Acute adenoviral cardiac infection elicits an arrhythmogenic substrate prior to inflammatory myocardial remodeling and myocarditis

Abstract

AbstractViral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a leading cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological host immune responses. However, little is known regarding how viral infection can acutely induce an arrhythmogenic substrate prior to the immune response. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology in the research setting. We have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy. By optical mapping we find decreases in conduction velocity concomitant with increased phosphorylation of Cx43Ser368, a residue known to regulate gap junction channel function. Additional to changes in gap junctions, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreasedIK1andIKscurrent density. Turning to human systems, we find that human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368and disrupts calcium transients synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients, while preceding the pathological remodeling of subsequent myocarditis disease progression.