Molecular mechanisms of cardiac complications associated with COVID-19.

Abstract

The COVID-19 pandemic has had a devastating global impact, resulting in over 5,000,000 deaths. In the United States alone, over 1,000,000 individuals have died from COVID-19. Cardiovascular complications of COVID-19 include arrhythmias, heart failure, and myocardial infarction and COVID-19 has differentially impacted racial and ethnic groups. Ethnic minority groups, including African Americans and Hispanics, have a higher risk of COVID-19 hospitalization and death, independent of their socioeconomic, lifestyle and health-related factors. Our data indicate substantial proteomic remodeling of cardiac tissues from SARS-CoV-2 infected mice including upregulation of arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy and dilated cardiomyopathy pathways. Markers of collagen deposition were significantly enriched in the COVID-19 group and confirmed by Masson’s trichrome staining in the hearts of SARS-CoV-2 infected mice. Inflammatory cell infiltration, rupture of cardiomyocytes and significantly increased thrombotic events were also observed. Cardiac tissues of COVID-19 patients exhibited oxidative stress, inflammatory and adrenergic signaling, and calcium dyshomeostasis. Furthermore, we have observed posttranslational modifications of cardiac RyR2 calcium release channels from human COVID-19 hearts including increased PKA phosphorylation and oxidation of RyR2 known as the “leaky phenotype” of these channels. These biochemical changes correlated with the cardiomyopathic pathways activation identified by whole cell proteomic analyses in the hACE2 mouse model of COVID-19.