Development of therapeutic therapy for regression of cardiac hypertrophy in hypertrophic cardiomyopathy

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Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by idiopathic hypertrophy of the left ventricule. In HCM patients, sudden death occurs owing to lethal arrhythmia in young age and diastolic heart failure can be sometimes developed. Medical approach for regression of hypertrophy in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through ryanodine receptor(RyR2) might predispose to abnormal hypertrophy in HCM patients. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse(TG) model of familial hypertrophic cardiomyopathy-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 is induced by beta-adrenergic stimulation in TG cardiomyocytes. Dantrolene, which was found to stabilize RyR2 inhibited Ca2+ leak. These results suggest that stabilization of RyR2 and subsequent inhibition of Ca2+ leak might play a pivotalrole for regression of abnormal hypertrophy in HCM patients.