早期复极人群心源性猝死的机制与危险分层

Sudden cardiac death (SCD) caused partly by primary cardiac electrophysiologic abnormality in patients without structure heart diseases. The early repolarization pattern (ERP), which is characterized by an elevation≥0.1 mV of the QRS-ST junction (J point) in the inferior and/or lateral leads on 12-lead electrocardiography, with either QRS notching or slurring, has been considered to be a benign finding on electrocardiography in the healthy population. However, studies recently showed that ERP has been associated with vulnerability to ventricular fibrillation and increased risk of SCD. The mechanisms for ERP and how the ERP increasing the risk of SCD remain unclear. We make a hypothesis that the subjects with ERP may divided into low and high risk subgroups, just like Brugada syndrome and long Q-T syndrome. To test this hypothesis, based on our medical databases of subjects with ERP, we will assess the risk of SCD in Chinese with ERP, and found the method of SCD risk stratification for subjects with ERP. At the same time, using the blood and myocardial tissue samples of subjects with ERP, we will study molecular genetics and cardiac electrophysiologic mechanisms for ERP and the method of SCD risk stratification based on these mechanisms, which from the gene structure of cardiac ion channels (mutation and polymorphism), ion channels phenotype (using patch clamp skill), and the functional characteristic of ion channels of the myocardial cells stem from induced pluripotent stem cells ( iPSCs) of immediate families of SCD patients caused by ERP. Our study will be helpful to the stratification prevention and treatment for the SCD caused by ERP.

心源性猝死（SCD）部分发生于无器质性心脏病的原发性心脏电生理异常。以往认为早期复极是"良性"的心电图表现，但近年国外及我们的研究显示早期复极增加心源性猝死的风险。早期复极及其引起SCD的机制不明。正如Brugada综合征、先天性长Q-T综合征一样，我们假设早期复极人群中也存在SCD的高危和低危亚群。为证实上述假设，我们利用业已初步建成的早期复极人群医学资料数据库：（1）评估中国人早期复极SCD的风险；（2）创建早期复极SCD的临床危险分层方法；（3）基于早期复极人群的生物样本，从心脏离子通道基因结构（突变和多态）、离子通道功能表型（膜片钳技术）和早期复极SCD病人直系亲属的特异性诱导多能干细胞（iPSCs）来源心肌细胞的离子通道功能特性（iPSCs技术和膜片钳技术）等层面探寻早期复极SCD的分子遗传学和电生理学机制及危险分层方法，为分层防治早期复极所致SCD提供科学的决策依据。

近年来国外及我们的研究显示早期复极增加心脏性猝死的风险。我们对早期复极及其引起心脏性猝死的机制进行了研究。..我们前瞻性地分析了18231例早期复极合并动脉硬化风险因素的人群，结果显示早期复极明显增加合并动脉硬化风险因素人群的心脏性猝死（HR 1.91）、冠心病死亡（HR 1.80）和所有原因死亡（HR 1.35）的风险。早期复极出现在下壁、J点抬高幅度大有更高的心脏性猝死的风险。我们研究了心电图特征在早期复极合并心脏骤停的危险分层中的作用。与100例没有合并心脏骤停的早期复极相比，57例早期复极合并心脏骤停病人的J / R比值更大 (P < 0.001)，多因素Logistic回归分析显示J / R比值高和水平/下斜型 ST段是早期复极合并心脏骤停的独立风险因素。研究结果提示J / R比值和ST段形态可作为早期复极个体是否发生心脏骤停的危险分层指标。..通过全基因组测序，我们发现了可能与早期复极心跳骤停存在关系的突变基因 KCNH2、KCNE1等。我们研究了KCNH2基因（hERG基因）突变在早期复极综合征中的作用。与KCNH2-WT通道比较，突变基因KCNH2-K801T通道稳态电流密度及稳态电流峰值显著增加，通道失活速度减慢，复活速度加快。我们的研究显示KCNH2基因的错义突变K801T可导致KCNH2通道功能增强，这可能是导致早期复极综合征的主要原因之一。我们也研究了KCNE1突变在早期复极伴心跳骤停中的作用，结果显示KCNE1-S38G和KCNQ1的共表达降低了IKs的尾电流密度。与KCNE1-WT相比，KCNE1-S38G的表达和膜定位下降。我们的研究结果表明S38G突变引起 KCNE1蛋白表达减少和KCNE1蛋白膜转运失效，导致IKs功能丧失。另外，我们的Meta分析显示大环内酯类抗生素的使用可增加心脏性猝死和心血管死亡的风险。