Circulation April 12, 2022 Issue

This week, please join author Enrico Ammirati and Guest
Editor Stephane Heymans as they discuss the article "Prevalence,
Characteristics, and Outcomes of COVID-19–Associated Acute
Myocarditis."


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-host. 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. Well,
Carolyn, this week's feature on this April 12, we are going to
review COVID-19–associated acute myocarditis,
looking at the prevalence and the outcomes. But before we get to
that feature discussion, how about we grab a cup of coffee and
discuss some of the other articles in the issue, and maybe there
could be a quiz in there somewhere.


Dr. Carolyn Lam:


Oh, yikes.


 Dr. Greg Hundley:


But before we get to that quiz, Carolyn, would you like to go
first?


Dr. Carolyn Lam:


I would, and we're starting with a topic that we rarely talk
about, it's about neurodevelopmental impairment. We know that
it's common in children with congenital heart disease, yet
postnatal variables explain only 30% of the variance in outcomes.
To explore whether the antecedence for neuro development
disabilities might begin in utero, these authors, led by Dr.
Rollins from Boston Children's Hospital and Harvard Medical
School, analyzed whether fetal brain volume predicted subsequent
neuro development outcome in children with congenital heart
disease. To do this, the authors studied fetuses with isolated
congenital heart disease and social demographically comparable
healthy controlled fetuses, all undergoing fetal brain MRI and
two year neurodevelopmental evaluation.


 Dr. Greg Hundley:


Ah, Carolyn, wonderful, interesting article that we're taking on
here in Circulation. What did this group find?


Dr. Carolyn Lam:


In children with congenital heart disease, a smaller total brain
volume on fetal MRI correlated with worse neurodevelopmental
outcome at two years of age, across all domains of development
and adaptive function. A predictive model, including total brain
volume, along with sociodemographic and medical data, accounted
for up to 45% of the variance in neurodevelopmental outcome
within the congenital heart disease group. Fetal brain volume was
the most consistent predictor of outcomes across
neurodevelopmental domains compared with other sociodemographic
and medical or surgical variables.


 Dr. Greg Hundley:


Very nice, Carolyn. Well, my first paper comes to us from the
world of preclinical science. Okay, Carolyn, we're going to start
it with the infamous Carolyn's quiz. Here we go.


Dr. Carolyn Lam:


Wait a minute, we should put a rule here, no quizzes on
preclinical basic science, especially stuff we can't pronounce.


 Dr. Greg Hundley:


Ah, yes, but seems to me, there's a heart failure expert on the
team. Always remember, you can phone a friend because we have our
wonderful Augie Rivera, our production manager, who is available
and you can call on him at any time. Okay, here's the quiz, is
Cam Kinase II helpful to cure or harmful to exacerbate heart
disease?


Dr. Carolyn Lam:


Oh goodness, Greg. Okay. Cam Kinase II, I know it's
Calcium-calmodulin Kinase II. I know there are different
isoforms, and I'm cheating here a bit because last week we talked
about targeting CaM Kinase II in heart disease. I'm going to
guess harmful, I'm going to guess dealing with something with
calcium overload, but I'm sure there's more to the story.


 Dr. Greg Hundley:


Carolyn, getting onto to the article, cardiac
ischemia-reperfusion injury really has emerged as an important
therapeutic target for ischemic heart disease, the leading cause,
as we know, of morbidity and mortality worldwide. Currently,
there is no effective therapy for reducing ischemia-reperfusion
injury. Calcium II Calmodulin dependent Kinase II, or CaM Kinase
II plays, a pivotal role in the pathogenesis of severe heart
conditions, including ischemia-reperfusion injury. Therefore,
pharmacological inhibition of CaM Kinase II could be an important
strategy in the protection against myocardial damage and cardiac
diseases. But to date, however, there is no drug targeting CaM
Kinase II for the clinical therapy of heart disease. Furthermore,
currently, there is no selective inhibitor of CaM Kinase II
Delta, the major CaM Kinase II isoform, in the heart.


Dr. Carolyn Lam:


Wow. What did the authors do?


 Dr. Greg Hundley:


Okay, Carolyn. A small molecule kinase inhibitor library, and a
high throughput screening system for kinase activity of CaM
Kinase II Delta9, the most abundant CaM Kinase II Delta splice
variant in the human heart, were used to screen for CaM Kinase II
Delta inhibitors. Using cultured neonatal rat ventricular
myocytes and human embryonic stem cell derived cardiomyocytes, as
well as in vivo mouse models, in conjunction with myocardial
injury induced by ischemia-reperfusion or hypoxia-reoxygenation
and CaM Kinase II Delta9 over expression, this team, led by
Professor Yan Zhang, from Peking University, sought to
investigate the protection of Hesperidin against cardiomyocyte
death and cardiac diseases.


