Pacing-Induced Chronic Atrial Fibrillation Impairs Sinus Node Function in Dogs
Background We assessed the effects of pacing-induced chronic atrial fibrillation (AF) on sinus node function, intra-atrial conduction, and atrial refractoriness.
Methods and Results In 15 mongrel dogs (20 to 30 kg), AV nodal block was produced by radiofrequency catheter ablation, and a ventricular-inhibited (VVI) pacemaker (Minix 8330, Medtronic) was implanted and programmed to pace at 80 pulses per minute. In 11 of these dogs, right atrial endocardial pacing leads were connected to a pulse generator (Itrel 7432, Medtronic) and set at a rate of 20 Hz to induce AF. Corrected sinus node recovery time, P-wave duration, 24-hour Holter ECG to assess AF duration, maximal heart rate in response to isoproterenol (10 μg/min), intrinsic heart rate after administration of atropine (0.04 mg/kg) and propranolol (0.1 mg/kg), and atrial effective refractory periods (ERPs) were obtained at baseline (EPS-1) and after 2 to 6 weeks (EPS-2) of VVI pacing alone (n=4) or VVI pacing and rapid atrial pacing (n=11). At EPS-2, corrected sinus node recovery time and P-wave duration were prolonged, maximal heart rate and intrinsic heart rate were decreased, atrial ERPs were shortened, and the duration of AF was increased significantly compared with EPS-1. These changes partially reversed toward baseline 1 week after conversion to sinus rhythm. Sinus node function and AF inducibility observed in the control dogs that underwent ventricular pacing alone (n=4) did not change.
Conclusions Pacing-induced chronic AF induces sinus node dysfunction, prolongs intra-atrial conduction time, shortens atrial refractoriness, and perpetuates AF, changes that reverse gradually after termination of AF.
Atrial fibrillation is one of the most common cardiac arrhythmias. Allessie et al1 experimentally confirmed the hypothesis of Moe and Abildskov2 that AF is based on multiple wavelets of reentry. Clinical studies have shown that AF can be associated with sick sinus syndrome,3 abnormal intra-atrial conduction,4 5 atrial enlargement,6 7 and decreased atrial refractoriness4 and that chronic AF is associated with significant damage to the sinus node, the perinodal tissue, and the sinus nodal artery.8 However, induced nonsustained AF caused only minor overdrive suppression of automaticity.9 Recently, Wijffels et al10 and Morillo et al11 showed chronic burst or rapid atrial pacing–induced chronic AF and produced electrophysiological changes in the atrium, but sinus node function was not explored. The objective of the present study was to evaluate the effects of pacing-induced AF on sinus node function, intra-atrial conduction, and atrial refractoriness in a closed-chest canine model.
Fifteen conditioned mongrel dogs of either sex weighing 20 to 30 kg were used for this study. The dogs were initially sedated with butorphanol (1 to 3 mg IM) and anesthetized with sodium thiopental (30 mg/kg IV). The dogs were then intubated with a cuffed endotracheal tube and placed on the fluoroscopy table on a V-shaped board to keep the animal in the supine position. Anesthesia was maintained by ventilation with 2% to 3% isoflurane mixed with room air at a rate of 1.5 to 3.0 L/min.
AV Junction Ablation
An 8F introducer was placed percutaneously in the right femoral vein by the Seldinger technique, and a 6F steerable quadripolar ablation catheter with a 4-mm tip electrode (Webster) was advanced to the AV node region under fluoroscopic guidance. Bipolar electrograms were recorded from the distal tip electrodes of the ablation catheter. Complete AV block was produced by delivering RF energy (20 to 30 W/s for 30 seconds) between the most distal tip electrode placed at a recording site with a large atrial electrogram and His bundle deflection and an indifferent dispersive patch electrode over the lateral chest wall. The resulting complete AV block was monitored for 30 minutes. If needed, repeat RF pulses (30 to 35 W for 30 seconds) were delivered to produce permanent complete AV block. In the 15 dogs used for this study, the mean±SD number of delivered RF pulses to create permanent complete AV block was 2.8±1.7 (range, 1 to 6). Late recovery of AV nodal conduction did not occur in these dogs.
