Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis

JACC Review Topic of the Week

Rika Kawakami, MD; Atsushi Sakamoto, MD; Kenji Kawai, MD; Andrea Gianatti, MD; Dario Pellegrini, MD; Ahmed Nasr, MD; Bob Kutys, PA; Liang Guo, PHD; Anne Cornelissen, MD; Masayuki Mori, MD; Yu Sato, MD; Irene Pescetelli, MD; Matteo Brivio, MD; Maria Romero, MD; Giulio Guagliumi, MD; Renu Virmani, MD; Aloke V. Finn, MD


J Am Coll Cardiol. 2021;77(3):314-325. 

In This Article

Pathophysiology of COVID-19–Induced Myocyte Infection/Injury

Acute myocarditis is a disease with variable clinical progression and presentation, making it one of the most challenging diagnoses in cardiology. Several mechanisms are hypothesized to be involved in the pathogenesis of COVID-19–induced myocarditis. To date, there is very little evidence supporting direct destruction of cardiomyocytes through the occurrence of virus-mediated lysis with damage to cardiac structures, resulting in myocyte injury and cardiac dysfunction. The quantification of viral load in 39 consecutive autopsy cases from Germany demonstrated that SARS-CoV-2 could be documented in 24 of 39 (61.5%) hearts with 16 of 39 (41%) having copy numbers higher than 1,000 copies per ug RNA.[6] Virus replication of SARS-CoV-2 defined by detection of the (−) strand replicate of the RNA genome was documented in 5 of the patients with the highest viral load, but in situ hybridization confirmed the virus presence in interstitial cells within cardiac tissue but not in myocytes. Virus presence was not associated with increased infiltration of mononuclear cells into the myocardium, and no myocarditis was present in any of these cases according to the Dallas criteria.

Another potential mechanism of cardiac injury that has been proposed is direct entry of the virus into endothelial cells in the heart without necessarily entering myocytes. Direct endothelial infection has been documented in autopsy hearts as well as in glomerular endothelial cells using electronic microscopy with identification of virus particles, although in some cases their appearance and location within cells was not typical of coronavirus infected cells.[7–9] We believe other techniques such as in situ hybridization should be used to confirm such findings. In our own experience using both techniques, we have not been able to document a single case of endothelial infection by SARS-CoV-2 in the heart. From these data, it seems difficult to conclude that endothelial tropism is a major mechanism of COVID-19–induced cardiac injury without more confirmation.

Another, and perhaps better supported, idea is that cardiac injury can be induced via hyperactivation of the immune system characterized by the release of multiple inflammatory mediators, including interleukins, tumor necrosis factors, and so on. Circulating levels of these factors that exceed normal thresholds can result in collateral damage. The term cytokine storm has been used to describe this condition, which has been reported in severely ill COVID-19 patients.[10] Microvascular and macrovascular thrombi that result from the activation of platelets, neutrophils, and other proteins may contribute to vascular occlusion and cell death.[11] We recently reported a case of myocardial infarction and cardiogenic shock caused by cardiac microvascular thrombosis in a young woman with COVID-19.[12] In this case, the virus was not detectable by polymerase chain reaction (PCR) in the heart. However, the exact pathogenesis of cardiac injury induced by COVID-19 infection remains to be elucidated, but we believe the most compelling evidence points toward cytokine-storm–related effects.