the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance based lipoprotein profiling and lipids.

Dr. Carolyn Lam:

Wow, what an interesting approach to study patients and families with hypocholesterolemia for once instead of hyper. Interesting. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the investigative team found that this unique LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase without affecting triglyceride lipase activity. And second, the hypocholesterolemic phenotype related to LIPC-E97G variant is due to an increased clearance of cholesterol within triglyceride-rich lipoprotein remnants predominantly by extrahepatic tissues.

Dr. Carolyn Lam:

Wow, so what are the implications?

Dr. Greg Hundley:

Right, Carolyn. So the novel gain of function variant in LIPC potentially represents the second cause of familial combined hypocholesterolemia after loss of function variants in ANGPTL3. And second, this study highlights an unexpected and critical role of the phospholipase activity of hepatic lipase encoded by LIPC in LDL-C metabolism and identifies it as a potential novel drug target. And then finally, Carolyn, additional data, I think, are warranted to clarify the impact of LIPC-E97G-related combined hypocholesterolemia on atherosclerosis and atherosclerotic cardiovascular disease due to the occurrence of documented coronary stenosis and evolutive carotid atherosclerosis in index cases.

Dr. Carolyn Lam:

Oh, very, very interesting. Thanks, Greg. Well, let's wrap up with the discussion of what else is in today's issue. There's an In Depth paper by Dr. Hadley on protecting cardiovascular health from wildfire smoke. There's also a Research Letter by Dr. Mevorach on myocarditis after BNT162b2 COVID-19 third booster vaccine in Israel.

Dr. Greg Hundley:

Right, Carolyn. And then I've got an exchange of letters from Professors Condello and Doenst regarding the article Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis from the REMOVE study: Results From a Multicenter Randomized Controlled Trial. Well, how about we get on to that feature discussion and learn a little bit more about COVID-19 vaccine and SARS-CoV-2 infection.

Dr. Carolyn Lam:

Let's go, Greg, thanks.

Dr. Greg Hundley:

Listeners, welcome to this September 6th feature discussion. And with us today, very interesting topic pertaining to vaccination for SARS-CoV-2 virus prevention. And we have with us Dr. Keith Channon from Oxford, England, to discuss this very interesting paper.

Well, Keith, welcome. I wanted to start by asking you, can you describe for us a little the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Keith Channon:

Thanks, Greg, for the opportunity to join you in this interesting conversation today. A group of cardiologists in the UK based at the University of Oxford, and principally at the University of Edinburgh, have been interested in the question as to whether COVID infection and/or COVID vaccination might lead to a higher incidence of myocarditis. And this is a topic that has been the subject of previous publications in the field.

And the provocation for us undertaking this study is that those previous studies have tended to be relatively small, and they've also not been able to necessarily test the details, time association, between myocarditis occurring in relation to sequential doses of vaccination. And that's important because, of course, we're now all receiving sequential doses of booster vaccines, and also those vaccines are often delivered, different vaccine types to different people in different countries. So we wanted to test whether there does appear to be a significant association between the occurrence of myocarditis and both COVID infection and the sequential different COVID vaccinations.

Dr. Greg Hundley:

Very nice. So Keith, can you describe for us, what study population did you enroll for this initiative? And then also, what was your study design?

Dr. Keith Channon:

Thank you. So, one of the really exciting things about this type of study and probably what makes it unique is that in countries with healthcare system, like that in the UK, which is the National Health Service, and universities, such as the University of Oxford and the University of Edinburgh, where there are very strong academic links between researchers and the National Health Service, we've been able to leverage an enormous data set, which is almost 43 million people in the UK who underwent vaccination against COVID-19. And rather than having to follow up 43 million people as part of a research study, we were able to take advantage of National Health Service centralized coded hospital records, number one. Number two, we took advantage of the UK's national database on COVID vaccination. And number three, we were able to look at hospital outcomes and also COVID testing.

