Skip Navigation

Cardiovascular Research 2001 50(1):75-84; doi:10.1016/S0008-6363(00)00320-5
© 2001 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Derakhchan, K.
Right arrow Articles by Nattel, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Derakhchan, K.
Right arrow Articles by Nattel, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF

Katayoun Derakhchana,b, Christine Villemaireb, Mario Talajicb and Stanley Nattela,b,*

aDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
bResearch Center and Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8

* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca

Received 7 June 2000; accepted 4 December 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 Acknowledgments
 References
 
Background: Clinical trials suggest that sotalol and dofetilide are much more effective in preventing atrial fibrillation (AF) than in terminating it. This study evaluated potential mechanisms of discordant sotalol and dofetilide effects on AF termination vs. prevention. Methods: We applied 240-electrode epicardial mapping and programmed stimulation in a vagotonic dog model of AF before and after dofetilide or sotalol. Results: Under control conditions, sustained AF could be induced by single S2 extrastimuli that caused unidirectional block and macroreentry. Sotalol (2 mg/kg) and dofetilide (0.04 mg/kg) failed to terminate AF in any dog, but prevented AF induction by S2 stimuli in 19/22 (86%) and 4/5 (80%) of animals, respectively. With sotalol and dofetilide, unidirectional block still occurred, but wavefront reentry failed. The prevention of S2-induced reentry was related to large increases in the effective refractory period (ERP) at a BCL of 1000 ms, leading to ERPs that exceeded the conduction delay following S2. Reverse use-dependent effects resulted in smaller ERP increases at BCLs closer to the AF cycle length. Although the number of zones of reactivation per cycle during sustained AF were decreased by sotalol and dofetilide, the changes were small and insufficient to terminate AF. Conclusions: Sotalol and dofetilide prevent AF initiation by premature depolarizations at doses that fail to terminate vagotonic AF, by increasing ERP at the basic cycle length beyond the associated conduction delay that leads to reentry.

KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Supraventricular arrhythmia


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 Acknowledgments
 References
 
Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and causes a wide range of potential complications [1]. The treatment of AF remains problematic [2]. A better understanding of the mechanisms determining antiarrhythmic drug efficacy would help in improving therapy. With the awareness of the risks of potent class I antiarrhythmic drugs obtained from the Cardiac Arrhythmia Suppression Trial [3] and subsequent analyses [2], antiarrhythmic drug development shifted to class III agents [4]. Clinical trials have shown class III drugs to be relatively ineffective in terminating AF, but effective in preventing AF recurrence [5]. Experimental studies in vagotonic and atrial tachycardia-related models of sustained AF have demonstrated a limited capacity of clinically-relevant doses of rapid delayed rectifier (IKr)-selective blocking class III agents to terminate AF [6–8]. In a previous report from our laboratory, we suggested that reverse use-dependent actions may limit class III efficacy at the rapid rates of AF, but permit them to prevent AF induction by atrial premature complexes (APCs) at slower resting sinus rates [6]. This concept has never been tested experimentally. We therefore designed the present study to (1) determine whether sotalol and dofetilide doses that are ineffective in terminating AF are capable of preventing AF induction by APCs and (2) use epicardial mapping to evaluate the mechanism by which AF induction is prevented.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 Acknowledgments
 References
 
2.1 General preparation
The investigation conforms 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).

Adult mongrel dogs (27.2±0.6 kg) were anesthetized with morphine (2 mg/kg i.m., 0.5 mg/kg i.v. every 2 h) and {alpha}-chloralose (120 mg/kg i.v., 29.25 mg/kg/h i.v.), and ventilated at 20–25/min. Arterial blood gases were measured every 2 h and kept in the physiological range (SaO2>90%, pH 7.38–7.44). Catheters were inserted into a femoral artery and both femoral veins. Body temperature was maintained at 37–39°C with a temperature-control system.

