MOLECULAR MECHANISMS OF INHERITED CARDIOMYOPATHIES

Diane Fatkin, Robert M. Graham, Victor Chang Cardiac Research Institute, Darlinghurst, NSW.

Cardiomyopathies are diseases of heart muscle that may result from a diverse array of conditions that damage the heart and other organs and impair myocardial function, including infection, ischemia, and toxins. However, they may also occur as primary diseases restricted to striated muscle. Over the past decade, the importance of inherited gene defects in the pathogenesis of primary cardiomyopathies has been recognised, with mutations in some 18 genes having been identified as causing hypertrophic cardiomyopathy (HCM) and/or dilated cardiomyopathy (DCM). Defining the role of these genes in cardiac function and the mechanisms by which mutations in these genes lead to hypertrophy, dilation, and contractile failure are major goals of ongoing research. Pathophysiological mechanisms that have been implicated in HCM and DCM include the following: defective force generation, due to mutations in sarcomeric protein genes; defective force transmission, due to mutations in cytoskeletal protein genes; myocardial energy deficits, due to mutations in ATP regulatory protein genes; and abnormal Ca²⁺ homeostasis, due to altered availability of Ca²⁺ and altered myofibrillar Ca²⁺ sensitivity. Recent advances in the understanding of these mechanisms wil be considered here. These insights should ultimately lead to new approaches for the diagnosis, prognostic stratification, and treatment of patients with heart failure.