Impact Of Vagal Modulation On Atrial Electrical Remodeling

Impact of Vagal Activity on Atria Electrical Remodeling in DogsObjective: 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 RemodelingObjective: 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 dogsObjective: 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.