Dr. Carolyn Lam:


Oh, wow. Please tell us, so what happened?


 Dr. Greg Hundley:


Right, Carolyn. Several important findings. First, Hesperidin,
the Aurora B kinase inhibitor, with antitumor activity in vitro
directly bound to CaM Kinase II Delta and specifically blocked
its activation in an ATP competitive manner. Second, Carolyn,
functionally, Hesperidin ameliorated both ischemia-reperfusion
and over express CaM Kinase II Delta9 induced cardiomyocyte
death, myocardial damage, and heart failure in both rodents and
human embryonic stem cell derived cardiomyocytes. And then,
finally, Carolyn, in an in vivo BALB/C nude mouse model, with
xenografted tumors of human cancer cells, Hesperidin delayed
tumor growth without inducing cardiomyocyte death or cardiac
injury.


Dr. Carolyn Lam:


Wow. Goodness, Greg, that's impressive. Okay, what's the take
home message?


 Dr. Greg Hundley:


Well, Carolyn, these results suggest that Hesperidin is a
specific small molecule inhibitor of CaM Kinase II Delta with
dual functions of cardioprotective and antitumor effects. These
findings not only suggests that Hesperidin is a promising leading
compound for clinical therapy of cardiac ischemia-reperfusion
injury, and heart failure, but also could provide a strategy for
the joint therapy of cancer and cardiovascular disease caused by
anti-cancer treatment.


Dr. Carolyn Lam:


Wow, Greg, that is an amazing summary. Thank you. Well, for my
last paper, I'd like to tell you about a study in which authors
led by Dr. Lubo Zhang from Loma Linda University in California,
and the colleagues, tested the hypothesis that microRNA-210
protects the heart from myocardial ischemia-reperfusion injury by
controlling mitochondrial bio energetics and reactive oxygen
species flux. Myocardial infarction in an acute setting of
ischemia-reperfusion was examined via comparing loss versus gain
of function experiments in microRNA-210 deficient and wall type
mice.


 Dr. Greg Hundley:


Ah, Carolyn, another really interesting paper from the world of
preclinical science. What were the results here?


Dr. Carolyn Lam:


MicroRNA-210 deficiency induced an ischemic sensitive phenotype
and exaggerated acute myocardial infarction and cardiac
dysfunction after MI in males in a gender dependent pattern in a
murine model of myocardial infarction. The study identified a
novel mechanism of MicroRNA-210 targeting mitochondrial
glycerol-3-phosphate dehydrogenase in controlling mitochondrial
energy metabolism, and reactive oxygen species flux, and
improving cardiac function in the setting of acute
ischemic-reperfusion injury. Thus, the present findings reveal
new insights into the mechanisms and therapeutic targets for
treatment of ischemic heart disease.


 Dr. Greg Hundley:


Oh, beautiful descriptions, Carolyn. Well, my next papers come
from the mail bag, and there is a great Research Letter from
Professor Downing entitled “Critical Illness Among Patients
Hospitalized With Acute COVID-19 With and Without Congenital
Heart Defects.” Carolyn, there's a second Research Letter from
Professor Zhao entitled “Dual Genetic Lineage Tracing Reveals
Capillary to Artery Formation in the Adult Heart.”


Dr. Carolyn Lam:


Nice. There's also an On My Mind paper by Dr. Mintz on
“Prioritizing Quad Therapy and the Path Forward in
Guideline-Directed Medical Therapy for Patients with Heart
Failure with Reduced Ejection Fraction.” Cool, Greg, thank you.
Now, let's go to our feature discussion, shall we?


 Dr. Greg Hundley:


You bet. To learn more about the prevalence and outcomes in
COVID-19–associated acute myocarditis.


Dr. Carolyn Lam:


Acute myocarditis is thought to be a rare cardiovascular
complication of COVID-19, or is it? Well, we have minimal data
available in case reports, but really not a large scale study
until today's issue and today's feature paper, which really aims
to look at the prevalence, baseline characteristics, in hospital
management and outcomes for patients with
COVID-19–associated acute myocarditis.


Dr. Carolyn Lam:


I'm so pleased to have the first author with us, Dr. Enrico
Ammirati from Niguarda Hospital in Milano, Italy, as well as our
guest editor, Dr. Stephane Heymans from Maastricht University
Medical Center in The Netherlands. Welcome, gentlemen. Enrico,
thank you, thank you, thank you for this very important study.
Could you please tell us what you did and what you found?


Dr. Enrico Ammirati:


Carolyn, it's a pleasure to be here with you and Stephane. We
performed, let's say, large study on myocarditis associated with
the COVID-19. That is a multicenter study, including 23 centers
in the United States and in Europe. The senior author is
Professor Marco [Metra], from Brasia, and the co first author is
Dr. Laura Lupi, again, from Brasia. What we have done was to
better characterize the prevalence of in-hospital myocarditis
among the patients hospitalized with the COVID-19 diagnosis.


