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Cardiovascular Research 2002 54(2):476-481; doi:10.1016/S0008-6363(02)00231-6
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Suppression of atrial fibrillation by multisite and septal pacing in a novel experimental model

Ruediger Becker*, Julia C Senges, Alexander Bauer, Kirsten D Schreiner, Frederik Voss, Wolfgang Kuebler and Wolfgang Schoels

University of Heidelberg, Department of Cardiology, Heidelberg, Germany

* Corresponding author. University of Heidelberg/Department of Cardiology, Bergheimer Strasse 58, 69115 Heidelberg, Germany. Tel.: +49-6221-568-855; fax: +49-6221-565-514 ruediger_becker{at}med.uni-heidelberg.de

Received 1 August 2001; accepted 18 December 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: To evaluate the preventive efficacy of multisite and septal atrial pacing in an experimental model. Methods: Sterile right atrial pericarditis was induced in 12 foxhounds to provide an anatomical substrate for atrial fibrillation (AF). As a trigger mechanism, atrial extrasystoles were simulated by constant asynchronous pacing at a cycle length of 1000 ms from randomly selected right or left atrial electrodes, using a biatrial epicardial multielectrode with 128 bipoles. Additionally, a transvenous pacing lead was screwed into the interatrial septum. Four electrodes located in the high and low right (HRA/LRA) and left atrium (HLA/LLA) were selected for preventive multisite stimulation. Constant pacing at a cycle length 30 ms below sinus rate was applied from the following site(s): HRA, septal, HRA+LRA, HRA+LLA, HRA+LRA+LLA and HRA+LRA+HLA+LLA (order randomized). Number and duration of AF episodes were studied during 10 min intervals, separated by 5 min pauses, respectively. To validate the model, the protocol was repeated 10 min after i.v. bolus administration of D,L-sotalol (1 mg/kg body weight). Results: The number of AF episodes decreased with increasing number of pacing sites, reaching statistical significance compared to HRA stimulation for quadruple-site and single-site septal pacing only (P<0.05). Single-site septal was as efficient as quadruple-site pacing in suppressing AF. The duration of AF episodes was not significantly affected by the pacing configuration. D,L-sotalol almost completely suppressed AF irrespective of the pacing configuration used. Conclusions: In this novel experimental model, quadruple-site and septal pacing effectively suppress paroxysmal AF.

KEYWORDS AF, Atrial fibrillation; AT, Activation time; CL, Cycle length; ERP, Effective refractory period; HLA, High left atrium; HRA, High right atrium; IVC, Inferior vena cava; LLA, Low left atrium; LRA, Low right atrium; SVC, Superior vena cava


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Previous clinical studies have suggested that multisite atrial pacing may suppress paroxysmal AF in selected patients. Bifocal pacing was primarily introduced by Daubert et al., who demonstrated that stimulation from the HRA and the distal coronary sinus (‘biatrial pacing’) suppresses atrial tachyarrhythmia recurrences in patients with severe interatrial conduction delay [1]. Subsequently, Saksena et al. introduced an alternative approach using pacing electrodes positioned in the HRA and at the coronary sinus ostium (‘dual-site right atrial pacing’). Although preliminary data in patients with drug refractory paroxysmal AF and coexisting bradyarrhythmia were encouraging [2,3], the efficacy of multisite pacing remains a matter of controversy [4,5], awaiting further clarification through ongoing prospective randomized trials [5,6]. As an alternative approach, single-site septal pacing has recently been introduced [7–10], and according to preliminary data, seems to be at least more efficient than conventional HRA pacing for prevention of AF [11]. However, none of the clinical studies actually provides any data or even a striking hypothesis on the mechanisms by which preventive pacing should suppress AF. Experimentally, when comparing the effects of single-, septal- and multisite pacing on electrophysiological parameters, no difference was found with respect to local refractory periods or dispersion of refractoriness. There was, however, a significant difference with respect to total activation times and the number of electrodes with a change in the direction of activation; both parameters being most markedly affected by triple-site, quadruple-site and single-site septal pacing [12]. Thus, we hypothesized that preventive pacing should be effective through multidirectional activation, thereby resolving functional conduction blocks. The present study was, therefore, designed to analyze whether respective effects on electrophysiological parameters actually translate into preventive effects on AF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
All animal experiments conformed with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.1 Model description
2.1.1 Anatomical substrate: sterile pericarditis
As an anatomical substrate for AF, sterile pericarditis was induced in 12 healthy foxhounds (body weight 29±4 kg, range 25–34). The dogs were anesthetized with i.v. pentobarbital (0.5 mg/kg), intubated and ventilated with nitrous oxide and oxygen (70/30%). ECG leads I, II and III were continuously monitored on a VR 12® recorder (Electronics for Medicine, Pleasantville, NY). Sterile pericarditis was induced using a modification of the technique introduced by Page et al. [13]. Briefly, after right lateral thoracotomy and pericardiotomy, the right atrial surface was generously dusted with sterile talcum powder, and a single layer of gauze was sutured on the right atrial free wall. The pericardiotomy was then repaired, and the chest was carefully closed in layers. Postoperative care included administration of antibiotics and potent analgesics (buprenorphin).

