SARS-CoV-2 variants divergently infect and damage cardiomyocytes in vitro and in vivo

SARS-CoV-2 variants are known to exhibit different tropism and pathogenicity in respiratory cells, but their effect on cardiomyocytes (CMs) is unclear. Cardiac infection and damage induced by SARS-CoV-2 variants were examined using human induced pluripotent stem cell-derived (hiPSC-) CMs. Different variants exhibited distinct tropism, mechanism of viral entry and pathology in the heart. Omicron BA.2 efficiently infected CMs in vitro and in vivo, induced the most severe phenotype, and exhibited transcriptomic changes indicative of increased cardiac dysfunction, compared to other variants tested. Bioinformatics analysis identified transcription factors predicted to regulate the unique transcriptome induced by Omicron BA.2. Increased infectivity of Omicron BA.2 is attributed to its ability to infect independently of TMPRSS2, which is absent in CMs. Here we reveal previously unknown differences in how different SARS-CoV-2 variants infect and damage CMs. Omicron BA.2, which is generally considered mild, is capable of inducing severe CM damage in vitro and in vivo. Our study highlights the need for further investigations to define the pathogenesis of cardiac complications arising from different SARS-CoV-2 variants.