“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.
“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, which fits the traditional myocarditis criteria, Dr. 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,” Dr. 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 upregulated 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, said in an interview.
“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.”
Dr. 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.