After recovery for 4–6 days, the dogs were subjected to an extended midsternal thoracotomy under general anesthesia maintained by halothane 1%. After pericardectomy, a custom-designed electrode array was placed on the epicardial surface of both atria, in order to provide a free choice of pacing sites in both atria. This multielectrode contained 128 bipoles with an interpolar distance of 1–2 mm and an interelectrode distance of 3–5 mm. Details regarding electrode design and surgical procedure have been previously described [12,14]. During the experiments, body temperature was adjusted to 37 °C with a heating lamp. A 256-channel multiplexer mapping system developed at the University of Limburg in Maastricht, The Netherlands, was used for on-line monitoring of all 128 electrograms [15]. Additionally, all data were recorded on video tape for off-line digitization (sampling rate 2000 Hz) and computer analysis.

2.1.2 AF trigger: atrial ‘extrasystoles’
Using a Biotronik UHS 20® universal heart stimulator, induction of atrial fibrillation was attempted through asynchronous pacing at a cycle length of 1000 ms at four times diastolic threshold from randomly selected right or left atrial pacing sites during sinus rhythm. Thus, frequent atrial extrasystoles with varying coupling intervals were simulated. The first site where at least one episode of atrial fibrillation was inducible during 3 min was used as an induction electrode throughout the experiment. During asynchronous pacing from this trigger electrode, number and duration of AF episodes were analyzed within 10 min intervals of constant preventive pacing at a cycle length 30 ms below sinus rate from the following pacing site(s): HRA, septal, HRA+LRA, HRA+LLA, HRA+LRA+LLA, and HRA+LRA+HLA+LLA (order randomized; each induction phase separated by a 5 min pause). The protocol was repeated 10 min after i.v. administration of 1 mg D,L-sotalol/kg body weight. Fig. 1 illustrates the multielectrode in place and indicates the location of the pacing electrodes.


Figure 1
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  		Fig. 1 Posterior view of the heart with multielectrode in place. The shaded areas represent the location of pacing electrodes. LA/RA, left/right atrium; HRA/LRA, high/low right atrium; HLA/LLA, high/low left atrium; LAA/RAA, left/right atrial appendage; S/IVC, superior/inferior vena cava; PV, pulmonary veins.

 
2.2 Definitions
2.2.1 Arrhythmias
Atrial fibrillation was defined as a rapid atrial rhythm (rate >260 beats/min) characterized by variability of the beat-to-beat cycle length, polarity, morphology, and/or amplitude of recorded bipolar atrial electrograms [16]. As originally described, atrial flutter was defined as a rapid atrial rhythm (rate >240 beats/min) characterized by a constant beat-to-beat cycle length, polarity, morphology, and amplitude of the recorded bipolar electrograms [17]. To qualify as AF or atrial flutter, a minimum episode duration of 2 s was required.

2.2.2 AF trigger parameters
The prematurity index was calculated as the coupling interval of effective trigger stimuli (ms) divided by the basic cycle length (ms), respectively. The term window of inducibility was used to describe the difference between the longest and the shortest coupling interval of all effective trigger stimuli in a dog.

2.3 Statistics
Data are presented as mean±S.D. For comparative statistics, either ANOVA followed by a Tukey Kramer HSD test for multiple comparisons (JMP® software version 3.1, SAS Institute, SAS Campus Drive, Cary, NC 27513, USA) or a Student's t-test for unpaired data (MS Excel v7.0) were used, as appropriate. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
In the 12 dogs studied, a total of 335 atrial tachyarrhythmia episodes were encountered. Of all episodes, 313 (93%) were classified as atrial fibrillation and 22 (7%) as atrial flutter. Individual episodes tended to be short and were always self-terminating, with a mean episode duration of 19±44 s (range 2–460).

Fig. 2 displays characteristic electrogram tracings from an AF episode encountered during HRA pacing in dog no.6. A tightly coupled trigger stimulus applied at the posterior RA (*1) induced an AF episode lasting 18 s. The electrograms typically exhibit polymorphic potentials with varying amplitude and short, irregular cycle lengths. For all dogs (n=12), the AA interval during AF averaged 104±22 ms (Table 1).


Figure 2
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  		Fig. 2 Original electrogram tracings from dog no.6 illustrating onset, maintenance and termination of an AF episode during HRA pacing (total episode duration 18 s). Baseline stimulation artifacts are marked by arrows. A tightly coupled induction stimulus (*1) in the posterior RA triggers AF. *trigger stimuli reflecting constant asynchronous pacing at a cycle length of 1000 ms. E, electrode number; E66, HRA; E77, LLA; E100, HLA.

 

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  		Table 1 AF trigger parameters and AA intervals during HRA pacing at baseline

 
The trigger electrodes used in individual experiments were located in various regions of the right (n=6) and left atrium (n=6). To further characterize the model, individual trigger parameters were determined for all AF episodes that occurred during HRA pacing. The prematurity index of effective trigger stimuli averaged 0.36±0.09, indicating that AF induction required relatively short coupling intervals in the range of 1/3 of the baseline pacing CL (Table 1). The window of inducibility also tended to be narrow, as specified in Table 1.

At baseline, the pacing cycle length was 473±180 ms (range 290–780 ms). Of all pacing configurations, HRA pacing displayed the greatest number of AF episodes within the 10 min sampling interval. Basically, the episode number was found to decrease with an increasing number of pacing electrodes, reaching statistical significance compared to HRA stimulation for quadruple-site and single-site septal pacing only (Table 2). Interestingly, single-site septal pacing was as efficient as quadruple-site pacing in suppressing AF (Table 2). With respect to the duration of individual episodes, no significant differences were encountered between the pacing configurations used (Table 2).


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  		Table 2 Number and duration of atrial tachyarrhythmia episodes at baseline

 
After administration of D,L-sotalol, the mean pacing CL was adjusted to 707±232 ms due to a marked drop in sinus CL from 504±186 ms at baseline down to 736±237 ms 10 min after bolus injection. As evaluated during HRA pacing, atrial activation patterns remained basically unaffected; particularly, no evidence of slow conduction or conduction block was encountered. Thus, total atrial activation times also remained unchanged (83±7 vs. 85±8 ms, baseline vs. D,L-sotalol, P=n.s.). D,L-sotalol was found to suppress AF almost completely, irrespective of the pacing configuration applied (Table 3).


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  		Table 3 Number and duration of atrial tachyarrhythmia episodes after D,L-sotalol

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In a novel experimental model of extrasystole-induced paroxysmal AF, this study demonstrated that quadruple-site and septal pacing significantly reduce the number of AF paroxysms compared to conventional HRA pacing, whereas dual-site and triple-site atrial pacing merely produced a tendency toward AF suppression not reaching statistical significance. Administration of D,L-sotalol almost completely suppressed AF independent of the pacing configuration applied. Apart from the results with triple-site stimulation, these data indicate a correlation of the effect on electrophysiological parameters with the effect on arrhythmia prevention. Thus, it might be assumed that the effect of preventive pacing is primarily based on a change in the direction and timing of atrial activation, thereby potentially resolving functional conduction blocks.

