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.     

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)     

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.     

Anatomy and physiology of the right interganglionic nerve: implications for the pathophysiology of inappropriate sinus tachycardia

Objective: To simulate inappropriate sinus tachycardia (IST) in experimental animals. Background: We recently found that epinephrine injected into the anterior right ganglionated plexi (ARGP) adjacent to the sinoatrial (SA) node induced an arrhythmia simulating IST. Methods: In 19 anesthetized dogs, via a right thoracotomy, the course of the interganglionic nerve (IGN) from the right stellate ganglion along the superior vena cava to the heart was delineated. High‐frequency stimulation (HFS; 0.1 msec duration, 20 Hz, 4.5–9.3 V) was applied to IGN at the junction of innominate vein and SVC. Results: HFS of the IGN significantly increased the sinus rate (SR) (baseline: 156 ± 19 beats/minutes [bpm], 4.5 V: 191 ± 28 bpm*, 8.0 V: 207 ± 23 bpm*, 9.3 V: 216 ± 18 bpm*; *P < 0.01 compared to baseline) without significant changes in A‐H interval or blood pressure. P‐wave morphology, ice mapping, and noncontact mapping indicated that this tachycardia was sinus tachycardia. In 8 of 19 dogs, injecting hexamethonium (5 mg), a ganglionic blocker, into the ARGP attenuated the response elicited by IGN stimulation (baseline: 160 ± 21 bpm, 4.5 V: 172 ± 32 bpm, 8.0 V: 197 ± 32 bpm*, 9.3 V: 206 ± 26 bpm*; *P < 0.05 compared to baseline). In 19 of 19 animals, after formaldehyde injection into the ARGP, SR acceleration induced by IGN stimulation was markedly attenuated (baseline: 149 ± 17 bpm, 4.5 V: 151 ± 21 bpm, 8.0 V: 155 ± 23 bpm, 9.3 V: 167 ± 24 bpm*; *P < 0.05 compared to baseline). Conclusions: HFS of the IGN caused a selective and significant acceleration of the SR. A significant portion of IGN traverses the ARGP or synapses with the autonomic ganglia in the ARGP before en route to the SA node. Dysautonomia involving the IGN and/or ARGP may play an important role in IST.     

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     

Stimulation of the intrinsic cardiac autonomic nervous system results in a gradient of fibrillatory cycle length shortening across the atria during atrial fibrillation in humans

Autonomic Stimulation Promotes AFCL Gradients in AF. Introduction: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high‐frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect. Methods and Results: During AF in 25 patients, HFS was delivered to presumed GP sites to provoke a bradycardic vagal response and AFCL was continuously monitored from catheters placed in the pulmonary vein (PV), coronary sinus (CS), and high right atrium (HRA). A total of 163 vagal responses were identified from 271 HFS episodes. With a vagal response, the greatest reduction in AFCL was seen in the PV adjacent to the site of HFS (16% reduction, 166 ± 28 to 139 ± 26 ms, P < 0.0001) followed by the PV‐atrial junction (9% reduction, 173 ± 21 to 158 ± 20 ms, P < 0.0001), followed by the rest of the atrium (3–7% reduction recorded in HRA and CS). Without a vagal response, AFCL changes were not observed. In 10 patients, atropine was administered in between HFS episodes. Before atropine administration, HFS led to a vagal response and a reduction in PV AFCL (164 ± 28 to 147 ± 26 ms, P < 0.0001). Following atropine, HFS at the same GP sites no longer provoked a vagal response, and the PV AFCL remained unchanged (164 ± 30 to 166 ± 33 ms, P = 0.34). Conclusions: Activation of the parasympathetic component of the cardiac ANS may cause heterogenous changes in atrial AFCL that might promote PV drivers. (J Cardiovasc Electrophysiol, Vol. pp. 1‐8)     

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.     

Interactive atrial neural network: Determining the connections between ganglionated plexi

