Evidence of Autoinflammation as the Principal Mechanism of Myocardial Injury in SARS-CoV-2 PCR-Positive Autopsy Hearts

Abstract

Background Disease from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains the third leading cause of death in the United States, after cancer and heart disease. Many patients infected with this virus develop cardiovascular complications including myocardial infarctions, stroke, arrhythmia, heart failure, and sudden cardiac death. Specifically, patients with SARS-CoV-2 have a high prevalence of severe myocardial injury (20–28%). The purpose of this study is to understand the primary mechanism of myocyte injury in patients infected with SARS-CoV-2. Methods We investigated a consecutive cohort of 84 medical examiner cases who died with PCR-positive SARS-CoV-2 (COVpos) infection prior to availability of therapy or vaccines. We compared them to a consecutive cohort of 42 age- and sex-matched controls who were PCR-negative for SARS-CoV-2 (COVneg). Formalin-fixed paraffin embedded sections of left and right ventricle were examined on each case using antibodies directed against CD42 (platelets), CD15 (myeloid cells), CD68 (monocytes), C4d, Fibrin, CD34 (stem cell antigen), CD56 (natural killer cells), and Myeloperoxidase (MPO) (neutrophils and NETs). Slides were scanned using an Aperio slide scanner and viewer and each digital slide was entirely examined at 5x,10x and 20x. Each slide was graded using a 0–3 scale where 3 indicates the marker was present in every field at 20x. We used a Welch 2-sample T-test to determine significance. Results We found a significant difference between COVpos and COVneg samples for all markers, all of which were significant at p < 0.001. The most prominent features were neutrophils (CD15, MPO) and MPO positive debris suggestive of NETS and were located in or around arterioles, venules, and capillaries. A similar distribution of platelets, monocytes, and C4d was seen in COVpos cases. Fibrin was found scattered in arterioles, venules, interstitial regions, and within ventricular cavities. CD34 highlighted vascular alterations of endothelial cells in some but not all cases. Conclusion Autoinflammation is the primary mechanism of myocyte injury observed in COVpos hearts. The significant increase in platelets, monocytes, and neutrophils and the presence of neutrophil NETs, C4d, and fibrin suggest that myocardial injury involves neutrophils, NETosis, coagulation, complement activation, and monocyte accumulation.