After complete AV block was created, a bipolar endocardial tined ventricular pacing lead (Medtronic 5028) was advanced into the right ventricular apex through a small incision in the external jugular vein and positioned under fluoroscopic guidance at a site with a low pacing threshold in the right ventricular apex. The pacing lead was then connected to a programmable VVI pacemaker (Minix 8330, Medtronic) that was implanted in a subcutaneous pocket in the lateral neck of the dogs and set at 80 pulses per minute. To pace the atria, a bipolar endocardial screw-in pacing lead (Medtronic 4058M) was advanced into the right atrium under fluoroscopic guidance through a second incision in the external jugular vein and implanted in the interatrial septum or right atrial free wall at a site at which the pacing threshold was <1.0 V. The lead was then connected to a pulse generator (Itrel 7432, Medtronic) that was implanted in a subcutaneous pocket in the anterior part of the neck and programmed to pace at 20 Hz, pulse width 4.5 ms, and voltage three times diastolic pacing threshold.
The neck incisions were closed in layers, and the animals received care according to the guidelines of the Indiana University Laboratory Animal Resource Center Animal Care Committee in an approved facility by skilled personnel. Analgesics and other medications were administered as needed. A series of EPSs and post-EPS observations were then performed after the dogs recovered from surgery.
Assessment of Intra-Atrial Conduction and Measurement of Atrial ERP
A 6F quadripolar electrode catheter was introduced percutaneously through the femoral vein into the right atrium. Bipolar pacing was performed from the most distal electrode pair, and atrial electrograms were recorded from the proximal electrode pair. The same catheter position was used to determine the PA interval, measured from the onset of the P wave on the surface ECG to the onset of the local atrial ECG at the lead insertion site, and the atrial ERPs at each EPS. P-wave duration was obtained from the surface ECG at a paper speed of 200 mm/s.
The ERPs were determined by the standard extrastimulus technique with a programmable stimulator (Medtronic 5325 Programmable Stimulator) with a 2-ms rectangular stimulus at twice diastolic threshold (measured before each ERP determination). The ERP was determined at basic drive cycle lengths (S1S1 interval) of 400, 350, 300, and 250 ms. The ERPs were determined in triplicate, and values were within 1 ms of each other or the data were discarded and the determinations were repeated.12
Assessment of Sinus Node Function
SNRT was determined by bipolar pacing with a programmable stimulator (Medtronic 5325) for 30 seconds at progressively shorter drive cycle lengths (400, 350, 300, and 250 ms) with the distal two electrodes of the catheter placed at a high right atrial position near the sinus node region. The longest time interval from the last paced atrial depolarization to the first spontaneous sinus cycle was recorded as the SNRTmax. CSNRTmax was determined by subtracting the mean SCL measured before the beginning of atrial pacing from the SNRTmax.
Induction of episodes of AF was attempted by premature atrial stimulation and by burst pacing the atria for 5 to 10 seconds (10 to 20 Hz, rectangular stimulus with a duration of 2 ms, three times diastolic threshold) after 1 hour of rapid atrial pacing. The five consecutive RCLs after spontaneous termination of induced AF were measured. CRCLs were obtained by subtracting from the RCLs the mean spontaneous SCL before induction of AF. Sinus RCL patterns were also obtained after overdrive stimulation of the atria at a pacing cycle length of 250 ms. Percentage CRCL was obtained by dividing the CRCL by the spontaneous SCL: %CRCL=(CRCL/SCL)×100. MHR was then determined by intravenous infusion of isoproterenol (10 μg·mL−1·min−1) for 15 minutes. The animals were then allowed to recover for 40 minutes to wash out the infused isoproterenol.
Pharmacological autonomic blockade of muscarinic and β-adrenergic receptors was induced by intravenous administration of atropine (0.04 mg/kg) and propranolol (0.1 mg/kg). Unpublished data from our laboratory have shown that 0.2 mg/kg propranolol depresses ventricular contractility and sinus node automaticity significantly. Since the animals in the present study underwent multiple invasive interventions in a relatively short period of time, we used a lower dose of propranolol to prevent increased mortality and sinus node depression. This dose was sufficient to block heart rate increases in response to isoproterenol infusion (10 μg/min). The CSNRT and CRCL determinations were repeated in the same fashion as before the induction of pharmacological autonomic blockade. The spontaneous sinus rate after intravenous injection of atropine and propranolol was determined as the IHR.
