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.