晚Na电流为各型长QT综合征药物治疗共同靶点的机制探讨：从细胞到临床

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.

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。

遗传性或获得性长QT综合征（LQTS），以反复发作的晕厥，抽搐，甚至猝死为临床特征，心电图上表现为以QT间期延长和发生尖端扭转型室速（TdP）。本课题组前期研究发现晚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。因此我们提出假设：阻断晚Na电流可能成为LQTS相关的心脏性猝死或快速终止TdP及治疗其他相关的心律失常新的特异靶点。在本项目资助下，我们主要完成了以下工作（1）发现晚钠电流抑制剂美西律可以预防获得性长QT综合征患者尖端型扭转型室速的发作；（2）晚钠电流抑制剂美西律可以显著改善LQT8患者心电图表现，预防恶性心律失常事件的发生。（3）在晚钠电流分布不均一性与频率依赖性复极离散关系的研究中，我们发现晚钠电流在四个心腔分布完全不同，即左室密度>右室>左房/右房，晚钠电流分布的不均一性对复极频率依赖性的区域性不一致性改变具有重要贡献，在延长动作电位药物的作用下，这种影响更加明显。晚钠电流的分布不同导致了不同心腔之间复极时间的不同，以及复极频率依赖性改变的差异。此外，项目负责人严干新在本项目的资助下发表了多篇综述论文并组织国际四大心律学会(APHRS、EHRA、HRS、SOLAECE)撰写了J波综合征国际专家共识。