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Guidelines for Endothelial Testing

Autopsy findings in fatal COVID vs. fatal influenza: It’s all about endothelial dysfunction.

EBioMedicine 2021 Jan 7;63:103182.
SARS-CoV-2 leads to a small vessel endotheliitis in the heart
Affiliations collapse
Affiliations
  • 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.
Keywords: ACE2-receptor; COVID-19; Coronary arteries;
Endothelial dysfunction; Epicardial capillaries; Epicardial nerves; Microangiopathy.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
Fig. 6. Intramyocardial small vessels in a COVID-19 patient. a) Small vessel endotheliitis with endothelial swelling, denudation, subendothelial lymphocytes and macrophages (arrows). b) ACE2 receptor immunohistochemistry. c) CD4 stain. d) CD68 stain.
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