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

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.

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。

三度房室传导阻滞（III atrioventricular block, AVB）是一种常见的缓慢性心律失常，目前缺乏有效的治疗药物，永久性起搏器的植入是目前治疗III AVB的主要方法。右室心尖部是常用的起搏导线的放置部位，然而，近年来多项研究表明右室心尖部起搏可以导致心脏电传导和机械传导异常，继而导致心力衰竭，但具体病理机制未明。本研究发现心肌病相关致病基因的变异是导致三度房室传导阻滞的患者发生心力衰竭的遗传学因素；右室心尖部起搏作为非生理性额外刺激，可能会加速心脏结构改变以及心力衰竭的发生，尤其是携带了心肌病相关致病基因变异的患者；本研究发现的两个LMNA基因变异（R216C和L379F）可以改变LMNA蛋白的核膜定位，引起细胞核形状改变，可能通过影响核酸分子或蛋白质之间的结合功能，导致多种转录调控因子的运输和功能异常，激活PI3K-Akt和Ras信号通路等凋亡通路，最终导致变异组乳鼠心肌细胞在血清饥饿后凋亡率显著升高，最终引起传导阻滞和心力衰竭；基因检测有利于发现心衰风险较高的患者，进行临床预警，通过探究相关基因变异的致病机制，研究治疗策略。