我们预实验发现晚Na电流是心脏复极频率依赖性调节的重要成分，各种原因致复极延缓均可增大该电流。因此提出假设：阻断晚Na电流可能成为预防长QT综合征（LQTS）心性猝死或快速终止尖端扭转型室速（TdP）新的特异靶点。本课题包括基础研究和临床研究，即从细胞到临床：采用全细胞膜片钳技术探讨临床用药美西律、雷诺嗪对晚Na电流的阻断特点；采用兔正常及LQT模型（LQT1，LQT2，LQT3，LQT7，LQT8）冠脉灌注心室楔形标本，观察美西律、雷诺嗪对心室复极、跨壁复极离散、频率依赖性的影响，并比较各LQT亚型对药物的反应。临床研究中对门诊和住院TdP发作患者随机分组，分别给予传统治疗和传统加美西律治疗，观察终止TdP时间、QTc 及Tp-e间期、QT/Tp-e比值、QT-RR斜率变化。对临床不能确定LQTS分型患者进行遗传关联研究确定病因，目的是观察美西律对各种病因致LQTS治疗的安全性和有效性。

Long QT syndrome (LQTS), either inherited or acquired, is a disorder of delayed ventricular repolarization characterized by a prolonged QT interval on ECG and propensity to torsades de pointes (TdP). Clinical manifestations of TdP include syncope, "seizure" or sudden cardiac death. Congenital LQTS with 13 susceptible genes encoding potassium, sodium and calcium channels affects an estimated 1 in 2500 people. Acquired LQTS particularly drug-induced is more common. However, physicians who see patients are frustrated by the paucity of long term, i.e. prevention of cardiac events, and short term, i.e. acute termination of TdP, drug options in LQTS.Our previous study has demonstrated that the late sodium current (INa,L) functions a key ionic current in modulating rate-adaptation of cardiac repolarization and is amplified under conditions of delayed ventricular repolarization regardless of the underlying causes. Therefore, we hypothesize that inhibition of INa,L is a novel and common pharmacotherapeutic target for LQTS. Our proposed project consists of two parts: basic research and clinical application, i.e. from cells to bedside. Firstly, we will test a clinically safe sodium channel blocker mexiletine for its preferential inhibition of INa,L using the whole-cell voltage-clamping technique; and then examine its effect on ventricular repolarization, transmural dispersion of repolarization (TDR) and the rate adaptation in LQTS models (LQT1, LQT2, LQT3, LQT7 and LQT8) established in the isolated rabbit ventricular wedge preparation. The information obtained in the basic research will be translated to clinical application in respect to the safety and efficacy of the INa,L blockers in termination of clinical TdP. Patients with TdP will be enrolled in the clinical part of the study. Subjects will be randomized to receive either the conventional treatment for TdP or mexiletine in addition to the conventional treatment. The rationale behind this proposed project is straightforward: delayed ventricular repolarization regardless of causes is associated with an increase in INa,L due to its slow inactivation and recovery kinetics that further exaggerates bradycardia- or pause-dependent QT and Tp-e prolongation, leading to TdP. We believe that inhibition of INa,L is an effective and common pharmacotherapeutic target for acute termination of TdP in LQTS. Our preliminary observations using the INa,L inhibitors in basic and clinical LQTS and TdP are very promising and indicate a great likelihood of a major breakthrough in management of all types of LQTS.