BACKGROUND: The electrophysiologic functions of the intrinsic cardiac autonomic nervous system (ANS) are not well understood. OBJECTIVES: The purpose of this study was to investigate the functional interactions between ganglionated plexi within the intrinsic cardiac ANS. METHODS: The hearts of 21 dogs were exposed via right and/or left thoracotomy to expose the (1) anterior right ganglionated plexi near the caudal end of the sinoatrial node, (2) inferior right ganglionated plexi at the junction of inferior vena cava and atria, and (3) superior left ganglionated plexi near the junction of left superior pulmonary vein and left pulmonary artery. Ganglionated plexi were stimulated at 0.6 to 8.0 V (square waves, 20 Hz, 0.1-ms duration). Sinus rate, AH interval during atrial pacing, and ventricular rate during atrial fibrillation were compared before and after ganglionated plexi stimulation and after their ablation. RESULTS: Anterior right ganglionated plexi stimulation induced significant AH prolongation and slowing of ventricular rate and sinus rate. When inferior right ganglionated plexi was ablated, slowing of sinus rate by anterior right ganglionated plexi stimulation was unaltered, but inhibition of AV conduction was eliminated. Superior left ganglionated plexi stimulation induced similar effects on sinus and AV nodal function, and sinus rate slowing was markedly attenuated by anterior right ganglionated plexi ablation. Ablation of both anterior right ganglionated plexi and inferior right ganglionated plexi eliminated AV conduction inhibition but not sinus rate slowing by superior left ganglionated plexi stimulation. CONCLUSION: This study provides functional evidence for the interconnections between ganglionated plexi to modulate sinus and AV nodal function, supporting clinical evidence that interconnections within the intrinsic cardiac ANS are critical elements in identifying the targets for atrial fibrillation ablation.     

Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE)

Objective:  To simulate complex fractionated atrial electrograms (CFAE) during sustained atrial fibrillation (AF) in experimental animals.
Background:  The mechanism(s) underlying CFAE has not been fully elucidated.
Methods:  Twenty-two dogs were subjected to a right and/or left thoracotomy. A gauze patch soaked with acetylcholine (ACh) was placed on the right atrial appendage (RAA) to induce sustained AF. During AF, varying concentrations of ACh (1, 10, 100 mM) were "painted" on the RA where electrograms showed regular organized activity. In another six dogs, anterior right ganglionated plexi (ARGP) near the sino-atrial node and inferior right GP (IRGP) at the junction of inferior vena cava and atria were sequentially ablated. In five dogs, ACh was injected into ARGP to induce CFAE.
Results:  During sustained AF, local "painting" with ACh 1 mM and 10 mM induced intermittent CFAE in 1 of 11 and 10 of 11 dogs, respectively. With 100 mM ACh, all 11 showed CFAE (two intermittent, nine continuous). In six other dogs, continuous CFAE induced by topical application of 100 mM ACh were markedly attenuated by ARGP + IRGP ablation. In another five of five dogs, ACh injection into ARGP induced a gradient of CFAE with the continuous CFAE always occurring near the ARGP and CFAE also occurring at left pulmonary vein-atrial junctions. During ARGP ablation, AF was terminated in all five dogs immediately after regularization of the rotor-like electrograms or continuous CFAE.
Conclusions:  This study demonstrates an autonomic basis for CFAE formation, suggesting that graded hyperactive states of the autonomic nervous system (ANS) may induce various types of CFAE observed clinically.     

Intrinsic cardiac autonomic stimulation induces pulmonary vein ectopy and triggers atrial fibrillation in humans

Autonomic Stimulation Induces PV Ectopy and AF. Introduction: The induction of atrial fibrillation (AF) by pulmonary vein (PV) ectopy is well described. The triggers for these PV ectopy are not so well understood. The intrinsic cardiac autonomic nervous system (ANS) has been suggested as a potential upstream regulator that may cause PV ectopy and atrial fibrillation (AF). We hypothesized that activation of the ANS by high frequency stimulation (HFS) of atrial ganglionated plexi (GP) can initiate PV ectopy. Methods and Results: During sinus rhythm in 12 patients undergoing ablation for paroxysmal AF, short bursts of HFS, synchronized to the local atrial refractory period, were delivered at presumed GP sites. Electrograms were recorded from catheters placed in the PV, coronary sinus (CS) and high right atrium (HRA). A total of 112 episodes of HFS were recorded, producing ectopic activity in 91 of 112 (81%) episodes. Of these 91 episodes, there were 46 episodes of isolated single ectopic beats, 5 episodes of double ectopic responses, 24 episodes of ectopy/tachycardia lasting <30 s, and 16 episodes of AF lasting >30 s. In 63 of 91 episodes, the PV catheter was placed adjacent to the stimulated GP, resulting in ectopy recorded earliest in the PV catheter in 48 of 63 (76%) episodes. In one patient, reproducible ectopy was shown to occur following AV nodal conduction delay in response to HFS. Without HFS, neither AV nodal conduction delay nor ectopy occurred. Conclusions: This study has demonstrated a direct link between activation of the intrinsic cardiac autonomic nervous system and pulmonary vein ectopy in humans . (J Cardiovasc Electrophysiol, Vol. 22, pp. 638‐646, June 2011)     

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。     

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)     

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)     