The heart was exposed via a sternotomy and a pericardial cradle created. A programmable stimulator (Digital Cardiovascular Instruments, Berkeley, CA) was used to stimulate the right atrium with 2-ms, twice diastolic-threshold pulses. A ventricular demand pacemaker was used to stimulate the ventricles at 80/min when the ventricular rate became excessively slow. The vagus nerves were isolated and divided in the neck. To block cardiac β-adrenergic effects, nadolol was administered at 0.5 mg/kg i.v., followed by 0.25 mg/kg i.v. every 2 h. The sinus node was crushed to permit atrial capture at cycle lengths comparable to resting cycle lengths (800–1000 ms) in man.

2.2 AF model
Experiments were performed in a well-characterized model of vagotonic AF [6,7]. This model was chosen over the atrial-tachycardia model [8,9] because repeated inductions of AF were needed to characterize susceptibility to AF induction by APCs. Repeated episodes of sustained AF would require repeated electrical cardioversions in the atrial-tachycardia model. Sustained vagotonic AF can be terminated by stopping vagal stimulation, without requiring electrical cardioversion, and permitting the subsequent resumption of vagotonic conditions by re-instituting vagal stimulation during sinus rhythm.

Bipolar hook electrodes (stainless steel insulated with Teflon except for the distal 1–2 cm) were inserted within and parallel to each vagus nerve. Bipolar stimulation (0.1-ms square-wave pulses, 10 Hz, 60% of voltage for asystole) was applied (Grass DS-9F stimulator) continuously during AF, the measurement of ERP and conduction velocity (CV), and AF induction.

2.3 Measurement of electrophysiological variables
Activation maps for CV measurements were obtained after 45 s of pacing at the right atrial appendage at basic cycle lengths (BCLs) of 200, 300, 400 and (whenever possible)1000 ms. Fifteen basic (S1) stimuli were followed by a premature (S2) stimulus at an S1S2 interval that was reduced by 10-ms decrements from the BCL, with the ERP defined as the longest S1S2 interval failing to produce a response. AF was then induced with single S2s at a BCL of 1000 ms (or the longest cycle length maintaining 1:1 capture if the spontaneous cycle length was <1000 ms), beginning 100 ms beyond the ERP and decrementing by 10-ms intervals. Each coupling interval was studied twice before concluding that AF could not be induced. AF was defined as a rapid (<450/min), irregular atrial rhythm with varying atrial electrogram morphology and as sustained if >20 min without spontaneous termination. A 2-s window of activation data was acquired during AF to analyze activation patterns and measure AF cycle length (AFCL). AF was considered inducible if induced reproducibly on at least two consecutive occasions at a given S1S2 coupling interval.

The AFCL was calculated at each of 50 widely-distributed sites by counting cycles over a 2-s activation window. The results at all sites were averaged to obtain the overall mean AFCL. The activation pattern during AF was studied by constructing sequential activation maps. Zones of reactivation were defined as discrete areas of early activation adjacent to zones of late activation in a cycle, that were reactivated at the onset of the next cycle. The number of reactivation zones was determined for three successive AF cycles in each dog under each condition.

CV was determined by analyzing activation during continuous longitudinal propagation at five electrode sites in Bachmann's bundle (Fig. 1). Distance from the proximal site was plotted against activation time, and CV was determined from the slope of the best-fit regression line (Fig. 1C). The same sites were used for all conduction velocity measurements for each experiment. The wavelength was calculated as CVxERP.


Figure 1
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 (A) Schematic diagram of the electrode array attached to Bachmann's bundle, which was used for conduction velocity (CV) measurement along with isochrone map from a representative dog. (B) Atrial electrograms at sites used for conduction velocity measurements and corresponding activation times. (C) Linear regression of distance against local activation time, as obtained from the set of electrograms at the left of panel B. CV was determined from the slope of the best-fit regression line.

