迷走神经调控对心房电重构影响的实验研究
|
摘要
第一部分迷走神经活动对心房电重构的影响
目的:心房电重构在心房颤动(房颤)的发生和维持中起着重要作用。迷走神经与房颤密切相关。然而,关于迷走神经与心房电重构关系的研究尚少。本实验目的在于研究迷走神经干预对心房电重构的影响。
方法:24只杂种犬随机分为3组,为排除交感神经对心房电重构的影响,3组犬均应用美托洛尔阻断交感神经效应。A组10只犬心房电重构过程中无迷走神经干预,B组8只犬应用阿托品阻断迷走神经效应,C组6只犬在心房电重构过程中同时进行迷走神经刺激。在右心房(RA)、冠状静脉窦(CS)和右心室(RV)放置多极电极导管。通过RA电极导管进行600次/分心房起搏30分钟构建急性心房电重构模型。在右心房快速起搏前后测量基础状态(无迷走神经刺激)和迷走神经刺激下的心房有效不应期(ERP)和房颤易感窗口(VW)。结果:A组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前明显缩短(P均<0.05)。B组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前无明显变化(P均> 0.05)。C组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前明显缩短(P均<0.05)。A组及C组右心房快速起搏后ERP缩短值明显大于B组(P <0.05),但A组及C组ERP缩短值没有明显差异(P >0.05)。基础状态下,三组实验犬在右心房快速起搏前后均不能诱发房颤(VW接近0)。迷走神经刺激下,B组实验犬在右心房快速起搏前后也不能诱发房颤(VW接近0),但A组及C组实验犬右心房快速起搏后较起搏前容易诱发房颤(P均<0.05)。
结论:短期的右心房快速起搏能够缩短心房的有效不应期,导致心房电重构。快速心房刺激所致的心房电重构过程中伴随着迷走神经兴奋性增强。迷走神经兴奋性增强及迷走神经刺激加重心房电重构,导致房颤易感性增加。迷走神经阻滞能减轻心房电重构,降低房颤易感性。
第二部分上腔静脉隔离对心房电重构的影响
目的:上腔静脉隔离(SVCI)主要通过阻断触发病灶治疗阵发性房颤,对于持续性房颤患者,SVCI是否通过改变心房基质而具有治疗效应目前尚不明确。心房电重构在房颤的发生和维持中起着重要作用,而迷走神经对心房电重构有重要影响。上腔静脉与迷走神经脂肪垫毗邻,因而,本研究假设SVCI能够导致犬的心房去迷走神经效应,减轻心房电重构,从而改变房颤的基质。
方法:成年杂种犬18只,随机分为A和B组各9只。全身麻醉后分离双侧颈部交感迷走神经干。静脉应用美托洛尔阻断交感神经的影响。A组直接通过右心房600次/分起搏30分钟构建急性心房电重构模型。B组在完成SVCI后再构建急性心房电重构模型。分别于心房电重构前后在右心耳(RAA)、冠状静脉窦近端(CSp)和冠状静脉窦远端(CSd)测量基础状态下(无颈部交感迷走神经干刺激)及迷走神经刺激下的心房有效不应期(ERP)、房颤易感窗口(VW)和窦性周长(SCL)。对消融部位的心肌进行组织病理学检查。
结果:(1)A组迷走神经刺激后心房率明显减慢(心房电重构前:基础状态及迷走神经刺激下的心率分别为171±19次/分和44±39次/分,P <0.05);心房电重构后:基础状态及迷走神经刺激下的心率分别为162±15次/分和30±15次/分, P <0.05)。B组行SVCI后迷走神经刺激后心房率减慢程度明显降低(心房电重构前:135±19次/分VS 114±31次/分,P=0.109;电重构后:基础状态及迷走神经刺激时的心率分别为137±26次/分VS136±30次/分,P=0.984)。(2)A组基础状态下的ERP在心房电重构后明显缩短(CSd的ERP分别为97.78±16.41 vs 85.56±15.90 ms,P=0.005;RAA的ERP分别为100±20.62 vs 82.22±19.86 ms,P =0.021)。迷走神经刺激下的ERP在心房电重构后也明显缩短( CSd的ERP分别为48.89±32.96 vs 28.89±16.16 ms,P =0.034;RAA的ERP分别为48.89±29.34 vs 25.56±8.82 ms,P =0.053)。B组基础状态下心房电重构后较重构前测得ERP变化无统计学意义(CSd的ERP分别为95.56±22.97 vs 96.67±18.03 ms, P =0.729 ; RAA的ERP分别为94.44±12.36 vs 94.44±16.67ms, P =1)。迷走神经刺激时心房电重构后测得的ERP较重构前亦无明显变化(CSd的ERP分别为85.56±16.67 vs 88.89±15.37 ms, P =0.471;RAA的ERP分别为90±12.5 vs 94.44±16.67, P =0.426)。A组基础状态下电重构所致的ERP缩短值较B组明显增加(CSd:12.22±9.72 vs 2.22±8.33 ms, P =0.032; RAA:22.22±18.56 vs–3.33±7.07 ms, P =0.001)。A组迷走神经刺激时电重构所致的ERP缩短值较B组亦明显增加(CSd:20±23.45 vs 1.11±13.64 ms, P =0.053; RAA:23.33±30.82 vs 0±13.23 ms, P =0.053)。(3)A组基础状态下心房电重构前后均不能诱发房颤(VW接近0)。迷走神经刺激时,房颤易感窗口在心房电重构后明显增大(冠状静脉窦远端的VW分别为24.44±23.51 vs 52.22±23.80 ms,P =0.009;高位右心房的VW分别为23.33±19.36 vs 38.89±13.97 ms,P =0.0007)。B组心房电重构前后基础及迷走神经刺激下均不能诱发房颤(VW接近0)。(4)心肌病理检查表明SVCI导致了消融位点的心外膜脂肪垫内神经节损伤
结论: SVCI导致了心房局部去迷走神经效应,减轻了心房电重构,抑制了迷走神经介导性房颤。
第三部分针对碎裂电位消融对心房电重构的影响
目的:在心房颤动(房颤)过程中,在心房某些部位可以记录到高频低幅的碎裂电图(complex fractionated atrial electrogram,CFAE),针对CFAE消融是目前治疗房颤的重要手段之一。但是,针对CFAE消融治疗房颤的机制目前尚不清楚。心房电重构是房颤的发生和维持的电生理基础。因而,本研究假设针对CFAE消融能够减轻心房电重构,从而改变房颤的基质。
方法:17只杂种犬分为二组。A组10只犬房间隔穿刺后诱发房颤并标测CFAE分布,之后直接以600次/分起搏右心房30分钟构建急性心房电重构模型,与B组针对CFAE消融后心房电重构前后数据进行比较,观察针对CFAE消融对心房电重构的影响。B组7只犬先通过双侧颈部交感-迷走神经干刺激诱发房颤,在房颤过程中标测并记录CFAE的分布部位,并针对CFAE消融。针对CFAE消融后构建急性心房电重构模型,观察针对CFAE消融对心房电重构的影响。分别于心房电重构前后在右心耳(RAA)、冠状静脉窦近端(CSp)和冠状静脉窦远端(CSd)测量基础状态下(无颈部交感迷走神经干刺激)及迷走神经刺激下的心房有效不应期(ERP)、房颤易感窗口(VW)和窦性周长(SCL)。对消融部位的心肌进行组织病理学检查。
结果:(1)A组迷走神经刺激后心房率明显减慢(心房电重构前:基础状态及迷走神经刺激下的心率分别为167±15次/分和47±21次/分,P <0.05);心房电重构后:基础状态及迷走神经刺激下的心率分别为163±17次/分和38±12次/分, P <0.05)。B组针对CFAE消融后迷走神经刺激后心房率减慢程度明显降低(心房电重构前:159±13次/分VS 148±27次/分,P>0.05;电重构后:基础状态及迷走神经刺激时的心率分别为161±23次/分VS 157±28次/分,P>0.05)。(2)A组基础状态下的ERP在心房电重构后明显缩短(LAA的ERP分别为100±16.99 vs 86±15.06 ms,P=0.003;RAA的ERP分别为104±23.19 vs 84±19.56 ms,P =0.008)。迷走神经刺激下的ERP在心房电重构后也明显缩短(LAA的ERP分别为50±31.27 vs 31±16.63 ms,P =0.02;RAA的ERP分别为49±27.67 vs 28±11.35 ms,P =0.05)。B组基础状态下心房电重构后较重构前测得ERP变化无统计学意义(LAA的ERP分别为98.57±8.99 vs 105.71±11.34 ms, P > 0.05 ; RAA的ERP分别为105.71±27.61 vs 105.71±25.07ms, P>0.05)。迷走神经刺激时心房电重构后测得的ERP较重构前亦无明显变化(LAA的ERP分别为90±19.15 vs 94.29±25.73 ms, P>0.05;RAA的ERP分别为84.29±41.17 vs92.86±30.39, P>0.05)。A组基础状态下电重构所致的ERP缩短值较B组明显增加(LAA:14±10.75 vs -7.14±9.51 ms, P <0.001; RAA:20±18.86 vs 0±8.16 ms, P =0.02)。A组迷走神经刺激时电重构所致的ERP缩短值较B组亦明显增加(LAA:19±22.33 vs -4.29±9.76 ms, P =0.02; RAA:19±27.67 vs -8.57±19.52 ms, P =0.04)。(3)A组基础状态下心房电重构前后均不能诱发房颤(VW接近0)。迷走神经刺激时,房颤易感窗口在心房电重构后明显增大(LAA的VW分别为51±24.69 vs 26±22.71 ms,P =0.01;RAA的VW分别为40±16.33 vs 27±21.63ms,P =0.006)。B组心房电重构前后基础及迷走神经刺激下均不能诱发房颤(VW接近0)。(4)心肌病理检查表明针对CFAE消融导致了消融位点的心外膜脂肪垫内神经节损伤
结论:针对CFAE消融导致了心房局部去迷走神经效应,减轻了心房电重构,抑制了迷走神经介导性房颤。
Impact of Vagal Activity on Atria Electrical Remodeling in Dogs
Objective: Atrial fibrillation (AF) is the most common arrhythmia and its prevalence increases with the aging of the population. Atrial electrical remodeling (AER) including the shortening of action potential duration and atrial effective refractory period (ERP), the decrease of rate adaptation and wavelength index, and so on, plays an important role in the pathogenesis and maintenance of AF. Many studies have demonstrated that atrial vagal denervation could result in the decrease of vulnerability to AF. Furthermore, recent data have proved that mapping and ablation of fatty pats thereby vagal innervation to the heart was very effective in AF interventional treatment. However, little is known regarding the mechanisms of vagal denervation for treatment of AF: eradication of triggering foci or modification of substrates. The study is aimed to elucidate the effects of vagal intervention on AER in order to explore the mechanisms of the vagal denervation for the AF treatment.
Methods: Twenty four adult mongrel dogs of either sex weighing 10 to 15 kg were anesthetized with sodium pentobarbital (150mg/kg IV) ,additional amounts of 250 to 500 mg per 60 minutes to 120 minutes were given as necessary to maintain anesthesia during the study. They were ventilated with room air by a cuffed endotracheal tube, and a constant oximetry was monitored throughout the experiment. Metoprolol was administered (0.2 mg/kg initial bolus with a maintenance dose of 0.2 mg/kg per hour) in order to exclude the influence of sympathetic activity. Multipolar catheters were placed into high right atria (RA), coronary sinus (CS) and right ventricle (RV). Bilateral cervical sympathovagal trunks were decentralized. AER was established by rapid pacing right atrium at the rate of 600 beats per minute for 30 minutes. ERP and vulnerability window (VW) were measured to evaluate the effects of the AER on the atrial electrophysiology and vulnerability of AF. Atrioventricular node ablation and temporary pacemaker were applied in case of the bradycardia induced by vagal stimulation and tachycardia due to induction of AF. Twenty four dogs were randomized into 3 groups. Sympathetic activity was blocked by administration of metoprolol in 3 groups. The changes of vagal modulation to atria after AER were observed in 10 dogs without vagal interruption in group A. The effects of vagal intervention on AER were investigated in 8 dogs with administration of atropine in group B. The impact of aggressively vagal activity on AER was studied in 6 dogs with bilateral cervical sympathovagal trunks stimulation during AER in group C. ERP and VW were measured before and after remodeling with and without vagal stimulation in all groups.
