SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis

• Published in: JACC. Basic to translational science Vol. 6; no. 4; pp. 331 - 345
• Main Authors: Bailey, Adam L., Dmytrenko, Oleksandr, Greenberg, Lina, Bredemeyer, Andrea L., Ma, Pan, Liu, Jing, Penna, Vinay, Winkler, Emma S., Sviben, Sanja, Brooks, Erin, Nair, Ajith P., Heck, Kent A., Rali, Aniket S., Simpson, Leo, Saririan, Mehrdad, Hobohm, Dan, Stump, W. Tom, Fitzpatrick, James A., Xie, Xuping, Zhang, Xianwen, Shi, Pei-Yong, Hinson, J. Travis, Gi, Weng-Tein, Schmidt, Constanze, Leuschner, Florian, Lin, Chieh-Yu, Diamond, Michael S., Greenberg, Michael J., Lavine, Kory J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021; Elsevier
• Subjects: cardiomyocyte; Cardiovascular; Clinical Research; coronavirus disease 2019; engineered heart tissue; myocarditis; severe acute respiratory syndrome coronavirus 2; COVID-19; EHT; ACE2; SARS-CoV-2; severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; myocarditis; cardiomyocyte; hPSC; engineered heart tissue; LV; coronavirus disease-2019; human pluripotent stem cell(s); left ventricle; engineered heart tissues; angiotensin converting enzyme 2; severe acute respiratory syndrome-coronavirus-2; ACE2, angiotensin converting enzyme 2; LV, left ventricle; COVID-19, coronavirus disease-2019; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; hPSC, human pluripotent stem cell(s); EHT, engineered heart tissues
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2021.01.002

[Display omitted] •SARS-CoV-2 directly infects cardiomyocytes in patients with COVID-19 myocarditis and does not infect cardiac macrophages, fibroblasts, or endothelial cells.•COVID-19 myocarditis is characterized by a myeloid-rich inflammatory infiltrate.•SARS-CoV-2 infects cardiomyocytes through an ACE2 and endosomal cysteine protease dependent pathway.•Infection of hPSC-derived cardiomyocytes and engineered heart tissues show that cytokine production, sarcomere disassembly, and cell death were a direct consequence of cardiomyocyte infection.•SARS-CoV-2 reduces cardiomyocyte contractility through sarcomere breakdown and cardiomyocyte cell death. There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease.