Author + information
- Received May 30, 2005
- Revision received August 18, 2005
- Accepted October 10, 2005
- Published online February 21, 2006.
- Yoshihide Takahashi, MD⁎ (, )
- Pierre Jaïs, MD,
- Mélèze Hocini, MD,
- Prashanthan Sanders, MBBS, PhD1,
- Martin Rotter, MD2,
- Thomas Rostock, MD3,
- Li-Fern Hsu, MBBS,
- Frédéric Sacher, MD,
- Jacques Clémenty, MD and
- Michel Haïssaguerre, MD
- ↵⁎Reprint requests and correspondence:
Dr. Yoshihide Takahashi, Service de Rythmologie, Hôpital Cardiologique du Haut-Lévêque, Avenue de Magellan, 33604 Bordeaux-Pessac, France.
Objectives The goal of the present prospective study is to evaluate the impact of vagal excitation on ongoing atrial fibrillation (AF) during pulmonary vein (PV) isolation.
Background The role of vagal tone in maintenance of AF is controversial in humans.
Methods Twenty-five patients (18 with paroxysmal AF, 7 with chronic AF) were selected by occurrence of vagal excitation during AF (atrioventricular [AV] block: R-R interval >3 s) produced by PV isolation. Fibrillatory cycle length (CL) in the targeted PV and coronary sinus (CS) were determined before, during, and after vagal excitation. The CL was available at PV ostium during vagal excitation in 11 patients.
Results Forty-eight episodes of vagal excitation were observed. During vagal excitation, CL abruptly decreased both in CS and PV (CS, 164 ± 20 ms to 155 ± 23 ms, p < 0.0001; PV, 160 ± 22 ms to 143 ± 28 ms, p < 0.0001), and both returned to the baseline value with resumption of AV conduction. The decrease in PVCL occurred earlier (2.5 ± 1.5 s vs. 4.0 ± 2.6 s, p < 0.01) and was of greater magnitude than that in CSCL (16 ± 16 ms vs. 8 ± 9 ms, p < 0.01). A sequential gradient of CL was observed from PV to PV ostium and CS during vagal excitation (138 ± 29 ms, 149 ± 24 ms, and 159 ± 26 ms, respectively). The decrease in CL was significantly greater in paroxysmal than in chronic AF (CS, 11 ± 9 ms vs. 5 ± 7 ms, p < 0.05; PV, 23 ± 25 ms vs. 8 ± 14 ms, p < 0.05).
Conclusions Vagal excitation is associated with shortening of fibrillatory CL. This occurs earlier in PV with a sequential gradient to PV ostium and CS, suggesting that vagal excitation enhances a driving role of PV.
The role of autonomic tone in the onset, maintenance, and termination of atrial fibrillation (AF) has been suggested in humans (1–6). In an animal model, vagal nerve stimulation decreases refractoriness and facilitates the induction and maintenance of AF (7,8), and this effect is prevented by ablation of the atrial parasympathetic nerve system (9,10). However, the mechanism of vagal excitation contributing to the maintenance of AF has not been clear in humans.
The goal of the present study is to investigate changes in AF cycle length (CL) during vagal excitation produced by radiofrequency (RF) energy delivery for pulmonary vein (PV) disconnection in patients with paroxysmal and chronic AF.
Among 314 consecutive patients (213 with paroxysmal AF, 101 with persistent or chronic AF) who underwent AF ablation in our institution, PV isolation was performed during ongoing AF in 272 patients (171 with paroxysmal AF, 101 with persistent or chronic AF). Twenty-five patients (9.2%; 18 with paroxysmal AF, 7 with chronic AF) were selected based on the occurrence of atrioventricular (AV) block with an R-R interval >3 s during AF produced by RF energy application for PV isolation. The occurrence of vagal excitation during sinus rhythm (sinus bradycardia or hypotension) was not included in the present study. The mean age was 55 ± 9 years, two women were included, and AF duration was 88 ± 72 months. All patients had no structural heart disease except for one with aortic valve replacement. No patient was diagnosed with vagotonic AF.
Twenty-five patients, matched for age, gender, structural heart disease, classification of AF, and duration of AF, were selected as control patients for clinical outcome (Table 1).