 
2.4 Activation mapping
Five silicon plaques containing 240 bipolar electrodes were attached to the epicardial surface of both atria [8,10]. Electrodes consisted of Teflon-coated stainless steel wires (270 µm diameter) with interpolar distances of 1 mm, inter-electrode distances 3–6 mm. A decapolar ring-electrode catheter (10 electrodes, 2.5 mm inter-polar and 10 mm inter-electrode distance) was inserted via the femoral vein and positioned fluoroscopically adjacent to the septum to record five bipolar septal electrograms. Electrogram signals were filtered (10–450 Hz), digitized (12-bit resolution and 1-kHz sampling rate), and transmitted into a Silicon Graphics computer. Activation times were analyzed off-line with computer-determined peak-amplitude criteria. All computer-selected events were verified manually.

2.5 Experimental protocol
The effects of sotalol (loading dose of 2 mg/kg followed by infusion of 1 mg/kg/h) and dofetilide (loading dose 0.04 mg/kg, infusion 0.008 mg/kg/h) were studied. The doses were established by preliminary experiments to produce significant and constant atrial ERP prolongation without terminating AF in most dogs. All drugs were administered via infusion pump, with drug solutions prepared on the day of each experiment and (for dofetilide) protected from light. Vagal stimulation parameters were defined as described above, and maintenance of AF during 20 min of vagal stimulation under control conditions was verified. AF was then re-initiated and maintained for 20 min, to confirm AF stability. AF was then terminated and AERP and CV were measured at four BCLs (200, 300, 400 and 1000 ms) during vagal stimulation. If AF was induced by single S2s at a BCL of 1000 ms, an activation window was obtained for subsequent mapping and AF was terminated. Following a 5-min rest period, vagal stimulation was re-initiated and AF induction re-tested at the same coupling interval. The window of vulnerability was defined as the range of coupling intervals over which AF was consistently induced by single extrastimuli.

AF was then re-induced during vagal stimulation, and a drug given after 5 min of AF. If AF was not stopped 20 min after drug administration, activation data were obtained and vagal stimulation was discontinued to return to sinus rhythm. Electrophysiologic measurements were then repeated during vagal stimulation, and induction of AF attempted. If sustained AF could not be induced, an S3 was introduced at the shortest S1–S2 interval maintaining capture to define the ERP of the APC initiated by S2, activation data were obtained and the experiment was terminated.

2.6 Statistical analysis
Data are expressed as mean±S.E. Statistical comparisons were made with ANOVA followed a range test (Bonferroni-adjusted t for two-way ANOVA and Tukey's test for one-way ANOVA).


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 Acknowledgments
 References
 
3.1 Electrophysiologic effects during atrial pacing
Neither sotalol nor dofetilide altered CV at any BCL (Fig. 2, left), nor was CV altered for the APC induced at the smallest S1S2 producing capture (Fig. 2, right). Both drugs significantly prolonged atrial ERP, with changes increasing with increasing BCL (reverse use-dependence, Fig. 3). Changes in wavelength also showed reverse use-dependence (Fig. 4).


Figure 2
View larger version (40K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Left: Conduction velocity measured at cycle lengths of 200, 300, 400 and 1000 ms, during vagal stimulation under control conditions and after sotalol or dofetilide infusion. Right: Conduction velocity of the activation initiated by S2 at the shortest S1S2 interval achievable. Values are mean±S.E.

 

Figure 3
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Effects of sotalol and dofetilide on atrial effective refractory period (ERP). The atrial ERP was measured at basic cycle lengths (BCL) of 200, 300, 400 and 1000 ms. Values are mean±S.E. ***P<0.001 for frequency-dependence of drug action. Explicit P values are shown vs. control at each BCL.

 

Figure 4
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Rate-dependent effects on wavelength (WL). ***P<0.001 for frequency-dependence of drug action. Explicit P values are shown vs. control at each BCL.

 
3.2 Effects on AF
Neither sotalol nor dofetilide terminated AF in any dog, but both drugs prevented AF induction by single extrastimuli. Under control conditions, single extrastimuli induced sustained AF in all dogs, with a vulnerable window from 97±5 to 111±7 ms in the sotalol group and 83±4 to 96±8 ms in the dofetilide group. Sotalol prevented AF induction by extrastimuli in 19/22 dogs (86%) and dofetilide prevented AF induction in 4/5 dogs (80%).

