SARS-CoV2 infection of iPSC-derived cardiac cells predicts novel cytopathic features in COVID-19 patients

Mounting clinical evidence indicates severe pathological consequences from COVID-19 in the heart. Here we examine cardiac susceptibility and response to SARS-CoV-2 using human induced pluripotent stem cell-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells. Of these cell types, SARS-CoV-2 can only productively infect cardiomyocytes, and does so via an endolysosomal mechanism. Transcriptomic profiling of infected cells revealed changes in protein homeostasis and cardiomyocyte contractility, and activation of innate immune response pathways. In addition, we observed a striking pattern of myofibrillar fragmentation, with specific cleavage at the M-line. Numerous cardiomyocytes also lacked nuclear DNA in tissue culture experiments and COVID-19 autopsy specimens. These novel cardiac pathologies induced by SARS-CoV-2 strongly motivate the development of targeted cardioprotective strategies to prevent acute and long-term heart failure in COVID-19 patients. Overall design: human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells were infected with SARS-CoV-2 and compared with uninfected cells 48 hours after infection, at several multiplicities of infection.