Pathogenesis of Diverse Clinical and Pathological Phenotypes in Hypertrophic Cardiomyopathy

Myocardial contractility is generally believed to be increased in hypertrophic cardiomyopathy. I propose the opposite--that cardiac myocyte contractility is decreased in this disorder. Accordingly, the contractile deficit provides the primary stimulus for increased expression of trophic factors in the heart, which leads to hypertrophy, interstitial fibrosis, and other phenotypes. Variation among individuals in expression of trophic factors would account for the variability of phenotypes. Gene transfer studies in cardiac myocytes showing impaired contractility and increased expression of trophic factors in the myocardium of patients with hypertrophic cardiomyopathy support this hypothesis. Testing of the hypothesis would require measurement of contractility of cardiac myocytes isolated from patients with hypertrophic cardiomyopathy, identification of the main trophic factors in the hearts of these patients, and investigation of whether their inhibition can prevent or lead to regression of the cardiac phenotypes.