Anti-arrhythmic drugs were discontinued ≥5 half-lives before ablation except for amiodarone, which was taken by six patients (24%) at the time of the procedure. All patients had effective anticoagulation for > 1 month and transesophageal echocardiography before ablation. A written informed consent was obtained from all patients.
A 6-F quadripolar catheter (Xtrem, Ela Medical, Montrouge, France) was positioned in the coronary sinus (CS). A 10-pole circumferential catheter (Lasso, Biosense-Webster, Diamond Bar, California) for PV ostial mapping and a 4-mm irrigated-tip ablation catheter (Biosense-Webster) were used. Surface electrocardiogram and intracardiac electrograms were filtered from 30 to 500 Hz and measured at a paper speed of 100 mm/s with a digital amplifier/recording system (Bard Electrophysiology, Lowell, Massachusetts). A single bolus dose of 50 IU/kg of heparin was administered after the transseptal puncture and repeated only for procedures lasting more than four hours.
The RF application was performed at 1 cm proximal to the ostium of all PVs with a power limit of 30 W. When RF was applied at the anterior and inferior rim of the left PVs, delivered power was limited as 25 W. If ipsilateral PVs were located closely, these two PVs were isolated en bloc. Ablation catheter was dragged every 30 to 60 s during continuous RF delivery. The end point was a disappearance or dissociation of the PV potentials on a circumferential catheter. When a vagal response with an R-R interval > 5 s was observed, RF delivery was discontinued.
The mean CL in the CS (CSCL) and the targeted PV (PVCL) were determined at the following times: 1) before the commencement of RF application (baseline), 2) 5 s before, 3) during, and 4) 5 s after the episode of vagal excitation. The CSCL was selected because of the stability of catheter allowing reproducible serial measurement. In addition, CL was available at the PV ostium in 11 patients during vagal excitation. The mean CL was defined as an average of 30 consecutive cycles. They were measured with a dedicated system (Bard Electrophysiology), and the detection of potentials was manually checked with online calipers at a paper speed of 100 mm/s. If an R-R interval during vagal excitation was shorter than a total duration of 30 consecutive cycles, CSCL and PVCL were determined by averaging all cycles during the episode of vagal excitation. A continuous or fragmented activity or a potential interval < 50 ms was counted as a single activity. A decrease in PVCL or CSCL of ≥ 10 ms during vagal excitation was considered as a significant decrease. The timing of onset of a significant decrease in PVCL and CSCL was measured from the last QRS before vagal excitation.
All variables are reported as mean ± SD. Comparison between groups was performed with the Student ttest. Sequential data measurements were analyzed by repeated-measures analysis of variance followed by the Tukey post hoc test for multiple comparisons. Categorical variables were compared with the Fisher exact test. p < 0.05 was considered to indicate statistical significance.
Forty-eight episodes of vagal excitation were observed, and the R-R interval during these episodes was 8.7 ± 4.1 s (range, 3.0 to 19.6 s). The targeted PV was the left superior PV in 19, the left inferior PV in 7, the right superior PV in 1, and the right inferior PV in 1 patient.
The RF site producing vagal excitation was observed at a discrete location at approximately 1 cm proximal to the ostium of each vein: the anterosuperior ostium of the left superior PV, the inferior ostium of the left inferior PV, the anterior (septal) ostium of the right superior PV, and the anterior (septal) ostium of the right inferior PV.
CL in the CS and PV
The CSCL and PVCL before RF delivery producing vagal excitation were 166 ± 21 ms and 156 ± 23 ms, respectively (p = 0.03). Changes in CL during vagal excitation were analyzed in 39 episodes because PV potentials had disappeared in 9 episodes when vagal excitation was observed.
There was no change in CSCL and PVCL from baseline to 5 s before vagal excitation (CSCL, 165 ± 22 ms to 164 ± 20 ms, p = NS; PVCL, 158 ± 23 ms to 160 ± 22 ms, p = NS) (Fig. 1).The CSCL and PVCL decreased abruptly during vagal excitation to 155 ± 23 ms and 143 ± 28 ms (p < 0.0001, p < 0.0001, respectively; vs. 5 s before vagal excitation), and the magnitude of decline was significantly greater in PVCL than in CSCL (16 ± 16 ms vs. 8 ± 9 ms, p < 0.01) (Fig. 1). The PVCL was shorter than the CSCL during vagal excitation in 31 episodes (79%). In 13 episodes, the mean CL at the PV ostium was measured during vagal excitation (PV ostium CL). There was a sequential gradient of CL between the PV, PV ostium, and CS during vagal excitation (PVCL, 138 ± 29 ms; PV ostium CL, 149 ± 24 ms; CSCL, 159 ± 26 ms) (Fig. 2).
