Circulation September 6, 2022 Issue

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.