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

• Published in: Cardiovascular Research Vol. 116; no. 14; pp. 2207 - 2215
• Main Authors: 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 H, Frangakis, Achilleas S, Milting, Hendrik, Zeiher, Andreas M, Klingel, Karin, Cinatl, Jindrich, Dendorfer, Andreas, Eschenhagen, Thomas, Tschöpe, Carsten, Ciesek, Sandra, Dimmeler, Stefanie
• Format: Journal Article Web Resource
• Language: English
• Published: England Oxford University Press 01.12.2020
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - pharmacology; Angiotensin-Converting Enzyme 2 - metabolism; Antiviral Agents - pharmacology; Apoptosis - drug effects; Caco-2 Cells; Cathepsins - metabolism; COVID-19 - drug therapy; COVID-19 - metabolism; COVID-19 - pathology; COVID-19 - virology; Heart Diseases - drug therapy; Heart Diseases - metabolism; Heart Diseases - pathology; Heart Diseases - virology; Host-Pathogen Interactions; Humans; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myocytes, Cardiac - virology; Reactive Oxygen Species - metabolism; SARS-CoV-2 - drug effects; SARS-CoV-2 - pathogenicity; Signal Transduction; COVID-19; ACE2; SARS-CoV-2; Heart slice; Cardiomyocyte; Cardiosphere
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvaa267

Abstract Aims Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. Methods and results Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it 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 signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. Conclusion This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. Graphical Abstract