Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease characterized by an increase in left ventricular wall mass in the absence of another cause for hypertrophy. Because hypertrophy is a fundamental response of the heart and may be both adaptive and maladaptive, the study of HCM provides a window to an important physiologic cardiac process. Approximately 15% of cases are the results of a mutation in the beta myosin heavy chain (betaMHC), a dominant protein in the thick filaments of muscle fibers. These filaments interdigitate with thin filaments composed of actin and associated proteins. The two sets of proteins slide past each other to produce muscle contraction powered by the hydrolysis of ATP at the enzymatic portion of the myosin. In this actomyosin interaction a series of biochemical and corresponding structural changes occur in cyclic fashion. We have identified 30 mutations in the betaMHC gene and have described their distribution on the three-dimensional structure of myosin as solved by Rayment et al. Their clustering into 4 regions have suggested that they may interfere with the actomyosin crossbridge interaction in different portions of the cycle, thus leading to the inefficient molecular motors with different structural and functional defects. The physiologic study of these molecules casts light on the process by which chemical energy is transduced to directed movement in the actomyosin interaction. Other proteins in the contractile apparatus of muscle fibers have been shown to cause HCM when mutated as well. However, the pathway by which the inefficient structural and enzymatic portions of the contractile apparatus lead to the process of hypertrophy remain unknown. It remains likely that this unknown cascade of signaling events may also be inappropriately initiated in the absence of mechanical defects and either modify or also directly lead to hypertrophy. Our laboratory is currently using the HCM families to pursue this other line of investigation.
