An immunology model for accelerated coronary atherosclerosis and unexplained sudden death in the COVID-19 era

The immunological basis for cardiac deaths remote from potential triggering viral infection, including SARS-CoV-2 infection, remains enigmatic. Cardiac surface inflammation, including the pericardium, epicardium and superficial myocardium with associated coronary artery vasculitis in infant Kawasaki Disease (KD) and multisystem inflammatory syndrome in children (MIS-C) is well recognised. In this perspective, we review the evidence pointing towards prominent post-viral infection related epicardial inflammation in older subjects, resulting in atherosclerotic plaque destabilisation with seemingly unrelated myocardial infarction that may be temporally distant from the actual infectious triggers. Cardiac surface inflammation in the relatively immune cell rich tissues in the territory though where the coronary arteries traverse is common in the adult post-COVD pneumonic phase and is also well described after vaccination including pre-COVID era vaccinations. Immunologically, the pericardium/epicardium tissue was known to be critical for coronary artery territory atherosclerotic disease prior to the COVID-19 era and may be linked to the involvement of the coronary artery vasa vasorum that physiologically oxygenates the coronary artery walls. We highlight how viral infection or vaccination-associated diffuse epicardial tissue inflammation adjacent to the coronary artery vasa vasorum territory represents a critical unifying concept for seemingly unrelated fatal coronary artery atherosclerotic disease, that could occur soon after or remote from infection or vaccination in adults. Mechanistically, such epicardial inflammation impacting coronary artery vasa vasorum immunity acts as gateways towards the slow destabilisation of pre-existing atherosclerotic plaques, with resultant myocardial infarction and other cardiac pathology. This model offers immunologists and academic cardiologists an immunopathological roadmap between innocuous viral infections or vaccinations and seemingly temporally remote "unrelated" atherosclerotic disease with excess cardiac deaths.