儿茶酚胺敏感性室速（CPVT）是罕见恶性遗传性心律失常疾病。氟卡尼治疗CPVT 效果良好，具体机制尚存争论。前期工作课题组证实：氟卡尼治疗CPVT的机制为 钠通道的阻断效应；钠通道在心室肌细胞体部及端侧的动力学存在差异，而这种差异又决定钠 通道阻滞剂疗效的不同。基于CPVT的主要病理生理机制“RyR2钙漏和触发活动”发生在心肌细 胞体部，我们提出“心肌细胞区域性钠通道动力学差异是氟卡尼安全有效治疗CPVT的基石”核心假说。本项目立足于前期基础，利用CPVT转基因小鼠，从整体-组织-细胞-亚细胞水平，探 讨氟卡尼选择性阻滞心肌细胞体部以治疗CPVT而不影响心肌传导的机制；并以CPVT心肌细胞存 在超微组织重构为切入点，在亚细胞水平探索CPVT钠通道重构的分子基础。本课题将阐明氟卡尼有效、安全治疗CPVT的新机制，为确立钠通道阻滞剂的区域选择性作用理论及其临床应用的扩展提供依据。

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and highly lethal form of inherited arrhythmogenic disease, the prevalence of CPVT is about 1/10000. Flecainide is effective in the management of CPVT, the underlying mechanism is debated. Previously we have demonstrated that blocking sodium channel is the mechanism for the flecainide treatment in CPVT; the kinetics of sodium channel is the determination of the efficacy of sodium channel blockers (SCB);there are some discrepancies of the kinetics between sodium channel in the cell midsection (M) or at the cell end (ID). Based on the pathophysiology of calcium leak and triggered activity in CPVT occurred in the midsection of cell. we propose that the discrepancies of sodium channel kinetics allow us to use flecainide to treat CPVT and avoid its proarrhythmias which manifests the conduction delay by blocking sodium channel in the cell end. In the present project, we plan to prove our hypothesis in CPVT transgenic mice CASQ2R33Q. Part 1. We explore underlying mechanisms of flecainide preferentially blocking sodium channel in the cell midsection, but not in the cell end. We also investigate the underlying mechanisms of distinct efficacy of different SCB in the treatment of CPVT. Part 2. We explore molecular basis of ultrastructional remodeling of sodium channel in CPVT. This study will clarify the new mechanism for the effectiveness and safety of flecainide treatment in CPVT, in addition we will establish the theory of the selective action of SCB and a new therapeutic strategy of SCB for heart diseases.