Dr. Enrico Ammirati:


And then, we tried to describe the outcome and the clinical
characteristic at presentation. First of all, we define the
myocarditis as a definitive or probable. That was based on the
presence of cardiac magnetic resonance imaging consistent with
myocarditis plus increase in troponin plus presence of symptoms
that are compatible with an acute myocarditis. Alternatively, the
patients must have a positive endomyocardial biopsy.


Dr. Enrico Ammirati:


The first result was that among more than 56,000 patients
hospitalized in these hospitals, the rough prevalence of
myocarditis was around 2.4 among 1000 hospitalized patients. The
second main message was that the prognosis, we divided the
population, we spitted the population in two groups. Patients
with an ongoing and concurrent pneumonia and patient with
myocarditis, but without evidence on CT of pneumonia. What we
have found it was that among 57% of cases of COVID patients, you
can have a myocarditis without pneumonia. So this is an
interesting and new finding, and we compare the clinical
characteristic of this patient comparing with the patient with
the pneumonia. And we found that generally patient with pneumonia
were older comparing with the patient with the isolated
myocarditis and the prognosis of patients was worse comparing
with the patient with just myocarditis.


Dr. Enrico Ammirati:


The outcome was around, overall, the outcome of this population
that had median age of 38 year was an incidence of 6% of death.
And if we look at the patient with the concurrent pneumonia, the
outcome was worse. Then we have other findings that are of
potential interest. And that is, for instance, that in 55% of
patients, corticosteroids were used, and that is consistent with
the idea that corticosteroids can work in this setting. We have
also data on the presence of such Coronavirus, two in the heart,
in patient that undergo vital search. And it was just in 21% of
cases that underwent genome research in the myocardium. So I
would say that these are the main findings of this research.


Dr. Carolyn Lam:


Oh, wow. First of all, heartfelt congratulations more than fifth,
almost 57,000 hospitalized patients with COVID-19 and 23
hospitals across us and Europe. Stefan, you really appreciate
that you served as guest editor here. Could you tell us some of
your initial reactions, put the findings in context, perhaps?


Dr. Stephane Heymans:


Yes, yes. For sure. Enrico, indeed, I would like to concur with
this congratulations on this beautiful study. It's a lot of work
to collect this data and also to try to distinguish myocarditis
from all other possible cause of cardiac injury. When I first saw
this data, I think, oh, how difficult should be to make a
diagnosis of myocarditis. And, of course, increased troponins are
often seen in those COVID-19 hospitalized patients. Cardiac MRI
is quite a specific for any non-ischemic myopathy. Yeah, I was
wondering, so are these cardiac MRI images suggestive of acute
myocarditis, but a really specific, sensitive enough to make a
definite accurate diagnosis of COVID 19 related myocarditis, or
could also be severe illness related to COVID-19 sepsis of
pneumonia, give similar images on cardiac MRI?


Dr. Enrico Ammirati:


Stephane, this is a very good point. We haven't studied so in
detail the cardiac injury in patients with the viral pneumonia,
with the other viruses, so we cannot say that this kind of
cardiac involvement is specific for such Coronavirus too. But
what I can say is that this population is a population of highly
likely acute myocarditis because if you look at simple clinical
characteristics, and you can find that the median age is 38
years. This is the first reassuring a clinical characteristic
because if we compare with the age of the population, of the
laboratory registry of acute myocarditis we published in 2018 in
Circulation, the media age was 36.


Dr. Enrico Ammirati:


Then, another point in support of our finding is that in the end,
we have both present of edema and positive LG in patients with
consistent myocarditis on magnetic resonance imaging. So, I know
that probably edema can be associated with either other form of
myocardial injury that are not necessary so specific for
myocarditis. But if you look at troponin increase in this
population, the median increase was 55 folds above the upper
reference limit, so it was not just a small increase. It was a
huge increase in troponin.


 


Dr. Enrico Ammirati:


Specifically, in patients that were above 45 years, we have a
confirmation that was no coronary artery disease associated, to
assure the readers that likely these are myocarditis. But as you
said, we cannot be 100% sure about that. And you mentioned an
important point, we cannot say that, also, in other form of viral
disease, we can have a myocardial injury that can be very similar
to myocarditis.


Dr. Stephane Heymans:


Yes. Thank you so much for your clear answer. It just underscores
how sick a COVID-19 can make you because the numbers you're
getting is two [in] 1000, you would say, okay, that's a small
number, but still, there's so many more patients with a cardiac
injury related to COVID-19. Indeed, to put it into context, so
common viral myocarditis occurs in one to 10, 100,000, so the
COVID-19 related myocarditis is up to 100 times more with your
numbers. And of course, the common viral myocarditis, it's at the
same age, similar age around 36, means a young, relatively young
age.