Results: (1) Effect of vagal modulation on AERP.In group A, ERP decreased significantly after AER compared with that before AER both at baseline (84±19.55ms vs 104±23.19ms at RA,P =0.008; 87±17.03ms vs 100±16.99ms at CS , P=0.0007) and during the vagal stimulation (26±8.43ms vs 51±28.46ms at RA,P =0.03; 30±15.63ms vs 49±31.07ms at CS,P=0.02) . In group B, ERP remained unchanged before and after AER both at baseline (112.5±21.21ms vs 115±14.14ms at RA , P>0.05 ;117.5±11.65ms vs 115±19.27ms at CS , P>0.05 ) and during vagal stimulation(111.25±18.08ms vs 116.25±11.88ms at RA,P>0.05;110±9.26ms vs 110±18.52ms at CS,P >0.05). In group C, ERP decreased significantly after AER compared with that before AER both at baseline (95±22.58ms vs 106.67±24.22ms at RA,P =0.0009; 85±22.58ms vs 13.33±20.66ms at CS,P =0.04) and during vagal stimulation (31.67±14.72ms vs 56.67±33.27ms at RA, P=0.04; 38.33±29.27ms vs 61.67±29.94ms at CS, P =0.02). ERP shortening after AER in group A and C inecreased significantly than that in group B at baseline(20±18.86ms in group A, 2.5±14.88ms in group B and 11.67±4.08ms in group C at RA;13±8.23ms in group A, -5±16.9ms in group B and 16.67±15.06ms in group C at CS) and vagal stimulation(25±29.53ms in group A, 5±11.95ms in group B and 25±22.58ms in group C at RA; 19±22.34ms in group A, 0±16.9ms in group B and 23.33±16.33ms in group C at CS) (all P<0.05), while there is no significant difference between group A and C (all P >0.05).(2) Effect of vagal modulation on VW. Atrial fibrillation was rarely induced at baseline (VW close to 0) before and after AER in all groups. VW increased signifycantly during vagal stimulation after AER in group A (40±16.33ms vs 27±21.63ms at RA, P =0.006; 51±24.69ms vs 26±22.71ms at CS,P =0.01) and group C (76.67±38.82ms vs 26.67±28.75ms at RA,P =0.04; 53.33±39.33ms vs 21.67±23.17ms at CS,P =0.02), while VW remained unchanged in group B (VW close to 0).
Conclusions: Short-term AER results in the decrease of ERP. AER is accompanied by the increases of atrial vagal modulation. The increased vagal activity and vagal stimulation promote AER, thereby increase the susceptibility to atrial fibrillation. The interrupted vagal activity attenuates AER, thereby suppresses the atrial fibrillation mediated by vagal stimulation.
Impact of Superior Vena Cava Isolation on Atrial Electrical Remodeling
Objective: Atrial fibrillation (AF) is the most common sustain arrhythmia. Numerous studies have shown that superior vena cava (SVC) isolation is effective method in suppressing AF by blocking the triggering or driving foci in some patients with paraxysmal AF. However, little has been known about the role of SVC isolation in suppression of sustained AF eventhough SVC isolation has been regarded as an ablative strategy . Atrial electrical remodeling(AER) plays an important role in the pathogenesis and maintainenance of AF. This study aimed to investigate effects of SVC isolation on AER in order to explore the neceesserity of SVC isolation for persisteny AF ablation.
Methods: 18 adult mongrel dogs under general anesthesia were randomized into A group and B group. Bilateral cervical sympathovagal trunks were decentralized. Metoprolol was given to block sympathetic effects. AER was performed by 600bpm pacing through right atrial catheter for 30 minutes in A group in 9 dogs. AER was performed after SVC isolation guided by Lasso catheter on the junction of right atrium and SVC in B group in 9 dogs. Atrial effective refractory period(ERP), vulnerability window(VW) of AF ,and sinus cycle length(SCL) were measured at baseline(without vagal stimulation) and vagal stimulation at right atrial appendage (RAA), distal coronary sinus (CSd) and paroximal coronary sinus (CSp) before and after AER. The underlying tissue was excised from ablative sites and the same sites without ablation as control specimens and fixed in buffered neutral formalin. Serial sections were stained with haematoxylin and eosin for microscopic examination.
Results: (1) SCL shortened significantly during vagal stimulation before and after AER in A group (all P value <0.05), while SCL remained unchanged during vagal stimulation before and after AER (all P value >0.05) . It suggests that SVC isolation eliminate vagal regulation on sinus node.In Group A, ERP shortened significantly at baseline (97.78±16.41 vs 85.56±15.90 ms at CSd, P= 0.005, 100±20.62 vs 82.22±19.86 ms at HRA, P=0.021) after AER. ERP decreased also significantly during vagal stimulation (48.89±32.96 vs 28.89±16.16 ms at CSd, P = 0.034, 48.89±29.34 vs 25.56±8.82 ms at HRA, P= 0.053) after AER. It suggests that rapid atrial pacing result in not only AER but also change of atrial electrophysicological properties due to vagal modulation. In group B, ERP remained unchanged before and after rapid atrial pacing both at baseline (95.56±22.97 vs 96.67±18.03 ms at CSd, P = 0.729, 94.44±12.36vs 94.44±16.67 ms at HRA), P=1 and during vagal stimulation (85.56±16.67 vs 88.89±15.37 ms at CSd, P = 0.471, 90±12.35 vs 94.44±16.67 ms at HRA, P=0.426). ERP shortening mediated by AER in Group A increased significantly than that in group B at baseline (12.22±9.72 vs 2.22±8.33 ms at CSd, P=0.032; 22.22±18.56 vs -3.33±7.07 ms at HRA, P= 0.001) and during vagal stimulation (20±23.45 vs 1.11±13.64 ms at CSd, P = 0.053; 23.33±30.82 vs 0±13.23 ms at HRA, P= 0.053). It suggests that SVC isolation relieve AER due to partly vagal dennervation.In Group A, AF could not be induced at baseline (VW close to 0) before and after AER. VW increased significantly during vagal stimulation after AER(24.44±23.51ms VS 52.22±23.80ms at CSd,P=0.009; 23.33±19.36ms VS 38.89±13.97ms at HRA,P=0.0007) . In group B, AF could not be induced at baseline and during vagal stimulation (VW close to 0) before and after AER. It suggests that SVC isolation may contribute to the suppression of AF mediated by vagal activity and the AER. (2) Histological sections showed numerrious nerves distribution alone SVC septum. In control specimens, the ganglia contained numerous nerve cells and was surrounded by fibrous and fatty tissue. After ablation, the ganglia were damaged. Some parts of the fibrous capsule of ganglia were thinned or broken. Neurons distributed sparsely in the ganglia, while among these neurons neuroglia increased in number. And concentration of nucleus appeared in some neurons of ganglia.
Conclusions: AER can decrease ERP and enhance the vagal modulation to atria, thereby increase the susceptibility to atrial fibrillation triggered by vagus. SVC isolation can release AER, which maybe contribute to the attenuated vagal modulation to atria.
Impact of ablation focused on the complex fractionated atrial electrogram on atrial electrical remodeling in dogs
Objective: Ablation targeting complex fractionated atrial electrogram (CFAE) has been demonstrated to be effective for atrial fibrillation. Some promising observation have shown that the distribution of CAFE has a relationship with the efferent vagal innervation to atria. However, mechanisms of CFAE ablation for atrial fibrillation remained controversy. This study aimed to observe the impact of CAFP ablation on atrial electrical remodeling (AER) in order to investigate mechanisms of CFAE ablation in treatment of atrial fibrillation because AER plays an important role in the pathogenesis and maintainenance of atrial fibrillation.
Methods: 17 adult mongrel dogs under general anesthesia were random- ized into A group and B group. Bilateral cervical sympathovagal trunks were decentralized. Metoprolol was given to block sympathetic effects. AER was performed by 600bpm pacing through right atrial catheter for 30 minutes in A group in 10 dogs. AER was performed after CAFE abaltion guided by multipolar catheters or Ensite mapping system in B group in 7 dogs. Multipolar catheters were placed into the right and left atrium and coronary sinus. CAFP was recorded by multipolar catheters or Ensite mapping system during atrial fibrillation induced by S1S2 stimul- ation during sympathovagal trunks stimulation. Atrial effective refractory period (ERP), vulnerability window (VW) of atrial fibrillation, and sinus rhythm cycle length (SCL) were measured at right atrial appendage (RAA), left atrial appendage (LAA), distal coronary sinus(CSd) and proximal coronary sinus(CSp) at baseline (without vagal stimulation) and during vagal stimulation before and after ablation. The underlying tissue were excised from ablative sites and the same sites without ablation as control specimens. Serial sections were taken and stained with hematoxylin and eosin for microscopic examination.
Results: (1) SCL shortened significantly during vagal stimulation before and after AER in A group (all P value <0.05), while SCL remained unchanged during vagal stimulation before and after AER (all P value >0.05) . It suggests that CAFE abaltion eliminate vagal regulation on sinus node. (2) In Group A, ERP shortened significantly at baseline (100±16.99 vs 86±15.06 ms at LAA, P= 0.003, 104±23.19 vs 84±19.56 ms, P=0.008 at RAA) after AER. ERP decreased also significantly during vagal stimulation (50±31.27 vs 31±16.63 ms at LAA, P = 0.02, 49±27.67 vs 28±11.35 ms, P= 0.05 at RAA) after AER. It suggests that rapid atrial pacing result in not only AER but also change of atrial electrophys- icological properties due to vagal modulation. In group B, ERP remained unchanged before and after rapid atrial pacing both at baseline (98.57±8.99 vs 105.71±11.34 ms at LAA, P>0.05, 105.71±27.61vs 105.71±11.34 ms at HRA,P>0.05) and during vagal stimulation (90±19.15 vs 94.29±25.73 ms at LAA, P>0.05, 84.29±41.17 vs 92.86±30.39 ms at RAA,P>0.05). ERP shortening mediated by AER in Group A increased significantly than that in group B at baseline (14±10.75 vs -7.14±9.51 ms at LAA, P=0.001; 20±18.86 vs 0±8.16 ms at RAA, P= 0.02) and during vagal stimulation (19±22.33 vs -4.29±9.76 ms at RAA, P = 0.02; 19±27.67 vs -8.57±19.52 ms at RAA, P= 0.04). It suggests that CAFE abaltion relieve AER due to partly vagal dennervation.(3)In Group A, AF could not be induced at baseline (VW close to 0) before and after AER. VW increased significantly during vagal stimulation after AER(51±24.69 ms VS 26±22.71ms at LAA, P=0.01; 40±16.33ms VS 27±21.63ms at HRA,P=0.006) . In group B, AF could not be induced at baseline and during vagal stimulation (VW close to 0) before and after AER. It suggests that CAFE abaltion may contribute to the suppression of AF mediated by vagal activity and the AER. (4) Histological sections showed numerrious nerves distrib- ution in CAFE area. In control specimens, the ganglia contained numerous nerve cells and was surrounded by fibrous and fatty tissue. After ablation, the ganglia were damaged. Some parts of the fibrous capsule of ganglia were thinned or broken. Neurons distributed sparsely in the ganglia, while among these neurons neuroglia increased in number. And concentration of nucleus appeared in some neurons of ganglia.
Conclusions: AER can decrease ERP and enhance the vagal modulation to atria, thereby increase the susceptibility to atrial fibrillation triggered by vagus. CAFE abaltion can release AER, which maybe contri- bute to the attenuated vagal modulation to atria.