To understand the mechanisms by which sotalol and dofetilide prevented AF induction, we analyzed activation maps during AF induction under control conditions and then after drug during application of the most closely-coupled extrastimuli with capture. Fig. 5A shows the induction of AF by a single S2 during stimulation at the right atrial appendage under control conditions. Activation maps are shown, along with selected electrograms at the left. The impulse resulting from the last pulse of the basic train (S1) spreads down the right atrial free wall towards the AV ring, and across Bachmann's bundle to the left atrium. The upper end of the septum is activated at 71 ms, and the lower end of the septum is activated with a conduction delay (defined as conduction time from initial activation near the stimulation site to activation of the distal septum) of 97 ms. The ERP of the complex resulting from S1 was 100 ms, and an S2 was applied 110 ms after S1 (a coupling interval 10 ms greater than the ERP), resulting in the activation shown in the middle panel. This premature complex showed slowed activation, with a conduction delay to the distal septum of 126 ms. This delay is greater than the ERP at the stimulation site, permitting reactivation in the right atrial appendage and resulting in the unstimulated reentrant activation (B3) at the right.


Figure 5
View larger version (63K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Induction of atrial reentry by programmed electrical stimulation under control conditions (panel A) and during sotalol infusion (panel B). Selected electrograms (left) are followed by activation maps of three successive cycles corresponding to the activation windows delimited by the vertical lines superimposed on the electrograms. The premature beat (S2) was delivered at a coupling interval just beyond the atrial ERP. Asterisks on the activation maps indicate stimulation sites. S1, S2, S3=activations induced by S1, S2 and S3, respectively. B3=spontaneous cycle following S2 beat. CD=conduction time from stimulation site to distal septum; ERP=effective refractory period at stimulation site. Arrows indicate direction of wavefront propagation. Double line is site of failure of reentry, presumably due to persistent right atrial refractoriness. Isochrone lines (20-ms isochrones) were generated automatically by a validated computer algorithm. Note that septal activation times (shown in boxes) were out of the epicardial plane and were intentionally excluded from epicardial isochrone calculation.

 
Fig. 5B shows the results of programmed stimulation at the same site in the same dog after sotalol administration. Activation during the last basic complex (left) was not significantly changed by sotalol. Sotalol substantially increased the ERP of basic beats, from 100 (under control) to 220 ms. The middle panel shows the activation resulting from an S2 delivered 230 ms (10 ms greater than the ERP) following S1. The conduction delay to the distal septum was 106 ms and no reentry followed. The right panel shows activation resulting from the earliest complex that could be initiated by an S3 at the same stimulation site, with an S2–S3 interval of 140 ms, which also failed to induce reentry. The ERP of the complex resulting from S2 was thus 130 ms, longer than the septal conduction delay and potentially accounting for the failure of reentry from the distal septum to the right atrium for the complex initiated by S2. It should be noted that the conduction delay to the distal septum for the complex initiated by S3 was 140 ms, which was likely just greater than the ERP at the RA appendage. The lack of reentry with S3 must then be due to block at a site in the reentrant pathway with an ERP longer than the ERP at the RA appendage, or to reentry actually involving a region more proximal in the septum than the distal recording site.

Fig. 6A shows the induction of reentry under control conditions in a dog from the dofetilide group. The septal conduction delay resulting from the earliest S2 with capture (middle panel) was 101 ms (of the same order as the basic ERP at the right atrial appendage), activating the distal septum at 228 ms. This delay was sufficient to activate the right atrial free wall 24 ms later (at 252 ms), resulting in the reentrant response shown at the right. Fig. 6B shows failure of reentry for the earliest-coupled S2 and S3 with capture in the presence of dofetilide. Once again, the septal conduction delay associated with S2 was substantially less than the ERP of the activation caused by S2 (140 ms), accounting for the failure of reentry from the septum to the right atrium.


Figure 6
View larger version (62K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 Same format as Fig. 5, for a dog receiving dofetilide.

