慢性迷走神经刺激联合心脏再同步化治疗心力衰竭的实验研究

Heart failure charactered by complex clinical syndromes is a main reason of hospitalization and death. During the past two to three decades, the treatment of heart failure including pharmaceuticals and cardiac resynchronization devices is still not convincingly associated with improvements in hard clinical outcomes. Two factors including the decline of myocardial function modulated by cardiac remodeling during the progression of heart failure and cardiac arrest caused by arrhythmias were associated with autonomic dysregulation characterized by a sustained increase in sympathetic drive and withdrawal of parasympathetic activity. Considerable interest has emerged recently in modulating vagal activity (vagal nerve stimulation,VNS) as a therapeutic target for chronic heart failure. Though preliminary data suggest that this intervention provides subjective and objective improvements, important gaps in knowledge remain. Moreover, little is known about impact of chronic vagal stimulation for heart failure on arrhythmia susceptibility and no reasearch clarify the comparison of CRT with VNS and evalute the combined therapy(CRT/VNS). This study focuses on evaluation of those above in an established canine model of intracoronary microembolisation-induced heart failure. Our study contains two parts. First, We analyze the changes of indexes of cardiac electrophysiology, cardiac strcture remodeling, biochemistry, molecular biology between VNS group and control group to assess the impact of vagal stimulation on electrophysiology and the potential mechanisms. Second, by comparing the indexes of cardiac electrophysiology and cardiac strcture remodeling with canine treated with CRT and CRT/VNS, We investigate the potential of VNS to clinical application. The appreciation of possible mechanism and comparable with other treatments will surely establish new treatment methods for heart failure.

尽管心脏再同步化治疗（CRT）心力衰竭（心衰）已取得一定疗效，但仍有近1/3患者无反应，且有致心律失常风险。心衰死亡原因为心肌收缩力下降及心律失常导致心衰加重和心脏猝死，而二者均与自主神经失衡相关。迷走神经刺激（VNS）已成为干预自主神经失衡的有效方法，初步的研究数据显示了其有改善心衰作用，但是VNS治疗心衰能否改变心脏电重构及心律失常易感性尚不清楚，CRT联合VNS治疗心衰国内外尚无报道。本研究通过冠脉微栓塞构建心衰模型，在此基础上进行两部分实验：首先研究VNS治疗心衰对心衰犬心脏结构及心电生理的影响，揭示VNS治疗心衰和可能降低心律失常易感性的可行性和可能机制。在此基础上进一步研究VNS联合CRT治疗心衰的可行性和疗效。通过心脏电生理、心脏超声、生物化学、分子生物学及组织病理学检查，明确实验组（不同干预亚组）和对照组实验犬心脏结构和功能的改变，为探索心衰治疗的新途径奠定理论和应用基础。

尽管心脏再同步化治疗（CRT） 心力衰竭（心衰）已取得一定疗效，但仍有近1/3患者无反应，且有致心律失常风险。心衰死亡原因为心肌收缩力下降及心律失常导致心衰加重和心脏猝死，而二者均与自主神经失衡相关。迷走神经刺激（VNS）已成为干预自主神经失衡的有效方法，初步的研究数据显示了其改善心衰的作用，但是 VNS 治疗心衰能否改变心脏电重构及心律失常易感性尚不清楚，CRT联合VNS治疗心衰国内外尚无报道。本实验进行两部分研究：首先研究 VNS 治疗心衰对心衰犬心脏结构及心电生理的影响，揭示 VNS 治疗心衰和可能降低心律失常易感性的可行性和可能机制：实验显示快速心房起搏刺激短期内即能引起炎症反应、血管内皮功能相关指标发生变化及氧化应激反应，单纯自主神经刺激对炎症反应、内皮细胞功能及氧化应激反应的影响不明显，但自主神经活性增强却能加重快速心房起搏对炎症反应、内皮细胞功能及氧化应激反应的影响，自主神经活性增强可能与房颤具有协同作用，共同导致机体炎症反应、氧化应激水平升高，进而导致心房肌的电重构及结构重构，加速房颤及心衰的进展。在此基础上进一步研究 VNS 联合 CRT 治疗心衰的可行性和疗效。通过心脏电生理检查、心脏超声检查、生物化学测定、分子生物学分析及组织病理学检查，相比对照组，实验组（不同干预亚组）实验犬心脏结构和功能的改善，开辟心衰治疗的新思路，提高心衰治疗效果。