Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia

Intrinsic Cardiac Ganglia Activity Inhibited by Low‐Level Vagal Stimulation . Introduction: We hypothesized that low‐level vagosympathetic stimulation (LL‐VNS) can suppress atrial fibrillation (AF) by inhibiting the activity of the intrinsic cardiac autonomic nervous system (ICANS). Methods and Results: Wire electrodes inserted into both vagosympathetic trunks allowed LL‐VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrode catheters were attached to atria, atrial appendages and all pulmonary veins. Electrical stimulation at the anterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state of the ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL‐VNS. Neural activity was recorded from the ARGP or SLGP. ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL‐VNS (10% or 50% below threshold) at all tested sites. Sham LL‐VNS failed to induce these changes. The effects of LL‐VNS were mediated by inhibition of the ICANS, as evidenced by (1) LL‐VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL‐VNS, and (3) the spatial gradient of the ERP and WOV from the PV‐atrial junction toward the atrial appendage was eliminated by LL‐VNS. Conclusions: LL‐VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS. (J Cardiovasc Electrophysiol, Vol. 22, pp. 455‐463)     

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)     

Antiarrhythmic effects of vasostatin-1 in a canine model of atrial fibrillation

Antiarrhythmic Effects of Vasostatin‐1 . Background: We examined the antiarrhythmic effects of vasostatin‐1, a recently identified cardioregulatory peptide, in canine models of atrial fibrillation (AF). Methods and Results: In 13 pentobarbital‐anesthetized dogs bilateral thoracotomies allowed the attachment of multielectrode catheters to superior and inferior pulmonary veins and atrial appendages (AA). Rapid atrial pacing (RAP) was maintained for 6  hours. Each hour, programmed stimulation was performed to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3  hours, vasostatin‐1, 33  nM, was injected into the anterior right (AR) ganglionated plexus (GP) and inferior right (IR) GP every 30  minutes (n = 6). Seven dogs underwent 6  hours of RAP only (controls). At baseline, acetylcholine, 100  mM, was applied on the right AA and AF duration was recorded before and after injection of vasostatin‐1, 33  nM, into the ARGP and IRGP. In separate experiments (n = 8), voltage–sinus rate response curves (surrogate for GP function) were constructed by applying high‐frequency stimulation to the ARGP with incremental voltages with or without vasostatin‐1. Vasostatin‐1 significantly decreased the duration of acetylcholine‐induced AF (11.0 ± 4.1 vs 5.5 ± 2.6 min, P = 0.02). The cumulative WOV (the sum of individual WOVs) significantly increased (P < 0.0001) during the first 3  hours and decreased toward baseline in the presence of vasostatin‐1 (P < 0.0001). Cumulative WOV in controls steadily increased. Vasostatin‐1 blunted the slowing of sinus rate with increasing stimulation voltage of ARGP. Conclusions: Vasostatin‐1 suppresses AF inducibility, likely by inhibiting GP function. These data may provide new insights into the role of peptide neuromodulators for AF therapy. (J Cardiovasc Electrophysiol, Vol. 23, pp. 771‐777, July 2012)     

自主神经干预对心房恢复性质的影响

目的 研究心脏自主神经干预对心房恢复性质的影响.方法 正常成年杂种犬10只,开胸后将多极电生理导管缝置于肺静脉、左右心耳和左右心房处,应用Ag-AgCl电极记录标测部位单相动作电位,在基础状态和颈部迷走神经刺激条件下构建标测部位恢复曲线,分别对标测部位进行快速电刺激,记录心房颤动（房颤）诱发时的起搏周长和持续时间.心脏自主神经节（GP）消融后重复上述步骤.结果 GP消融前迷走神经刺激同基础状态相比显著缩短动作电位时限（APD）,降低恢复曲线最大斜率（Smax）,抑制APD电交替,但房颤容易发生（P＜0.05）.GP消融后,APD较消融前显著延长,恢复曲线Smax增大,APD电交替提前,但房颤不易诱发（P＜0.05）;GP消融后迷走神经刺激效应明显减弱.GP消融前迷走神经刺激能显著增加APD恢复曲线Smax离散度（0.5±0.2对0.3±0.1,P＜0.05）,而GP消融能显著降低APD恢复曲线Smax离散度（0.2±0.1对0.3±0.1,P＜0.05）.结论 恢复曲线的斜率并不能完全解释房颤的诱发和维持,心房APD电交替可能对房颤的诱发并无预测作用,恢复性质的离散可能是诱发房颤的重要因素.     