So we were able to put together those three data sets for us to understand who developed COVID infection, who received COVID vaccination, and if so, which vaccine and when, and who then was admitted to hospital with a coded diagnosis of myocarditis. And in 43 million people, even though myocarditis is a very uncommon outcome, there were sufficient cases in that very large population to draw statistically meaningful conclusions.

I think that the UK is probably one of the few countries where this type of research can be done. And academic organizations, like our universities, the National Health Service, and also cardiovascular research funders, such as the British Heart Foundation, have put in a lot of resource and effort into giving us those capabilities to answer questions like this, and it's turned out to be a very powerful capability.

Dr. Greg Hundley:

Very nice. And so Keith, can you describe for us your study results?

Dr. Keith Channon:

So the study looked at a large 43 million people approximately over a period of time during the early to mid-phase of the COVID pandemic and looked at the likelihood that people would be diagnosed with myocarditis following either vaccination or COVID test positive. And we compared that likelihood with the likelihood of myocarditis occurring outside of those periods; because, of course, myocarditis occurs reasonably commonly in the general population. So this is another powerful aspect of the study design. It has a curated approach to look at the incidence of myocarditis in the 28 days after either vaccination or COVID infection, and it corrects, or it controls for that relative to the incidence of myocarditis outside of those sampling periods.

And what we found simply is that there is indeed, as previous studies have shown, a small but significant association between receiving a COVID-19 vaccine and being diagnosed with myocarditis in the following 28 days. However, in the population as a whole, the risk of myocarditis after vaccination is substantially lower than the risk of developing myocarditis after COVID infection, and I think that's an important finding. When we looked at subgroups, which is interesting, we found that the highest risk of developing myocarditis was in men less than age 40, so younger men, and that was one finding. And also, there did seem to be some differences in the risk of myocarditis occurring after different sequential vaccine doses.

Dr. Greg Hundley:

Keith, just a quick clarification point, what vaccines did you examine?

Dr. Keith Channon:

So in the UK, the three vaccines that have been largely used of the AstraZeneca Oxford viral vaccine, ChAdOx1, which was of course introduced very early in the UK, along with the Pfizer mRNA vaccine, and then laterally, Moderna vaccine, which of course in the UK was brought in rather later. And I think that's interesting because, as we can go on and discuss, there do appear to be some possible differences between those vaccines in terms of the likelihood of being diagnosed with myocarditis afterwards. But of course, even our experiment in 43 million people is not a perfect design because it's an observational study, and the periods in the pandemic when people were receiving principally the first two vaccines, which were by far the most numerous, was a different period in the natural history of the pandemic than when we started administering Moderna.

So it is important to recognize that it was not a prospectively controlled randomized trial of different vaccines; it was an observational study of pretty much a whole country and how it responded to the implementation of those different vaccines, which were all given to different people at different times of the pandemic. And of course, different times of the pandemic means that many different people will have already had a COVID infection and then gone on to have a booster or third vaccination. So, if you like, the immunological landscape in which these different vaccines were given in this very large population will have been different.

Dr. Greg Hundley:

Right. So I understand there are differences in timing, great point, but did you see any differences in the occurrence of myocarditis relative to either of the mRNA vaccines versus the adenovirus vaccine?

Dr. Keith Channon:

Yeah, we did. What we found is that, interestingly, there did appear to be a higher likelihood of being diagnosed with myocarditis in the 28 days after the mRNA-1273 vaccine, Moderna vaccine, and that was particularly, as I've already said, in men younger than the age of 40 years. I should say again, of course, that vaccine was given to the smallest number of people in the UK and it also tended to be rolled out later, so it was the second or third dose of the vaccine where that signal was most seen. But again, the second and third dose was by definition typically the booster vaccine later on in the pandemic. But that's what we found.

