Autonomic Nerve Activity and Paroxysmal Atrial Fibrillation

描述(申请人提供)：这项研究项目的广泛和长期目标是检验以下假设：同时交感迷走神经放电是阵发性心房颤动(PAF)的直接触发因素，切断自主神经和心脏之间的连接可以减少PAF的发生率。自主神经系统被认为在PAF的调节中起重要作用。然而，还没有研究证明自主神经放电与活动动物的PAF机制之间存在直接关系。自主神经放电触发房颤的机制也鲜为人知。本研究旨在完成以下具体目标：(1)在短期快速心房起搏诱发的自发性房颤犬模型上，长期同步记录心电图、血压、左右星状神经节活动和心脏迷走神经活动。这些数据将被用来检验这样的假设，即交感迷走神经的同时激活是活动犬PAF最常见的直接触发因素。(2)我们将进行高密度肺静脉标测，以验证刺激星状神经节和迷走神经可以在PAF犬模型中诱发肺静脉重复快速活动的假说。这一结果将被用来检验交感迷走神经刺激可以从以自主神经末梢密度增加为特征的重塑肺静脉诱发局灶性放电的假设。(3)冷冻消融左侧星状神经节和心脏迷走神经，建立与目标1相同的PAF动物模型，长期同步记录心电图、血压和自主神经活动。这一结果将被用来检验选择性心脏交感神经和迷走神经切断可以显著降低PAF发生率的假设。(4)在有或无去甲肾上腺素和乙酰胆碱注入的情况下，我们将同时进行犬肺静脉的膜电位和细胞内钙标测。这一结果将用于验证去甲肾上腺素和乙酰胆碱同时刺激犬PV的假说，该假说是通过钙瞬变触发机制促进触发活动的。

DESCRIPTION (provided by applicant): The broad and long-term objective of this research project is to test the hypothesis that simultaneous sympathovagal discharges are the immediate triggers of paroxysmal atrial fibrillation (PAF) and that severing the connection between the autonomic nerves and the heart can reduce the incidence of PAF. Autonomic nervous system is thought to be important in mediating PAF. However, no studies have documented a direct relationship between autonomic nerve discharges and the mechanisms of PAF in ambulatory animals. The mechanisms by which autonomic nerve discharges trigger AF are also poorly understood. The research project is designed to accomplish the following specific aims: (1) We will perform long-term simultaneous recordings of electrocardiogram (ECG), blood pressure, right and left stellate ganglion nerve activity and cardiac vagal nerve activity in a canine model of spontaneous PAF induced by short-term rapid atrial pacing. The data will be used to test the hypothesis that simultaneous sympathovagal activation is the most common immediate trigger of PAF in ambulatory dogs. (2) We will perform high density mapping of pulmonary veins to test the hypothesis that repetitive rapid activities in these veins can be induced by stimulation of stellate ganglia and vagal nerves in this canine model of PAF. The results will be used to test the hypothesis that sympathovagal stimulation can induce focal discharges from the remodeled pulmonary veins characterized by an increased density of autonomic nerve endings. (3) We will perform cryoablation of the left stellate ganglion and cardiac vagal nerves in the same animal models of PAF as that described in Aim 1. We will then perform long-term simultaneous recordings of ECG, blood pressure and autonomic nerve activities. The results will be used to test the hypothesis that selective cardiac sympathetic and vagal denervation can significantly reduce the incidence of PAF. (4) We will perform simultaneous membrane potential and intracellular calcium mapping of canine pulmonary veins with or without norepinephrine and acetylcholine infusion. The results will be used to test the hypothesis simultaneous norepinephrine and acetylcholine stimulation in canine PV in vitro promotes triggered activity through Ca transient triggering mechanisms.