Comparison of atrial fibrillation inducibility by electrical stimulation of either the extrinsic or the intrinsic autonomic nervous systems

Objectives  To study the effects of bilateral vagosympathetic nerve stimulation (VNS) and ganglionated plexi stimulation (GPS) on atrial refractoriness and inducibility of atrial fibrillation (AF). Methods  Studies were performed in fourteen adult mongrel dogs anesthetized with Na-pentobarbital, 30 mg/kg. VNS was achieved by insertion of wires into the left and right VN trunks. An octapolar catheter was attached to contact the right superior pulmonary vein (RSPV) and other octapolar catheter electrodes were sutured to the right atrial (RA) free wall and appendage (RAA). GPS was performed via a plaque electrode sutured to the fat pad containing the anterior right (AR) GP. VNS and GPS were matched to decrease heart rate by ∼50%. Programmed stimulation delivered from the RSPV or RAA at 2×, 4× and 10× threshold (TH) allowed the determination of atrial refractory period (ARP) and the AF inducibility. The latter was quantitated by the cumulative window of vulnerability (WOV), i.e., the longest minus the shortest coupling interval during which AF was induced at 2×, 4×, 10×, TH combined. Results  Programmed electrical stimulation at the RSPV showed that the ARP was significantly shorter for both VNS and GPS than baseline (baseline, 113 ± 22 ms; VNS, 94 ± 26 ms; GPS, 85 ± 31 ms) but there was no significant difference in ARP between VNS and GPS. In contrast, the cumulative WOV was significantly wider with GPS (39 ± 36 ms) than either the baseline state (1 ± 1 ms) or with VNS (14 ± 26 ms), p < 0.05. Moreover, pacing from RAA showed a significantly greater cumulative WOV for VNS (33 ± 36 ms) vs both baseline and GPS (1 ± 4 ms and 15 ± 26 ms, respectively, p < 0.05). The heart rate slowing caused by GPS and VNS was not significantly different, 82 ± 11/min vs 82 ± 7/min. Conclusions  These data indicate a distinct functional separation of autonomic nerve innervation to the atria from the extrinsic and intrinsic nervous systems. AF is more liable to occur due to intrinsic nerve stimulation at the PVs whereas peripheral atrial sites are more readily inducible for AF due to the extrinsic neural input. Supported, in part by grant #0650077Z from the American Heart Association (SSP), grant #K23HL069972 from the National Heart, Lung and Blood Institute (SSP) and from the Helen and Wil Webster Research Fund of the Oklahoma University Research Foundation.     

低强度自主神经节刺激对心房电生理特性的影响

目的研究6h低强度自主神经节（GP）刺激对犬心房电生理性质的影响。方法22只成年杂种犬开胸暴露心脏,在左右心房、左右心耳及肺静脉缝置多极电极导管用以记录和刺激。实验组16只犬同时在左上GP及右前GP予以6h低强度高频刺激（0．1—1．0V）,使心率下降10％。对照组6只犬在心房远离GP处给于同样6h低强度刺激（无心房激动）。刺激前、刺激开始时及6h刺激后测定各部位有效不应期（ERP）及心房颤动（房颤）易颤窗口（WOV）。结果在实验组犬中,GP刺激开始时ERP及WOV较刺激前差异均无统计学意义,GP刺激6h后各部位ERP均显著缩短,总WOV显著增加（127＋35对0对0,P〈O．05）。对照组中,刺激前、刺激开始时及刺激6h后ERP及WOV（3±2对0对0,P〉0．05）差异均无统计学意义。结论6h低强度GP刺激可致心房电生理性质显著改变,并有利于房颤发生,提示长期低强度自主神经系统激活可形成有利于房颤发生的电生理基质。     