目的:心房电重构在心房颤动(房颤)的发生和维持中起着重要作用。迷走神经与房颤密切相关。然而,关于迷走神经与心房电重构关系的研究尚少。本实验目的在于研究迷走神经干预对心房电重构的影响。
方法:24只杂种犬随机分为3组,为排除交感神经对心房电重构的影响,3组犬均应用美托洛尔阻断交感神经效应。A组10只犬心房电重构过程中无迷走神经干预,B组8只犬应用阿托品阻断迷走神经效应,C组6只犬在心房电重构过程中同时进行迷走神经刺激。在右心房(RA)、冠状静脉窦(CS)和右心室(RV)放置多极电极导管。通过RA电极导管进行600次/分心房起搏30分钟构建急性心房电重构模型。在右心房快速起搏前后测量基础状态(无迷走神经刺激)和迷走神经刺激下的心房有效不应期(ERP)和房颤易感窗口(VW)。结果:A组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前明显缩短(P均<0.05)。B组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前无明显变化(P均> 0.05)。C组犬右心房快速起搏后基础状态下及迷走神经刺激时的ERP较起搏前明显缩短(P均<0.05)。A组及C组右心房快速起搏后ERP缩短值明显大于B组(P <0.05),但A组及C组ERP缩短值没有明显差异(P >0.05)。基础状态下,三组实验犬在右心房快速起搏前后均不能诱发房颤(VW接近0)。迷走神经刺激下,B组实验犬在右心房快速起搏前后也不能诱发房颤(VW接近0),但A组及C组实验犬右心房快速起搏后较起搏前容易诱发房颤(P均<0.05)。
结论:短期的右心房快速起搏能够缩短心房的有效不应期,导致心房电重构。快速心房刺激所致的心房电重构过程中伴随着迷走神经兴奋性增强。迷走神经兴奋性增强及迷走神经刺激加重心房电重构,导致房颤易感性增加。迷走神经阻滞能减轻心房电重构,降低房颤易感性。
第二部分上腔静脉隔离对心房电重构的影响
目的:上腔静脉隔离(SVCI)主要通过阻断触发病灶治疗阵发性房颤,对于持续性房颤患者,SVCI是否通过改变心房基质而具有治疗效应目前尚不明确。心房电重构在房颤的发生和维持中起着重要作用,而迷走神经对心房电重构有重要影响。上腔静脉与迷走神经脂肪垫毗邻,因而,本研究假设SVCI能够导致犬的心房去迷走神经效应,减轻心房电重构,从而改变房颤的基质。
方法:成年杂种犬18只,随机分为A和B组各9只。全身麻醉后分离双侧颈部交感迷走神经干。静脉应用美托洛尔阻断交感神经的影响。A组直接通过右心房600次/分起搏30分钟构建急性心房电重构模型。B组在完成SVCI后再构建急性心房电重构模型。分别于心房电重构前后在右心耳(RAA)、冠状静脉窦近端(CSp)和冠状静脉窦远端(CSd)测量基础状态下(无颈部交感迷走神经干刺激)及迷走神经刺激下的心房有效不应期(ERP)、房颤易感窗口(VW)和窦性周长(SCL)。对消融部位的心肌进行组织病理学检查。
结果:(1)A组迷走神经刺激后心房率明显减慢(心房电重构前:基础状态及迷走神经刺激下的心率分别为171±19次/分和44±39次/分,P <0.05);心房电重构后:基础状态及迷走神经刺激下的心率分别为162±15次/分和30±15次/分, P <0.05)。B组行SVCI后迷走神经刺激后心房率减慢程度明显降低(心房电重构前:135±19次/分VS 114±31次/分,P=0.109;电重构后:基础状态及迷走神经刺激时的心率分别为137±26次/分VS136±30次/分,P=0.984)。(2)A组基础状态下的ERP在心房电重构后明显缩短(CSd的ERP分别为97.78±16.41 vs 85.56±15.90 ms,P=0.005;RAA的ERP分别为100±20.62 vs 82.22±19.86 ms,P =0.021)。迷走神经刺激下的ERP在心房电重构后也明显缩短( CSd的ERP分别为48.89±32.96 vs 28.89±16.16 ms,P =0.034;RAA的ERP分别为48.89±29.34 vs 25.56±8.82 ms,P =0.053)。B组基础状态下心房电重构后较重构前测得ERP变化无统计学意义(CSd的ERP分别为95.56±22.97 vs 96.67±18.03 ms, P =0.729 ; RAA的ERP分别为94.44±12.36 vs 94.44±16.67ms, P =1)。迷走神经刺激时心房电重构后测得的ERP较重构前亦无明显变化(CSd的ERP分别为85.56±16.67 vs 88.89±15.37 ms, P =0.471;RAA的ERP分别为90±12.5 vs 94.44±16.67, P =0.426)。A组基础状态下电重构所致的ERP缩短值较B组明显增加(CSd:12.22±9.72 vs 2.22±8.33 ms, P =0.032; RAA:22.22±18.56 vs–3.33±7.07 ms, P =0.001)。A组迷走神经刺激时电重构所致的ERP缩短值较B组亦明显增加(CSd:20±23.45 vs 1.11±13.64 ms, P =0.053; RAA:23.33±30.82 vs 0±13.23 ms, P =0.053)。(3)A组基础状态下心房电重构前后均不能诱发房颤(VW接近0)。迷走神经刺激时,房颤易感窗口在心房电重构后明显增大(冠状静脉窦远端的VW分别为24.44±23.51 vs 52.22±23.80 ms,P =0.009;高位右心房的VW分别为23.33±19.36 vs 38.89±13.97 ms,P =0.0007)。B组心房电重构前后基础及迷走神经刺激下均不能诱发房颤(VW接近0)。(4)心肌病理检查表明SVCI导致了消融位点的心外膜脂肪垫内神经节损伤
结论: SVCI导致了心房局部去迷走神经效应,减轻了心房电重构,抑制了迷走神经介导性房颤。
第三部分针对碎裂电位消融对心房电重构的影响
目的:在心房颤动(房颤)过程中,在心房某些部位可以记录到高频低幅的碎裂电图(complex fractionated atrial electrogram,CFAE),针对CFAE消融是目前治疗房颤的重要手段之一。但是,针对CFAE消融治疗房颤的机制目前尚不清楚。心房电重构是房颤的发生和维持的电生理基础。因而,本研究假设针对CFAE消融能够减轻心房电重构,从而改变房颤的基质。
方法:17只杂种犬分为二组。A组10只犬房间隔穿刺后诱发房颤并标测CFAE分布,之后直接以600次/分起搏右心房30分钟构建急性心房电重构模型,与B组针对CFAE消融后心房电重构前后数据进行比较,观察针对CFAE消融对心房电重构的影响。B组7只犬先通过双侧颈部交感-迷走神经干刺激诱发房颤,在房颤过程中标测并记录CFAE的分布部位,并针对CFAE消融。针对CFAE消融后构建急性心房电重构模型,观察针对CFAE消融对心房电重构的影响。分别于心房电重构前后在右心耳(RAA)、冠状静脉窦近端(CSp)和冠状静脉窦远端(CSd)测量基础状态下(无颈部交感迷走神经干刺激)及迷走神经刺激下的心房有效不应期(ERP)、房颤易感窗口(VW)和窦性周长(SCL)。对消融部位的心肌进行组织病理学检查。
结果:(1)A组迷走神经刺激后心房率明显减慢(心房电重构前:基础状态及迷走神经刺激下的心率分别为167±15次/分和47±21次/分,P <0.05);心房电重构后:基础状态及迷走神经刺激下的心率分别为163±17次/分和38±12次/分, P <0.05)。B组针对CFAE消融后迷走神经刺激后心房率减慢程度明显降低(心房电重构前:159±13次/分VS 148±27次/分,P>0.05;电重构后:基础状态及迷走神经刺激时的心率分别为161±23次/分VS 157±28次/分,P>0.05)。(2)A组基础状态下的ERP在心房电重构后明显缩短(LAA的ERP分别为100±16.99 vs 86±15.06 ms,P=0.003;RAA的ERP分别为104±23.19 vs 84±19.56 ms,P =0.008)。迷走神经刺激下的ERP在心房电重构后也明显缩短(LAA的ERP分别为50±31.27 vs 31±16.63 ms,P =0.02;RAA的ERP分别为49±27.67 vs 28±11.35 ms,P =0.05)。B组基础状态下心房电重构后较重构前测得ERP变化无统计学意义(LAA的ERP分别为98.57±8.99 vs 105.71±11.34 ms, P > 0.05 ; RAA的ERP分别为105.71±27.61 vs 105.71±25.07ms, P>0.05)。迷走神经刺激时心房电重构后测得的ERP较重构前亦无明显变化(LAA的ERP分别为90±19.15 vs 94.29±25.73 ms, P>0.05;RAA的ERP分别为84.29±41.17 vs92.86±30.39, P>0.05)。A组基础状态下电重构所致的ERP缩短值较B组明显增加(LAA:14±10.75 vs -7.14±9.51 ms, P <0.001; RAA:20±18.86 vs 0±8.16 ms, P =0.02)。A组迷走神经刺激时电重构所致的ERP缩短值较B组亦明显增加(LAA:19±22.33 vs -4.29±9.76 ms, P =0.02; RAA:19±27.67 vs -8.57±19.52 ms, P =0.04)。(3)A组基础状态下心房电重构前后均不能诱发房颤(VW接近0)。迷走神经刺激时,房颤易感窗口在心房电重构后明显增大(LAA的VW分别为51±24.69 vs 26±22.71 ms,P =0.01;RAA的VW分别为40±16.33 vs 27±21.63ms,P =0.006)。B组心房电重构前后基础及迷走神经刺激下均不能诱发房颤(VW接近0)。(4)心肌病理检查表明针对CFAE消融导致了消融位点的心外膜脂肪垫内神经节损伤
结论:针对CFAE消融导致了心房局部去迷走神经效应,减轻了心房电重构,抑制了迷走神经介导性房颤。
Impact of Vagal Activity on Atria Electrical Remodeling in Dogs
Objective: Atrial fibrillation (AF) is the most common arrhythmia and its prevalence increases with the aging of the population. Atrial electrical remodeling (AER) including the shortening of action potential duration and atrial effective refractory period (ERP), the decrease of rate adaptation and wavelength index, and so on, plays an important role in the pathogenesis and maintenance of AF. Many studies have demonstrated that atrial vagal denervation could result in the decrease of vulnerability to AF. Furthermore, recent data have proved that mapping and ablation of fatty pats thereby vagal innervation to the heart was very effective in AF interventional treatment. However, little is known regarding the mechanisms of vagal denervation for treatment of AF: eradication of triggering foci or modification of substrates. The study is aimed to elucidate the effects of vagal intervention on AER in order to explore the mechanisms of the vagal denervation for the AF treatment.
Methods: Twenty four adult mongrel dogs of either sex weighing 10 to 15 kg were anesthetized with sodium pentobarbital (150mg/kg IV) ,additional amounts of 250 to 500 mg per 60 minutes to 120 minutes were given as necessary to maintain anesthesia during the study. They were ventilated with room air by a cuffed endotracheal tube, and a constant oximetry was monitored throughout the experiment. Metoprolol was administered (0.2 mg/kg initial bolus with a maintenance dose of 0.2 mg/kg per hour) in order to exclude the influence of sympathetic activity. Multipolar catheters were placed into high right atria (RA), coronary sinus (CS) and right ventricle (RV). Bilateral cervical sympathovagal trunks were decentralized. AER was established by rapid pacing right atrium at the rate of 600 beats per minute for 30 minutes. ERP and vulnerability window (VW) were measured to evaluate the effects of the AER on the atrial electrophysiology and vulnerability of AF. Atrioventricular node ablation and temporary pacemaker were applied in case of the bradycardia induced by vagal stimulation and tachycardia due to induction of AF. Twenty four dogs were randomized into 3 groups. Sympathetic activity was blocked by administration of metoprolol in 3 groups. The changes of vagal modulation to atria after AER were observed in 10 dogs without vagal interruption in group A. The effects of vagal intervention on AER were investigated in 8 dogs with administration of atropine in group B. The impact of aggressively vagal activity on AER was studied in 6 dogs with bilateral cervical sympathovagal trunks stimulation during AER in group C. ERP and VW were measured before and after remodeling with and without vagal stimulation in all groups.
