Autonomic Nerve Activity and Paroxysmal Atrial Fibrillation

描述(申请人提供)：该研究项目的广泛和长期目标是开发基于机制的治疗犬模型中的阵发性房性快速性心律失常，包括阵发性房颤(PAF)和阵发性房性心动过速(PAT)。众所周知，自主神经系统(ANS)在控制心率和心脏收缩能力方面都很重要。在之前的资助期间，我们成功地开发了记录活动犬自主神经活动的方法，并证明了它们在起搏诱发心力衰竭和间歇性快速心房起搏的狗的心律失常发生中的重要性。我们还首次开发了记录心脏内源性神经活动(ICNA)的方法，以证明其在触发活动犬房颤中的重要性。然而，在我们将这些新发现转化为患者护理之前，还需要进行更多的研究。我们建议在下一个资金阶段实现以下具体目标：目标1：GP消融对房颤的影响。在冷冻消融心脏左上GP(SLGP)和马歇尔韧带(LOM)GP的情况下，记录双侧星状神经节神经活动(SGNA)和迷走神经活动。这一结果将被用来检验这样的假设：(1)GP消融可以预防活动犬的自发性PAT和PAF，(2)GP消融的抗心律失常作用至少部分依赖于成功地减少ECNA和ICNA之间的协调放电。目的2：低位迷走神经刺激对心脏神经活动和自发性房性快速性心律失常的影响。我们将同时测量左侧星状神经节神经活动(SGNA)和左侧上GP神经活动(SLGPNA)，同时对走行犬进行LL-VNS或Sham VNS。神经记录和组织学结果将被用来验证这样的假设：(1)LL-VNS导致左侧星状神经节SGNA减少，并伴有结构性神经重构；(2)LL-VNS可以减少间歇性快速心房起搏犬PAT和PAF的发生率。目的3：持续房颤时迷走神经对房室传导的影响。我们将进行一项研究来检验这一假说，即在持续性房颤时，左侧VNS可以通过激活下腔静脉-下房GP(IVC-IAGP)来调节房室结传导，以及VNS可以通过同时减少SGNA和增加IVC-IAGPNA来改善心室率控制。目的4：心力衰竭时不同的外源性心脏神经活动与ICNA重构。我们将同时进行SGNA、韧带马歇尔神经活动(LOMNA)和起搏诱导的心力衰竭期间的左心室(LV)压力记录，以检验(1)LOMNA直接控制基线时的左室收缩能力，(2)心力衰竭增加SGNA但减少LOMNA，导致神经对左室收缩的无效控制。(3)心衰时房性快速性心律失常是SGNA引起的，而不是LOMNA引起的。所有这四个目标都具有重要的临床意义，并可能导致控制房颤和心力衰竭的新的治疗方法。 公共卫生相关性：在美国和其他发达国家，房颤是最常见的心律失常。这项研究项目与公众健康相关，因为它建议研究心房颤动的神经机制，并开发基于机制的治疗这种重要的心律失常。

DESCRIPTION (provided by applicant): The broad and long-term objective of this research project is to develop mechanism-based therapies for paroxysmal atrial tachyarrhythmias including paroxysmal atrial fibrillation (PAF) and paroxysmal atrial tachycardia (PAT) in canine models. It is known that the autonomic nervous system (ANS) is important in controlling both heart rhythm and cardiac contractility. In the previous funding period, we successfully developed methods to record autonomic nerve activities in ambulatory dogs, and documented their importance in cardiac arrhythmogenesis in dogs with pacing-induced heart failure and intermittent rapid atrial pacing. We also for the first time developed methods to record intrinsic cardiac nerve activity (ICNA) to document its importance in triggering AF of ambulatory dogs. However, more studies need to be done before we can translate these new findings to patient care. We propose to pursue the following specific aims in the next funding period: Aim 1: Effects of GP ablation on AF. We will record bilateral stellate ganglion nerve activity (SGNA) and vagal nerve activity in dogs with and without cryoablation of superior left GP (SLGP) and ligament of Marshall (LOM) GPs in the heart. The results will be used to test the hypotheses that (1) GP ablation prevents spontaneous PAT and PAFs in ambulatory dogs and (2) The antiarrhythmic effects of GP ablation depends at least in part on successful reduction of coordinated firing between ECNA and ICNA. Aim 2: Effects of low-level vagus nerve stimulation (LL-VNS) on cardiac nerve activity and spontaneous atrial tachyarrhythmias. We will simultaneously measure left stellate ganglion nerve activity (SGNA) and superior left GP nerve activity (SLGPNA) while performing either LL-VNS or sham VNS in ambulatory dogs. The nerve recordings and histological findings will be used to test the hypothesis that (1) LL-VNS results in reduced SGNA, accompanied by structural neural remodeling in the left stellate ganglion and (2) LL-VNS can reduce the incidence of PAT and PAF in dogs with intermittent rapid atrial pacing. Aim 3: Effects of VNS on atrioventricular (AV) conduction during sustained AF. We will perform a study to test the hypothesis that left VNS can modulate AV node conduction through the activation of the inferior vena cava-inferior atrial GP (IVC- IAGP) during sustained AF, and that VNS can improve ventricular rate control by simultaneously reducing the SGNA and increasing IVC-IAGPNA. Aim 4: Differential extrinsic cardiac nerve activity (ECNA) and ICNA remodeling in heart failure. We will perform simultaneous SGNA, ligament of Marshall nerve activity (LOMNA) and left ventricular (LV) pressure recordings at baseline and during pacing-induced heart failure to test the hypotheses that (1) LOMNA directly control LV contractility at baseline, (2) Heart failure increases SGNA but reduces LOMNA, leading to ineffective neural control of LV contraction. (3) SGNA, not LOMNA, is responsible for atrial tachyarrhythmias in heart failure. All four aims have significant clinical relevance, and may lead to novel therapeutic approaches to controlling AF and heart failure. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is the most common arrhythmia in the United States and other developed countries. This research project is relevant to public health because it proposes to investigate the neural mechanisms of atrial fibrillation and to develop mechanism-based therapy of this important cardiac arrhythmia.