Cardiac involvement in SARS-CoV-2 infection

C. Gross (Hannover)¹, A. Pavlou (Hannover)², S. Chatterjee (Hannover)³, B. Nilsson-Payant (Hannover)⁴, L. M. Busker (Hannover)², F. Moeselaken (Hannover)⁵, K. Hülskotter (Hannover)⁵, H. Kefalakes (Hannover)⁶, S. Clever (Hannover)⁷, M. von Köckritz-Blickwede (Hannover)⁸, S. Perlman (Iowa)⁹, A. Volz (Hannover)⁷, C. Bär (Hannover)³, W. Baumgärtner (Hannover)⁵, T. Thum (Hannover)³, T. Pietschmann (Hannover)⁴, U. Kalinke (Hannover)², J. Bauersachs (Hannover)¹, G. Amanakis (Hannover)^1
1Medizinische Hochschule Hannover Kardiologie und Angiologie Hannover, Deutschland; ²TWINCORE Centre for Experimental and Clinical Infection Research Institute for Experimental Infection Research Hannover, Deutschland; ³Medizinische Hochschule Hannover Institut für Molekulare und Translationale Therapiestrategien, OE-8886 Hannover, Deutschland; ⁴TWINCORE Centre for Experimental and Clinical Infection Research Institute of Experimental Biology Hannover, Deutschland; ⁵University of Veterinary Medicine Hannover Department of Pathology Hannover, Deutschland; ⁶Medizinische Hochschule Hannover Department of Gastroenterology, Hepatology, Infectious Diseases and Endokrinology Hannover, Deutschland; ⁷University of Veterinary Medicine Hannover Institute of Virology Hannover, Deutschland; ⁸University of Veterinary Medicine Hannover Research Center for Emerging Infections and Zoonoses Hannover, Deutschland; ⁹University of Iowa Department of Microbiology and Immunology Iowa, USA

Cardiac involvement in COVID19, in terms of myocarditis and troponin release, is associated with higher mortality in patients. However, the underlying mechanisms remain poorly understood. Cardiac involvement may be due to a) direct infection of the myocardium by SARS-CoV-2, b) cytokines produced by other organs, or both.

To test hypothesis (a) we infected cardiomyocytes derived from human induced pluripotent stem cells with a wild-type variant (Munich isolate) of SARS-CoV-2. These cardiomyocytes exhibit up-regulated inflammasome activity and necroptosis. Inhibition of either cascade (necrostatin-1 for necroptosis, and MCC950 for the inflammasome) confers protection from the cardiotoxicity induced by SARS-CoV-2. Of note, contrary to other cell types, cyclosporine A, an inhibitor of mitochondrial permeability transition, does not exert a protective effect in this model.

For hypothesis (b) we established an in-vivo mouse model. We hypothesized that, similar to other RNA cardiotropic viruses, the inability to control SARS-CoV-2 infection is caused by defects in type I interferon signaling. We infected wild-type C57BL/6J mice (WT) and mice lacking the type I interferon receptor (IFNAR^-/-) with a mouse-adapted SARS-CoV-2 strain (MA30). Contrary to our hypothesis, IFNAR^-/- mice exhibited a milder progress of the infection, as assessed by clinical scoring and weight loss, and less calcium-induced mitochondrial swelling in cardiac tissue compared to WT mice. To our surprise, immunohistochemistry revealed that the murine myocardium of both WT and IFNAR^-/- mice (in contrast to the lung) was free of SARS-CoV-2.

This is an ongoing study; however, the data obtained so far indicate that cardiac involvement in COVID19 is complex and multifactorial. The direct cardiotoxicity seen in the in-vitro model may be apparent in severe cases where the immune response fails to control the disease. This is in accordance with other studies showing upregulation of the inflammasome in peripheral blood mononuclear cells in patients with severe COVID19 complicated by acute respiratory distress syndrome. The in-vivo data from the present study suggest that milder cases of COVID19 may still exhibit cardiac involvement and mitochondrial dysfunction due to cytokine release from other organs, and that type I interferon signaling has a detrimental effect in controlling the SARS-CoV-2 infection.