Ablation of Ligament of Marshall Attenuates Atrial Vulnerability to Fibrillation Induced by Inferior Left Atrial Fat Pad Stimulation in Dogs

Ligament of Marshall and Atrial Fibrillation Induction. Background: The role of ligament of Marshall (LOM) in the mechanism of “vagal” atrial fibrillation (AF) is still unknown. Objective: To investigate the impact of LOM ablation on atrial vulnerability to AF induced by inferior left atrial fat pad (ILAFP) stimulation in dogs. Methods: AF inducibility and atrial effective refractory period (ERP) were elevated before and after LOM ablation in 8 of 14 dogs (the ablation group). Same protocol but without LOM ablation was conducted in the remaining 6 dogs (the control group). The activation patterns of LOM and left pulmonary veins (LPVs) during sustained AF were analyzed. The distribution of epicardial cholinergic nerve fibers between LOM and ILAFP was investigated in the control group. Results: Ablation of LOM significantly attenuated AF inducibility (87.5% vs 33.3%, P < 0.001) and prolonged ERPs of the structures in contiguity with LOM (P < 0.05) in the ablation group. In contrast, there was no significant change in ERPs and AF inducibility in the control group. During sustained AF, fractionated atrial electrograms were more common in the LOM area than the LPVs (84% vs 18% of the analyzed episodes, P < 0.001). In 46.7% of the episodes with identifiable LOM spikes, atrial potentials, and LOM spikes were related in 2:1 or 3:2 pattern during the intermittent organized activity. Acetylcholinesterase staining revealed a close cholinergic nerved relationship between LOM and ILAFP. Conclusions: LOM plays a critical role in maintaining AF induced by stimulation of ILAFP. Ablation of LOM can markedly attenuate AF inducibility in this model. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1024‐1030, September 2010)     

心脏自主神经节消融治疗睡眠呼吸暂停并发心房颤动的实验研究

目的研究心脏自主神经节（GP）消融对睡眠呼吸暂停（sA）并发心房颤动（房颤）的影响。方法成年杂种犬13只，采用随机数字法分为2组。第1组先制作SA模型再行GP消融（n=7），分别在基础状态、SA1h和GP消融后记录心电图、采集动脉血及测量心房、肺静脉和上腔静脉的不应期（ERP）和心房易颤窗口（WOV）；第2组先行GP消融再制作SA模型（n=6），分别在基础状态、GP消融后和SA1h后收集或测量以上参数。比较心率、血压、动脉血气、心率变异性（HRV）和各部位ERP、WOV在两组之间和消融前后的变化。结果第1组在SA过程中，心率、血压先上升后下降，SA1h末HRV低频／高频比值（LF／HF）减小[（0．6±0．2）对（0．8±0．2），P〈0．05]，各部位ERP显著缩短，2WOV显著增加（P〈0．05）。GP消融后LF／HF增大[（1．1±0．3）对（0．8±0．2），P〈0．05]，各部位ERP显著延长，EWOV显著减小（P〈0．05）。第2组在GP消融后，SA过程中心率、血压同样先上升后下降，各部位ERP不同程度缩短，但LF／HF和EWOV变化则不明显。无论先SA或者先消融GP，两组犬在SA1h末均出现低氧血症、高碳酸血症和酸中毒。结论自主神经活性的变化在SA并发的房颤中起着重要作用，消融心脏GP可以逆转或阻止SA导致的房颤。     

An acute model for atrial fibrillation arising from a peripheral atrial site: evidence for primary and secondary triggers