The CL was maintained at the decreased value until discontinuation of RF application (Fig. 3).In one episode, shortening of PVCL persisted >1 min after discontinuation of RF application, whereas CSCL returned to the value before vagal excitation simultaneous to the resumption of AV conduction in all of the other episodes. A significant decrease in PVCL and CSCL (gradient ≥10 ms) was observed in 23 (59%) and 20 (51%) of 39 episodes, respectively. In these episodes, the significant decrease in PVCL appeared earlier than that in CSCL by 1.6 ± 1.6 s (2.5 ± 1.5 s vs. 4.0 ± 2.6 s after the last QRS, p < 0.01).
Five seconds after vagal excitation, the CSCL had returned to the value before vagal excitation (163 ± 20 ms, p = NS, vs. before AV block) (Fig. 1), whereas the PVCL 5 s after vagal excitation was significantly shorter than that before vagal excitation (156 ± 25 ms, p < 0.05, vs. before vagal excitation) (Fig. 1).
Changes in CSCL and PVCL were observed both in patients with paroxysmal AF and in patients with chronic AF (Figs. 4 and 5).⇓⇓However, the decreases in CSCL and PVCL were significantly greater in patients with paroxysmal AF than chronic AF (CSCL, 11 ± 9 ms vs. 5 ± 7 ms, p < 0.05; PVCL, 23 ± 25 ms vs. 8 ± 14 ms, p < 0.05).
Radiofrequency was applied repeatedly at the site where vagal excitation had been produced. In all patients except one, an additional one to three RF applications abolished vagal excitation. Vagal excitation was still reproduced in one patient despite six RF applications.
In patients with paroxysmal AF, AF terminated during PV isolation in 15 of 18 patients (83%) in the study group, and in 15 of 18 patients (83%; p = NS) in the control group, respectively. In patients with chronic AF, AF did not terminate in both groups during PV isolation. The PV isolation was performed in all patients, and additional substrate modification was performed in 15 patients in both groups, respectively (Table 1).
The study and control group were followed for 6.2 ± 5.5 months and 7.7 ± 4.0 months since the last procedure, respectively (p = NS). There was no significant difference in the number of patients who required antiarrhythmic after the last procedure and the arrhythmia-free rate between the two groups. The incidence of the repeated procedure was lower in the study group without statistical significance (Table 1).
Major findings in the present study are as follows. 1) The PVCL and CSCL decreased during vagal excitation produced during RF applications at the PV ostia. The change in PVCL occurred earlier and persisted longer, and the decline was greater than that in CSCL. 2) The acceleration of the fibrillatory CL was significantly greater in patients with paroxysmal AF than in those with chronic AF. 3) There was no difference in the long-term clinical outcome between the study group and a control group.
Vagal tone and fibrillatory CL
Acetylcholine and vagal nerve stimulation have been used in animal AF models to induce AF (7,8,11), and vagal denervation prevents the induction of AF, confirming the role of vagal tone in these animal models (9,10). Enhanced vagal tone shortens action potential duration and atrial refractoriness, which may shorten the wavelength and fibrillatory CL. It has been considered, therefore, that a greater number of wavelets can coexist and AF is more likely to be sustained during vagal excitation.
The effect of vagal tone on the fibrillatory CL is not only addressed by multiple wavelets theory. Stable micro–re-entrant sources (rotor) have been observed during AF in the presence of acetylcholine in Langendorff-perfused sheep hearts (12), and this is hypothesized to be the mechanism of AF. A rotor accelerates and is stabilized in the presence of a high concentration of acetylcholine (13,14). Thus, rotor can also cause acceleration of fibrillatory CL by enhanced vagal tone. Furthermore, vagal stimulation combined with sympathetic stimulation has been shown to induce triggered activity in the PV (15).
