INHERITED CARDIAC DISEASES--HYPERTROPHIC CARDIOMYOPATHY

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Hypertrophic cardiomyopathy (HCM), is an inherited heart disease, characterized by cardiac hypertrophy. HCM patients are often symptomatic and are prone to sudden death (SD). We have been engaged in developing therapeutic strategies that improve symptoms and prognosis of HCM patients and elucidating the genetic-molecular basis of HCM. About 25% of HCM patients have obstruction to left ventricular outflow. We have shown that DDD pacing improves symptoms and relieves the obstruction in patients with drug-refractory symptoms in most patients with obstructive HCM. Beneficial hemodynamic adaptive changes and regression of cardiac hypertrophy were noted following chronic pacing. This novel therapy is therefore an attractive alternative to cardiac surgery. A study is ongoing to determine whether this novel therapy can prevent progression of the disease in HCM children. Elucidation of a possible molecular basis for the regression of the cardiac hypertrophy will be invaluable in the management of other cardiac diseases also characterized by cardiac hypertrophy. We have identified 18 distinct mutations in the beta-MHC gene located on chromosome 14, in 30 unrelated kindreds, and mutation- specific natural histories are being determined. Other families have been identified in which the disease is not linked to the beta-MHC gene. Linkage studies are being performed to identify other genes that can also cause HCM. We have demonstrated that mutant messenger RNA and beta- myosin are present in slow skeletal muscle of affected patients. Skeletal muscle myofibers containing mutant ~-myosin have been shown to have abnormal contractile properties. Beta-myosin purified from skeletal muscle of patients with distinct betaMHC gene mutations has been shown to have abnormal function in an in-vitro motility assay. Histochemical analyses show that 60% of patients with ~MHC gene mutations have skeletal myopathy - specifically, 'central core disease', a very rare, non- progressive myopathy characterized by loss of mitochondria from the center of some of the slow myofibers. Recently, the 3-dimensional structure of chicken skeletal muscle myosin has been described. Homology between this myosin and human cardiac myosin has allowed us to study the location of the mutations in terms of functional domains of the molecular motor.