颈动脉窦压力感受器电刺激干预自主神经重构对心力衰竭后室性心律失常的影响

Ventricular arrhythmias are the direct cause of sudden cardiac death in many patients with heart failure (HF). The interactions of cardiac autonomic neural remodeling, structural remodeling, and electrical remodeling constitute to the substrates of ventricular arrhythmias in HF. Pharmacological therapies targeting cardiac remodeling, such as β-blockers, show dramatic effects on HF, and significantly reduce the incidence of ventricular arrhythmias and sudden cardiac death. .Taking advantage of suppressing sympathetic activity, carotid baroreceptor stimulation (CBS) has shown strength in treating resistant hypertension and heart failure clinically in recent years..Our preliminary data show that short-term CBS amends abnormal cardiac electrophysiological characteristics, prevents atrial fibrillation caused by rapid atrial pacing and ventricular arrhythmias under acute myocardial infarction conditions. .We hypothesize that CBS may suppress ventricular arrhythmias through preventing autonomic neural remodeling in HF..To test this hypothesis, we plan to establish HF canine models by rapid right ventricular pacing and apply CBS at two voltages, moderate-level CBS which reduces blood pressure by 10% and low-level CBS which is 80% of the lowest effective voltage. Then, observe the effects on autonomic neural remodeling and incidence of ventricular arrhythmias, and investigate the effects of CBS on β-adrenergic receptor signaling pathway and angiotensin II –AT1 receptor signaling pathway in ventricular myocytes. The cardiac structural and electrical remodeling will also be investigated. .The results will provide new insights into the role of autonomic neural remodeling in the underlying mechanisms of ventricular arrhythmias and provide new strategies to prevent ventricular arrhythmias in patients with HF.

室性心律失常是导致心力衰竭（心衰）患者高猝死率的直接原因。心脏自主神经重构、结构重构和电重构交互影响，共同构成心衰时室性心律失常的发生基质。.抗心脏重构治疗，如β受体阻滞剂等可显著减少心衰后室性心律失常和猝死。颈动脉窦压力感受器电刺激（CBS）因可抑制交感神经活性，近年来用于顽固性高血压和心衰的临床治疗，并取得了一定效果。我们前期研究发现：短程的CBS可以影响心脏电生理学特性，抑制心房颤动和急性心肌梗死后室性心律失常的发生。.我们假设：CBS可通过干预自主神经重构抑制心衰后室性心律失常的发生。.本项目拟用快速心室起搏制作犬心衰模型，观察中等强度和低强度的CBS对自主神经重构和室性心律失常的影响，并探索CBS对β受体和Ang II受体信号通路的影响；同时观察两种强度CBS对结构重构和电重构的影响。本项目结果有望从自主神经重构的角度为心衰后室性心律失常的发生机制提供新思路，为其防治提供新策略。

恶性室性心律失常是导致慢性心力衰竭（心衰）患者高猝死率的直接原因。自主神经重塑被证实在室性心律失常的发生和维持中发挥重要作用，自主神经重塑参与心脏的结构重构和离子通道重构的发生。颈动脉压力感受器刺激(CBS)可通过抑制交感神经张力、增强迷走神经张力再平衡自主神经系统。.本项目旨在研究CBS对心衰后室性心律失常的影响及其机制。.本项目采用右心室心尖快速起搏制作犬心衰模型，并观察心衰时心脏自主神经重塑、结构重构以及电生理特性的改变，以及低强度CBS和中等强度CBS对它们的影响。结果显示右心室心尖快速起博8周可成功制作犬心衰模型，主要表现为左心室明显扩张，左室收缩、舒张功能明显降低，以及明显的结构重构、自主神经重塑和电重构。低强度CBS和中等强度CBS均可不同程度改善心脏的结构和功能异常，降低心肌纤维化水平，改善心室电生理特性，降低心室颤动易感性，抑制左侧星状神经节重塑，且中等强度CBS可抑制左心室自主神经重塑。低强度CBS可显著抑制左心室Kv4.3离子通道蛋白表达的降低，中等强度CBS可显著抑制Kv4.3、KCNQ1和Cav1.2离子通道蛋白表达的降低。中等强度CBS对心脏结构和功能、心室电生理特性、自主神经重构和离子重构的保护作用优于低强度CBS。.上述结果表明，CBS可通过调节自主神经重构和离子通道表达异常，从而发挥抑制心衰犬心室颤动易感性的作用。CBS可能成为治疗心衰后恶性室性心律失常的有效手段。