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

Adam L Bailey; Oleksandr Dmytrenko; Lina Greenberg; Andrea L Bredemeyer; Pan Ma; Jing Liu; Vinay Penna; Emma S Winkler; Sanja Sviben; Erin Brooks; Ajith P Nair; Kent A Heck; Aniket S Rali; Leo Simpson; Mehrdad Saririan; Dan Hobohm; W Tom Stump; James A Fitzpatrick; Xuping Xie; Xianwen Zhang; Pei-Yong Shi; J Travis Hinson; Weng-Tein Gi; Constanze Schmidt; Florian Leuschner; Chieh-Yu Lin; Michael S Diamond; Michael J Greenberg; Kory J Lavine

doi:10.1016/j.jacbts.2021.01.002

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

JACC Basic Transl Sci. 2021 Apr;6(4):331-345. doi: 10.1016/j.jacbts.2021.01.002. Epub 2021 Feb 26.

Authors

Adam L Bailey¹, Oleksandr Dmytrenko², Lina Greenberg³, Andrea L Bredemeyer², Pan Ma², Jing Liu², Vinay Penna², Emma S Winkler¹, Sanja Sviben⁴, Erin Brooks⁵, Ajith P Nair⁶, Kent A Heck⁷, Aniket S Rali⁸, Leo Simpson⁶, Mehrdad Saririan⁹, Dan Hobohm⁹, W Tom Stump³, James A Fitzpatrick^{4

10}, Xuping Xie¹¹, Xianwen Zhang¹¹, Pei-Yong Shi¹¹, J Travis Hinson^{12

13}, Weng-Tein Gi¹⁴, Constanze Schmidt¹⁴, Florian Leuschner¹⁴, Chieh-Yu Lin¹, Michael S Diamond^{1

2

15}, Michael J Greenberg³, Kory J Lavine^{1

2

16}

Affiliations

¹ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
² Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
³ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, Missouri, USA.
⁵ Department of Pathology & Laboratory Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA.
⁶ Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
⁷ Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.
⁸ Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
⁹ Valleywise Health/Creighton University, Phoenix, Arizona, USA.
¹⁰ Departments of Neuroscience, Cell Biology & Physiology, and Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri, USA.
¹¹ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
¹² Departments of Cardiology, Genetics and Genome Sciences, UConn Health, Farmington, Connecticut, USA.
¹³ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
¹⁴ Department of Internal Medicine III, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
¹⁵ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

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.

Keywords: ACE2, angiotensin converting enzyme 2; COVID-19, coronavirus disease-2019; EHT, engineered heart tissues; LV, left ventricle; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; cardiomyocyte; coronavirus disease 2019; engineered heart tissue; hPSC, human pluripotent stem cell(s); myocarditis; severe acute respiratory syndrome coronavirus 2.

Abstract

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