Holter Monitoring to Determine the Inducibility and Duration of AF
At the first EPS, the inducibility and duration of AF were assessed by burst pacing or extrastimulus pacing of the atria. The maximum duration of induced AF was shown to be short (<2 minutes) at this first study. Therefore, we did not obtain a 24-hour Holter recording to assess the duration of induced AF before initiation of chronic rapid atrial pacing. After 2 to 6 weeks of rapid atrial pacing, the atrial pulse generator was turned off, and 24-hour Holter recordings were obtained in all 11 dogs. All tapes were scanned manually, and all areas of questionable accuracy were verified by direct printout. All recordings were made with two-channel tape recorders (Marquette Electronics) and two bipolar leads.
First EPS (EPS-1, groups 1, 2, and 3)
The first EPS was performed 3 days after surgery in 4 control animals (group 1, sham dogs) and 11 study animals (group 2, n=6 dogs, and group 3, n=5 dogs). Anesthesia was induced with sodium thiopental (30 mg/kg) and maintained with 2% to 3% isoflurane mixed with 2 L/min room air. A 6F quadripolar catheter was placed percutaneously in the high right atrium under fluoroscopic guidance. Lead II ECG, bipolar high right atrial electrograms, and arterial blood pressure were recorded continuously during the study and stored on a videotape for later analysis of the data with a computer software program (Lab View, National Instruments). P-wave duration and PA-interval measurements were obtained as described earlier. Inducibility and duration of AF were assessed by premature atrial stimulation during ERP testing, and if AF was not induced by this method, the atria were then paced rapidly for 1 hour, and burst pacing was then used to test inducibility of AF. The atrial ERP was determined at a high right atrial site close to the atrial pacing lead insertion site. The site was kept constant for each study by use of the atrial lead insertion site as an anatomic landmark.
After atrial ERP measurements were obtained, the catheter tip was positioned in the sinus node region under fluoroscopic guidance, and sinus node automaticity was tested after 1 hour of rapid atrial pacing–induced AF as mentioned above. MHR and IHR were determined, and SNRT measurements were repeated during autonomic blockade. At the end of the study, the atrial pulse generator was turned on and the atria were paced (rate, 20 Hz; 4.5-ms impulse width and three times diastolic threshold) for 2 to 6 weeks to induce sustained AF in the study animals (groups 2 and 3).10 11
Second EPS (EPS-2, groups 1, 2, and 3)
In the control animals (group 1) after 2 to 6 weeks of VVI pacing without rapid atrial pacing, inducibility and duration of AF were assessed. EPS-2 was performed under general anesthesia as described for the EPS-1 protocol. After 2 to 6 weeks of high-rate atrial pacing in the 11 study dogs (groups 2 and 3), the atrial pulse generator was turned off, and the duration of AF was assessed by 24-hour Holter ECG monitoring. EPS-2 was performed after spontaneous termination of pacing-induced sustained AF. The dogs in groups 2 and 3 were in sinus rhythm for 6 to 12 hours before data on sinus node function and atrial refractoriness were obtained. Atrial ERPs, SNRTs, and IHR and MHR data were obtained in the same fashion as during the first EPS.
Third and fourth EPSs (EPS-3 and EPS-4, group 3)
Reversibility of the effects of chronic rapid atrial pacing was assessed in 5 dogs (group 3) as follows. After 2 to 6 weeks of chronic rapid atrial pacing, atrial pacing was turned off to assess the duration of pacing-induced AF with 24-hour Holter monitoring. Two days (EPS-3) and 1 week (EPS-4) after conversion of pacing-induced AF to sinus rhythm, EPS-3 and EPS-4 were performed under general anesthesia as for EPS-1 and EPS-2. Atrial ERPs, SNRTs, and IHR and MHR data were obtained in the same way as during EPS-1 and EPS-2.
