Umberto Maccio1, Annelies S Zinkernagel2, Srikanth Mairpady Shambat2, Xiankun Zeng3, Gieri Cathomas4, Frank Ruschitzka5, Reto A Schuepbach6, Holger Moch1, Zsuzsanna Varga7. 1. Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zurich, Schmelzbergstrasse 12., Zurich CH-8091, Switzerland. 2. Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zurich, Switzerland. 3. United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States. 4. Reference Pathology for Infectious Diseases, Cantonal Hospital Liestal, Baselland, Switzerland. 5. Department of Cardiology, University Hospital Zurich, University of Zurich, Switzerland. 6. Institute of Intensive Care, University Hospital Zurich, University of Zurich, Switzerland. 7. Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zurich, Schmelzbergstrasse 12., Zurich CH-8091, Switzerland. Electronic address: zsuzsanna.varga@usz.ch.
Abstract
BACKGROUND: SARS-CoV-2 infection (COVID-19 disease) can induce systemic vascular involvement contributing to morbidity and mortality. SARS-CoV-2 targets epithelial and endothelial cells through the ACE2 receptor. The anatomical involvement of the coronary tree is not explored yet. METHODS: Cardiac autopsy tissue of the entire coronary tree (main coronary arteries, epicardial arterioles/venules, epicardial capillaries) and epicardial nerves were analyzed in COVID-19 patients (n = 6). All anatomical regions were immunohistochemically tested for ACE2, TMPRSS2, CD147, CD45, CD3, CD4, CD8, CD68 and IL-6. COVID-19 negative patients with cardiovascular disease (n = 3) and influenza A (n = 6) served as controls. FINDINGS: COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction. INTERPRETATION: ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19. FUNDING: No external funding was necessary for this study.
BACKGROUND:SARS-CoV-2 infection (COVID-19 disease) can induce systemic vascular involvement contributing to morbidity and mortality. SARS-CoV-2 targets epithelial and endothelial cells through the ACE2 receptor. The anatomical involvement of the coronary tree is not explored yet. METHODS: Cardiac autopsy tissue of the entire coronary tree (main coronary arteries, epicardial arterioles/venules, epicardial capillaries) and epicardial nerves were analyzed in COVID-19patients (n = 6). All anatomical regions were immunohistochemically tested for ACE2, TMPRSS2, CD147, CD45, CD3, CD4, CD8, CD68 and IL-6. COVID-19 negative patients with cardiovascular disease (n = 3) and influenza A (n = 6) served as controls. FINDINGS:COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction. INTERPRETATION:ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19. FUNDING: No external funding was necessary for this study.
Authors: Julian U G Wagner; Denisa Bojkova; Jindrich Cinatl; Stefanie Dimmeler; Mariana Shumliakivska; Guillermo Luxán; Luka Nicin; Galip S Aslan; Hendrik Milting; Joshua D Kandler; Andreas Dendorfer; Andreas W Heumueller; Ingrid Fleming; Sofia-Iris Bibli; Tobias Jakobi; Christoph Dieterich; Andreas M Zeiher; Sandra Ciesek Journal: Basic Res Cardiol Date: 2021-07-05 Impact factor: 17.165