 
Under control conditions, premature stimulation at the right atrial appendage generally appeared to cause reactivation of the right atrium via the septum. Fig. 7 shows mean data from dogs in which sotalol and dofetilide prevented AF induction by single electrically-induced APCs. Under control conditions, the conduction delay to the distal septum slightly exceeded the ERP of the activation caused by S1, permitting reentry. Both dofetilide and sotalol substantially increased the ERP, so that it exceeded the distal septal conduction delay and reentry was prevented.


Figure 7
View larger version (24K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 7 Comparison of the effects of sotalol and dofetilide on atrial effective refractory period (AERP) vs. conduction delay to distal septum. Under control conditions, the conduction delay was slightly greater than the AERP, allowing the occurrence of atrial reentry. Sotalol and dofetilide did not alter conduction delay, but greatly increased AERP, thereby preventing AF induction. Values are mean±S.E.

 
Fig. 8A shows consecutive cycles (defined as the shortest interval with activation at all sites) during AF before and after sotalol. Zones of reactivation are indicated by the stars. Sotalol decreased slightly the number of zones of reactivation and prolonged the cycle length, consistent with an increase in the ERP; however, multiple reactivation zones are present both before and after the drug. Fig. 8B shows the same type of data for a dog in the dofetilide group, illustrating qualitatively similar phenomena to those seen with sotalol. Fig. 9 shows a quantitative analysis of the AFCL (panel A) and number of reactivation zones (panel B) before and after each drug. Both drugs increased AFCL and decreased the number of reactivation zones per cycle; however, the decrease in the number of reactivation zones was relatively modest, from just above six to just above five.


Figure 8
View larger version (55K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 8 Activation maps of two consecutive cycles during sustained AF before and after drug infusion in representative dogs. Isochronal lines are drawn at 20-ms intervals. Asterisks indicate reactivation zones, defined as zones activated early in one cycle (adjacent to late-activated zones) which are then re-activated early in the next cycle. During sotalol and dofetilide infusion, there was a modest reduction in the number of zones of reactivation and an increase in AF cycle length.

 

Figure 9
View larger version (30K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 9 Top: AFCL before and after drug infusion. Bottom: Number of reactivation zones per cycle, based on the type of data shown in Fig. 8, as calculated during three successive cycles of AF under each condition.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 Acknowledgments
 References
 
In the present study, clinical doses of sotalol and dofetilide failed to convert sustained AF in a vagotonic dog model. Nonetheless, the same doses were highly effective in preventing AF initiation by electrically induced atrial premature beats. The mechanism by which the initiation of intra-atrial reentry was prevented appeared to be a strong increase in the ERP at long basic cycle lengths, which exceeded the conduction delay associated with premature activation.

4.1 Efficacy of class III drugs in preventing AF compared to their ability to terminate the arrhythmia
Numerous studies attest to the greater efficacy of class III drugs, and more specifically sotalol and dofetilide, in preventing AF compared to their ability to terminate the arrhythmia. In a controlled trial, Hohnloser et al. [5] found that sotalol converted significantly fewer AF patients than quinidine to sinus rhythm, but that their efficacy in AF prevention is equivalent. Two other studies found sotalol to be inferior to quinidine for AF cardioversion [11,12], and an additional study found sotalol to be significantly less effective than flecainide [13]. In contrast, sotalol has been found to be as effective as quinidine [14,15] and propafenone [16,17] and more effective than placebo [18] in preventing AF recurrence.

Two small studies failed to demonstrate efficacy of dofetilide in AF conversion [19,20]. Subsequent larger studies showed that dofetilide is more effective than placebo in terminating AF and atrial flutter; however, dofetilide conversion rates for AF are relatively low: 14.5% in one study [21] and 24% in the other [22]. In contrast, dofetilide is clearly effective in preventing AF recurrence [23]. Thus, the clinical evidence suggests that sotalol and dofetilide are more effective in preventing AF than in terminating it.

