Molecular Etiology and Pathogenesis of Hereditary Cardiomyopathy

Cardiomyopathy is defined as a cardiac disease caused by functional abnormality of cardiac muscle, and the etiology of the functional abnormality includes both extrinsic and intrinsic factors. Cardiomyopathy caused by the intrinsic factors is defined as idiopathic or primary cardiomyopathy, and there are several clinical phenotypes, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The major intrinsic factor is gene mutations, and linkage studies, as well as candidate gene approaches, have deciphered multiple disease genes for hereditary primary cardiomyopathy. Of note is that mutations in the same disease gene can be found in different clinical phenotypes of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical phenotypes, such that increased and decreased Ca(2+) sensitivity because of sarcomere mutations are associated with HCM and DCM, respectively. In addition, recent data have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of the sarcomere (ie, stiff sarcomere and loose sarcomere, respectively). More recently, mutations in the components of the I region can be found in hereditary cardiomyopathy, further complicating the etiology of primary cardiomyopathy.