Background: We previously demonstrated that acetylcholine (Ach) injected into cardiac ganglionated plexi (GP) causes pulmonary vein (PV) ectopy initiating atrial fibrillation (AF).
Objective: To determine the effects of Ach applied at non-PV sites.
Methods: Overall, 54 dogs were anesthetized with Na-pentobarbital. A right and left thoracotomy allowed the placement of multielectrode catheters to record from the superior PVs, mid portion of the atrium and the atrial appendages (AA). A monophasic action potential (MAP) was recorded from the AA. Ach (1, 10, 100 mM) was applied sequentially to the AA.
Results: In 19 of 26 animals, Ach 100 mM on the right (n = 15) or left (n = 4) AA induced focal, sustained AF (≥10 minutes) with rapid regular firing (cycle length = 37 ± 7 ms) at the AA. A clamp with teeth placed across the AA caused arrest in the AA. However, AF was sustained only when PV sites adjacent to the GP manifested complex fractionated atrial electrograms (CFAE). Clamping the AA prior to Ach (100 mM) application resulted in focal AF arising at the PVs but not at the AA. When a clamp without teeth was applied prior to Ach application, no AF at either AA or PV site could be induced.
Conclusion: Isolation of the focal AF at the AA (primary trigger) by clamping caused cessation of activity in the AA, but AF continued due to secondary triggers arising from PVs. The possible mechanism(s) responsible for these findings are discussed, and various ancillary experiments (n = 28) were added to help elucidate mechanisms.     

The atrial neural network as a substrate for atrial fibrillation

Background

Previously, we showed that the ganglionated plexi (GP) on the atrium can play a critical role in the initiation and maintenance of atrial fibrillation (AF). We tested the role of the atrial neural network as a substrate for AF without the influence of the GP.

Methods

In pentobarbital-anesthetized open-chest dogs, two barriers across the left/right atrial appendage (AA) divided the AA into smaller and larger areas of approximately similar size, 2?cm2. Electrical stimulation of the superior left and right GP allowed measurement of the greatest percent slowing of the heart rate prior to atrial excitation (n?=?7). Acetylcholine (Ach; 1, 10, and 100?mM) was applied to the smaller and then to the larger area. In 22 dogs, the effects on AF duration in response to Ach applied to the atria were tested after GP ablations and atropine applied to the atria.

Results

GP function was unchanged by various concentrations of Ach applied to the smaller or larger areas of the atria. However, AF duration was significantly longer for each Ach concentration when applied to the larger versus the smaller area (p????0.01). AF was attenuated by GP ablations and atropine, but the differences between small and large areas were maintained.

Conclusion

Ach on a larger area of the atria significantly increased the induced AF duration compared to an area half the size without changes in GP function suggesting that recruiting a larger area of the atrial neural network provided more of an AF substrate.     

Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi

Introduction . The mechanism(s) whereby atrial ectopy induces atrial fibrillation (AF) is still poorly understood.
Methods and Results . In 12 dogs, we determined the refractory period (RP) along the right atrium (RA) and right superior pulmonary vein (RSPV), and AF inducibility with and without concurrent stimulation of the anterior right ganglionated plexi (ARGP) at the base of the RSPV. Multielectrode catheters were attached to the RSPV and RA with the distal electrodes close to ARGP. The RP and window of vulnerability (WOV), i.e., the longest S₁–S₂ minus the shortest S₁–S₂ at which AF was induced, were measured before and during incremental levels of ARGP stimulation. Mapping of the onset of AF was performed using the EnSite® mapping system (St. Jude Medical, St. Paul, MN, USA) positioned in the RA.
A single premature depolarization (PD) from the RSPV that did not induce AF without ARGP stimulation could do so with ARGP stimulation. The onset of AF consistently arose at the myocardium subtending the ARGP. With GP stimulation, the average WOV at the RSPV-atrial junction was significantly wider than at the RA appendage (65 ± 27 vs. 8 ± 17 msec, P < 0.05) or further along the RSPV sleeve (48 ± 39 vs. 10 ± 20 msec, P < 0.05). Even without GP stimulation, high intensity (10–20 mA) premature stimuli delivered at the RA appendage induced AF, originating from atrial tissue subtending the ARGP, presumably due to axonal conduction that activated the ARGP.
Conclusion . GP stimulation, subthreshold for atrial excitation, converts isolated PDs into AF-inducing PDs, suggesting that autonomic tone may play a critical role in the initiation of paroxysmal AF.     

