SARS-CoV-2 spike protein-induced inflammation underlies proarrhythmia in COVID-19.

Cardiac manifestations are common in severe COVID-19 with 2% of non-ICU patients and 59% of non-survivors impacted. Per recent CDC data, COVID-19 patients are at 1.7 higher risk of arrhythmia. AF, which is the most common arrhythmia, is a frequent complication of acute and long COVID-19. High cardiac expression of the SARS-CoV2 receptor, ACE2, has led to the assumption that infectious virus likely underlies cardiac complications. However, this remains to be verified. We therefore compared the histologic and molecular findings in human cardiac tissue from fatal COVID-19 cases and age-matched controls. Hematoxylin and eosin (H&E) stains revealed histologic changes including multifocal endothelial cell swelling and degeneration plus microvascular thrombi in COVID-19 cases. qRT-PCR and in situ hybridization (ISH) identified trace amounts of viral nucleocapsid RNA and no nucleocapsid protein in the COVID-19 hearts. However, 7/11 COVID-19 hearts were positive for viral spike protein. Further validation by immunohistochemistry (IHC) revealed viral spike protein in all 11 COVID-19 hearts. Co-expression analysis identified viral spike protein mostly in ACE2+ interstitial macrophages/pericytes that were activated as evidenced by increased IL6 and TNFα expression. Previously, we identified a novel arrhythmia mechanism wherein inflammation-induced vascular endothelial dysfunction triggers cardiomyocyte structural remodeling, particularly of intercalated disc (ID) components including connexin-43 (Cx43) gap junctions and NaV1.5 sodium channels, and thereby promotes arrhythmias. We therefore investigated ID structure in our human samples. Both Cx43 and NaV1.5 showed marked lateral migration in myocytes of COVID-19 hearts, consistent with previous experiments with inflammatory insults in murine hearts. Preliminary results in spike protein-injected mice showed increased arrhythmia burden, as well as structural remodeling and protein migration consistent with human results. These findings suggest that the viral spike protein, and not direct infection by SARS-CoV2, results in the pathophysiology of cardiac dysfunction in fatal COVID-19.