Abstract 14137: SARS-CoV-2 Spike Protein-Induced Inflammation Underlies Proarrhythmia in COVID-19

Abstract

Cardiac manifestations are common in severe Coronavirus disease 2019 (COVID-19) with rates reported from 2% in non-ICU patients to 59% in non-survivors. Recent CDC data show that 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. It has been reported that the SARS-CoV2 receptor, ACE2, is highly expressed in the heart, leading to the prevalent assumption that infectious virus likely underlies cardiac complications. However, the pathophysiology of cardiac disease in severe COVID-19 has yet to be clarified. 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 in the COVID-19 samples, most notably multifocal endothelial cell swelling and degeneration plus microvascular thrombi. Distribution of SARS-CoV2 RNA and nucleocapsid protein expression was investigated by qRT-PCR and in situ hybridization (ISH). Trace amounts of viral RNA and no nucleocapsid protein were detected in the COVID-19 hearts. However, 7/11 COVID-19 hearts were positive for viral spike protein. Further validation by immunohistochemistry (IHC) showed that viral spike protein was detected in all 11 COVID-19 hearts. Co-expression analysis revealed that viral spike protein localized mostly to the 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 Na V 1.5 sodium channels, and thereby promotes arrhythmias. We therefore investigated ID structure in our human samples. Both Cx43 and Na V 1.5 showed marked lateral migration in myocytes of COVID-19 hearts, consistent with previous experiments with inflammatory insults in murine hearts. 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.