Myocardial Inflammation and Sudden Death in the Inherited Cardiomyopathies

The best studied of the inherited cardiomyopathies-hypertrophic (HCM), dilated (DCM) and arrhythmogenic (ACM)-present overlapping clinical phenotypes with varying, often unrecognized, risk of sudden death. Risk assessment is informed by patient sex and by the specific disease-causing variant. HCM and arrhythmogenic right ventricular cardiomyopathy (ARVC) remain important causes of sudden death. A phenotype mimicking DCM in patients with inherited ACM is associated with premature sudden death in families with overlapping DCM and ACM phenotypes. The role of inflammation as a determinant of disease development and progression and sudden death is poorly understood but potentially important. Sudden death registries report myocarditis as the cause in 5% to 13%; examination of 30 hearts from victims of ARVC sudden death found focal myocarditis in areas of myocyte necrosis in 20 (67%). The link to specific disease-causing variants remains to be explored, including genetic determinants of the immune response. Clinical and experimental studies support immune- and autoimmune-mediated disease in DCM and ACM. Immunosuppression in biopsy-proven noninfectious myocarditis and inflammatory DCM is a treatment option. Recognition of ACM requires greater focus on distinguishing ACM from DCM. The potential to recognize disease before adverse events and to characterize patients who may benefit from immunosuppression or device therapy highlights the importance of more comprehensive genetic and immunologic characterization of patients with myocarditis and in those with a family history or clinical presentation of an inherited cardiomyopathy. This review will examine from a predominantly clinical perspective the potential importance of myocardial inflammation as a determinant of sudden death in inherited HCM, DCM, and ACM.