右室心尖部起搏导致心力衰竭的基因机制及干预策略研究

项目名称： 右室心尖部起搏导致心力衰竭的基因机制及干预策略研究

项目编号： No.81470460

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 浦介麟

作者单位： 中国医学科学院阜外医院

项目金额： 73万元

中文摘要： 随着人口老龄化，我国缓慢性心律失常的发病率和永久起搏器植入量不断上升。然而，长期右室心尖部起搏导致部分患者左心功能下降甚至严重心力衰竭，这是长期困扰起搏领域的难题。本课题组对877例患者随访发现，完全性右心室起搏导致19%的患者心功能下降，其中5%出现严重心衰，危及生命。对1例严重心衰患者基因检测示LMNA L379V突变。因此，我们假设：右室心尖部起搏诱发严重心衰具有遗传背景，早期发现致病基因、阐明发病机理对右室心尖部起搏诱发心衰的预警和干预具有重要价值。本研究拟对所有这类心衰患者进行基因检测，以期发现更多的致病基因及突变位点；采用转基因细胞和动物模型，研究起搏对携带LMNA L379V突变体心肌细胞Rho GTPase和ERK信号通路的影响及心脏功能的改变，阐明发病机理；通过干预相关信号通路和将右室起搏升级为左、右室同步起搏，探究药物作用靶点和临床治疗方法，为解决这一难题提供新的思路。

中文关键词： 心力衰竭；基因突变；三度房室传导阻滞；心脏起搏器；防治策略

英文摘要： With an aging population, both the incidence of bradycardia and the amount of permanent pacemaker implantation are increasing. However, long-term right ventricular apical pacing may lead to decreased left ventricular function and even severe heart failure in some patients, which has been a long-standing problem of the pacing field. Our research team followed up 877 patients and found that complete right ventricular pacing led to declined cardiac function in 19% of the population, of which 5% developed life-threatening heart failure. One of the patients undertook genetic testing and showed LMNA L379V mutation. Therefore, we assume that: there are genetic backgrounds in the ones with right ventricular apical pacing -induced heart failure, early detection of disease-causing genes and elucidating the pathogenesis are of great value for early warning and intervention of right ventricular apical pacing -induced heart failure. In this study, all the heart failure patients will take genetic testing in order to find more disease-causing genes and mutations ; by using cellular and transgenic animal models, we aim to study the influence and the impact of pacing to Rho GTPase and ERK signaling pathway as well as the cardiac function in cardiomyocytes and heart carrying LMNA L379V mutantion; what's more, through intervention of the relevant signaling pathways and upgrading to the left and right ventricular resynchronization pacing , we can explore new drug targets and clinical treatment methods to solve this problem.

英文关键词： heart failure;gene mutaion;third degree atrioventricular block;cardiac pacemaker;prevention and treatment