Inducibility of Atrial Fibrillation After GP Ablations and “Autonomic Blockade”: Evidence for the Pathophysiological Role of the Nonadrenergic and Noncholinergic Neurotransmitters

Abstract

Autonomic Blockade and Atrial Fibrillation. Background: Recent clinical reports that used cholinergic and adrenergic blockade (CAB) as an alternative to ganglionated plexi (GP) ablation to terminate atrial fibrillation (AF) showed mixed results. We investigated the role of other neurotransmitters in AF inducibility.Methods: In 23 pentobarbital anesthetized dogs, a left and right thoracotomy allowed the attachment of electrode catheters to the left and right pulmonary veins and atrial appendages (AA). Programmed stimulation was used to determine the effective refractory periods (ERP) and AF inducibility, measured by the window of vulnerability (WOV). AF duration in response to acetylcholine (Ach; 100 mM) applied to the AA was measured before and after GP ablation + CAB and with vagus nerve stimulation (VNS). After GP ablation + CAB, Ach induced AF duration was determined in response to vasoactive intestinal peptide (VIP) and its specific antagonist ([Ac-Tyr1,D-phe2]-VIP).Results: GP ablation + CAB significantly prolonged ERP, eliminated WOV, and suppressed the duration of Ach induced AF (P ≤ 0.01 for all). Also slowing of the heart rate by VNS was essentially blocked; however, with Ach 100 mM applied to the AA, VNS, and VIP applied to the AA markedly prolonged AF duration. This effect was blocked by the VIP antagonist.Conclusions: Neither GP ablation nor CAB can fully suppress AF inducibility arising from the atrial neural network. Our findings suggest that other neurotransmitters, such as VIP released during VNS, can promote sustained AF despite GP ablation and "autonomic blockade," which may further define the substrate for AF outside the pulmonary vein-

What Tissue Does Circumferential PV Isolation Actually Modulate?

“…The authors conclude that PV firing may be secondary to an ‘upstream’ abnormality within the CANS. These results, and substantial prior data 8, 24 , are consistent with this intriguing hypothesis. However, one major caveat is that localizing human atrial ganglionated plexi is not trivial.…”

Device-Based Autonomic Modulation in Arrhythmia Patients: the Role of Vagal Nerve Stimulation

“…In a canine pacing-induced AF model, VNS became pro-arrhythmic at intensities that decreased heart rate more than 40% [70]. High-intensity VNS reduces atrial effective refractory period (AERP) [68, 71], may preferentially affect right AERP more than left [72], increases AERP dispersion [68, 73, 74], causes a heterogeneity in atrial conduction leading to wave front breaks [75, 76], reduces AF threshold, and prolongs duration of AF [77]. The pro-arrhythmic effects of VNS that lead to AF have been shown to be mediated by acetylcholine activation of nicotinic receptors [71] and VIP [77].…”

Autonomic cardiac innervation

“…However, some caution in effectiveness of these therapies comes from the residual presence of scar tissue or fibrosis that will continue to serve as a substrate for arrhythmia generation 245 . In addition, a potential role of the parasympathetic neuropeptide vasoactive intestinal polypeptide was demonstrated for promotion of atrial fibrillation in a canine model, 246 suggesting that pharmacological block strategies may need to consider neuropeptides as well as classical neurotransmitters.…”