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

肥厚型心肌病(HCM)是一种以特发性左心室肥大为特征的心肌疾病。在肥厚型心肌病患者中，年轻时因致命性心律失常而猝死，有时可发展为舒张性心力衰竭。肥厚性心肌病患者肥厚消退的医学方法仍然难以捉摸。在这里，我们假设通过兰诺定受体(RyR2)的舒张期钙泄漏可能是肥厚性心肌病患者异常肥厚的易感因素。为了验证这一假设，我们在家族性肥厚型心肌病相关心肌肌钙蛋白T突变的转基因小鼠(TG)模型中研究了通过RyR2的钙泄漏的致病作用。TG心肌细胞通过缺陷RyR2的舒张期钙泄漏是由β-肾上腺素能刺激引起的。丹曲林是一种稳定RyR2的药物，它能抑制钙离子的泄漏。这些结果提示，RyR2的稳定和随后的钙泄漏的抑制可能在肥厚性心肌病患者异常肥厚的消退中起关键作用。

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.