4.2 Novel findings and relationship to previous literature
Our study is the first of which we are aware to demonstrate, in an experimental model of AF, differential efficacy of class III drugs for AF termination vs. prevention that parallels clinical observations. In addition, we gained insights into the mechanism by which these drugs prevented AF initiation by APCs with the use of epicardial mapping. Efficacy in preventing AF initiation was associated with substantial ERP prolongation at rates comparable to sinus rhythm in man, such that the ERP exceeded the conduction delay that produced reentry under control conditions. Epicardial mapping also provided insights into the failure of sotalol and dofetilide to terminate AF, in that despite increasing the AFCL these drugs failed to reduce the number of reactivation zones per AF cycle in any important way. Allessie et al. [24] have previously shown that vagal AF is maintained by an average of four to six functional reentry wavefronts. Although both dofetilide and sotalol reduced the number of reactivation zones during AF significantly, the number of such zones decreased from just over six to just over five per cycle, an effect insufficient to terminate AF. The differential efficacy of these agents in AF prevention vs. termination is therefore likely related to their reverse use-dependent actions on ERP, such that ERP is more prolonged at slower rates like those of sinus rhythm than during AF. This possibility was suggested by an earlier study in our laboratory [6], but has never before been tested experimentally.

Previous studies have shown that clinically relevant doses of sotalol [6,25] and dofetilide [8] are relatively ineffective in terminating vagotonic AF. Our finding of an important role of the septum in AF initiation are compatible with previous observations in the sterile pericarditis model [26]. In contrast to our findings, Wijffels et al. [27] reported that a variety of antiarrhythmic drugs (hydroquinidine, cibenzoline, flecainide and d-sotalol) terminate chronic AF in goats with tachycardia-induced remodeling, but do not prevent the reinitiation of AF. Reasons for the discrepancy are not clear, but could be related to different species (dog vs. goat), models (vagotonic vs. tachycardia-remodeling AF), or methods of drug infusion (loading and maintenance vs. single infusion rate causing progressive increases in drug concentration). In the Wijffels study, d-sotalol did not appear to alter atrial ERP, which could explain the failure to prevent AF initiation, but still leaves the ability to terminate AF unexplained. One clinical study has demonstrated efficacy for sotalol in preventing early re-initiation of AF by APCs following internal cardioversion of the arrhythmia [28].

4.3 Limitations
The model we used was vagotonic AF. We chose this model primarily because sustained AF can readily be terminated by stopping vagal nerve stimulation, without having to resort to electrical cardioversion. This is an important advantage for a study evaluating vulnerability to AF initiation by premature atrial extrastimuli in a milieu that supports sustained AF, because AF is induced repeatedly over the course of the study. A requirement for repeated electrical cardioversion would introduce a substantial additional variable to the study (electrophysiological effects of repeated cardioversion), and the waiting times necessary for restabilization after each cardioversion would greatly lengthen the study, decreasing feasibility and increasing the risk of systematic time-dependent changes. Although enhanced vagal tone may be important in many clinical cases of AF [29], a prominent role of vagal tone is not observed in the majority of cases. Nonetheless, the responses of vagotonic AF to antiarrhythmic drugs resemble those for chemical cardioversion of recent-onset clinical AF [30], and some of the primary electrophysiological features of vagotonic AF (decreased ERP, decreased ERP rate-adaptation and increased ERP heterogeneity) resemble those observed in tachycardia-induced atrial remodeling [9,31]. The lack of sotalol efficacy observed in the present study has also been reported in patients with vagal AF [32]. Nonetheless, it should be recognized that the arrhythmic substrate in vagal AF likely differs from other animal models and from the substrate in chronic AF in man.

The second important point is that although the present study obtained results with class III drugs very similar to those observed clinically (more efficacy in AF prevention than termination), we do not wish to imply that the mechanisms responsible for differential efficacy in the present study are the only factors underlying the clinical observations. For example, sustained AF causes atrial remodeling. We have observed much lower efficacy of dofetilide in terminating AF in dogs with atrial tachycardia-induced remodeling than in dogs with AF sustained in a heart failure substrate [8]. Thus, some of the inefficacy of class III drugs in terminating sustained AF of longer duration may be due to alterations in the AF substrate caused by tachycardia-induced remodeling. Furthermore, we only evaluated drug effects on the substrate for AF initiation and maintenance. We did not study drug effects on the triggers for initiation of AF, such as APCs, suppression of which could also play a role in the prevention of AF initiation.