Results: (1) Effect of vagal modulation on AERP.In group A, ERP decreased significantly after AER compared with that before AER both at baseline (84±19.55ms vs 104±23.19ms at RA,P =0.008; 87±17.03ms vs 100±16.99ms at CS , P=0.0007) and during the vagal stimulation (26±8.43ms vs 51±28.46ms at RA,P =0.03; 30±15.63ms vs 49±31.07ms at CS,P=0.02) . In group B, ERP remained unchanged before and after AER both at baseline (112.5±21.21ms vs 115±14.14ms at RA , P>0.05 ;117.5±11.65ms vs 115±19.27ms at CS , P>0.05 ) and during vagal stimulation(111.25±18.08ms vs 116.25±11.88ms at RA,P>0.05;110±9.26ms vs 110±18.52ms at CS,P >0.05). In group C, ERP decreased significantly after AER compared with that before AER both at baseline (95±22.58ms vs 106.67±24.22ms at RA,P =0.0009; 85±22.58ms vs 13.33±20.66ms at CS,P =0.04) and during vagal stimulation (31.67±14.72ms vs 56.67±33.27ms at RA, P=0.04; 38.33±29.27ms vs 61.67±29.94ms at CS, P =0.02). ERP shortening after AER in group A and C inecreased significantly than that in group B at baseline(20±18.86ms in group A, 2.5±14.88ms in group B and 11.67±4.08ms in group C at RA;13±8.23ms in group A, -5±16.9ms in group B and 16.67±15.06ms in group C at CS) and vagal stimulation(25±29.53ms in group A, 5±11.95ms in group B and 25±22.58ms in group C at RA; 19±22.34ms in group A, 0±16.9ms in group B and 23.33±16.33ms in group C at CS) (all P<0.05), while there is no significant difference between group A and C (all P >0.05).(2) Effect of vagal modulation on VW. Atrial fibrillation was rarely induced at baseline (VW close to 0) before and after AER in all groups. VW increased signifycantly during vagal stimulation after AER in group A (40±16.33ms vs 27±21.63ms at RA, P =0.006; 51±24.69ms vs 26±22.71ms at CS,P =0.01) and group C (76.67±38.82ms vs 26.67±28.75ms at RA,P =0.04; 53.33±39.33ms vs 21.67±23.17ms at CS,P =0.02), while VW remained unchanged in group B (VW close to 0).
Conclusions: Short-term AER results in the decrease of ERP. AER is accompanied by the increases of atrial vagal modulation. The increased vagal activity and vagal stimulation promote AER, thereby increase the susceptibility to atrial fibrillation. The interrupted vagal activity attenuates AER, thereby suppresses the atrial fibrillation mediated by vagal stimulation.
Impact of Superior Vena Cava Isolation on Atrial Electrical Remodeling
Objective: Atrial fibrillation (AF) is the most common sustain arrhythmia. Numerous studies have shown that superior vena cava (SVC) isolation is effective method in suppressing AF by blocking the triggering or driving foci in some patients with paraxysmal AF. However, little has been known about the role of SVC isolation in suppression of sustained AF eventhough SVC isolation has been regarded as an ablative strategy . Atrial electrical remodeling(AER) plays an important role in the pathogenesis and maintainenance of AF. This study aimed to investigate effects of SVC isolation on AER in order to explore the neceesserity of SVC isolation for persisteny AF ablation.
Methods: 18 adult mongrel dogs under general anesthesia were randomized into A group and B group. Bilateral cervical sympathovagal trunks were decentralized. Metoprolol was given to block sympathetic effects. AER was performed by 600bpm pacing through right atrial catheter for 30 minutes in A group in 9 dogs. AER was performed after SVC isolation guided by Lasso catheter on the junction of right atrium and SVC in B group in 9 dogs. Atrial effective refractory period(ERP), vulnerability window(VW) of AF ,and sinus cycle length(SCL) were measured at baseline(without vagal stimulation) and vagal stimulation at right atrial appendage (RAA), distal coronary sinus (CSd) and paroximal coronary sinus (CSp) before and after AER. The underlying tissue was excised from ablative sites and the same sites without ablation as control specimens and fixed in buffered neutral formalin. Serial sections were stained with haematoxylin and eosin for microscopic examination.
Results: (1) SCL shortened significantly during vagal stimulation before and after AER in A group (all P value <0.05), while SCL remained unchanged during vagal stimulation before and after AER (all P value >0.05) . It suggests that SVC isolation eliminate vagal regulation on sinus node.In Group A, ERP shortened significantly at baseline (97.78±16.41 vs 85.56±15.90 ms at CSd, P= 0.005, 100±20.62 vs 82.22±19.86 ms at HRA, P=0.021) after AER. ERP decreased also significantly during vagal stimulation (48.89±32.96 vs 28.89±16.16 ms at CSd, P = 0.034, 48.89±29.34 vs 25.56±8.82 ms at HRA, P= 0.053) after AER. It suggests that rapid atrial pacing result in not only AER but also change of atrial electrophysicological properties due to vagal modulation. In group B, ERP remained unchanged before and after rapid atrial pacing both at baseline (95.56±22.97 vs 96.67±18.03 ms at CSd, P = 0.729, 94.44±12.36vs 94.44±16.67 ms at HRA), P=1 and during vagal stimulation (85.56±16.67 vs 88.89±15.37 ms at CSd, P = 0.471, 90±12.35 vs 94.44±16.67 ms at HRA, P=0.426). ERP shortening mediated by AER in Group A increased significantly than that in group B at baseline (12.22±9.72 vs 2.22±8.33 ms at CSd, P=0.032; 22.22±18.56 vs -3.33±7.07 ms at HRA, P= 0.001) and during vagal stimulation (20±23.45 vs 1.11±13.64 ms at CSd, P = 0.053; 23.33±30.82 vs 0±13.23 ms at HRA, P= 0.053). It suggests that SVC isolation relieve AER due to partly vagal dennervation.In Group A, AF could not be induced at baseline (VW close to 0) before and after AER. VW increased significantly during vagal stimulation after AER(24.44±23.51ms VS 52.22±23.80ms at CSd,P=0.009; 23.33±19.36ms VS 38.89±13.97ms at HRA,P=0.0007) . In group B, AF could not be induced at baseline and during vagal stimulation (VW close to 0) before and after AER. It suggests that SVC isolation may contribute to the suppression of AF mediated by vagal activity and the AER. (2) Histological sections showed numerrious nerves distribution alone SVC septum. In control specimens, the ganglia contained numerous nerve cells and was surrounded by fibrous and fatty tissue. After ablation, the ganglia were damaged. Some parts of the fibrous capsule of ganglia were thinned or broken. Neurons distributed sparsely in the ganglia, while among these neurons neuroglia increased in number. And concentration of nucleus appeared in some neurons of ganglia.
Conclusions: AER can decrease ERP and enhance the vagal modulation to atria, thereby increase the susceptibility to atrial fibrillation triggered by vagus. SVC isolation can release AER, which maybe contribute to the attenuated vagal modulation to atria.
Impact of ablation focused on the complex fractionated atrial electrogram on atrial electrical remodeling in dogs
Objective: Ablation targeting complex fractionated atrial electrogram (CFAE) has been demonstrated to be effective for atrial fibrillation. Some promising observation have shown that the distribution of CAFE has a relationship with the efferent vagal innervation to atria. However, mechanisms of CFAE ablation for atrial fibrillation remained controversy. This study aimed to observe the impact of CAFP ablation on atrial electrical remodeling (AER) in order to investigate mechanisms of CFAE ablation in treatment of atrial fibrillation because AER plays an important role in the pathogenesis and maintainenance of atrial fibrillation.
Methods: 17 adult mongrel dogs under general anesthesia were random- ized into A group and B group. Bilateral cervical sympathovagal trunks were decentralized. Metoprolol was given to block sympathetic effects. AER was performed by 600bpm pacing through right atrial catheter for 30 minutes in A group in 10 dogs. AER was performed after CAFE abaltion guided by multipolar catheters or Ensite mapping system in B group in 7 dogs. Multipolar catheters were placed into the right and left atrium and coronary sinus. CAFP was recorded by multipolar catheters or Ensite mapping system during atrial fibrillation induced by S1S2 stimul- ation during sympathovagal trunks stimulation. Atrial effective refractory period (ERP), vulnerability window (VW) of atrial fibrillation, and sinus rhythm cycle length (SCL) were measured at right atrial appendage (RAA), left atrial appendage (LAA), distal coronary sinus(CSd) and proximal coronary sinus(CSp) at baseline (without vagal stimulation) and during vagal stimulation before and after ablation. The underlying tissue were excised from ablative sites and the same sites without ablation as control specimens. Serial sections were taken and stained with hematoxylin and eosin for microscopic examination.
Results: (1) SCL shortened significantly during vagal stimulation before and after AER in A group (all P value <0.05), while SCL remained unchanged during vagal stimulation before and after AER (all P value >0.05) . It suggests that CAFE abaltion eliminate vagal regulation on sinus node. (2) In Group A, ERP shortened significantly at baseline (100±16.99 vs 86±15.06 ms at LAA, P= 0.003, 104±23.19 vs 84±19.56 ms, P=0.008 at RAA) after AER. ERP decreased also significantly during vagal stimulation (50±31.27 vs 31±16.63 ms at LAA, P = 0.02, 49±27.67 vs 28±11.35 ms, P= 0.05 at RAA) after AER. It suggests that rapid atrial pacing result in not only AER but also change of atrial electrophys- icological properties due to vagal modulation. In group B, ERP remained unchanged before and after rapid atrial pacing both at baseline (98.57±8.99 vs 105.71±11.34 ms at LAA, P>0.05, 105.71±27.61vs 105.71±11.34 ms at HRA,P>0.05) and during vagal stimulation (90±19.15 vs 94.29±25.73 ms at LAA, P>0.05, 84.29±41.17 vs 92.86±30.39 ms at RAA,P>0.05). ERP shortening mediated by AER in Group A increased significantly than that in group B at baseline (14±10.75 vs -7.14±9.51 ms at LAA, P=0.001; 20±18.86 vs 0±8.16 ms at RAA, P= 0.02) and during vagal stimulation (19±22.33 vs -4.29±9.76 ms at RAA, P = 0.02; 19±27.67 vs -8.57±19.52 ms at RAA, P= 0.04). It suggests that CAFE abaltion relieve AER due to partly vagal dennervation.(3)In Group A, AF could not be induced at baseline (VW close to 0) before and after AER. VW increased significantly during vagal stimulation after AER(51±24.69 ms VS 26±22.71ms at LAA, P=0.01; 40±16.33ms VS 27±21.63ms at HRA,P=0.006) . In group B, AF could not be induced at baseline and during vagal stimulation (VW close to 0) before and after AER. It suggests that CAFE abaltion may contribute to the suppression of AF mediated by vagal activity and the AER. (4) Histological sections showed numerrious nerves distrib- ution in CAFE area. In control specimens, the ganglia contained numerous nerve cells and was surrounded by fibrous and fatty tissue. After ablation, the ganglia were damaged. Some parts of the fibrous capsule of ganglia were thinned or broken. Neurons distributed sparsely in the ganglia, while among these neurons neuroglia increased in number. And concentration of nucleus appeared in some neurons of ganglia.
Conclusions: AER can decrease ERP and enhance the vagal modulation to atria, thereby increase the susceptibility to atrial fibrillation triggered by vagus. CAFE abaltion can release AER, which maybe contri- bute to the attenuated vagal modulation to atria.
引文
1. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995; 92: 1954–1968.
2. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202-2209.
3. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
4. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
5. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibril- ation time course and mechanisms.Circulation,1996;94:2968-2974.
6. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolo- nged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
7. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulat- ion, 1997; 96: 3710–3720.
8. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
9. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
10. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol.1999;22: 880-886.
11. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
12. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
13. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995; 91: 2235–2244.
14. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardio- vasc Electrophysiol, 2005; 16: 879-84
15. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
16. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004,109: 327-334.
17. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation,2000;102:2744-2780.
18. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
19. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation.Heart Rhythm, 2006; 3(4) : 387-396.
20. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implic- ations for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
21. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
22. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibril- ation. Heart Rhythm,2005; 2: 27–34.
23. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation,2005; 112: 789–797.
24. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endoc- ardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177–1182
25. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3:701-708.
1. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation, 2000;102:67–74
2. Lu TM, Tai CT, Hsieh MH, et al. Electrophysiologic characteristics in initiation of paroxysmal atrial fibrillation from a focal area. J Am Coll Cardiol, 2001; 37:1658–1664
3. Goya M, Ouyang F, Ernst S, et al. Electroanatomic Mapping and Catheter Ablation of Breakthroughs From the Right Atrium to the Superior Vena Cava in Patients With Atrial Fibrillation. Circulation, 2002; 106(11): 1317 - 1320.
4. Yeh HI, Lai YJ, Lee SH, et al. Heterogeneity of myocardial sleeve morphology and gap junctions in canine superior vena cava. Circulation, 2001; 104:3152– 3157
5. Lee SH, Chen YJ, Tai CT, et al. Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing. Basic Res Cardiol, 2005; 100:14–21
6. Yeh HI, Lai YJ, Lee SH, et al. Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing. Basic Res Cardiol, 2006;101(4):269-80.
7. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation, 1997;95: 2573- 2584.
8. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
9. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation. 2000;102:2744- 2780.
10. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofre- quency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999;22: 880-886.
11. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
12. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atriareduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91: 2235-2244.
13. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 2004, 109: 327-334.
14. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995, 92: 1954-1968.
15. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycar dia-induced atrial electrical remodeling.Circulation,1998, 98:2202-2209.
16. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circula- tion, 2000;101:2007-2017.
17. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibrillation time course and mechanisms.Circulation,1996;94:2968-2974.
18. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
19. Verma A, Patel D, Famy T, et al. Efficacy of adjuvant anterior left atrial ablation during intracardiac echocardiography-guided pulmonary vein antrum isolation for atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(2): 151- 156.
20. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol. 2007;18(12):1261-6.
21. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
22. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044-2053.
23. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrialfibrillation. Heart Rhythm,2005; 2: 27-34.
24. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789-797.
25. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
26. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
27. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmo- nary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177-1182
28. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
1. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
2. Katritsis D, Giazitzoglou E, Korovesis S, et al. Staged circumferential and ostial pulmonary vein ablation for the treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2007;30(1):102-8.
3. O'neill MD, Jais P, Takahashi Y, et al. The stepwise ablation approach for chronic atrial fibrillation-Evidence for a cumulative effect. J Interv Card Electro- physiol. 2006;16(3):153-67.
4. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
5. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
6. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
7. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibril- ation. Heart Rhythm,2006; 3(1): 27–34.
8. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789–797.
9. Shan Z, Van Der Voort PH, Blaauw Y, et al. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572–580.
10. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626-33.
11. Razavi M, Zhang S, Delapasse S, et al. The effects of pulmonary vein isolation on the dominant frequency and organization of coronary sinus electrical activityduring permanent atrial fibrillation. Pacing Clin Electrophysiol. 2006;29(11): 1201-8.
12. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
13. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005 ;16(8):879-84.
14. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
15. Takahashi Y, Jais P, Hocini M, et al.Shortening of fibrillatory cyclelength in the pulmonary vein during vagal excitation. JACC,2006,47:774-780.
16. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implica- tions for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
17. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation,2000;102:2744-2780.
18. Chevalier P, Obadia JF, Timour Q, et al.Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs.Pacing Clin Electrophysiol. 1999; 22:880-886.
19. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
20. Elvan A, Pride HP, Eble JN, et al Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235–2244.
21. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
22. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 2004, 109: 327-334.
23. Lemery R, Birnie D, Tang AS, et al. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. HeartRhythm, 2006; 3(4) : 387-396.
24. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation, 2006; 114: 876-885.
25. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation. Circulation, 1998; 98: 2608 - 2614.
26. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
27. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
28. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177–1182
29. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
30. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995; 92: 1954–1968.
31. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202- 2209.
32. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
33. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
34. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibrilla- tion time course and mechanisms.Circulation,1996;94:2968-2974.
35. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
36. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circula- tion, 1997; 96: 3710–3720.
37. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
38. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
1. EI-Sherif N. Paroxysmal atrial fibrillation.Induction by carotid sinus compression and prevention by atropine.Br Heart,1972; 34(10):1024-1029.
2. Coumel P. Role of the autonomic nervous system in paroxysmal atrial fibrillation. In: Touboul PC, Waldo AL, eds. Atrial Flutter. Armonk, NY: Futura Publishing Co; 1996:248–161.
3. Lombardi F, Tarricone D, Tundo F, et al. Autonomic nervous system and parox- ysmal atrial fibrillation: a study based on the analysis of RR interval changes before, during and after paroxysmal atrial fibrillation. European Heart Journal, 2004; 25(14):1242-1248.
4. van den Berg MP, Haaksma J, Brouwer J, et al. Heart Rate Variability in Patients With Atrial Fibrillation Is Related to Vagal Tone. Circulation, 1997; 96:1209- 1216.
5. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
6. Scherlag BJ, Patterson E, Po S. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
7. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007; 18: 123-127.
8. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
9. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Deter- mining the connections between ganglionated plexi. Heart Rhythm 2007;3:56– 63.
10. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
11. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocar- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4:1177–1182.
12. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
13. Ardell JL,Randall WC. Selective vagal innervation of sinoatrial and atriaovent- ricular nodes in canine heart.Physiol,1986;20:H767-H773.
14. Yuan BX,Ardell JL,Carlson MD,et al.Gross and microscopic anatomy of canine intrinsic cardiac nervous system.Anat Rec 1994;239:75-87.
15. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of human intrinsic cardiac nervous system.Anat Rec 1997;247:289-298.
16. Singh S, Johnson PI, Javed A, et al. Monoamine-and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia. Circulation,1999;99:411-419.
17. Marion K, Wharton J, Sheppard M, et al. Distribution, morphology, and neurochemistry of endocardial and epicardial nerve terminal aborizations in the human heart. Circulation, 1995; 92: 2343-2351
18. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
19. Ho SY, Cabrora JA, Tran VH, et al. Architecture of the pulmonary veins:revel- ance to radiofrequency ablation.Heart,2001;86:265-270.
20. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
21. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
22. Nakagawa H, Yokoyama K, Wu R, et al. Comparison of areas of farctionated atrial potentials and location of autonomic ganglionated plexi between patients with paroxysmal, persistent and permanent atrial fibrillation. Heart Rhythm, 2006; 3(5s): 56.
23. Tsai CF, Chen SA, Tai CT, et al. Bezold-Jarisch-like reflex during radiofre- quency ablation of the pulmonary vein tissue in patients with paroxysmal focal atrial fibrillation. Cardiovasc Electrophysiol, 1999;10: 27-35.
24. Hsieh MH, Chiou CW, Wen ZC, et al. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation,1999;30:2237- 2243.
25. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
26. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial, JAMA, 2005; 293: 2634–2640.
27. Dixit S, Gerstenfeld EP, Ratcliffe SJ, et al. Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study. Heart Rhythm. 2008;5(2):174-81.
28. Fagundes RL, Mantica M, De Luca L, et al. Safety of single transseptal puncture for ablation of atrial fibrillation: retrospective study from a large cohort of patients. J Cardiovasc Electrophysiol. 2007 ;18(12):1277-81.
29. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
30. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
31. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
32. Pappone C, Augello G, Sala S, et al.A randomized trial of circumferential pulmo- nary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibril- ation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340-7.
33. Oral H, Pappone C, Chugh A, et al., Circumferential pulmonary-vein ablation for chronic atrial fibrillation, N Engl J Med ,2006;354: 934–994.
34. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study), Eur Heart J ,2006; 27: 216–221.
35. Bertaglia E, Zoppo F, Tondo C, et al. Early complications of pulmonary vein catheter ablation for atrial fibrillation: a multicenter prospective registry on procedural safety. Heart Rhythm. 2007 ;4(10):1265-71.
36. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004, 109: 327-334.
37. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995;92: 1954–1968.
38. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202-2209.
39. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
40. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
41. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibril- ation time course and mechanisms.Circulation,1996;94:2968-2974.
42. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolo- nged rapid atrial pacing is associated with heterogeneous changes in atrial sym- pathetic innervation. Circulation, 2000; 101:1185-1192.
43. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circul- ation,1997; 96: 3710–3720.
44. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
45. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
46. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
47. Katritsis D, Giazitzoglou E, Korovesis S, et al. Staged circumferential and ostial pulmonary vein ablation for the treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2007; 30(1): 102-8.
48. O'neill MD, Jais P, Takahashi Y, et al. The stepwise ablation approach for chronic atrial fibrillation-Evidence for a cumulative effect. J Interv Card Electro- physiol. 2006;16(3):153-67.
49. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrilla- tion. Heart Rhythm,2006; 3(1): 27–34.
50. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789–797.
51. Shan Z, Van Der Voort PH, Blaauw Y, et al. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572–580.
52. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626-33.
53. Razavi M, Zhang S, Delapasse S, et al. The effects of pulmonary vein isolation on the dominant frequency and organization of coronary sinus electrical activity during permanent atrial fibrillation. Pacing Clin Electrophysiol. 2006;29(11): 1201-8.
54. Takahashi Y, Jais P, Hocini M, et al.Shortening of fibrillatory cyclelength in the pulmonary vein during vagal excitation. JACC,2006,47:774-780.
55. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implicat- ions for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
56. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995; 91: 2235–2244.
57. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol.1999;22: 880-886.
58. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
59. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
60. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping ofganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
61. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial Fibrillation. Circulation, 1998; 98: 2608 - 2614.
62. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
63. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
1. Cappato R, Calkins H, Chen S, et al. Worldwide Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial Fibrillation. Circulation, 2005; 111: 1100 - 1105.
2. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA, 2005; 293(21): 2634-2640.
3. Dixit S, Gerstenfeld EP, Ratcliffe SJ, et al. Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study. Heart Rhythm. 2008;5(2):174-81.
4. Fagundes RL, Mantica M, De Luca L, et al. Safety of single transseptal puncture for ablation of atrial fibrillation: retrospective study from a large cohort of patients. J Cardiovasc Electrophysiol. 2007 ;18(12):1277-81.
5. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
6. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
7. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
8. Pappone C, Augello G, Sala S, et al.A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340-7.
9. Oral H, Pappone C, Chugh A, et al., Circumferential pulmonary-vein ablation for chronic atrial fibrillation, N Engl J Med ,2006;354: 934–994.
10. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study), Eur Heart J ,2006; 27: 216–221.
11. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation, 2000;102:67–74
12. Lu TM, Tai CT, Hsieh MH, et al. Electrophysiologic characteristics in initiation of paroxysmal atrial fibrillation from a focal area. J Am Coll Cardiol, 2001; 37:1658–1664
13. Goya M, Ouyang F, Ernst S, et al. Electroanatomic Mapping and Catheter Ablation of Breakthroughs From the Right Atrium to the Superior Vena Cava in Patients With Atrial Fibrillation. Circulation, 2002; 106(11): 1317 - 1320.
