SARS-CoV-2 leads to a small vessel endotheliitis in the heart

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.

Keywords: ACE2-receptor; COVID-19; Coronary arteries; Endothelial dysfunction; Epicardial capillaries; Epicardial nerves; Microangiopathy.

Fig. 1

Summary of immunohistological findings (ACE2, CD68, CD45, CD4, CD3, CD8) in the coronary tree and epicardial nerves in COVID-19 positive and COVID-19 negative control patients. The COVID-19 negative control groups were selected as influenza A positive and a second cohort with cardiovascular diseases.

Fig. 2

Fig. 2a and 2b: Representative immunostains and H&E sections from COVID-19-positive patients. An endotheliitis of small vessels and a neuritis with prevalence of CD4-positive and CD68-positive inflammatory cells are demonstrated along with a strong expression of ACE2 receptor. The red (CD31) stains show endothelial cell, the brown reaction products (all other stains) mark positively stained inflammatory cells. Relevant immunostains (CD68, CD45, CD68, ACE2) show a trend being the highest in the capillaries and venules and less pronounced in the main coronary arteries in a semi-quantitative analysis.

Fig. 3

Fig. 3a and 3b: Representative immunostains and H&E sections from COVID-19-negative control patients with cardiovascular disease. Note the scattered presence of inflammatory cells in the control cohort.

Fig. 4

Fig. 4a and 4b: Representative immunostains and H&E sections from COVID-19-negative control patients with influenza A / viral pneumonia infection. Note the scattered presence of inflammatory cells in the control cohort.

Fig. 5

Lymphocytic inflammation (arrows) of epicardial nerve (a), venule (b) and capillary (c) from a COVID-19-positive patient. Lympho-monocytic cells infiltrate and damaged endothelia of small vessels (endotheliitis). Nerves are infiltrated too, not only in vasa nervorum but also in endonevrium and perineurium. H&E sections.

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.