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The COVID-19 literature has been peppered with reports about myocarditis accompanying the disease. If true, this could, in part, explain some of the observed cardiac injury and arrhythmias in seriously ill patients, but also have implications for prognosis.
But endomyocardial biopsies and autopsies, the gold-standard confirmation tests, have been few and far between. That has led some cardiologists to question the true rate of myocarditis with SARS-CoV-2, or even if there is definitive proof the virus causes myocarditis.
Predictors of death in COVID-19 are older age, cardiovascular comorbidities, and elevated troponin or NT-proBNP — none of which actually fit well with the epidemiology of myocarditis due to other causes, Alida L.P. Caforio, MD, Padua University, Padua, Italy, told theheart.org | Medscape Cardiology. Myocarditis is traditionally a disease of the young, and most cases are immune-mediated and do not release troponin.
Moreover, myocarditis is a diagnosis of exclusion. For it to be made with any certainty requires proof, by biopsy or autopsy, of inflammatory infiltrates within the myocardium with myocyte necrosis not typical of myocardial infarction, said Caforio, who chaired the European Society of Cardiology’s writing committee for its 2013 position statement on myocardial and pericardial diseases.
“We have one biopsy-proven case, and in this case there were no viruses in the myocardium, including COVID-19,” she said. “There’s no proof that we have COVID-19 causing myocarditis because it has not been found in the cardiomyocytes.”
Other case reports include cardiac magnetic resonance (CMR) findings typical of acute myocarditis in a man with no lung involvement or fever but a massive troponin spike; and myocarditis presenting as reverse Takotsubo syndrome in a woman undergoing CMR and endomyocardial biopsy.
A CMR analysis in May said acute myocarditis, by 2018 Lake Louise Criteria, was present in eight of 10 patients with “myocarditis-like syndrome,” and a study just out June 30 said the coronavirus can infect heart cells in a lab dish.
Among the few autopsy series, a preprint on 12 COVID-19 patients in the Seattle area showed coronavirus in the heart tissue of one patient.
“It was a low level, so there’s the possibility that it could be viremia, but the fact we do see actual cardiomyocyte injury associated with inflammation, that’s a myocarditis pattern. So it could be related to the SARS-CoV-2 virus,” said Desiree Marshall, MD, director of autopsy and after-death services, University of Washington Medical Center, Seattle.
The “waters are a little bit muddy,” however, as the patient had a coinfection clinically with influenza and methicillin-susceptible Staphylococcus aureus, which raises the specter that influenza could also have coTntributed, she said.
Data pending publication from two additional patients show no coronavirus in the heart. Acute respiratory distress syndrome pathology was common in all patients, but there was no evidence of vascular inflammation, such as endotheliitis, Marshall said.
SARS-CoV-2 cell entry depends on the angiotensin-converting-enzyme 2 (ACE2) receptor, which is widely expressed in the heart and on endothelial cells and is linked to inflammatory activation. Autopsy data from three COVID-19 patients showed endothelial cell infection in the heart and diffuse endothelial inflammation, but no sign of lymphocytic myocarditis.
“There are some experts who believe we’re likely still dealing with myocarditis but with atypical features, while others suggest there is no myocarditis by strict classic criteria,” said Peter Liu, MD, chief scientific officer/vice president of research, University of Ottawa Heart Institute, Canada.
“I don’t think either extreme is accurate,” he said. “The truth is likely somewhere in between, with evidence of both cardiac injury and inflammation. But nothing in COVID-19, as we know today, is classic; it’s a new disease, so we need to be more open minded as new data emerge.”
Part of the divide may indeed stem from the way myocarditis is defined. “Based on traditional Dallas criteria, classic myocarditis requires evidence of myocyte necrosis, which we have, but also inflammatory cell infiltrate, which we don’t consistently have,” he said. “But on the other hand, there is evidence of inflammation-induced cardiac damage, often aggregated around blood vessels.”