The data are expressed as mean±SEM, except for the duration of AF, which is presented as median (minimum, maximum). For statistical analysis, two-way repeated-measures ANOVA was used, with each animal serving as its own control. Since the duration of AF was not distributed normally, comparisons before and after chronic pacing were made by Wilcoxon signed-rank test. A value of P<.05 was set as statistically significant.
Effects of AV Junction Ablation and Chronic VVI Pacing on Inducibility of AF, Atrial Refractoriness, and Sinus Node Function (Group 1)
In group 1 dogs (control group), the inducibility and duration of AF were not changed after complete AV block and VVI pacing for 2 to 6 weeks compared with normal sinus rhythm and AV synchrony (maximum pacing-induced AF duration, <30 seconds). Table 1⇓ summarizes the data on the effects of AV junction ablation and subsequent chronic ventricular pacing on sinus node function and atrial refractoriness.
Effect of Acute Versus Chronic Rapid Atrial Pacing on Sinus Node Function (Groups 2 and 3)
Fig 1⇓, left, shows that the CSNRT 2 to 6 weeks after pacing-induced AF was significantly prolonged compared with the CSNRT determined after 1 hour of pacing-induced AF. Fig 1⇓, right, shows that induction of pharmacological autonomic blockade further increased the difference in the CSNRT between 1 hour and 2 to 6 weeks of rapid atrial pacing. The CSNRT data from each dog are summarized in Table 2⇓.
Fig 2⇓, left, shows that the sinus RCL pattern of the five consecutive postpacing sinus cycles after overdrive suppression with pacing for 30 seconds at a pacing cycle length of 250 ms was shifted upward by chronic pacing-induced AF compared with 1 hour of pacing-induced AF (P<.01). Induction of pharmacological autonomic blockade further increased the difference in the sinus RCL pattern of all five return cycles (Fig 2⇓, right, P<.01). The percentage prolongation of the first corrected return cycle after overdrive stimulation at a pacing cycle length of 250 ms was more pronounced after 2 to 6 weeks of pacing-induced AF (30±5%) compared with 1 hour of pacing-induced AF (19±4%). However, the sinus RCL pattern (Fig 3⇓, left) and percentage sinus RCL pattern (Fig 3⇓, right) after spontaneous termination of AF did not differ significantly (P=NS) between 1 hour and 2 to 6 weeks of rapid atrial pacing.
Fig 4⇓, left, shows that the stable spontaneous SCL increased after 2 to 6 weeks of pacing-induced AF (ΔSCL=43±24 ms, P<.05) and intravenous atropine and propranolol injection prolonged the SCL more after 2 to 6 weeks of rapid pacing than after 1 hour of pacing-induced AF (ΔSCL=130±43 ms, P<.01). Fig 4⇓, right, shows that the MHR in response to intravenous isoproterenol infusion (10 μg·mL−1·min−1) was attenuated after 2 to 6 weeks of rapid atrial pacing (ΔMHR=18±8.6 bpm, P<.01).
Effect of Acute Versus Chronic Rapid Atrial Pacing–Induced AF on Intra-Atrial Conduction, Atrial Refractoriness, and Inducibility and Duration of AF (Groups 2 and 3)
The P-wave duration and the PA interval increased from 52±8 and 26±9 ms, respectively, at baseline (EPS-1) to 78±15 and 37±11 ms after 2 to 6 weeks of pacing-induced AF (EPS-2) (P<.05, Fig 5⇓). The atrial ERP was significantly shorter after 2 to 6 weeks of pacing-induced AF compared with 1 hour of rapid atrial pacing. The curve relating the basic drive cycle length and the duration of atrial ERP showed shortening of atrial ERP with shortening of the basic drive cycle lengths after 1 hour of pacing-induced AF. However, this latter curve was shifted downward at all basic drive cycle lengths after 2 to 6 weeks of pacing-induced AF (Fig 6⇓). The duration of atrial ERPs became independent of basic drive cycle length after 2 to 6 weeks of rapid atrial pacing.
