低强度迷走神经刺激调控心脏自主神经功能治疗心房颤动的机制研究

项目名称： 低强度迷走神经刺激调控心脏自主神经功能治疗心房颤动的机制研究

项目编号： No.81470597

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： 盛夏

作者单位： 浙江大学

项目金额： 73万元

中文摘要： 房颤机制研究一直是近年的热点，大量研究结果表明心脏自主神经系统在房颤的发生、维持中扮演重要角色。近一个世纪的研究始终认为迷走神经刺激是致房颤的，而我们既往的实验结果却发现与传统观念不同，低强度迷走神经刺激可以治疗房颤的。这主要是通过对心脏内源性自主神经丛功能的调控来实现的。但是外源性的刺激是如何影响到心脏内源性神经系统的功能，这个在整个作用机制中承前启后的最重要一环尚是未知数。本研究通过在体急、慢性房颤模型中进行不同强度的迷走神经刺激以及离体心脏自主神经元细胞在不同的电场强度中进行培养的方法，观察不同强度的迷走神经电刺激对心脏自主神经丛神经元细胞形态、构成、超微机构、跨膜电流和功能的不同效应，研究神经生长因子与该效应的相关性的，探讨其可能的分子生物学机制，明确低强度迷走神经刺激可否通过调控神经营养因子介导的神经元细胞肥厚和乙酰胆碱释放影响心脏自主神经丛的功能，从而起到治疗和预防房颤的作用。

中文关键词： 心房颤动；迷走神经；自主神经

英文摘要： Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, but The mechanisms responsible for AF are still uncertain.A lot of sutdies had showed the role of the ANS in the initiation, maintenance, and termination of AF.In the past century, the vagal stimulation was known as the facilitated factor for AF. But in the present report, we have describe a nonpharmacologic, nonablative methodology to reverse and prevent the AF. Contrary to the popular notion, low level vagosympathetic stimulation (LL-VNS) may serve as a novel therapeutic modality to treat AF, particularly to prevent AF from progressing to persistent forms of this arrhythmia.Inhibition of the intrinsic cardiac autonomic nerve system (ANS) by LL-VNS may be responsible for these salutary results. LL-VNS may serve as a novel therapeutic modality to treat AF related to acute or chronic atrial remodeling or a hyperactive state of the intrinsic cardiac ANS. We hypothesize that the mechanism responsible for the atrial antifibrillatory effect of LL-VNS may be due to inhibition of the intrinsic cardiac ANS by the extrinsic cardiac ANS. But how do LL-VNS influence neuronal firing within the cardiac autonomic ganglionated plexi? we still know nothing about this process.In the first part of this study, we will build the chronic AF animal model by atrial rapid pacing in vivo.Then we will implant a neurostimulator subcutaneously which is connect to the right cervical vagosympathetic trunks to stimulate the vagus for six months by different intensity. Histo- and cytofluorescence experiments will be done to analysis the tissue from ARGP.In this protocl, we want to know whether different intensity vagal stimualtion can affect the AF burden, AF cycle length and the morphology of neuron cells in ARGP. We also like to know the activity of neuron in GP by the gene and protein expression of NGS and NT-3. In the second part, we will incubate neuron cells from GPs of the rat in the different electric field strengths.It has been shown that the strong electric field can causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3-mediated acetylcholine upregulation. We will change the intensity and sequency of electric field, and want to find out whether low level electric field can prevent or reversal the effect of strong elctric field to neuron cell. Further research will be done to help us understand the possible mechanism, including the regulation mechanism of NSG and NT-3.LL-VNS is a potential therapy that is less invasive than catheter or surgical ablation, and may limit the duration of or even prevent AF thereby reducing the risk of thromboembolic events or cardiomyopathy. This study will provide laboratory basis for its clinical practice.

英文关键词： atrial fibrillation;vagus nerve;autonomic nerve