We studied two highly-selective IKr-blocking class III drugs. Our findings may not apply to all class III agents. Recent evidence suggests that ibutilide is a particularly useful drug as a primary agent [32,33] or accessory compound [35] in the termination of AF. Ibutilide has been shown superior in AF termination compared to sotalol [33] and procainamide [34]. This discrepancy may be due to an additional mechanism of ibutilide's class III action (enhancement of a plateau Na+ current) [36] in addition to IKr blockade [37].

The limitations of our mapping methods also need to be kept in mind. It appeared in many cases that reactivation involved the atrial septum and was directed towards the region of the initiating extrastimulus. However, endocardial activation (other than at the septum) is not accessed by the epicardial electrode arrays we used, and the resolution of all mapping systems is limited. Consequently, a degree of uncertainty remains regarding the precise pathways of reactivation and the underlying determinants.

Finally, we cannot completely exclude an interaction between sotalol and vagal effects. Sotalol has been shown to inhibit cholinesterase activity [38], and to reduce IK.Ach [39]. However, these actions are seen at concentrations (<300 and 100 µM, respectively) that are >6-fold the average concentrations (~15 µM) achieved by the doses used in the present study [6]. Furthermore, in previous studies we have shown that neither sotalol nor dofetilide at the doses we used alter the vagal frequency-heart rate change relationship [6,7].


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
Acknowledgments
 References
 
We found that sotalol and dofetilide are more effective in preventing AF initiation by APCs than in terminating sustained AF in a vagotonic model. The efficacy in preventing AF induction appeared to be due to strong increases in the AERP at slow rates, such that the maximum conduction delay was insufficient to allow for reentry. At the rapid rates of AF, alterations in atrial reactivation were relatively small, presumably because of reverse use-dependent effects on ERP, and insufficient to terminate AF. These results provide potential insights into the mechanisms by which sotalol and dofetilide prevent AF occurrence more effectively than they terminate the arrhythmia.

Time for primary review 34 days.


   Acknowledgments
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 Acknowledgments
References
 
Supported by the Medical Research Council of Canada and the Quebec Heart Foundation. The authors thank Emma De Blasio for skilled technical assistance and Diane Campeau for secretarial help with the manuscript.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 Acknowledgments
 References
 

