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Pathologic Link Detected Between COVID-19 and Myocarditis

Key findings

  • A large single-center study and multiple case reports have suggested that COVID-19 can cause myocarditis
  • This new study provides evidence of that link, reporting expression of angiotensin-converting enzyme 2 (ACE2), the receptor for the SARS-CoV-2 virus, in cardiomyocytes
  • ACE2 was upregulated in cardiomyocytes in tissue from patients with heart failure but not in control tissue, suggesting prior cardiovascular disease is a predominant driver of the increased expression of ACE2
  • ACE inhibitor use was not associated with increased ACE2 expression

In March 2020, researchers at Wuhan University in China reported in JAMA Cardiology that of 416 patients hospitalized with COVID-19, 20% had evidence of cardiac injury, which was associated with a fivefold increase in the need for mechanical ventilation and 51% mortality. Ever since, the cardiology community has been reporting cases of myocarditis associated with COVID-19 and debating whether SARS-CoV-2, the virus that causes COVID-19, can damage the heart directly.

Now, Patrick T. Ellinor, MD, PhD, director of the Cardiac Arrhythmia Service in the Corrigan Minehan Heart Center at Massachusetts General Hospital, and colleagues have provided evidence of a link between COVID-19 and myocarditis. In a letter to the editor of Circulation, they report finding angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in cardiomyocytes.

ACE2 Expression

Using heart tissue from a biobank, the researchers conducted bulk and single-nucleus RNA sequencing to measure ACE2 expression on left ventricles from 11 individuals with dilated cardiomyopathy (DCM), 15 individuals with hypertrophic cardiomyopathy (HCM) and 16 controls who did not have heart failure. They found:

  • ACE2 expression was strongest in pericytes, which line the microvasculature, but it was also detectable in vascular smooth muscle cells, fibroblasts and cardiomyocytes
  • Bulk RNA sequencing data showed no significant differences in ACE2 expression in DCM or HCM samples compared with controls
  • In DCM and HCM compared with controls, single-nucleus sequencing showed pronounced downregulation of ACE2 expression in fibroblasts, pericytes and vascular smooth muscle, and concomitant upregulation in cardiomyocytes

Thus, prior cardiovascular disease appears to be a predominant driver of the increased expression of ACE2 in cardiomyocytes.

Expression of Related Genes

The team also studied expression of the TMPRSS2 and CTSL genes, which facilitate membrane fusion and viral uptake during SARS-CoV-2 infection. TMPRSS2 was minimally expressed in myocardial cells, but CTSL was expressed at low levels in all cell types, including cardiomyocytes.

Effect of ACE Inhibitor Use

The researchers examined the effects of ACE inhibitor therapy on ACE2 expression in 14 of the HCM tissue samples (six from patients who had used an ACE inhibitor, eight from patients who had not). With ACE inhibitor use, there was a trend toward increased ACE2 expression in all myocardial cell types, but the differences were not statistically significant.

This preliminary research supports the statements by the American Heart Association, Heart Failure Society of America and American College of Cardiology that patients should continue using ACE inhibitors and angiotensin receptor blockers in the absence of compelling new data. Larger studies are urgently needed, including examination of ACE2 expression in tissue from patients without heart failure who used antihypertensives.

Learn more about the Cardiac Arrhythmia Service at Mass General

Refer a patient to the Corrigan Minehan Heart Center

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