Fig. 4

Graphical illustration of Mechanisms of Injury in COVpos Heart Tissue Sections Simplified graphical illustration of mechanisms of injury by SARS-CoV-2 in the heart. Graphic displays the mediators and cells which play a role in this process which predominantly involves cardiac vasculature. Lung infection with SARS-CoV-2 leads to hypoxia and activation of inflammatory cytokine elaboration in the blood of infected patients. Pericytes (P) have the highest concentration of ACE2 receptors in the heart. SARS-CoV-2 can thereby easily infect pericytes. ACE2 receptor downregulation causing accumulation of Angiotensin II promotes generation of cytokines (IL 6, IL 1b, TNF) accelerating inflammation. Toll Receptor (TLR) binding to ligands generated by infection activates intracellular signaling cascades which lead to inflammatory cytokine generation. Activation of endothelial cells (E) generates inflammatory cytokines as well as macrophage inhibitory factor (MIF) that leads to gaps in the vascular basement membrane promoting vascular permeability and extravasation of neutrophils, NETS, platelets, and Fibrin into the interstitium. Neutrophil (N) activation and neutrophil extracellular trap (NETS) generation (through the action of elastase and Peptidylarginine deiminase 4(PAD4) play a pivotal role. They stimulate coagulation and complement activation, creating positive feedback loops between endothelial cells and platelets. Platelets generate nitrous oxide (NO), another potent mediator. Endothelial cells elaborate von Willebrand factor (VWF) which is an important accelerator of coagulation. Cell necrosis caused by the autoinflammatory process exposes cellular and viral antigens that initiate adaptive immunity as well as autoimmunity against myocyte and endothelial antigens with homology to SARS-CoV-2 antigens such as heat shock protein (HSP). Myocyte injury can be initiated by direct infection, ischemia generated by the vascular injury and hypoxia, and by autoimmunity against myocyte antigens. Yellow labels indicate markers used in the study whose roles are highlighted in the diagram