Unveiling the genetic aetiology of <i>non-genetic</i> dilated cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular dilation and systolic dysfunction in the absence of coronary artery disease or abnormal loading conditions sufficient to cause global systolic impairment. While this condition has been traditionally classified as genetic and non-genetic, there is increasing evidence that the individual genetic background may eventually increase the susceptibility or act as disease modifier in the presence of an external cause for myocardial dilation and dysfunction. Methods: A comprehensive literature search was conducted to identify studies describing cohorts of patients with peripartum cardiomyopathy, alcoholic cardiomyopathy, chemotherapy-induced cardiomyopathy, myocarditis, and DCM associated with systemic immune-mediated diseases who systematically underwent genetic testing. Results: The studies identified showed a high proportion of pathogenic variants in genes associated with cardiomyopathy among patients affected with these conditions. These findings support the emerging 'two-hit' hypothesis, in which the cumulative impact of genetic and environmental risk factors increases the likelihood of developing the disease phenotype. Conclusions: This perspective summarizes the available data on the role of genetics in predisposing individuals to conditions that lead to a DCM phenotype, which were previously considered to be acquired or environmental.