We did find these interesting differences. The incidence of myocarditis was increased after all of the vaccine doses compared with the period when people had not received a vaccine, but this was a very modest increase for most of the vaccines; but for the mRNA vaccines, particularly Moderna, it seemed to be more strikingly increased in the 28 days after the second or third dose of the vaccine. So I guess the message from that result is that there do seem to be these intriguing differences, both in the response to different COVID vaccines, either viral or mRNA or indeed even different types of mRNA vaccine, and possibly after the different dose of vaccines. In other words, after second or third sequential doses.

Dr. Greg Hundley:

And Keith, you mentioned a few minutes ago that you also had an opportunity to examine situations where maybe a patient had a vaccine and then subsequently contracted COVID, or vice versa, maybe they had had COVID and then later on had a vaccine, did you find any differences in the incidence of myocarditis in those situations as opposed to, perhaps, patients that really never had a documented episode of a COVID infection and then always had received the two vaccines and the booster dose?

Dr. Keith Channon:

Yeah, that's a harder question and is less powerfully addressed by our study, even though we were able to temporally control for that. Previous COVID infection did not preclude the risk of myocarditis after subsequent vaccine doses, but it wasn't a big enough signal to be able to give much detail over the relative risk between... Because if you think of the permutations of COVID infection plus or minus three vaccines, there's a lot of different sequential steps there, but having had COVID first doesn't prevent this small but significant signal; having a vaccine before you then get COVID infection does reduce your risk of myocarditis along with pretty much all other COVID complications.

So I think that's a really important public health message here and indeed the overarching finding of our study, which you could argue is the least exciting one but perhaps the most important, which is that you have a higher likelihood of suffering with myocarditis after COVID infection compared with after a COVID vaccination. And if you have COVID vaccination, in general, your risk of myocarditis is lower, obviously your risk of COVID infection is lower, and your risk of getting myocarditis after that COVID infection, should you still get one is also lower. So I think these are very intriguing, interesting findings that might make us think about mechanism and vaccine policy, but ultimately there are very strong endorsement of getting vaccinated to prevent the consequences of COVID-19.

Dr. Greg Hundley:

Excellent point. And then, Keith, just quickly, next study that maybe your group is considering in this space with this large database?

Dr. Keith Channon:

Yes. Well, I think there are two aspects to the study. Our group, which, as I've said, focuses mainly on large epidemiological data sets, having established this infrastructure in the UK led by universities like Oxford and Edinburgh and funded by the British Heart Foundation and others, means that we now have this infrastructure. So the surveillance and the data collection and the analysis is ongoing and we'll be able to add more cases and more power and more data, and there will be other studies that we can look at.

Second, I think there are some really quite interesting mechanistic studies that could be done based on these provocative findings to try to understand which different types of vaccines and, indeed, the immune responses which those vaccines generate. How are they linked to myocarditis and, indeed, to other cardiac and even other organ complications from COVID-19? And there are ongoing studies in the UK and elsewhere in the world that are very much focused on looking at the organ-specific consequences of COVID infection in patients who've been vaccinated or not. For example, using detailed cardiac MRI to look at the heart and look for subclinical myocarditis and to correlate any evidence of subclinical myocarditis with the immune signature, both the antibody and the cellular immune response, in the blood from those patients.

So I think what we're going to see here are enormous epidemiological studies with n=43 million, and we're also going to see more mechanistic experimental medicine immunology studies to try and tease out mechanism, and I think to understand two things. One is how to protect ourselves best against COVID-19, and what are the best vaccines and how best to use them. And second, if we can learn something about the mechanisms of myocarditis along the way, that's a really useful bonus that's come out of this pandemic.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Keith Channon for bringing us this very interesting article from Great Britain highlighting that, overall, the risk of myocarditis is greater following SARS-CoV-2 infection as opposed to a COVID-19 vaccination, and even really remains modest following sequential doses, including the booster dose of some of the mRNA vaccines.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is a copyright of the American Heart Association 2022. 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.