胆碱能抗炎通路在缺血性心肌病室性心律失常中的作用及其机制研究

Ischemic cardiomyopathy is a type of end-stage coronary artery diseases with a poor prognosis, and the major direct causes of death in these patients with ischemic cardiomyopathy were the malignant ventricular arrhythmias. However, the mechanisms involved in the pathogenesis of the malignant ventricular arrhythmias in patients with ischemic cardiomyopathy are very complicated, and the development of myocardial fibrosis was the common cause. Previous studies have showed that inflammatory mechanisms and abnormal autonomic nervous system function play critical role in the pathogenesis of myocardial fibrosis and ventricular arrhythmias. Recently, many studies have demonstrated that cholinergic antiinflammatory pathway exerts antiinflammatory effects through activation of the vagus nerve. Therefore, we hypothesized that cholinergic antiinflammatory pathway might have a protective effects in reducing the risk of the malignant ventricular arrhythmias. In the present study, we will investigate whether activation of cholinergic antiinflammatory pathway reduces ventricular arrhythmias in a rat model of ischemic cardiomyopathy. The agonist and antagonist of α7 nicotinic acetylcholine receptor in different concentrations will be administered, and the right cervical vagus nerve will be cut off in the rats with ischemic cardiomyopathy. The risks of ventricular arrhythmias will be determined using electrophysiological study. The most novel insight of the study is that the nervous system may modulate the inflammatory response and ventricular arrhythmias in ischemic cardiomyopathy. The study will help elucidate the novel mechanism involved in the pathogenesis of ventricular arrhythmias in ischemic cardiomyopathy, and open new possibilities in the therapeutic management of ventricular arrhythmias in ischemic cardiomyopathy.

缺血性心肌病是终末期冠心病的一种类型，预后极差，其直接死因往往为恶性室性心律失常。缺血性心肌病导致室性心律失常机制非常复杂，心肌组织纤维化是其常见的病因。研究表明，炎症和自主神经功能失调在心肌纤维化与室性心律失常发生发展中起重要作用。新近提出的胆碱能抗炎通路通过激活迷走神经相关抗炎通路，既可以起到抗炎症，又具有兴奋迷走神经的作用。因此我们假设胆碱能抗炎通路在缺血性心肌病室性心律失常中具有保护性作用。本课题在我们既往研究基础上，从兴奋/阻滞α7-nAChR受体、激活/抑制胆碱能抗炎通路着手，通过程序电刺激诱发室性心律失常，评估室性心律失常发生的风险，明确胆碱能抗炎通路在缺血性心肌病室性心律失常发生发展中的作用。本项目最大特色是将缺血性心肌病室性心律失常的发生机制研究深入神经免疫学领域。开展此项研究，不仅对缺血性心肌病室性心律失常的发生发展机制提供新的认识，而且还可能为其治疗提供新靶点。

胆碱能抗炎通路在缺血性心肌病室性心律失常的发生发展中具有保护作用，本课题在我们既往研究的基础上，通过兴奋/阻滞α7-nAChR受体，激活/抑制胆碱能抗炎通路着手，结合迷走神经切断术，运用程序电刺激技术诱发室性心律失常，评估室性心律失常发生的风险，初步明确了胆碱能抗炎通路在缺血性心肌病室性心律失常的发生发展中起到保护作用。然后通过进一步的实验，阻滞可能的下游信号通路，探索胆碱能抗炎通路保护作用的机制，结果显示，在阻滞AMPK之后，胆碱能抗炎通路的保护作用显著降低，推测这可能与AMPK对能量代谢与炎症的调节作用相关，进一步的研究工作尚在进行，综合上述结果，本研究将缺血性心肌病室性心律失常的发生机制研究深入神经免疫学领域，为胆碱能抗炎通路及缺血性心肌病室性心律失常的发生发展机制提供了新的认识。