Dr. Stephane Heymans:


Indeed, this COVID-19 is probably a trigger in immune and maybe
genetic susceptible, young persons had to get myocarditis upon
COVID-19 disease. Whereas, the COVID-19 vaccination related
myocarditis, which is getting much more media attention, at
least, previous months, only occurs in one to five in 100,000
people. And those patients are completely recover and transplant
free. Survival is over 99%. To put it in context, it's still
quite severe at this COVID-19 related myocarditis.


Dr. Carolyn Lam:


Thank you so much. Stephane.


Dr. Enrico Ammirati:


Can I add some comments? First of all, we have to say that these
patients that died with myocarditis associated with the COVID-19,
died to complication related to ECMO. For instance, we had a
patient with a brain hemorrhage, and we had one patient who had a
complication related septic shock. So, myocarditis can be
something on top of a severe disease. We have a condition that is
as background that is quite severe, and we a further complication
related to myocarditis, so what we have seen is that, generally,
even comparing with the previous Lombardy Registry I referred
before the outcome of this patient was worse. Of course, it's
very difficult to compare studies that have been performed in
different centers during a different time period. But, of course,
if you think that most of viral myocarditis are secondary to cold
or flu, so the background condition is really mild.


Dr. Enrico Ammirati:


The main focus is the myocarditis. While in this patient, we have
a subpopulation where you have in a great proportion of them, a
severe myocarditis associated with a pneumonia. So you have the
double component and that can explain why this patient had a
worse outcome. Referring to them, vaccination, my thought is that
for the first time we have a large vaccine campaign in this range
of age, between 15 and 30 years or 35 years, that is the
population at higher risk for myocarditis, where we do not
generally perform large campaign for vaccination.


 


Dr. Enrico Ammirati:


In the end, it can be that we have seen more myocarditis related
to vaccination because it was the first time that we vaccinate
this kind of population. We have seen something similar with a
smallpox vaccination in the military population. And that's the
case because for other reason, that are not really related to the
health reason, we vaccinated a high-risk population for
myocarditis by itself. And we found that smallpox is more
associated with myocarditis. Probably, there are, as you said,
genetics per count that can explain in some patients an increase
risk of myocarditis, but that can be possible that is there is
also hormonal or epigenetics phenomena that can explain the
higher risk in this population for myocarditis, both for COVID
related or for vaccine related.


Dr. Stephane Heymans:


Ah, yeah. Enrico, could you remind me, was this incident of
prevalence of COVID-19 myocarditis more prevalent in male
patients compared to female when correcting for the background
numbers?


Dr. Enrico Ammirati:


In our population, the main population was exactly was about 60%.
There was just a slight increase in the number of cases in the
male population, but it was not such a large prevalence as you
expect in, let's say, uncomplicated myocarditis, where you can
find an 80% of male prevalence or in vaccine.


Dr. Stephane Heymans:


Indeed. In the common or the vaccine related myocarditis, it's
mainly young male, hetero sex, hormonal factors are being
involved, so probably, as you say, these COVID-19 patients have a
change in their immune background. And some of those, might some
of those also have already background cardiomyopathy or
myocarditis, maybe cardiomyopathy, that was not known yet. And
then with the COVID-19 might have developed a clinical
myocarditis/cardiomyopathy.


Dr. Enrico Ammirati:


When we look at the endostolic diameter of the left ventricle, I
can say that the diameter was in the normal range, so that can
support the idea that generate this patient did not have a
previous dilated cardiomyopathy, but I cannot say that this
patient had a known dilated cardiomyopathy before this event.


Dr. Carolyn Lam:


You know, once in a while, Augie, I get to do some of these
interviews, and it just takes off on its own. And I love it. And
there's nothing I need to do except to sit and listen, and to be
grateful that you are publishing this and having such a lovely
discussion on this podcast. Thank you, both of you. And, if I
could, just very quickly, do you have any take home clinical
messages now, from what you've seen, for someone who may be
managing one of these COVID-19 patients and suspecting anything?


Dr. Enrico Ammirati:


Can I add that, in the end, what I can, say based on this
research, is that likely myocarditis associated with COVID-19 is
worse compared with myocarditis associated to vaccine. So even if
we see that probably the prevalence is, again, high year with
COVID-19, but the most important point is that it's even worse
with myocarditis is associated with COVID-19 comparing with the
vaccine, so please get the vaccination.


Dr. Carolyn Lam:


Thank you. And you've been listening to Circulation on the Run.
From Greg and I, thank you for joining us today. I'm sure you're
so grateful, and have learned so much, as I have. And don't
forget to tune in again, next week.


Dr. Greg Hundley:


This program is 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.