The knowns and unknowns of cardiac autoimmunity in viral myocarditis

Abstract

Myocarditis can result from various infectious and non‐infectious causes that can lead to dilated cardiomyopathy (DCM) and heart failure. Among the infectious causes, viruses are commonly suspected. But the challenge is our inability to demonstrate infectious viral particles during clinical presentations, partly because by that point, the viruses would have damaged the tissues and be cleared by the immune system. Therefore, viral signatures such as viral nucleic acids and virus‐reactive antibodies may be the only readouts pointing to viruses as potential primary triggers of DCM. Thus, it becomes hard to explain persistent inflammatory infiltrates that might occur in individuals affected with chronic myocarditis/DCM manifesting myocardial dysfunctions. In these circumstances, autoimmunity is suspected, and antibodies to various autoantigens have been demonstrated, suggesting that immune therapies to suppress the autoimmune responses may be necessary. From this perspective, we endeavoured to determine whether or not the known viral causes are associated with development of autoimmune responses to cardiac antigens that include both cardiotropic and non‐cardiotropic viruses. If so, what their nature and significance are in developing chronic myocarditis resulting from viruses as primary triggers.

Autoimmune Myocarditis, Old Dogs and New Tricks

“…7,31 In both scenarios, whether due to tissue damage caused by repeated viral challenges or molecular mimicry between virus and heart antigens, autoreactive immune responses, both humoral and cellular, may induce pathogenic inflammation in lymphocytic myocarditis. 7,9,145 Specifically, coxsackievirus and adenovirus, the 2 most common causes of viral myocarditis, infect cardiomyocytes using the same receptor, CAR (coxsackievirus and adenovirus receptor). 146 Different viruses are known to utilize distinct host molecules for heart entry.…”

“…[6][7][8] Notably, researchers have speculated about immune responses against not only viruses but also heart autoantigens in the pathogenesis of viral myocarditis, suggesting a potential autoimmune mechanism. [9][10][11][12][13][14] Since the 1980s, numerous clinical studies have reported the presence of autoantibodies targeting heart antigens in patients with viral myocarditis, providing evidence of autoimmunity playing a role in this condition. [14][15][16][17][18] Animal studies utilizing a coxsackievirus B3-induced myocarditis mouse model have demonstrated that mice can develop autoimmune inflammation in the heart even after viral clearance.…”

“…19,20 Clinically, the presence of viral genomes in endomyocardial biopsies (EMBs) may not consistently correlate with active infection, implying that autoimmune inflammation triggered by the initial viral exposure could contribute to the development of myocarditis. 9,21 This phenomenon is exemplified by COVID-19-associated myocarditis, where cardiac damage and inflammation are indirectly caused by immune dysregulation. [21][22][23][24] Importantly, cardiac inflammation may persist post-COVID-19 recovery.…”