Pulmonary vein encircling ablation alters the atrial electrophysiologic response to autonomic stimulation

Objective Pulmonary vein encircling ablation is often effective in the treatment of atrial fibrillation (AF). The success of the procedure does not depend upon creation of continuous lines of block. Thus mechanisms by which pulmonary vein encircling can cure AF remain unclear. Stimulation of cardiac autonomic ganglia alters atrial refractoriness and potentiates AF. We hypothesized that pulmonary vein encircling alters atrial autonomic function and that these alterations account in part for prevention of AF recurrences following ablation. Methods Atrial effective refractory periods (ERP) and AF inducibility were quantified in ten dogs before and during central autonomic nerve stimulation. Pulmonary vein encircling ablation was then performed and electrophysiologic testing repeated. In two dogs subjected to sham procedures measurements were repeated without performance of ablation. Hearts were examined histologically. Results Autonomic nerve stimulation led to decreased atrial refractoriness and increased AF inducibility and duration. Each of these effects were attenuated following pulmonary vein encircling (e.g., mean ERP decreased before (−23.7 ± 1.8, p < 0.001) but not after ablation (−2.3 ± 1.9, p = 0.25); AF inducibility increased by 26% before vs. 5% after ablation). No attenuation was seen in the sham operated animals. Histologic analysis following pulmonary vein encircling demonstrated destruction of some but not all autonomic ganglia. Conclusion Autonomic stimulation shortens atrial refractory periods and potentiates AF. Pulmonary vein encircling ablation partially destroys atrial autonomic inputs, attenuates the refractory period shortening effect of autonomic stimulation and decreases AF inducibility. Destruction of autonomic ganglia may contribute to the anti-fibrillatory effects of pulmonary vein encircling and warrants further investigation. Potential conflict of interest: PSS is a consultant to and receives grant support from Biosense Webster Research Support. This study was supported by a research alliance with Medtronic Inc., Minneapolis, MN.     

The effects of caffeine on the inducibility of atrial fibrillation

Introduction

There is widespread belief that caffeine consumption is linked to atrial arrhythmias; however, there is a relative lack of systematic evidence to support the assertion. The purpose of this study was to investigate whether caffeine, in doses equivalent to daily use in the general population, alter the propensity for atrial fibrillation (AF) in an experimental model comparing normal and simulated predisposition to AF.

Methods and Material

Caffeine (caffeine Na benzoate, 50:50 mixture) was administered intravenously at 1, 3, and 5 mg/kg doses in dogs producing serum levels of 2 to 4, 5 to 7, and 8 to 10 μg/mL. To simulate focal AF, premature stimulation from the right superior pulmonary vein was delivered at 2×, 4×, and 10× threshold at a rate of 180/min (S₁-S₂ = 330 milliseconds) without and then with low-level stimulation of ganglionated plexi (GP) at the entrance of the right superior pulmonary vein. The window of vulnerability (WOV), a measure of the propensity for AF inducibility, was determined by the longest coupling interval of the premature beat (S₁-S₂) minus the shortest S₁-S₂, which induced AF. The cumulative WOV is the sum of the individually determined WOV.

Results

At each serum level of caffeine, the cumulative WOV was lower without rather than with GP stimulation compared with control. The cumulative WOV for both the stimulated, that is, predisposed to AF, and nonstimulated, that is, normal groups, exhibited a significantly lower average as compared with that exhibited by the control group (P ≤ .003-.02).

Conclusion

These findings suggest that the presence of caffeine may result in an unexpected reduction in the propensity for AF in healthy individuals and in those with a predisposition for AF (enhanced AF inducibility caused by the stimulation of the GP).     