4.1 Comparison with previous studies
To the best of our knowledge, this is the only experimental study available to date addressing the efficacy of multisite pacing in an experimental model of paroxysmal AF. This novel model combines a right atrial sterile pericarditis as an anatomical substrate with constant asynchronous pacing simulating frequent extrasystoles as a trigger for AF. Thus, multiple episodes of self-limiting AF (and atrial flutter) could be induced. The increasing efficacy in AF suppression with growing number of pacing sites supports the hypothesis that shortening of atrial activation time and multidirectional excitation can prevent functional conduction block [12]. In our previous study, both, triple- and quadruple-site stimulation were shown to effectively minimize total activation times. With four pacing sites, the effect was slightly more pronounced, but this difference did not reach statistical significance [12]. In the present study, the number of AF episodes decreased with an increasing number of pacing sites, reaching statistical significance with quadruple-site and single-site septal stimulation only. The inefficacy of triple-site stimulation was somewhat unexpected, but could possibly be explained by the following observations: Although not statistically significant, quadruple-site pacing tended to more markedly affect both, total AT and multidirectionality of activation. Thus, the combined effect on both parameters might be of relevance. This would also relate to septal pacing, being less efficient with respect to multidirectionality, but providing the shortest atrial AT. Furthermore, the number of electrode sites with a change in the direction of activation does not provide any information on the specific regions affected. It is quite conceivable that some areas are more crucial for the occurrence of AF than others. In that respect, the more cranial portions of the left atrium may play a role, being affected by septal- and quadruple-site pacing, but hardly by triple-site pacing.

While quadruple-site pacing would be difficult to establish in a clinical setting, septal pacing offers an attractive alternative to bifocal pacing configurations such as dual-site right atrial and biatrial pacing. Clinical studies have confirmed that P wave duration during septal pacing is significantly shorter than during sinus rhythm [7,10] and HRA pacing [9,10], and at least as short as during bifocal atrial pacing [9,10]. As far as AF suppression is concerned, a randomized crossover study in patients with sick sinus syndrome and paroxysmal AF has shown that septal pacing significantly reduces the number of episodes per month compared to conventional HRA pacing [11]. However, this pilot study needs to be confirmed by ongoing trials, and further studies are required to compare single-site septal and bifocal pacing configurations regarding their efficacy in AF suppression. According to clinical studies available to date, the efficacy of bifocal atrial pacing has been moderate and confined to a selected group of patients: Biatrial pacing has only been beneficial in drug refractory AF in the presence of marked interatrial conduction delay (P wave duration >120 ms) [1,18]. The benefits of dual-site right atrial pacing have been restricted to patients with drug refractory AF and coexisting bradyarrhythmia [2,3], whereas in patients paced for AF alone, this pacing configuration did not perform better than conventional HRA pacing [4]. The data obtained in the present study seem to indicate that multisite pacing may exert antifibrillatory effects even in the absence of bradyarrhythmia, depending on the number and location of pacing electrode(s).

As far as the suppression of AF by D,L-sotalol is concerned, our findings are in keeping with recently published data in a canine model of vagotonic AF induced by extrastimuli [19]. In spite of a lower dose of D,L-sotalol (1 mg vs. 2 mg/kg body weight), AF suppression was at least as efficient in the present study, indicating a more marked susceptibility of our model to antiarrhythmic interventions as compared to the vagotonic AF model [19].

4.2 Limitations
With respect to the mechanism of AF induction, the model applied in this study relates to extrasystole-induced AF alone. Although this is supposed to be the most common onset mechanism in human AF, clinical studies have shown that in most individuals the mode of AF induction varies from episode to episode, including mechanisms such as bradycardia, short–long cycles, tachycardias, and sudden increases or decreases in heart rate [20]. Furthermore, the sterile pericarditis applied in our model represents a substrate different from those usually underlying clinical AF. Thus, the findings obtained in this experimental model may not be readily applicable to clinical AF. As far as arrhythmia maintenance is concerned, multiple unstable re-entrant circuits have been demonstrated to underlie AF in the sterile pericarditis model [21], in keeping with the most common mechanism of maintenance supposedly encountered in humans [22]. AF suppression by the antiarrhythmic agent D,L-sotalol would also be consistent with clinical findings in paroxysmal AF. However, rather than referring to a specific AF substrate or induction/maintenance mode, the present study was primarily designed to experimentally evaluate the hypothetical mechanisms of AF prevention by multisite pacing outlined in our recent publication [12].

4.3 Clinical implications
The present study further substantiates the idea that the mechanism of preventive pacing is related to a reduction in atrial activation time and to the multidirectionality of atrial activation. Thus, respective pacing strategies should specifically address these parameters, combined with a search for strategically important locations of pacing site(s). At present, single-site septal pacing seems to be the most promising candidate fulfilling these requirements.

Time for primary review 29 days.


   Acknowledgements
 
This study was supported by a grant of the Deutsche Forschungsgemeinschaft, Bonn, Germany within the Sonderforschungsbereich 320 ‘Herzfunktion und ihre Regulation’, University of Heidelberg, Germany.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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