Autonomic Mechanism For Atrial Fibrillation

Clinical studies reported that most paroxysmal atrial fibrillation (AF) was due to rapid firing originating from pulmonary veins (PVs) or superior vena cava (SVC). Radiofrequency ablation for isolating PVs or SVC can reduce or prevent AF recurrence. Previous investigations have focused on the mechanism underlying rapid firing originating from PVs or SVC from histological and electrophysiological aspects. However, the results of numerous in vivo and in vitro studies on this subject have not conclusively defined a mechanism. Several studies suggested that PV isolation is not absolutely necessary for eliminating AF since ablation strategies targeting complex fractionated atrial electrograms (CFAE) or ganglionated plexus (GP) with PV or SVC potentials preserved are also effective. A clear understanding of the respective role of PV, SVC, CFAE and GP in the mechanisms for AF is extremely important for establishing the best target for AF ablation. Our previous studies indicated that the intrinsic cardiac autonomic nervous system is involved in the initiation of AF. Clinical data also reported that GP ablation can prevent paroxysmal AF and even chronic AF with significant atrial electrical remodeling in some patients. In this serial of experiments, the autonomic mechanisms for rapid firing, CFAE and atrial electrical remodeling were studied.Aims:1、To investigate the autonomic mechanism for rapid firing originating from PVs and atrial sites.2、To investigate the autonomic mechanism for rapid firing originating from SVC.3、To investigate the autonomic mechanism for CFAE.4、To investigate the autonomic mechanism for acute atrial electrical remodeling induced by rapid pacing.Methods:Adult healthy mongrel dogs weighing 20～25 kg were used. The chest was entered via a left or right thoracotomy at the 4th intercostal space. Multi-electrode catheters were sutured to allow recording and stimulation at the left and right PVs, both atria and atrial appendages (AA). A ring (Lasso) catheter was advanced into the SVC for recording and stimulation via the right jugular vein. Left and right vagosympathetic trunks were isolated for stimulation. All tracings from the electrode catheters were amplified and digitally recorded.1、High-frequency electrical stimulation (HFS,200Hz) coupled to each S1S1 (cycle length=330 msec) pacing stimulus was delivered within myocardial refractoriness to selectively stimulate local neural elements at each site. The lowest HFS voltage at which AF was induced, i.e., AF threshold, was determined before and after (1) ablation of ipsolateral or contralateral GP and (2) administration of autonomic blockers, esmolol or atropine.2、The effective refractoriness period (ERP) and window of vulnerability (WOV) of AF were determined during stimulation and after ablation of the GP in "the 3rd fat pad" (SVC-Ao GP). Rapid firing was induced by HFS within myocardial refractoriness at the SVC sleeves. The inducibility of rapid firing by HFS was measured after ablation of the SVC-Ao GP or the major atrial GP.3、Sustained AF was induced by local application of acetylcholine (Ach 10,100 mM) to the surface of the AA or by injection of Ach (10 mM) into the fat pads containing GP. The extent and degree of CFAE on the atrium were measured before and after ablation of ipsolateral GP.4、Rapid pacing (1200 bpm) was delivered at the left atrial appendage for 6 hours before and after ablation of the major atrial GP. ERP and WOV were measured at each site during each pacing hour and after GP ablation.Results:1、Rapid firing-mediated AF was induced by local HFS during myocardial refractoriness at each site. Ablation of left or right-sided GP on the atria significantly increased AF threshold at ipsolateral and contralateral PVs, atrium and atrial appendage. Administration of esmolol (1 mg/kg) or atropine (1 mg), significantly elevated AF threshold at all sites.2、HFS of the SVC-Ao GP induced more significant shortening of ERP and a greater increase in WOV at the SVC than other sites. Ablation of the SVC-Ao GP significantly increased the baseline ERP and decreased the baseline WOV only at the SVC. Rapid firing mediated-AF induced at SVC by HFS was eliminated by ablation of the SVC-Ao GP but was not altered by ablation of the major atrial GP.3、After AF was induced with Ach either by topical application to the AA or by direct injection into the GP, CFAE exhibited a significant gradient of progressively decreasing dominant frequency (DF) and incidence of CFAE (CFAE%) from the GP toward distant sites while regularity index (RI) progressively decreased in the opposite direction. Ablation of GP markedly attenuated CFAE and eliminated these gradients.4、In animals with rapid pacing first, ERP was markedly shortened in the first two hours and WOV was progressively widened throughout the 6-hour period. After GP ablation, ERP was significantly longer than before ablation and AF could not be induced at any site. In animals with GP ablation or administration of autonomic blockers first, rapid atrial pacing failed to shorten the ERP, and AF could not be induced in most dogs.Conclusions:1、Interconnected atrial autonomic network contributes to the formation of rapid firing from the PV and atrial sites in structurally normal hearts. Autonomic denervation suppresses or eliminates those rapid firings.2、The SVC-Ao GP not only acts as the "head-stage" for the extrinsic autonomic innervations to the heart, but also preferentially modulates electrophysiological and pathophysiological properties of the SVC sleeves. Activation of the SVC-Ao GP eliminates rapid firing originating from the SVC.3、Activation of the intrinsic cardiac autonomic nervous system plays an important role in the genesis of CFAE. Ablation of GP attenuates CFAE and eliminates the CFAE gradients.4、GP ablation reverses and prevents acute electrical remodeling induced by rapid atrial pacing, suggesting that the intrinsic cardiac autonomic nervous system is crucial for this process. The actions or hyperactivity of the autonomic nervous system itself may be a crucial element in acute atrial remodeling.