Wenxin Keli suppresses atrial substrate remodelling after epicardial ganglionic plexi ablation

BACKGROUND:

The chronic effects of ganglionic plexi (GP) ablation on atrial fibrillation (AF) inducibility have not been elucidated.

OBJECTIVE:

To investigate the effect of Wenxin Keli (WK) on the inducibility of AF and atrial substrate remodelling after epicardial GP ablation.

METHODS:

Twenty dogs were randomly divided into a sham-operated group, a GP ablation group and a WK-treated group. All animals underwent a left thoracotomy at the fourth intercostal space. AF inducibility was assessed by burst rapid pacing at the right atrium. Both the GP ablation group and the WK-treated group received four major GP ablations. In the WK-treated group, dogs were treated with oral WK once per day, and all animals were allowed to recover for eight weeks, after which AF inducibility and AF duration were measured again.

RESULTS:

After eight weeks of WK treatment, AF inducibility was lower than in the GP ablation group, and was similar to that of the sham-operated group. Compared with the sham-operated group, the levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in right atrial tissues were increased in GP ablation group (143.6±33.7 pg/mg versus 206.2±41.4 pg/mg, P=0.02; 75.3±12.1 pg/mg versus 141.3±64 pg/mg, P=0.03; and 175.1±42.5 pg/mg versus 351.7±101 pg/mg, P<0.01, respectively). There were no significant differences in levels of ANP, TNF-α and IL-6 in atrial tissues between the sham-operated group and WK treated group. Expression of connexin 43 in atrial tissues was increased after eight weeks of GP ablation, while WK administration inhibited connexin 43 remodelling.

CONCLUSIONS:

Epicardial GP ablation can induce atrial substrate remodelling, including Cx43 upregulation and increased levels of ANP, TNF-α and IL-6. These changes may be suppressed by long-term oral WK administration.     

Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing

Background The superior vena cava (SVC) might serve as the trigger and/or substrate for paroxysmal atrial fibrillation (AF). However, the electrophysiological properties of the SVC with chronic AF are unknown. The purposes of this study were to investigate the electrophysiological properties of the SVC and the electropharmacological effects of intravenous dl–sotalol on the canine SVC after chronic rapid atrial pacing (RAP). Methods and results In the control group, the effective refractory period (ERP), conduction velocity, and AF inducibility of the SVC were assessed in 6 normal dogs before and after an infusion of dl–sotalol. In the experimental group, the ERP, conduction velocity, and AF inducibility of the SVC were assessed before and after dl–sotalol administration in 10 dogs after 8 weeks of RAP. The SVC showed a shorter ERP, decreased slope of rate–adaptation of the ERP, increased ERP dispersion, a decreased conduction velocity, and increased inducibility and duration of AF initiated from the SVC in the RAP dogs. In the RAP dogs, intravenous dl–sotalol significantly increased the ERP, but dlsotalol did not change the slope of rate–adaptation of the ERP, dispersion of the ERP, conduction velocity, inducibility, or duration of AF initiated from the SVC. Conclusions The present study demonstrates that the canine SVC shows significant electrical remodeling and increased AF vulnerability after chronic RAP. Intravenous dl–sotalol was unable to decrease the inducibility or duration of AF initiated from the SVC.Supported in part by grants from the National Science Council (NSC 93-2314- B-341-001) and Shin Kong Wu Ho-Su Memorial Hospital (SKH-TMU-92-28, SKHTMU- NSC-93-01), Taipei, Taiwan, R.O.C.     

Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation

INTRODUCTION: Cervical vagal stimulation shortens the atrial effective refractory period (ERP) primarily in the high right atrium (HRA) and facilitates induction of atrial fibrillation (AF) by single premature HRA extrastimuli. We hypothesized that vagal denervation of the HRA prevents both ERP shortening in the HRA and AF induction during vagal stimulation. METHODS AND RESULTS: Vagal denervation of the HRA was achieved using radiofrequency catheter ablation (RFA) of the fat pad at the right pulmonary vein-atrial junction (RPV fat pad). Programmed stimulation was performed at each of four atrial sites to measure ERP and inducibility of AF during vagal stimulation. RPV fat pad RFA increased only the HRA ERP during vagal stimulation (70 +/- 8.7 vs 117 +/-14.8, P < 0.05). RPV fat pad RFA increased measures of dispersion of refractoriness, the standard deviation of ERP (24 +/- 2.1 vs 33 +/- 2.0, P < 0.01), and the standard deviation of AF cycle length (11 +/- 0.8 vs 22 +/- 1.7, P < 0.001) during vagal stimulation. RPV fat pad RFA increased the incidence of AF (15/28 vs 24/28, P < 0.05) and the vulnerability (22 +/- 4.7 vs 39 +/- 5.6, P < 0.01) to AF induction during vagal stimulation, particularly from left atrial premature beats. After RPV fat pad RFA, premature beats induced AF by causing conduction block primarily in the HRA and macroreentrant activation around the block. CONCLUSION: Partial right atrial vagal denervation facilitated rather than prevented initiation of vagally mediated AF.     

Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation.

OBJECTIVES: This study sought to systematically investigate the interactions between the extrinsic and intrinsic cardiac autonomic nervous system (ANS) in modulating electrophysiological properties and atrial fibrillation (AF) initiation. BACKGROUND: Systematic ganglionated plexi (GP) ablation to evaluate the extrinsic and intrinsic cardiac ANS relationship has not been detailed. METHODS: The following GP were exposed in 28 dogs: anterior right GP (ARGP) near the sinoatrial node, inferior right ganglionated plexi (IRGP) at the junction of the inferior vena cava and atria, and superior left ganglionated plexi (SLGP) near the junction of left superior pulmonary vein and left pulmonary artery. With unilateral vagosympathetic trunk stimulation (0.6 to 8.0 V, 20 Hz, 0.1 ms in duration), sinus rate (SR), and ventricular rate (VR) during AF were compared before and after sequential ablation of SLGP, ARGP, and IRGP. RESULTS: The SLGP ablation significantly attenuated the SR and VR slowing responses with right or left vagosympathetic trunk stimulation. Subsequent ARGP ablation produced additional effects on SR slowing but not VR slowing. After SLGP + ARGP ablation, IRGP ablation eliminated VR slowing but did not further attenuate SR slowing with vagosympathetic trunk stimulation. Unilateral right and left vagosympathetic trunk stimulation shortened the effective refractory period and increased AF inducibility of atrium and pulmonary vein near the ARGP and SLGP, respectively. The ARGP ablation eliminated ERP shortening and AF inducibility with right vagosympathetic trunk stimulation, whereas SLGP ablation eliminated ERP shortening but not AF inducibility with left vagosympathetic trunk stimulation. CONCLUSIONS: The GP function as the "integration centers" that modulate the autonomic interactions between the extrinsic and intrinsic cardiac ANS. This interaction is substantially more intricate than previously thought.     

Autonomic mechanism for chronic atrial electrical remodeling induced by rapid atrial pacing in ambulatory danines