右侧神经丛消融对阵发心房颤动伴窦性心动过缓心率的影响

目的:探讨环肺静脉消融的基础上,进一步进行右侧神经丛消融以观察消融对心率的影响。方法:12例心动过缓伴心房颤动的患者,其中男性9例,女性3例,平均年龄(60.58±9.25)岁,在完成环肺静脉隔离的基础上,进行解剖指导下右侧神经丛的消融。结果:12例均完成四个肺静脉隔离及上腔静脉去神经消融,消融上腔静脉过程中,心率由(72.92±5.30)次/min增加到(84.58±5.63)次/min,术后平均随访(18±8)个月,心房颤动成功率50%。心率由术前(56.67±4.87)次/min,增加到术后1w(68.92±6.20)次/min,术后6个月(65.75±4.09)次/min。心率变异性(SDNN)由术前(132.83±16.7)ms减少为术后1w(87.67±19.21)ms,术后6个月(109.75±18.65)ms。结论:在环肺静脉消融的基础上,进行解剖指导下的上腔静脉消融可以进一步提高心率,达到去迷走神经支配的目的。     

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.     

Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea

The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at -80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline; P=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27±5 versus 43±3 ms after atenolol; P=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by high-frequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events.     

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)     

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)     

Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation.

BACKGROUND: Numerous reports have demonstrated an association between autonomic tone and atrial fibrillation (AF). Pulmonary vein (PV) denervation during catheter ablation of AF has been shown to significantly reduce recurrence of AF. OBJECTIVES: The purpose of this study was to assess the safety and efficacy of high-frequency stimulation at mapping cardiac ganglionated plexuses in patients undergoing catheter ablation of AF. METHODS: Fourteen patients with a history of symptomatic AF underwent a single transseptal approach and electroanatomic mapping of the left atrium, right atrium, and coronary sinus. Using high-frequency stimulation with patients under general anesthesia (20-50 Hz, 5-15 V, pulse width 10 ms), mapping of ganglionated plexuses was performed. Radiofrequency (RF) ablation was performed during AF guided by complex fractionated atrial electrograms. Lesions were mostly delivered circumferentially in the antral area of the PVs, predominantly over and adjacent to regions of ganglionated plexuses. RESULTS: There was a mean of 4 +/- 1 (range 2-6) ganglionated plexuses per patient, and a mean total of 3 +/- 1 RF applications were delivered over positive vagal sites. Although a vagal response occurred infrequently during ablation (0.9%), postablation high-frequency stimulation failed to provoke a vagal response in 30 (88%) of 34 previously positive vagal sites that underwent ablation. CONCLUSION: Ganglionated plexuses can be precisely mapped using high-frequency stimulation and are located predominantly in the path of lesions delivered during ablation of AF. Objective documentation of modification of autonomic tone can be documented in the majority of patients. Future studies are required to determine the specific role of mapping and targeting of ganglionated plexuses in patients undergoing catheter ablation of AF.     

Chronic Augmentation of the Parasympathetic Tone to the Atrioventricular Node: A Nonthoracotomy Neurostimulation Technique for Ventricular Rate Control During Atrial Fibrillation

Long‐Term Cardiac Neurostimulation. Introduction: The right inferior ganglionated plexus (RIGP) selectively innervates the atrioventricular node. Temporary electrical stimulation of this plexus reduces the ventricular rate during atrial fibrillation (AF). We sought to assess the feasibility of chronic parasympathetic stimulation for ventricular rate control during AF with a nonthoracotomy intracardiac neurostimulation approach. Methods and Results: In 9 mongrel dogs, the small endocardial area inside the right atrium, which overlies the RIGP, was identified by 20 Hz stimulation over a guiding catheter with integrated electrodes. Once identified, an active‐fixation lead was implanted. The lead was connected to a subcutaneous neurostimulator. An additional dual‐chamber pacemaker was implanted for AF induction by rapid atrial pacing and ventricular rate monitoring. Continuous neurostimulation was delivered for 1–2 years to decrease the ventricular rate during AF to a range of 100–140 bpm. Implantation of a neurostimulation lead was achieved within 37 ± 12 min. The latency of the negative dromotropic response after on/offset or modulation of neurostimulation was <1 s. Continuous neurostimulation was effective and well tolerated during a 1–2 year follow‐up with a stimulation voltage <5 V. The neurostimulation effect displayed a chronaxie‐rheobase behavior (chronaxie time of 0.07 ± 0.02 ms for a 50% decrease of the ventricular rate during AF). Conclusion: Chronic parasympathetic stimulation can be achieved via a cardiac neurostimulator. The approach is safe, effective, and well tolerated in the long term. The atrioventricular nodal selectivity and the opportunity to adjust the negative dromotropic effect within seconds may represent an advantage over pharmacological rate control. (J Cardiovasc Electrophysiol, Vol. 21, pp. 193‐199, February 2010)