After 2 to 6 weeks of pacing-induced AF, sustained episodes of AF (duration, >1 hour) were easily inducible with single extrastimuli during measurement of atrial ERPs. There was a positive correlation between the duration of rapid atrial pacing and the inducibility and duration of AF, such that the duration of pacing-induced AF increased with longer periods of rapid pacing (r=.78, Fig 7⇓). There was a significant correlation between the duration of AF and atrial refractoriness at ERPs <120 ms (r=−.57, Fig 8⇓). Atrial ERPs >120 ms did not show a correlation with the duration of AF (Fig 8⇓). Atrial ERP data were obtained in all dogs after 2 to 3 weeks of pacing. However, in only 3 of the 11 dogs that had been paced for 4 to 6 weeks was the measurement of atrial ERPs feasible. In the remaining 8 dogs, data acquisition on sinus node function, intra-atrial conduction, and atrial refractoriness was attempted, but sustained episodes of AF were very easily inducible; therefore, we could not obtain any data after 4 to 6 weeks of rapid atrial pacing. The 24-hour Holter ECG recordings showed that after 2 to 6 weeks of rapid atrial pacing, sustained AF (>30 minutes' duration) was present after the atrial pulse generator was turned off (Fig 7⇓).
Reversibility of the Effects of Chronic Rapid Atrial Pacing (Group 3)
Table 3⇓ shows data obtained from five dogs after 1 hour of pacing-induced AF, 2 to 6 weeks of pacing-induced AF, and 2 days and 1 week after conversion to sinus rhythm. CSNRTs, MHRs, IHRs, and atrial ERPs gradually reversed toward baseline 2 days and 1 week after conversion of pacing-induced AF to sinus rhythm. However, there was still a significant difference in CSNRTs, MHRs, IHRs, and atrial ERPs between baseline and 1 week after conversion to sinus rhythm (Table 3⇓).
In this study, we demonstrated that pacing-induced AF for 2 to 6 weeks prolongs SNRTmax, CSNRTmax, and spontaneous SCL and decreases the intrinsic and maximal sinus rates. It also prolongs the P-wave duration and intra-atrial conduction time. We also confirmed that such pacing-induced AF markedly decreases atrial refractoriness and increases the duration of sustained AF.10 11
Sinus Node Automaticity
Normal sinus node function depends on a complex interaction of impulse formation in the pacemaker cells, propagation to the atria, and autonomic modulation. Overdrive suppression of sinus node automaticity has been widely used as a means to evaluate sinus node function.13 14 15 Prolongation of SNRT after overdrive stimulation of the atria may be due to this complex interaction between recovery of automaticity in sinus nodal pacemaker cells and sinoatrial conduction.16 Various degrees of atriosinus conduction block can occur at increasing pacing rates (>4.5 Hz) and prevent 1:1 capture of the nodal cells, and thus attenuate or prevent overdrive suppression of sinus nodal cells because of sinoatrial entrance block. Gomes et al17 showed that overdrive stimulation of the atria induces marked prolongation of sinoatrial conduction time for the first postpacing sinus return cycle, especially in patients with sick sinus syndrome. Kumagai et al4 noted that the SNRT in patients with chronic lone AF determined after electrical cardioversion was significantly longer than in a control group of patients.
The present study is, to the best of our knowledge, the first to demonstrate that pacing-induced AF for 2 to 6 weeks causes sinus node dysfunction. The first post–overdrive-pacing sinus RCL was significantly prolonged (Figs 1 and 2⇑⇑), suggesting that sinus automaticity, sinoatrial conduction time, or a combination of the two was significantly affected by pacing-induced AF. However, the sinus RCL pattern after spontaneous termination of AF was not affected by pacing-induced AF (Fig 3⇑). The reason for this is unknown, but it may be due in part to a high-degree atriosinus conduction block, consistent with the results of an in vitro study by Kirchhof and Allessie.9 They showed that in isolated rabbit hearts, concealed sinus node automaticity was present during AF and that only minimal overdrive suppression of sinus node automaticity occurred after spontaneous termination of AF.9
Mechanism of Sinus Node Dysfunction
Autonomic tone is very important in regulation of sinus node automaticity, sinoatrial conduction, and electrophysiological properties of the atrial myocardium.18 19 20 Pharmacological autonomic blockade of β-adrenergic and muscarinic receptors has been used to differentiate impaired autonomic modulation from intrinsic abnormal sinus node automaticity or sinoatrial conduction.14 15 21 22 23 24 In the present study, pacing-induced AF prolonged the intrinsic sinus rate and SNRT after overdrive suppression (Figs 1, 2, and 4⇑⇑⇑, left), suggesting a depression of sinus node automaticity and/or sinoatrial conduction. Induction of autonomic blockade further prolonged the spontaneous SCL (Fig 4⇑, left). The reason for this is unknown, but pacing-induced AF may have been associated with compromised hemodynamics, leading to enhanced sympathetic tone. Pharmacological autonomic blockade of the β-adrenergic receptors could have abolished the positive chronotropic effect of increased sympathetic tone. Interestingly, the first and second post–overdrive-pacing CRCLs were markedly prolonged after pacing-induced AF and the curves paralleled for the third to fifth consecutive sinus return beats (Fig 2⇑), indicating that chronic pacing affected intrinsic sinus node function significantly.
