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Cited by 257SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesViral Infections and Immunology Research

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

Open access
Bojkova, Denisa, Wagner, Julian U G, Shumliakivska, Mariana, Aslan, Galip S, Saleem, Umber, Hansen, Arne, Luxán, Guillermo, Günther, Stefan +14 more·2020·Cardiovascular Research
DOI 10.1093/cvr/cvaa267PMC PMC7543363

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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.

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  • Cardiomyocytes and pericytes express ACE2 and TMPRSS2, as well as other accessory proteins needed for viral infection by SARS-CoV-2.

    “Thus, cardiomyocytes and pericytes express ACE2 and TMPRSS2, as well as other accessory proteins (ie, NRP1 [neuropilin-1 receptor], CD147 , integrin α 5 β 1, and cathepsin B/L) needed for viral infection by SARS-CoV-2”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [23]

    Section 3.1 reports ACE2 and cathepsins B/L in human iPSC-derived cardiomyocytes, but finds TMPRSS2 only at very low levels by RNA sequencing and below detection by quantitative RT-PCR. Section 3.4 says these cells essentially lack TMPRSS2. Our copy does not establish the claim about pericytes or the listed NRP1, CD147, and integrin α5β1 proteins. (LLM, conf=0.90)

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Authors
Bojkova, D., Wagner, J. U. G., Shumliakivska, M., Aslan, G. S., Saleem, U., Hansen, A., Luxán, G., Günther, S., Pham, M. D., Krishnan, J., Harter, P. N., Ermel, U. H., Frangakis, A. S., Milting, H., Zeiher, A. M., Klingel, K., Cinatl, J., Dendorfer, A., Eschenhagen, T., Tschöpe, C., Ciesek, S., & Dimmeler, S.
Affiliations
  • Institute of Medical Virology, University of Frankfurt, Paul-Ehrlich-Str. 40, 60590 Frankfurt, Germany
  • Goethe University Frankfurt (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Max Planck Institute for Heart and Lung Research (DE)
  • University Hospital Frankfurt (DE)
  • University Hospitals of the Ruhr-University of Bochum (DE)
  • Universitätsklinikum Tübingen (DE)
  • German Center for Cardiovascular Research (DZHK), Germany
  • Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
Corresponding author
Dimmeler, Stefanie
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2020-09-23
Volume
116
Issue
14
Pages
2207-2215
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
DOI
10.1093/cvr/cvaa267
PMC
PMC7543363
OpenAlex
W3087106210
Cited by
257
References
6
Citations by year
2026: 7 · 2025: 17 · 2024: 40 · 2023: 47 · 2022: 50 · 2021: 84 · 2020: 12
FWCI
6.45
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Cardiovascular Research (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
  • German Center for Cardiovascular Research
  • DZHK
  • Excellence Strategy Program (Exc 2026)
  • German Heart Foundation
  • Pfizer Foundation
  • European Innovation Council (822455)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
Keywords
SARS-CoV-2, COVID-19 pandemic, cardiomyocytes, cardiotoxicity, iPSC-derived cardiomyocytes, cardiomyocyte beating, apoptosis, interferon signaling, ACE2, cathepsins, remdesivir, spike protein, cardiac injury
MeSH terms
Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Adenosine Monophosphate, Alanine, Antiviral Agents, Cathepsins, Heart Diseases, Humans, Signal Transduction, Apoptosis, Reactive Oxygen Species, Caco-2 Cells, Myocytes, Cardiac, Host-Pathogen Interactions

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