Infiltrating Monocytes Drive Cardiac Dysfunction in a Cardiomyocyte-Restricted Model of SARS-CoV-2 Infection

Cardiovascular manifestations of COVID-19 include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. SARS-CoV-2 RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26LSL-hAce2 mice with SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced myocardial viral replication and macrophage accumulation and suppressed the development of LV systolic dysfunction. These findings establish a mouse of model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both replication and resultant innate immune responses contribute to pathology Overall design: bulk RNAseq of murine hearts at 3 days post inoculation from naïve ctrl mice [MYH6-Cre (-) Rosa-LSL-hACE2 (+/-)], SARS-CoV-2 inoculated ctrl mice [MYH6-Cre (-) Rosa-LSL-hACE2 (+/-)] and SARS-CoV-2 inoculated hACE2-KI mice [MYH6-Cre (+) Rosa-LSL-hACE2 (+/-)]