Intra-Atrial Conduction, Atrial Refractoriness, and Inducibility of AF
Previous studies have shown that AF is associated with abnormal intra-atrial conduction,4 5 11 possibly because of electrical remodeling of the atria.10 Chronic atrial pacing induces marked changes in the atrial ultracellular architecture, along with an increase in atrial dimensions that correlates with the inducibility of sustained AF in dogs.11 Chronic AF also causes significant atrial enlargement in patients.7
The present study has confirmed the previous findings that chronic rapid atrial pacing decreases atrial refractoriness (Fig 5⇑), increases intra-atrial conduction time, and perpetuates AF (Fig 6⇑) and that the duration of the atrial ERP decreases markedly and becomes independent of drive cycle length after 2 to 6 weeks of rapid atrial pacing (Fig 6⇑).10 11 We have extended these observations by showing that sinus node dysfunction follows a prolonged period of rapid atrial pacing, so that it is quite possible that the electrical remodeling of the atria extends to the sinus node as well, resulting in sinus node dysfunction.25
Reversibility of the Chronic Rapid Atrial Pacing–Induced Changes in Sinus Node Function and Atrial Refractoriness
Wijffels et al10 showed that the sustained pacing-induced changes in atrial refractoriness and conduction velocity were fully reversible 1 week after conversion to sinus rhythm in the goat model. We found that the effects of sustained rapid atrial pacing on sinus node function and atrial refractoriness partially reversed toward control values 1 week after conversion to sinus rhythm. We postulate that reversible electrical remodeling occurs in the sinus node as well as in the atrial myocardium. Had we waited longer than 1 week, perhaps the changes would have returned to baseline. However, it is possible that increased atrial pressure associated with chronic asynchronous (VVI) pacing contributed to the delayed reversion of the rapid pacing–induced electrophysiological changes in the atrium, although the four control dogs showed no changes. Perhaps increased levels of atrial natriuretic peptide and the persistence of increased atrial pressure due to VVI pacing prevented or delayed complete reversion of the changes in sinus node function and atrial refractoriness resulting from chronic rapid atrial pacing–induced AF, even after 1 week of sinus rhythm.
This study does not give insight into the underlying mechanisms responsible for the sinus node dysfunction or the electrical remodeling that may have caused it. Although we did not perform histological studies, the reversibility of the electrophysiological changes makes postoperative pericarditis an unlikely cause. Additional studies would be needed to determine the role of atrial natriuretic peptide, neuropeptide Y, and other substances; the role of increased atrial pressure and changes in flow and metabolism during AF; and the ionic channels responsible for the fibrillation-induced changes in sinus node function, atrial refractoriness, and conduction.
The present study provides experimental evidence that pacing-induced chronic AF causes sinus node dysfunction. Clinical studies have shown that AF can be associated with sinus node dysfunction,3 4 which may play an important role in the induction and perpetuation of AF.13 26 In some patients, paroxysmal AF becomes chronic in time, a change that might be explained in part by the alterations in sinus node function, intra-atrial conduction, and atrial refractoriness. Future studies are needed to delineate the underlying mechanism(s) responsible for the sinus node dysfunction, whether it is fully reversible, and whether techniques such as atrial pacing after termination of AF might speed that reversibility. These fibrillation-induced electrophysiological changes and their potential reversibility may be relevant to patients with sick sinus syndrome.
