Cardiac SARS-CoV-2 infection is associated with distinct transcriptomic changes within the heart

  1. Diana Lindner
  2. Hanna Bräuninger
  3. Bastian Stoffers
  4. Antonia Fitzek
  5. Kira Meißner
  6. Ganna Aleshcheva
  7. Michaela Schweizer
  8. Jessica Weimann
  9. Björn Rotter
  10. Svenja Warnke
  11. Carolin Edler
  12. Fabian Braun
  13. Kevin Roedl
  14. Katharina Scherschel
  15. Felicitas Escher
  16. Stefan Kluge
  17. Tobias B. Huber
  18. Benjamin Ondruschka
  19. Heinz-Peter-Schultheiss
  20. Paulus Kirchhof
  21. Stefan Blankenberg
  22. Klaus Püschel
  23. Dirk Westermann
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Abstract

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Abstract

Background

Analyses in hospitalized patients and small autopsy series suggest that severe SARS-CoV-2 infection may affect the heart. We investigated heart tissue by in situ hybridization, immunohistochemistry and RNA sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19.

Methods

Left ventricular tissue from 95 deceased with diagnosed SARS-CoV-2 infection undergoing autopsy was analyzed and clinical data were collected. RNA was isolated to examine virus load of SARS- CoV-2 and its replication in the heart. A virus load >1000 copies per µg RNA was defined as relevant. Viral RNA and inflammatory cells were assessed using histology. RNA sequencing and gene ontology (GO) enrichment were performed in 10 cases with high cardiac virus load and 10 age-matched cases without cardiac infection.

Results

A relevant SARS-CoV-2 virus load was detected in 41 out of 95 deceased (43%). The median cardiac virus load was 7952 copies per µg RNA (IQR 2507, 32 005). In situ hybridization revealed SARS- CoV-2 RNA primarily in the interstitium or interstitial cells. Virus detection was not associated with increased inflammatory cells. Relevant cardiac infection was associated with increased expression of the entry factor TMPRSS2. Cardiac virus replication was found in 14/95 hearts (15%). Remarkably, cardiac virus replication was associated with shorter time between diagnosis and death. RNA sequencing revealed clear activation of immune response pathways to virus infection and destruction of cardiomyocytes. Hearts with high virus load showed activation of the GO term “extracellular exosomes”.

Conclusion

SARS-CoV-2 infection including virus replication and distinct transcriptomic alterations without signs of myocarditis demonstrate a cardiac involvement. In this autopsy series, cardiac replication of SARS-CoV-2 was associated with early death.

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