From inflammation to inheritance: rethinking myocarditis as the first signal of desmosomal cardiomyopathy

BACKGROUND: Acute myocarditis has traditionally been regarded as an acquired inflammatory disorder of the myocardium, most commonly triggered by viral infection or immune-mediated injury. However, emerging evidence suggests that in a substantial subset of patients, myocarditis may represent the initial clinical manifestation of an underlying genetic cardiomyopathy rather than a purely inflammatory disease. Recent advances in molecular genetics, cardiac magnetic resonance (CMR) imaging, and translational pathology have highlighted a growing overlap between myocarditis and inherited cardiomyopathies, particularly those associated with desmosomal dysfunction. MAIN BODY: Variants in desmosomal genes-most commonly involving desmoplakin (DSP), plakophilin-2 (PKP2), and desmoglein-2 (DSG2)-have increasingly been reported in patients presenting with myocarditis-like syndromes characterized by chest pain, troponin elevation, and CMR findings fulfilling the Lake Louise criteria. Observational and registry studies suggest that some of these patients subsequently experience recurrent episodes of myocardial injury, ventricular arrhythmias, and progressive fibrotic or fibrofatty myocardial remodeling, eventually developing phenotypic features consistent with arrhythmogenic cardiomyopathy (ACM). ACM is used throughout this review as an inclusive umbrella term encompassing classical arrhythmogenic right ventricular cardiomyopathy (ARVC) as well as biventricular and left-dominant variants. Experimental and translational studies further suggest mechanistic links between desmosomal dysfunction and myocardial inflammation, including DAMP-mediated innate immune activation and the generation of anti-desmoglein-2 (anti-DSG2) autoantibodies. While these observations support a possible role for autoimmunity, the causal contribution of these autoantibodies to myocardial injury and disease progression remains incompletely established and constitutes a proposed rather than confirmed model. CONCLUSION: The emerging relationship between myocarditis and desmosomal cardiomyopathy challenges the traditional distinction between inflammatory and genetic myocardial disease. Integrating genetic testing, advanced CMR imaging, arrhythmic surveillance, and emerging immunological biomarkers may facilitate earlier recognition of genetically mediated cardiomyopathy presenting as myocarditis-like episodes. Further prospective and mechanistic studies are needed to establish causality and evaluate therapeutic implications.