Selected Abbreviations and Acronyms
|CRCL||=||corrected sinus return cycle length|
|CSNRT||=||corrected sinus node recovery time|
|ERP||=||effective refractory period|
|IHR||=||intrinsic heart rate|
|MHR||=||maximal heart rate|
|RCL||=||return cycle length|
|SCL||=||sinus cycle length|
|SNRT||=||sinus node recovery time|
This study was supported in part by the Herman C. Krannert Fund, Indianapolis, Ind, and grant HL-52323-01 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Dr Elvan is a recipient of a research fellowship grant (R95006) from the Dutch Heart Foundation and the “De Gelderfonds,” Den Haag, Netherlands. The authors thank Naomi Fineberg, PhD, for the statistical analysis of the data and Edwin Duffin, PhD, of Medtronic, Inc, for help in obtaining the pacemakers.
- Received January 25, 1996.
- Revision received June 19, 1996.
- Accepted July 2, 1996.
- Copyright © 1996 by American Heart Association
Allessie MA, Lammers W, Bonke FIM, Hollen J. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando, Fla: Grune & Stratton, Inc; 1985:265-276.
Gomes JAC, Kang PS, Matheson M, Gough WB, El-Sherif N. Coexistence of sick sinus rhythm and atrial flutter-fibrillation. Circulation. 1981;63:80-86.
Kumagai K, Akimitsu S, Kawahira K, Kawanami F, Yamanouchi Y, Hiroki T, Arakawa K. Electrophysiological properties in chronic lone atrial fibrillation. Circulation. 1991;84:1662-1668.
Sanfilippo A, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, Weyman AE. Atrial enlargement as a consequence of atrial fibrillation: a prospective echocardiographic study. Circulation. 1990;82:792-797.
Kirchhof CJHJ, Allessie MA. Sinus node automaticity during atrial fibrillation in isolated rabbit hearts. Circulation. 1992;86:263-271.
Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. Circulation. 1995;92:1954-1968.
Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing: structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588-1595.
Elvan A, Pride HP, Eble JN, Zipes DP. Radiofrequency catheter ablation of the atria reduces the inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235-2244.
Nadeau RA, Roberge FA, Billette J. Role of the sinus node in the mechanism of cholinergic atrial fibrillation. Circ Res. 1970;27:129-138.
Narula OS, Samet P, Javier RP. Significance of the sinus node recovery time. Circulation. 1972;45:140-158.
Steinbeck G, Haberl R, Luderitz B. Effects of atrial pacing on atrio-sinus conduction and overdrive suppression in the isolated rabbit sinus node. Circ Res. 1980;46:859-869.
Gomes JA, Harlman RL, Chowdry IA. New application of direct sinus node recordings in man: assessment of sinus node recovery time. Circulation. 1984;70:663-671.
Schuessler RB, Bromberg BI, Boineau JP. Effect of neurotransmitters on the activation sequence of the isolated right atrium. Am J Physiol. 1990;258:H1632-H1641.
Smeets JLRM, Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. Circ Res. 1986;58:96-108.
Strauss HC, Bigger JT Jr, Saroff AL, Giardina ECG. Electrophysiologic evaluation of sinus node function in patients with sinus node dysfunction. Circulation. 1976;53:763-776.
Jordan JL, Yamaguchi I, Mandel WJ. Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome. Circulation. 1977;57:217-223.
Kang PS, Gomes JAC, Kelen G, El-Sherif N. Role of autonomic regulatory mechanisms in sinoatrial conduction and sinus node automaticity in sick sinus syndrome. Circulation. 1981;64:832-838.
Desai JM, Scheinman MM, Strauss HC, Massie B, O'Young J. Electrophysiologic effects of combined autonomic blockade in patients with sinus node disease. Circulation. 1981;63:953-960.
Benditt DG, Sakaguchi C, Goldstein MA, Lurie KG, Gornick CC, Adler SW. Sinus node dysfunction: pathophysiology, clinical features, evaluation, and treatment. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:1215-1247.