TY - JOUR T1 - SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis JF - bioRxiv DO - 10.1101/2020.11.04.364315 SP - 2020.11.04.364315 AU - Adam L. Bailey AU - Oleksandr Dmytrenko AU - Lina Greenberg AU - Andrea L. Bredemeyer AU - Pan Ma AU - Jing Liu AU - Vinay Penna AU - Lulu Lai AU - Emma S. Winkler AU - Sanja Sviben AU - Erin Brooks AU - Ajith P. Nair AU - Kent A. Heck AU - Aniket S. Rali AU - Leo Simpson AU - Mehrdad Saririan AU - Dan Hobohm AU - W. Tom Stump AU - James A. Fitzpatrick AU - Xuping Xie AU - Pei-Yong Shi AU - J. Travis Hinson AU - Weng-Tein Gi AU - Constanze Schmidt AU - Florian Leuschner AU - Chieh-Yu Lin AU - Michael S. Diamond AU - Michael J. Greenberg AU - Kory J. Lavine Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/05/2020.11.04.364315.abstract N2 - Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.Competing Interest StatementKory Lavine - Medtronic: DT-PAS/APOGEE trial advisory board. M.S.D. is a consultant for Inbios, Eli Lilly, Vir Biotechnology, NGM Biopharmaceuticals, and on the Scientific Advisory Board of Moderna. The Lavine laboratory has received funding and unrelated sponsored research agreements from Amgen. The Diamond laboratory has received funding and unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Lina Greenberg, W. Tom Stump, Michael Greenberg, Adam Bailey, Oleksandr Dmytrenko, Andrea Bredemeyer - None. ER -