14. Yeh HI, Lai YJ, Lee SH, et al. Heterogeneity of myocardial sleeve morphology and gap junctions in canine superior vena cava. Circulation, 2001; 104:3152– 3157
15. Lee SH, Chen YJ, Tai CT, et al. Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing. Basic Res Cardiol, 2005; 100:14–21
16. Yeh HI, Lai YJ, Lee SH, et al. Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing. Basic Res Cardiol, 2006;101(4):269-80.
17. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
18. Scherlag BJ, Patterson E, PoS. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
19. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007; 18: 123-127.
20. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
21. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Determ- ining the connections between ganglionated plexi. Heart Rhythm 2007;3:56–63.
22. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
23. Haissaguerre M,Jais P,Shah DC,et al.Spontaneous initiation of atrail fibrillation by ectopic beats originating in the pulmonary veins.N Engl Med,1998; 339: 659- 666.
24. Nakagawa H, Aoyama H, Beckman KJ, et al. Relation between pulmonary vein firing and extent of left atrial-pulmonary vein connection in patients with atrial fibrillation.Circulation, 2004; 109: 1523-1529.
25. Yamane T, Shah DC, Hocini M, et al. Dilatation is a marker of arrythmogenic pulmonary veins in focal initiated fibrillation.PACE,2000;23:641-649.
26. Hocini M, Ho SY, Kawana T,et al.Electrical conduction in canine pulmonary veins:electrophsiological and anatomic correlation.Circulation,2002;105: 2442- 2448.
27. Arora RM,Verheule SP,Scott LM,et al Arrhythmogenic substrate of the pumonary veins assessed by high-resolution optical mapping.Circulation, 2003.107: 1816- 1821.
28. Kumagai K,Ogawa M,Noguchi H,et a1.E1ectrophysiologic properties of pulmonary veins assessed using a multielectrode basket catheter.JACC,2004; 43:2281-2289.
29. Haissaguerre M,Sanders P,Hocini M.et a1.Changes in atrial fibrillation cycle length and inducibility during catheter ablation and their relation to outcome. Circulation,2004;109:3007-3013.
30. Verma A, Patel D, Famy T, et al. Efficacy of adjuvant anterior left atrial ablation during intracardiac echocardiography-guided pulmonary vein antrum isolation for atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(2):151-156.
31. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol. 2007;18(12):1261-6.
32. Chiou CW, Eble JN, Zipes DP. Efferent Vagal Innervation of the Canine Atria and Sinus and Atrioventricular Nodes: The Third Fat Pad. Circulation, 1997; 95(11): 2573 - 2584.
33. Ardell JL,Randall WC. Selective vagal innervation of sinoatrial and atriaoventr- icular nodes in canine heart.Physiol,1986;20:H767-H773.
34. Yuan BX,Ardell JL,Carlson MD,et al.Gross and microscopic anatomy of canine intrinsic cardiac nervous system.Anat Rec 1994;239:75-87.
35. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of human intrinsic cardiac nervous system.Anat Rec 1997;247:289-298.
36. Singh S, Johnson PI, Javed A, et al. Monoamine-and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia. Circulation,1999;99:411-419.
37. Marion K, Wharton J, Sheppard M, et al. Distribution, morphology and neurochemistry of endocardial and epicardial nerve terminal aborizations in the human heart. Circulation, 1995;92:2343-2351
38. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
39. Ho SY, Cabrora JA, Tran VH, et al. Architecture of the pulmonary veins: revel- ance to radiofrequency ablation.Heart,2001;86:265-270.
40. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
41. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
42. Nakagawa H, Yokoyama K, Wu R, et al. Comparison of areas of farctionated atrial potentials and location of autonomic ganglionated plexi between patients with paroxysmal, persistent and permanent atrial fibrillation. Heart Rhythm, 2006; 3(5s): 56.
43. Tsai CF, Chen SA, Tai CT, et al. Bezold-Jarisch-like reflex during radiofre- quency ablation of the pulmonary vein tissue in patients with paroxysmal focal atrial fibrillation. Cardiovasc Electrophysiol,1999;10: 27-35.
44. Hsieh MH, Chiou CW, Wen ZC, et al. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation,1999;30:2237- 2243.
45. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
46. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrilla- tion.Circulation,2004,109:327-334.
47. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999;22: 880–886.
48. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235–2244.
49. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
50. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
51. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhy- thm, 2006; 3(4) : 387-396.
52. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial Fibrillation. Circulation, 1998; 98: 2608 - 2614.
53. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
54. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation induci- bility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
55. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4:1177–1182.
1. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
2. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
3. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation, 1995; 91:2235–2244.
4. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter Ablation of Cardiac Autonomic Nerves for Prevention of vagal Atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
5. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal Atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999; 22:880–886.
6. Liu L, Nattel S. Differing sympathetic and vagal effects on Atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997; 273:H805–H816.
7. Smeets JLRM, Allessie MA, Lammers WJEP, et al. The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium: the role of heart rate, autonomic transmitters, temperature, and potassium. Circ Res. 1986;58:96–108.
8. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
9. Scherlag BJ, Patterson E, Po S. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
10. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007;18: 123-127.
11. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
12. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Deter- mining the connections between ganglionated plexi. Heart Rhythm 2007; 3:56–63.
13. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
14. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4: 1177–1182.
15. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
16. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
17. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004, 109: 327-334.
18. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995; 92: 1954–1968.
19. Yamashita T, Murakawa Y, Hayami N, et al. Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium. Circulation, 2000;101:2007-2017.
20. Fareh S, Villemaire C, Nattel S. Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused byTachy- cardia-Induced Atrial Electrical Remodeling. Circulation, 1998; 98:2202-2209.
21. Brundel BJJM, Van Gelder IC, Henning RH, et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation, 2001; 103: 684–690.
22. Pappone C, Oretoq Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of p tients with atrial fibrillation.Circulation.2001,10 4(21):2539-44
23. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
24. Goete A, Honeycut C, Langberg J. Electrical remodeling in atrial fibrillation.Time course and mechanisms. Circulation. 1996 Dee 1; 94(11): 2968-2974.
25. Vanoner DR, Pond AL, McCathy PM, et al. Outward K+ current densities and Kv1.5 expression a rereduced in chronic humana trial fibrillation. Circ Res,1997, 80 :772-781.
26. Attuel P, Childers R, Cauchemez B. Failure in the rate adaptation of the atrial refractory period:its relationship to vulnerability. Int J C a rdial.1982;2(2): 179- 197
27. Shiroshita-Takeshita A, Mitamura H, Shinagawa K, et al. Discordant temporal changes in electrophysiological properties during electrical remodeling and its recovery in the canine atrium. Jpn Heart J. 2002 ;43(2):167-81.
28. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na1/H1 Exchanger in Short-Term Atrial Electrophysiological Remodeling, Circulation, 2000, 101, 1861-1866.
29. Morillo CA, Klein GJ, Jones DL,.Guiraudon CM. Chronic rapid atrial pacing.Str uctural,fu nctional,an de lectrophysiologicalch aracteristicso fa n ew model of sustained atrial fibrillation. Circulation. 1995 Mar 1; 91(5):1588-1595.
30. Moriguchi M, Niwano S, Yoshizawa N,et al. Verapamil suppresses the inhomogeneity of electrical remodeling in a canine long-term rapid atrial stimul- ation model.Pacing Clin Electrophysiol. 2003 26(11):2072-2082.
31. Yu WC, Lin YK, Tai CT, et al. Early recurrence of atrial fibrillation after external cardioversion. Pacing Clin Electrophysiol. 1999;22(11):1614-9
32. Vanden Berg MP, Hassink RJ, Balje-Volker C. Role of the antonomic nervous system in vagal atrial fibrillation Heart, 2003; 89,333-335
33. Fynn SP, Todd D.M, Hobbs W JC, et al. Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation.A manifestation of atriale lectricalr emodellingi nh umans? Eur Heart. 20 01;22(19):1822-1834.
34. Miyauchi Y, Zhou S, Okuyama Y, et al.Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyerinnervation in Hearts with Chronic Left Ventricular Myocardial Infarction: Implications for Atrial Fibrillation. Circul- ation. 2003; 108(3):360-366.
35. Mori K, Hara Y, SaitoT, et al. Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells. Circulation, 1995; 91:2834-2843.
36. Jayachandran V, Sih H J, Winkle W, et al. Atrial Fibrillation Produced by Prolonged Rapid Atrial Pacing Is Associated With Heterogeneous Changes inAtrial Sympathetic Innervation. Circulation, 2000; 101:1185-1192.
37. Olgin J E, Sih H J, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial fibrillation Circulation, 1998; 98:2608-2614.
38. Massari VJ, Dickerson LW, Gray AL, et al .Neural control of left ventricular contractility in the dog heart: synaptic interactions of negative inotropic vagal preganglionic neurons : in the nucleus ambiguus with tyrosine hydroxylase immunoreactive terminals[J]. Circulation, 2001;103(8):1157-1163.
39. Blaauw Y, Tieleman RG, Brouwer J, et al. Tachycardia induced electrical remod- eling of the atrial and the autonomic nervous system in goats. PACE, 1999; 22:1656-1667.
40. Brundel BJ, Henning RH, Camping,HH, et al. Molecular mechanisms of remod- eling in human atrial fibrillation. Cardiovasc Res, 2002,54(2):315- 324.
41. Bosch RF, Scherer CR,Rub N,et al. Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits. J Am Coll Cardior, 2003, 41(5): 858-869.
42. Grammer JB, Bosch RF, Kuhlkamp V,et al. Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation. J Cardiocasc Electrophysiol. 2000;(6): 626-633.
43. Van Wagoner DR, Pond AL, McCarphy PM,et al. Atrial L-type Ca+ currents and human atrial fibrillation. Circ Res,1997;80(6):772-781.
44. Skasa M, Jungling E, Picht E, et al. L-type calcium currents in atrial myocytes from patients with persistent and non-persistent atrial fibrillation. Basic Res Cardior. 2110;96(2):151-159.
45. Gaspo R, Bou Abboud E,et al. Functional mechanisms underlying tachycardia- induced sustained atrial fibrillation in a chronic dog model. Circ Res. 1997; 81(4):512-25.
46. Gaspo R, Bosch RF, et al. Tachycardia-induced changes in Na+ current in a chronic dog model of atrial fibrillation. Cir Res, 1997,81:1045.
2. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202-2209.
3. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
4. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
5. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibril- ation time course and mechanisms.Circulation,1996;94:2968-2974.
6. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolo- nged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
7. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulat- ion, 1997; 96: 3710–3720.
8. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
9. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
10. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol.1999;22: 880-886.
11. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
12. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
13. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995; 91: 2235–2244.
14. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardio- vasc Electrophysiol, 2005; 16: 879-84
15. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
16. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004,109: 327-334.
17. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation,2000;102:2744-2780.
18. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
19. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation.Heart Rhythm, 2006; 3(4) : 387-396.
20. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implic- ations for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
21. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
22. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibril- ation. Heart Rhythm,2005; 2: 27–34.
23. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation,2005; 112: 789–797.
24. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endoc- ardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177–1182
25. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3:701-708.
1. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation, 2000;102:67–74
2. Lu TM, Tai CT, Hsieh MH, et al. Electrophysiologic characteristics in initiation of paroxysmal atrial fibrillation from a focal area. J Am Coll Cardiol, 2001; 37:1658–1664
3. Goya M, Ouyang F, Ernst S, et al. Electroanatomic Mapping and Catheter Ablation of Breakthroughs From the Right Atrium to the Superior Vena Cava in Patients With Atrial Fibrillation. Circulation, 2002; 106(11): 1317 - 1320.
4. Yeh HI, Lai YJ, Lee SH, et al. Heterogeneity of myocardial sleeve morphology and gap junctions in canine superior vena cava. Circulation, 2001; 104:3152– 3157
5. Lee SH, Chen YJ, Tai CT, et al. Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing. Basic Res Cardiol, 2005; 100:14–21
6. Yeh HI, Lai YJ, Lee SH, et al. Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing. Basic Res Cardiol, 2006;101(4):269-80.
7. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation, 1997;95: 2573- 2584.
8. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
9. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation. 2000;102:2744- 2780.
10. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofre- quency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999;22: 880-886.
11. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
12. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atriareduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91: 2235-2244.
13. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 2004, 109: 327-334.
14. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995, 92: 1954-1968.
15. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycar dia-induced atrial electrical remodeling.Circulation,1998, 98:2202-2209.
16. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circula- tion, 2000;101:2007-2017.
17. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibrillation time course and mechanisms.Circulation,1996;94:2968-2974.
18. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
19. Verma A, Patel D, Famy T, et al. Efficacy of adjuvant anterior left atrial ablation during intracardiac echocardiography-guided pulmonary vein antrum isolation for atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(2): 151- 156.
20. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol. 2007;18(12):1261-6.
21. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
22. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044-2053.
23. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrialfibrillation. Heart Rhythm,2005; 2: 27-34.
24. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789-797.
25. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
26. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
27. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmo- nary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177-1182
28. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
1. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
2. Katritsis D, Giazitzoglou E, Korovesis S, et al. Staged circumferential and ostial pulmonary vein ablation for the treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2007;30(1):102-8.
3. O'neill MD, Jais P, Takahashi Y, et al. The stepwise ablation approach for chronic atrial fibrillation-Evidence for a cumulative effect. J Interv Card Electro- physiol. 2006;16(3):153-67.
4. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
5. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
6. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
7. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibril- ation. Heart Rhythm,2006; 3(1): 27–34.
8. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789–797.
9. Shan Z, Van Der Voort PH, Blaauw Y, et al. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572–580.
10. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626-33.
11. Razavi M, Zhang S, Delapasse S, et al. The effects of pulmonary vein isolation on the dominant frequency and organization of coronary sinus electrical activityduring permanent atrial fibrillation. Pacing Clin Electrophysiol. 2006;29(11): 1201-8.
12. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
13. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005 ;16(8):879-84.
14. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
15. Takahashi Y, Jais P, Hocini M, et al.Shortening of fibrillatory cyclelength in the pulmonary vein during vagal excitation. JACC,2006,47:774-780.
16. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implica- tions for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
17. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.Circulation,2000;102:2744-2780.
18. Chevalier P, Obadia JF, Timour Q, et al.Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs.Pacing Clin Electrophysiol. 1999; 22:880-886.
19. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
20. Elvan A, Pride HP, Eble JN, et al Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235–2244.
21. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
22. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 2004, 109: 327-334.
23. Lemery R, Birnie D, Tang AS, et al. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. HeartRhythm, 2006; 3(4) : 387-396.
24. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation, 2006; 114: 876-885.
25. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation. Circulation, 1998; 98: 2608 - 2614.
26. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
27. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
28. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007; 4: 1177–1182
29. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
30. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995; 92: 1954–1968.
31. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202- 2209.
32. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
33. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
34. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibrilla- tion time course and mechanisms.Circulation,1996;94:2968-2974.
35. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation, 2000; 101:1185-1192.
36. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circula- tion, 1997; 96: 3710–3720.
37. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
38. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
1. EI-Sherif N. Paroxysmal atrial fibrillation.Induction by carotid sinus compression and prevention by atropine.Br Heart,1972; 34(10):1024-1029.
2. Coumel P. Role of the autonomic nervous system in paroxysmal atrial fibrillation. In: Touboul PC, Waldo AL, eds. Atrial Flutter. Armonk, NY: Futura Publishing Co; 1996:248–161.
3. Lombardi F, Tarricone D, Tundo F, et al. Autonomic nervous system and parox- ysmal atrial fibrillation: a study based on the analysis of RR interval changes before, during and after paroxysmal atrial fibrillation. European Heart Journal, 2004; 25(14):1242-1248.
4. van den Berg MP, Haaksma J, Brouwer J, et al. Heart Rate Variability in Patients With Atrial Fibrillation Is Related to Vagal Tone. Circulation, 1997; 96:1209- 1216.
5. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
6. Scherlag BJ, Patterson E, Po S. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
7. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007; 18: 123-127.
8. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
9. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Deter- mining the connections between ganglionated plexi. Heart Rhythm 2007;3:56– 63.
10. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
11. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocar- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4:1177–1182.
12. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atrial and sinus and atrioventricular nodes:the third fat pad.Circulation,1997;95:2573-2584.
13. Ardell JL,Randall WC. Selective vagal innervation of sinoatrial and atriaovent- ricular nodes in canine heart.Physiol,1986;20:H767-H773.
14. Yuan BX,Ardell JL,Carlson MD,et al.Gross and microscopic anatomy of canine intrinsic cardiac nervous system.Anat Rec 1994;239:75-87.
15. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of human intrinsic cardiac nervous system.Anat Rec 1997;247:289-298.
16. Singh S, Johnson PI, Javed A, et al. Monoamine-and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia. Circulation,1999;99:411-419.
17. Marion K, Wharton J, Sheppard M, et al. Distribution, morphology, and neurochemistry of endocardial and epicardial nerve terminal aborizations in the human heart. Circulation, 1995; 92: 2343-2351
18. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
19. Ho SY, Cabrora JA, Tran VH, et al. Architecture of the pulmonary veins:revel- ance to radiofrequency ablation.Heart,2001;86:265-270.
20. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
21. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
22. Nakagawa H, Yokoyama K, Wu R, et al. Comparison of areas of farctionated atrial potentials and location of autonomic ganglionated plexi between patients with paroxysmal, persistent and permanent atrial fibrillation. Heart Rhythm, 2006; 3(5s): 56.
23. Tsai CF, Chen SA, Tai CT, et al. Bezold-Jarisch-like reflex during radiofre- quency ablation of the pulmonary vein tissue in patients with paroxysmal focal atrial fibrillation. Cardiovasc Electrophysiol, 1999;10: 27-35.
24. Hsieh MH, Chiou CW, Wen ZC, et al. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation,1999;30:2237- 2243.
25. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
26. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial, JAMA, 2005; 293: 2634–2640.
27. Dixit S, Gerstenfeld EP, Ratcliffe SJ, et al. Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study. Heart Rhythm. 2008;5(2):174-81.
28. Fagundes RL, Mantica M, De Luca L, et al. Safety of single transseptal puncture for ablation of atrial fibrillation: retrospective study from a large cohort of patients. J Cardiovasc Electrophysiol. 2007 ;18(12):1277-81.
29. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
30. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
31. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
32. Pappone C, Augello G, Sala S, et al.A randomized trial of circumferential pulmo- nary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibril- ation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340-7.
33. Oral H, Pappone C, Chugh A, et al., Circumferential pulmonary-vein ablation for chronic atrial fibrillation, N Engl J Med ,2006;354: 934–994.
34. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study), Eur Heart J ,2006; 27: 216–221.
35. Bertaglia E, Zoppo F, Tondo C, et al. Early complications of pulmonary vein catheter ablation for atrial fibrillation: a multicenter prospective registry on procedural safety. Heart Rhythm. 2007 ;4(10):1265-71.
36. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004, 109: 327-334.
37. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995;92: 1954–1968.
38. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia- Induced atrial electrical remodeling.Circulation,1998; 98:2202-2209.
39. Yamashita T, Murakawa Y, Hayami N, et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K+ channels in rat atrium. Circulation, 2000; 101:2007-2017.
40. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+ exchanger in short-term atrial electrophysiological remodeling. Circulation, 2000; 101: 1861- 1866.
41. Goette A, Honeycntt C, Langberg JJ, et al. Electrical remodeling in atrial fibril- ation time course and mechanisms.Circulation,1996;94:2968-2974.
42. Jayachandran V, Sih H J, Winkle W, et al. Atrial fibrillation produced by prolo- nged rapid atrial pacing is associated with heterogeneous changes in atrial sym- pathetic innervation. Circulation, 2000; 101:1185-1192.
43. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented consciousgoats: Roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circul- ation,1997; 96: 3710–3720.
44. Miyauchi M, Kobayashi Y, Miyauchi Y, et al. Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing. PACE, 2004, 27 (1): 33-37.
45. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
46. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation mapping of the electrophysiologic substrate. J Am Coll Cardiol, 2004; 43: 2044–2053.
47. Katritsis D, Giazitzoglou E, Korovesis S, et al. Staged circumferential and ostial pulmonary vein ablation for the treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2007; 30(1): 102-8.
48. O'neill MD, Jais P, Takahashi Y, et al. The stepwise ablation approach for chronic atrial fibrillation-Evidence for a cumulative effect. J Interv Card Electro- physiol. 2006;16(3):153-67.
49. Rostock T, Rotter M, Sanders P, et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrilla- tion. Heart Rhythm,2006; 3(1): 27–34.
50. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation, 2005; 112: 789–797.
51. Shan Z, Van Der Voort PH, Blaauw Y, et al. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572–580.
52. Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 2006;113:626-33.
53. Razavi M, Zhang S, Delapasse S, et al. The effects of pulmonary vein isolation on the dominant frequency and organization of coronary sinus electrical activity during permanent atrial fibrillation. Pacing Clin Electrophysiol. 2006;29(11): 1201-8.
54. Takahashi Y, Jais P, Hocini M, et al.Shortening of fibrillatory cyclelength in the pulmonary vein during vagal excitation. JACC,2006,47:774-780.
55. Tan AY, Li H, Wachsmann HS, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implicat- ions for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006; 48:132-143.
56. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995; 91: 2235–2244.
57. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol.1999;22: 880-886.
58. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
59. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
60. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping ofganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
61. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial Fibrillation. Circulation, 1998; 98: 2608 - 2614.
62. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
63. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
1. Cappato R, Calkins H, Chen S, et al. Worldwide Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial Fibrillation. Circulation, 2005; 111: 1100 - 1105.
2. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA, 2005; 293(21): 2634-2640.
3. Dixit S, Gerstenfeld EP, Ratcliffe SJ, et al. Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study. Heart Rhythm. 2008;5(2):174-81.
4. Fagundes RL, Mantica M, De Luca L, et al. Safety of single transseptal puncture for ablation of atrial fibrillation: retrospective study from a large cohort of patients. J Cardiovasc Electrophysiol. 2007 ;18(12):1277-81.
5. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol. 2008;51(8):843-9.
6. Katritsis D, Wood MA, Giazitzoglou E, et al. Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. Europace. 2008;10(4): 419-24.
7. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol. 2008;23(1):1-8.
8. Pappone C, Augello G, Sala S, et al.A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340-7.
9. Oral H, Pappone C, Chugh A, et al., Circumferential pulmonary-vein ablation for chronic atrial fibrillation, N Engl J Med ,2006;354: 934–994.
10. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study), Eur Heart J ,2006; 27: 216–221.
11. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation, 2000;102:67–74
12. Lu TM, Tai CT, Hsieh MH, et al. Electrophysiologic characteristics in initiation of paroxysmal atrial fibrillation from a focal area. J Am Coll Cardiol, 2001; 37:1658–1664
13. Goya M, Ouyang F, Ernst S, et al. Electroanatomic Mapping and Catheter Ablation of Breakthroughs From the Right Atrium to the Superior Vena Cava in Patients With Atrial Fibrillation. Circulation, 2002; 106(11): 1317 - 1320.
14. Yeh HI, Lai YJ, Lee SH, et al. Heterogeneity of myocardial sleeve morphology and gap junctions in canine superior vena cava. Circulation, 2001; 104:3152– 3157
15. Lee SH, Chen YJ, Tai CT, et al. Electrical remodeling of the canine superior vena cava after chronic rapid atrial pacing. Basic Res Cardiol, 2005; 100:14–21
16. Yeh HI, Lai YJ, Lee SH, et al. Remodeling of myocardial sleeve and gap junctions in canine superior vena cava after rapid pacing. Basic Res Cardiol, 2006;101(4):269-80.
17. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
18. Scherlag BJ, Patterson E, PoS. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
19. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007; 18: 123-127.
20. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
21. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Determ- ining the connections between ganglionated plexi. Heart Rhythm 2007;3:56–63.
22. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
23. Haissaguerre M,Jais P,Shah DC,et al.Spontaneous initiation of atrail fibrillation by ectopic beats originating in the pulmonary veins.N Engl Med,1998; 339: 659- 666.
24. Nakagawa H, Aoyama H, Beckman KJ, et al. Relation between pulmonary vein firing and extent of left atrial-pulmonary vein connection in patients with atrial fibrillation.Circulation, 2004; 109: 1523-1529.
25. Yamane T, Shah DC, Hocini M, et al. Dilatation is a marker of arrythmogenic pulmonary veins in focal initiated fibrillation.PACE,2000;23:641-649.
26. Hocini M, Ho SY, Kawana T,et al.Electrical conduction in canine pulmonary veins:electrophsiological and anatomic correlation.Circulation,2002;105: 2442- 2448.
27. Arora RM,Verheule SP,Scott LM,et al Arrhythmogenic substrate of the pumonary veins assessed by high-resolution optical mapping.Circulation, 2003.107: 1816- 1821.
28. Kumagai K,Ogawa M,Noguchi H,et a1.E1ectrophysiologic properties of pulmonary veins assessed using a multielectrode basket catheter.JACC,2004; 43:2281-2289.
29. Haissaguerre M,Sanders P,Hocini M.et a1.Changes in atrial fibrillation cycle length and inducibility during catheter ablation and their relation to outcome. Circulation,2004;109:3007-3013.
30. Verma A, Patel D, Famy T, et al. Efficacy of adjuvant anterior left atrial ablation during intracardiac echocardiography-guided pulmonary vein antrum isolation for atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(2):151-156.
31. Arruda M, Mlcochova H, Prasad SK, et al. Electrical isolation of the superior vena cava: an adjunctive strategy to pulmonary vein antrum isolation improving the outcome of AF ablation. J Cardiovasc Electrophysiol. 2007;18(12):1261-6.
32. Chiou CW, Eble JN, Zipes DP. Efferent Vagal Innervation of the Canine Atria and Sinus and Atrioventricular Nodes: The Third Fat Pad. Circulation, 1997; 95(11): 2573 - 2584.
33. Ardell JL,Randall WC. Selective vagal innervation of sinoatrial and atriaoventr- icular nodes in canine heart.Physiol,1986;20:H767-H773.
34. Yuan BX,Ardell JL,Carlson MD,et al.Gross and microscopic anatomy of canine intrinsic cardiac nervous system.Anat Rec 1994;239:75-87.
35. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of human intrinsic cardiac nervous system.Anat Rec 1997;247:289-298.
36. Singh S, Johnson PI, Javed A, et al. Monoamine-and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia. Circulation,1999;99:411-419.
37. Marion K, Wharton J, Sheppard M, et al. Distribution, morphology and neurochemistry of endocardial and epicardial nerve terminal aborizations in the human heart. Circulation, 1995;92:2343-2351
38. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
39. Ho SY, Cabrora JA, Tran VH, et al. Architecture of the pulmonary veins: revel- ance to radiofrequency ablation.Heart,2001;86:265-270.
40. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
41. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
42. Nakagawa H, Yokoyama K, Wu R, et al. Comparison of areas of farctionated atrial potentials and location of autonomic ganglionated plexi between patients with paroxysmal, persistent and permanent atrial fibrillation. Heart Rhythm, 2006; 3(5s): 56.
43. Tsai CF, Chen SA, Tai CT, et al. Bezold-Jarisch-like reflex during radiofre- quency ablation of the pulmonary vein tissue in patients with paroxysmal focal atrial fibrillation. Cardiovasc Electrophysiol,1999;10: 27-35.
44. Hsieh MH, Chiou CW, Wen ZC, et al. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation,1999;30:2237- 2243.
45. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomic nervous system in patients with supraventricular tachycardia and paroxysmal atrial fibrillation. Am Coll Cardiol,1998;32: 732 -738.
46. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrilla- tion.Circulation,2004,109:327-334.
47. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999;22: 880–886.
48. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235–2244.
49. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–H816.
50. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
51. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhy- thm, 2006; 3(4) : 387-396.
52. Olgin J E, Sih HJ, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial Fibrillation. Circulation, 1998; 98: 2608 - 2614.
53. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272-1279.
54. Oh S, Zhang Y, Bibevski S, et al. Vagal denervation and atrial fibrillation induci- bility: epicardial fat pad ablation does not have long-term effects. Heart Rhythm. 2006, 3(6):701-708.
55. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4:1177–1182.
1. Razavi M, Zhang S, Yang D, et al. Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs. J Cardiovasc Electrophysiol. 2005;16: 879-884.
2. Liu Y, Zhang S, Dong Y, et al. Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation. Chinese Medical Journal, 2006;119: 2049-2055.
3. Elvan A, Pride HP, Eble JN, et al. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation, 1995; 91:2235–2244.
4. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter Ablation of Cardiac Autonomic Nerves for Prevention of vagal Atrial fibrillation. Circulation, 2000; 102: 2774 - 2780.
5. Chevalier P, Obadia JF, Timour Q, et al. Thoracoscopic epicardial radiofrequency ablation for vagal Atrial fibrillation in dogs. Pacing Clin Electrophysiol. 1999; 22:880–886.
6. Liu L, Nattel S. Differing sympathetic and vagal effects on Atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997; 273:H805–H816.
7. Smeets JLRM, Allessie MA, Lammers WJEP, et al. The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium: the role of heart rate, autonomic transmitters, temperature, and potassium. Circ Res. 1986;58:96–108.
8. Scherlag BJ, Patterson E, Po S. The neural basis of atrial fibrillation. Journal of Electrocardiology,2006; 39: S180–S183.
9. Scherlag BJ, Patterson E, Po S. The intrinsic cardiac nervous system and atrial fibrillation.Current Opinion in Cardiology, 2006; 21:51–54.
10. Chen L, Zhou S, Fishbein M, et al. New Perspectives on the Role of Autonomic Nervous System inthe Genesis of Arrhythmias. J Cardiovasc Electrophysiol, 2007;18: 123-127.
11. Chen PS, TanAY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm, 2007;4:S61–S64.
12. Hou Y, Scherlag BJ, Lin J, et al. The interactive atrial neural network: Deter- mining the connections between ganglionated plexi. Heart Rhythm 2007; 3:56–63.
13. Pokushalov E. The role of autonomic denervation during catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2008;23(1):55-9.
14. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocarp- dial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm, 2007;4: 1177–1182.
15. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation,2006;114:876-885.
16. Lemery R, Birnie D, Tang ASL. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm, 2006; 3(4) : 387-396.
17. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibril- ation.Circulation, 2004, 109: 327-334.
18. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation, 1995; 92: 1954–1968.
19. Yamashita T, Murakawa Y, Hayami N, et al. Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium. Circulation, 2000;101:2007-2017.
20. Fareh S, Villemaire C, Nattel S. Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused byTachy- cardia-Induced Atrial Electrical Remodeling. Circulation, 1998; 98:2202-2209.
21. Brundel BJJM, Van Gelder IC, Henning RH, et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation, 2001; 103: 684–690.
22. Pappone C, Oretoq Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of p tients with atrial fibrillation.Circulation.2001,10 4(21):2539-44
23. Takei M, Tsuboi M, Usui T, et al. Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs. Jpn Circ J. 2001;65(12):1077-81.
24. Goete A, Honeycut C, Langberg J. Electrical remodeling in atrial fibrillation.Time course and mechanisms. Circulation. 1996 Dee 1; 94(11): 2968-2974.
25. Vanoner DR, Pond AL, McCathy PM, et al. Outward K+ current densities and Kv1.5 expression a rereduced in chronic humana trial fibrillation. Circ Res,1997, 80 :772-781.
26. Attuel P, Childers R, Cauchemez B. Failure in the rate adaptation of the atrial refractory period:its relationship to vulnerability. Int J C a rdial.1982;2(2): 179- 197
27. Shiroshita-Takeshita A, Mitamura H, Shinagawa K, et al. Discordant temporal changes in electrophysiological properties during electrical remodeling and its recovery in the canine atrium. Jpn Heart J. 2002 ;43(2):167-81.
28. Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na1/H1 Exchanger in Short-Term Atrial Electrophysiological Remodeling, Circulation, 2000, 101, 1861-1866.
29. Morillo CA, Klein GJ, Jones DL,.Guiraudon CM. Chronic rapid atrial pacing.Str uctural,fu nctional,an de lectrophysiologicalch aracteristicso fa n ew model of sustained atrial fibrillation. Circulation. 1995 Mar 1; 91(5):1588-1595.
30. Moriguchi M, Niwano S, Yoshizawa N,et al. Verapamil suppresses the inhomogeneity of electrical remodeling in a canine long-term rapid atrial stimul- ation model.Pacing Clin Electrophysiol. 2003 26(11):2072-2082.
31. Yu WC, Lin YK, Tai CT, et al. Early recurrence of atrial fibrillation after external cardioversion. Pacing Clin Electrophysiol. 1999;22(11):1614-9
32. Vanden Berg MP, Hassink RJ, Balje-Volker C. Role of the antonomic nervous system in vagal atrial fibrillation Heart, 2003; 89,333-335
33. Fynn SP, Todd D.M, Hobbs W JC, et al. Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation.A manifestation of atriale lectricalr emodellingi nh umans? Eur Heart. 20 01;22(19):1822-1834.
34. Miyauchi Y, Zhou S, Okuyama Y, et al.Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyerinnervation in Hearts with Chronic Left Ventricular Myocardial Infarction: Implications for Atrial Fibrillation. Circul- ation. 2003; 108(3):360-366.
35. Mori K, Hara Y, SaitoT, et al. Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells. Circulation, 1995; 91:2834-2843.
36. Jayachandran V, Sih H J, Winkle W, et al. Atrial Fibrillation Produced by Prolonged Rapid Atrial Pacing Is Associated With Heterogeneous Changes inAtrial Sympathetic Innervation. Circulation, 2000; 101:1185-1192.
37. Olgin J E, Sih H J, Hanish S, et al. Heterogeneous Atrial Denervation Creates Substrate for Sustained Atrial fibrillation Circulation, 1998; 98:2608-2614.
38. Massari VJ, Dickerson LW, Gray AL, et al .Neural control of left ventricular contractility in the dog heart: synaptic interactions of negative inotropic vagal preganglionic neurons : in the nucleus ambiguus with tyrosine hydroxylase immunoreactive terminals[J]. Circulation, 2001;103(8):1157-1163.
39. Blaauw Y, Tieleman RG, Brouwer J, et al. Tachycardia induced electrical remod- eling of the atrial and the autonomic nervous system in goats. PACE, 1999; 22:1656-1667.
40. Brundel BJ, Henning RH, Camping,HH, et al. Molecular mechanisms of remod- eling in human atrial fibrillation. Cardiovasc Res, 2002,54(2):315- 324.
41. Bosch RF, Scherer CR,Rub N,et al. Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits. J Am Coll Cardior, 2003, 41(5): 858-869.
42. Grammer JB, Bosch RF, Kuhlkamp V,et al. Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation. J Cardiocasc Electrophysiol. 2000;(6): 626-633.
43. Van Wagoner DR, Pond AL, McCarphy PM,et al. Atrial L-type Ca+ currents and human atrial fibrillation. Circ Res,1997;80(6):772-781.
44. Skasa M, Jungling E, Picht E, et al. L-type calcium currents in atrial myocytes from patients with persistent and non-persistent atrial fibrillation. Basic Res Cardior. 2110;96(2):151-159.
45. Gaspo R, Bou Abboud E,et al. Functional mechanisms underlying tachycardia- induced sustained atrial fibrillation in a chronic dog model. Circ Res. 1997; 81(4):512-25.
46. Gaspo R, Bosch RF, et al. Tachycardia-induced changes in Na+ current in a chronic dog model of atrial fibrillation. Cir Res, 1997,81:1045.