SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

Bojkova, Denisa; Wagner, Julian U. G.; Shumliakivska, Mariana; Aslan, Galip S.; Saleem, Umber; Hansen, Arne; Luxán, Guillermo; Günther, Stefan; Pham, Minh Duc; Krishnan, Jaya; Harter, Patrick N.; Ermel, Utz; Frangakis, Achilleas; Zeiher, Andreas M.; Milting, Hendrik; Cinatl, Jindrich; Dendorfer, Andreas; Eschenhagen, Thomas; Ciesek, Sandra; Dimmeler, Stefanie

Background The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality in COVID-19 patients. It is unclear whether cardiac injury may have been caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here we investigate whether human cardiomyocytes are permissive for SARS-CoV-2 infection. Methods Infection was induced by two strains of SARS-CoV-2 (FFM1 and FFM2) in human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CM) and in two models of human cardiac tissue. Results We show that SARS-CoV-2 infects hiPS-CM as demonstrated by detection of intracellular double strand viral RNA and viral spike glycoprotein protein expression. Increasing concentrations of virus RNA are detected in supernatants of infected cardiomyocytes, which induced infections in CaCo-2 cell lines documenting productive infections. SARS-COV-2 infection induced cytotoxic and pro-apoptotic effects and abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a iPS-derived human 3D cardiosphere tissue models. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Conclusions The demonstration that cardiomyocytes are permissive for SARS-CoV-2 infection in vitro warrants the further in depth monitoring of cardiotoxic effects in COVID-19 patients. Clinical Perspective What is New? This study demonstrates that human cardiac myocytes are permissive for SARS-CoV-2 infection. The study documents that SARS-CoV-2 undergoes a full replicatory circle and induces a cytotoxic response in cardiomyocytes. Infection was confirmed in two cardiac tissue models, including living human heart slices. What are the Clinical Implications? The study may provide a rational to explain part of the cardiotoxicity observed in COVID-19 patients The demonstration of direct cardiotoxicity induced by SARS-CoV-2 warrants an in depth further analysis of cardiac tissue of COVID-19 patients and a close monitoring for putative direct cardiomyocyte injury. The established models can be used to test novel therapeutic approaches targeting COVID-19.