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

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‐atrial junctions. (J Cardiovasc Electrophysiol, Vol. 24, pp. 188‐195, February 2013)     

Localization of Left Atrial Ganglionated Plexi in Patients with Atrial Fibrillation

Background. The intrinsic cardiac autonomic nervous system (ICANS), which forms a neural network, has been shown to be a critical element responsible for the initiation and maintenance of atrial fibrillation (AF). We developed a technique to localize and ablate the ganglionated plexi (GP), which serves as the "integration centers" of the ICANS.
Method. The four major atrial GP are localized by delivering high frequency stimulation (HFS; 20 Hz, 10–150 V, 1–10 ms pulse width) to atrial tissue where GP are presumed to be located. Sites showing a parasympathetic response, which is arbitrarily defined as ≥50% increase in mean R-R interval during AF, was assigned as a GP site. Radiofrequency current is then applied to that site to eliminate the parasympathetic response. All patients received ablation of the four major atrial GP, followed by pulmonary vein antrum ablation.
Results. Our preliminary results showed that all the four major atrial GP can be identified in the vast majority of patients. The parasympathetic response can be eliminated by applying radiofrequency current. In the first 83 patients, the percent of patients free of symptomatic AF or atrial tachycardia after a single ablation procedure was 80% at 12 months and 86% at a mean follow-up of 22 months.
Conclusion. These results indicate additional benefits of GP ablation to PV antrum ablation and improvement with time, particularly ≥ 12 months after ablation. We postulate that this late benefit may result from destruction of the autonomic neurons in the GP that cannot regenerate.     

Autonomic Elements within the Ligament of Marshall and Inferior Left Ganglionated Plexus Mediate Functions of the Atrial Neural Network

Objectives: We sought to systematically investigate the role of the ligament of Marshall (LOM) and inferior left ganglionated plexi (ILGP) in modulating electrophysiological functions.
Methods: The following structures were exposed in 36 dogs: (1) LOM, (2) superior left GP (SLGP) near the junction of left superior pulmonary vein (LSPV) and left atrium, (3) ILGP near the left inferior pulmonary vein-atrial junction, (4) anterior right GP (ARGP) near the sino-atrial node, and (5) inferior right GP (IRGP) at the junction of inferior vena cava and atria. High frequency stimulation (HFS; 0.6-8.0 V, 20 Hz, 0.1 msec in duration) was applied to the LOM, SLGP, ILGP, ARGP, IRGP, or vagosympathetic trunk. Ventricular rate (VR) during atrial fibrillation (AF) was compared before and after ablation of GP in different sequences.
Results: ARGP + ILGP ablation but not ARGP ablation alone eliminated the VR slowing response induced by LOM stimulation, suggesting that all the autonomic innervation from the LOM to AV node passes the ILGP. LOM ablation attenuated the VR slowing response caused by SLGP or left vagosympathetic stimulation, suggesting that LOM modulates the autonomic innervation between the AV node and the left vagosympathetic trunk or SLGP. ARGP attenuated while ARGP + ILGP ablation eliminated the VR slowing response induced by left vagosympathetic stimulation, suggesting that both ARGP and ILGP modulate the AV nodal innervation of the extrinsic and intrinsic cardiac autonomic nervous system (ANS).
Conclusion: The LOM and ILGP function as the "integration centers" that modulate the autonomic interactions between extrinsic and intrinsic cardiac ANS on AV nodal function.     

Molecular Biology of the Voltage-Gated Potassium Channels of the Cardiovascular System

Cardiovascular K⁺ Channel Molecular Biology. K⁺ channels represent the most diverse class of voltage-gated ion channels in terms of function and structure. Voltage-gated K⁺ channels in the heart establish the resting membrane K permeability, modulate the frequency and duration of action potentials, and are targets of several antiarrhythmic drugs. Consequently, an understanding of K⁺ channel structure-function relationships and pharmacology is of great practical interest. However, the presence of multiple overlapping currents in native cardiac myocytes complicates the study of basic K⁺ channel function and drug-channel interactions in these cells. The application of molecular cloning technology to cardiovascular K⁺ channels has identified the primary structure of these proteins, and heterologous expression systems have allowed a detailed analysis of channel function and pharmacology without contaminating currents. To date six different K⁺ channels have been cloned from rat and human heart, and all have been functionally characterized in either Xenopus oocytes or mammalian tissue culture systems. This initial research is an important step toward understanding the molecular basis of the action potential in the heart. An important challenge for the future is to determine the cell-specific expression and relative contribution of these cloned channels to cardiac excitability.     

Functional Properties of the Superior Vena Cava (SVC)‐Aorta Ganglionated Plexus: Evidence Suggesting an Autonomic Basis for Rapid SVC Firing

Superior Vena Cava‐Aorta Ganglionated Plexus . Introduction: The mechanism underlying spontaneous rapid superior vena cava (SVC) firing that initiates atrial fibrillation (AF) remains poorly understood. We investigated the role of the SVC‐aorta‐ganglionated plexus (SVC‐Ao‐GP) in AF initiated by rapid firing from the SVC. Methods and Results: In 42 dogs, a circular catheter was positioned above the SVC‐atrial junction. Multielectrode catheters were sutured on atria, atrial appendages and pulmonary veins. The effective refractory period (ERP) and window of vulnerability (WOV) for AF were measured at all sites in the baseline state, during cervical vagosympathetic trunk stimulation and during SVC‐Ao‐GP stimulation, before and after SVC‐Ao‐GP ablation. AF inducibility was also assessed by delivering high‐frequency stimulation (HFS) within myocardial refractory period to the SVC before and after SVC‐Ao‐GP ablation. HFS applied to the SVC‐Ao‐GP slowed the sinus rate and/or atrioventricular conduction. 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. AF induced at the SVC by HFS during refractoriness was eliminated by ablation of the SVC‐Ao‐GP but was not altered by ablation of the 4 major atrial GP. Direct injection of acetylcholine into the SVC‐Ao‐GP initiated rapid firing from the SVC in every case. Conclusions: The SVC‐Ao‐GP preferentially modulates the electrophysiological function of the SVC sleeves and may contribute to rapid firing from the SVC. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1392‐1399, December 2010)