The heterogenous effect of vagal tone
The heterogeneous atrial electrophysiological property is an important factor contributing to the maintenance of AF (16,17). Acetylcholine released from nerve terminals has the effect in the millimeter-sized localized region (18). Thus, autonomic innervation is hypothesized to contribute to the heterogeneous electrophysiological property in atria, and this may be critical for perpetuation of AF. Olgin et al. (19) showed that heterogenous sympathetic denervation in the atrium is sufficient to produce sustained AF in an animal model. The present study shows a dispersion of accelerated CL between the PV and CS, which suggests heterogeneous distribution of vagal nerve terminals in patients with AF.
Arrhythmogenesis of the PV
The role of the PV in persisting AF was shown by prolongation of fibrillatory CL and non-inducibility of AF after disconnection of the PV (20). Arrhythmogenicity of the PV may be associated with particular electrophysiological and histologic characteristics of this region (21,22). Vulnerability of the PV to an increased vagal tone was shown in the present study, and this may be another property contributing to the arrhythmogenicity of the PV.
During vagal excitation, the PVCL is shorter than the CSCL, and the shortening of the PVCL occurred earlier and persisted longer than that in the CSCL. This suggests that increased vagal tone has direct effects on PVCL and the acceleration of the CSCL is secondary to that of the PVCL (Fig. 6).This is supported by a sequential gradient of CL to the PV ostium, and then to the CS. This suggests that high-frequency PV activity drives the rest of the atrium (23). Results of the present study indicated that PVs are important effectors of vagal excitation. Therefore, PV isolation may attenuate the arrhythmogenic effect of vagal tone in addition to elimination of triggering beats. This may be an additional mechanism that prevents clinical recurrence of AF (Fig. 6).
A decrease in CL during vagal excitation was greater in the PV than in the CS in both paroxysmal and chronic AF, indicating that the PV is vulnerable to vagal tone in both cohorts. However, a lesser change in CL during vagal excitation was shown in chronic AF. This suggests a lesser contribution of autonomic tone to arrhythmogenesis in chronic AF, which may be associated with the limited efficacy in PV isolation for chronic AF (24,25).
The mechanism of vagal excitation during RF application at the PV is hypothesized as thermal injury of vagal afferent receptors (26). Histologic study shows that nerve terminals with acetylcholinesterase activity are distributed widely in the left atrium roof, ostia of the PVs, and lateral RA (27), whereas RF application produces vagal excitation at discrete sites in clinical studies. Recently, it has been reported that abolition of vagal excitation by RF application is associated with better long-term outcome in AF catheter ablation (28). This was not confirmed in the present study; however, the present study was performed using a different methodology and end point without identifying vagal terminals or autonomic ganglia. Nakagawa et al. (29) reported that high-frequency pacing is feasible for identifying autonomic ganglia, and catheter ablation targeting the ganglia may effectively denervate the atrium. They achieved a better clinical outcome by catheter ablation targeting autonomic ganglia in addition to PV isolation in paroxysmal and persistent AF. However, the present study suggests that vagal denervation may have a lesser impact in chronic than in paroxysmal AF.
Vagal excitation in the present study was observed dominantly during ablation at the left-sided PVs, and its incidence was even lower than in the previous report (28) because we excluded sinus bradycardia and sinus arrest from the definition of vagal excitation, which is more commonly observed during ablation at the right-sided PVs. An increase in the R-R interval produced by RF application may be caused also by a decrease in sympathetic tone, which was not evaluated in the present study.
Although the present study indicates that vagal excitation contributes to arrhythmogenesis of AF, further studies are required to investigate the role of vagal tone in initiation and maintenance of AF in the clinical setting.
We acknowledge Bard Electrophysiology for development of a dedicated system for measuring fibrillatory cycle length.
↵1 Dr. Sanders is supported by the Neil Hamilton Fairley Fellowship from the National Health and Medical Research Council of Australia and the Ralph Reader Fellowship from the National Heart Foundation of Australia.
↵2 Dr. Rotter is supported by the Swiss National Foundation for Scientific Research, Bern, Switzerland.
↵3 Dr. Rostock is supported by the German Cardiac Society.
- Abbreviations and Acronyms
- atrial fibrillation
- cycle length
- coronary sinus
- cycle length in the coronary sinus
- pulmonary vein
- cycle length in the pulmonary vein
- Received May 30, 2005.
- Revision received August 18, 2005.
- Accepted October 10, 2005.
- American College of Cardiology Foundation
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