The situation is evolving in recent days, and new data under review demonstrated inflammatory infiltrates, fitting the traditional myocarditis criteria, Liu noted. Yet the viral etiology for the inflammation is still elusive in definitive proof.
In traditional myocarditis, there is an abundance of lymphocytes and foci of inflammation in the myocardium, but COVID-19 is very unusual, in that these lymphocytes are not as exuberant, he said. Lymphopenia or low lymphocyte counts occur in up to 80% of patients. Also, older patients, who initially made up the bulk of the severe COVID-19 cases, are less T-lymphocyte responsive.
“So the lower your lymphocyte count, the worse your outcome is going to be and the more likely you’re going to get cytokine storm,” Liu said. “And that may be the reason the suspected myocarditis in COVID-19 is atypical, because the lymphocytes, in fact, are being suppressed and there is instead more vasculitis.”
Recent data from myocardial gene expression analysis showed that the viral receptor ACE2 is present in the myocardium, and can be up-regulated in conditions such as heart failure, he said. However, the highest ACE2 expression is found in pericytes around blood vessels, not myocytes. “This may explain the preferential vascular involvement often observed.”
Cardiac Damage in the Young
Evidence started evolving in early April that young COVID-19 patients without lung disease, generally in their 20s and 30s, can have very high troponin peaks and a form of cardiac damage that does not appear to be related to sepsis, systemic shock, or cytokine storm.
“That’s the group that I do think has some myocarditis, but it’s different. It’s not lymphocytic myocarditis, like enteroviral myocarditis,” Leslie T. Cooper Jr., MD, a myocarditis expert at Mayo Clinic, Jacksonville, Florida, told theheart.org | Medscape Cardiology.
“The data to date suggest that most SARS cardiac injury is related to stress or high circulating cytokine levels. However, myocarditis probably does affect some patients, he added. “The few published cases suggest a role for macrophages or endothelial cells, which could affect cardiac myocyte function. This type of injury could cause the ST-segment elevation MI-like patterns we have seen in young people with normal epicardial coronary arteries.”
Cooper, who coauthored a report on the management of COVID-19 cardiovascular syndrome, pointed out that it’s been hard for researchers to isolate genome from autopsy samples because of RNA degradation prior to autopsy and the use of formalin fixation for tissues prior to RNA extraction.
“Most labs are not doing next-generation sequencing and, even with that, RNA protection and fresh tissue may be required to detect viral genome,” he said.
No Proven Therapy
Although up to 50% of acute myocarditis cases undergo spontaneous healing, recognition and multidisciplinary management of clinically suspected myocarditis is important. The optimal treatment remains unclear.
In a related commentary, Caforio and colleagues pointed out that the World Health Organization considers the use of IV corticosteroids controversial, even in pneumonia due to COVID-19, because it may reduce viral clearance and increase sepsis risk. Intravenous immunoglobulin is also questionable because there is no IgG response to COVID-19 in the plasma donors’ pool.
“Immunosuppression should be reserved for only virus-negative non-COVID myocarditis,” Caforio said in an interview. “There is no appropriate treatment nowadays for clinically suspected COVID-19 myocarditis. There is no proven therapy for COVID-19, even less for COVID-19 myocarditis.”
Although definitive publication of the RECOVERY trial is still pending, the benefits of dexamethasone — a steroid that works predominantly through its anti-inflammatory effects — appear to be in the sickest patients, such as those requiring ICU admission or respiratory support.
“Many of the same patients would have systemic inflammation and would have also shown elevated cardiac biomarkers,” Liu observed. “Therefore, it is conceivable that a subset who had cardiac inflammation also benefited from the treatment. Further data, possibly through subgroup analysis and eventually meta-analysis, may help us to understand if dexamethasone also benefited patients with dominant cardiac injury.”
Caforio, Marshall, Liu, and Cooper reported having no relevant conflicts of interest.