Objetives The mechanism for changes in the electrophysiological properties of the atria during rapid pacing induced atrial fibrillation(AF) is not well understood.We aimed to investigate the contribution of intrinsic cardiac autonomic nervous system(ICANS) in chronic atrial electrical remodeling and AF induced by rapid atrial pacing for 4 weeks. Methods Twelve adult mongrel dogs weighing 15 to 20 kg were assigned to two groups;group 1(experimental group,n= 7) and group 2(control group,n =5).All dogs were anesthetized with propofol and mechanically ventilated via endotracheal tubes.The chest was entered via bilateral mini-thoracotomy at the fourth intercostals space.Bipolar pacing electrode was sutured to the right atrial appendage.Four-electrode catheters(Biosense-Webster,Diamond Bar,CA) were secured to allow recording at the right and left atriaum.All tracings from the electrode catheters were amplified and digitally recorded using a computer-based Bard Laboratory System (CR Bard Inc,Billerica,MA).Electrograms were filtered at 50 to 500 Hz.Continuous rapid pacing(600 bpm, 2×threshold[TH]) was performed at the right atrial appendage. Ganglionated Plexi(GP) was localized by applying high frequency stimulation(HFS;20 Hz,0.1ms duration, 0.5 to 4.5 V)with a bipolar stimulation-ablation probe electrode (AtriCure,West Chester,OH).Group1 underwent ablation of bilateral GP and ligament of Marshall followed by 4-week pacing.Group 2 underwent sham operaton without ablation of GP and ligament of Marshall followed by 4-week pacing.The effective refractory period(ERP) and window of vulnerability(WOV) were measured at 2×TH before(baseline) and every week after GP ablation.WOV was defined as the difference between the longest and the shortest coupling interval of the premature stimulus that induced AF.GP consist of the anterior right ganglionated plexi(ARGP) located in the fat pad at the right superior pulmonary vein(RSPV)-atrial junction;the inferior right ganglionated plexi(IRGP) located at the inferior vena cava/right atr     

Neural mechanism of atrial fibrillation: insight from global high density frequency mapping

Frequency Mapping During Neurally Mediated AF. Background: It has been demonstrated that intrinsic cardiac autonomic activation of ganglionated plexi (GPs) exhibits a frequency gradient from the center to the periphery with limited mapping. Objective: We aimed to use a global mapping tool (Ensite Array) to identify the frequency distribution and clarify the interaction between the extrinsic/intrinsic autonomic systems. Methods: A mid sternal thoractomy was performed in anesthetized dogs. High frequency stimulation (20 Hz, 0.1 ms duration) was applied to locate the GPs and achieve vagosympathetic stimulation (VNS). There were 4 major GPs, which were located near the 4 pulmonary vein (PV) ostia, and a third fat pad (SVC‐Ao) GP that was located near the superior vena cava (SVC)‐right atrial (RA) junction. Results: Without VNS (n = 12), the left atrial (LA) mean (8.20 ± 0.11 vs 7.95 ± 0.30 Hz, P = 0.04) and max (9.86 ± 0.28 vs 9.43 ± 0.29 Hz, P = 0.03) DFs were higher during the PV ostial GP stimulation than the SVC‐Ao GP stimulation. The LA max DFs were located not only at the primary GPs but also the nearby secondary PV ostial GPs. The RA mean DF (8.36 ± 0.05 vs 7.99 ± 0.19 Hz, P = 0.04) was higher during SVC‐Ao GP stimulation than PV ostial GP stimulation. The max DF was located inside the SVC during SVC‐Ao GP stimulation and at the RA septum during PV ostial GP stimulation. With VNS (n = 12), the LA mean and max DFs between the PV ostial and SVC‐Ao GP stimulation were similar. The DF distribution shifted to non‐GP LA sites during both the PV ostial and SVC‐Ao GP stimulation. Conclusion: The findings indicate that the AF was caused by an interaction between the PV ostial GPs during intrinsic autonomic stimulation, whereas the non‐GP LA sites were responsible for the AF induced by an extrinsic neural input. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1049‐1056, September 2011)     

电刺激犬心室神经节丛对自主神经介导房颤的影响

目的 本研究探讨低频电刺激心室主动脉根部神经节丛（ganglionated plexi,GP）对肺静脉源性房颤(AF)诱发率的影响。方法 20只犬分别测量基础状态下,高频和低频电刺激主动脉根部GP时的心房有效不应期和肺静脉有效不应期。分别在基础状态下,高频和低频电刺激主动脉根部GP时,自肺静脉远端以程序刺激诱发AF和AF诱发率的变化。结果 高频电刺激主动脉根部GP 明显缩短心房的肺静脉的有效不应期,增加AF的诱发率。而低频电刺激使心房及肺静脉有效不应期呈延长趋势,并降低AF诱发率。结论 低频电刺激主动脉根部GP降低自主神经介导的AF诱发率。