  1. Waktare J.E., Camm A.J. Atrial fibrillation begets trouble. Heart (1997) 77:393–394.[Free Full Text]
  2. Nattel S. Newer developments in the management of atrial fibrillation. Am Heart J (1995) 130:1094–1106.[CrossRef][Web of Science][Medline]
  3. The Cardiac Arrhythmia Suppression Trial (CAST Investigators). Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New Engl J Med (1989) 321:406–412.[Abstract]
  4. Lazzara R. From first class to third class: recent upheaval in antiarrhythmic therapy — lessons from clinical trials. Am J Cardiol (1996) 78:28–33.[CrossRef][Web of Science][Medline]
  5. Hohnloser S.H., van de Loo A., Baedeker F. Efficacy and proarrhythmic hazards of pharmacologic cardioversion of atrial fibrillation: prospective comparison of sotalol versus quinidine. J Am Coll Cardiol (1995) 26:852–858.[Abstract]
  6. Wang J., Bourne G.W., Wang Z., Villemaire C., Talajic M., Nattel S. Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness. Circulation (1993) 88:1030–1044.[Abstract/Free Full Text]
  7. Nattel S., Liu L., St-Georges D. Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties. Cardiovasc Res (1998) 37:627–635.[Abstract/Free Full Text]
  8. Li D., Bénardeau A., Nattel S. Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation. Circulation (2000) 102:104–112.[Abstract/Free Full Text]
  9. Gaspo R., Bosch R.F., Talajic M., Nattel S. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation (1997) 96:4027–4035.[Abstract/Free Full Text]
  10. Fareh S., Benardeau A., Thibault B., Nattel S. The T-type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs. Circulation (1999) 100:2191–2197.[Abstract/Free Full Text]
  11. Halinen M.O., Huttunen M., Paakkinen S., Tarssanen L. Comparison of sotalol with digoxin–quinidine for conversion of acute atrial fibrillation to sinus rhythm (The Sotalol–Digoxin–Quinidine Trial). Am J Cardiol (1995) 76:495–498.[CrossRef][Web of Science][Medline]
  12. Ferreira E., Sunderji R., Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy (1997) 17:1233–1237.[Web of Science][Medline]
  13. Reisinger J., Gattereer E., Heinze G., et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol (1998) 81:1450–1454.[CrossRef][Web of Science][Medline]
  14. Southworth M.R., Zarembski D., Viana M., Bauman J. Comparison of sotalol versus quinidine for maintenance of normal sinus rhythm in patients with chronic atrial fibrillation. Am J Cardiol (1999) 83:1629–1632.[CrossRef][Web of Science][Medline]
  15. Juul-Moller S., Edvardsson N., Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation (1990) 82:1932–1939.[Abstract/Free Full Text]
  16. Reimold S.C., Cantillon C.O., Friedman P.L., Antman E.M. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol (1993) 71:558–563.[CrossRef][Web of Science][Medline]
  17. Lee S.H., Chen S.A., Tai C.T., et al. Comparisons of oral propafenone and sotalol as an initial treatment in patients with symptomatic paroxysmal atrial fibrillation. Am J Cardiol (1997) 79:905–908.[CrossRef][Web of Science][Medline]
  18. Benditt D.G., Williams J.H., Jin J., et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. Am J Cardiol (1999) 84:270–277.[CrossRef][Web of Science][Medline]
  19. Sedgwick M.L., Lip G., Rae A.P., Cobbe S.M. Chemical cardioversion of atrial fibrillation with intravenous dofetilide. Int J Cardiol (1995) 49:159–166.[CrossRef][Web of Science][Medline]
  20. Frost L., Mortensen P.E., Tingleff J., Platou E.S., Christiansen E.H., Christiansen N. Efficacy and safety of dofetilide, a new class I.I.I. antiarrhythmic agent, in acute termination of atrial fibrillation or flutter after coronary artery bypass surgery. Dofetilide Post-CABG Study Group. Int J Cardiol (1997) 58:135–140.[CrossRef][Web of Science][Medline]
  21. Falk R.H., Pollak A., Singh S.N., Friedrich T. Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. Intravenous Dofetilide Investigators. J Am Coll Cardiol (1997) 29:385–390.[Abstract]
  22. Norgaard B.L., Wachtell K., Christensen P.D., et al. Efficacy and safety of intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group. Am Heart J (1999) 137:1062–1069.[CrossRef][Web of Science][Medline]
  23. Torp-Pedersen C., Moller M., Bloch-Thomsen P.E., et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. New Engl J Med (1999) 341:857–865.[Abstract/Free Full Text]
  24. Allessie M.A., Lammers W.J.E.P., Bonke F.I.M., Hollen J. Cardiac electrophysiology and arrhythmias. Zipes D.P., Jalife J., eds. (1985) Orlando, FL: Grune & Stratton. 265–276.
  25. Wang J., Feng J., Nattel S. Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide. Circulation (1994) 90:2032–2040.[Abstract/Free Full Text]
  26. Kumagai K., Khrestian C., Waldo A.L. Simultaneous multisite mapping studies during induced atrial fibrillation in the sterile pericarditis model. Insights into the mechanism of its maintenance. Circulation (1997) 95:511–521.[Abstract/Free Full Text]
  27. Wijffels M.C., Dorland R., Allessie M.A. Pharmacologic cardioversion of chronic atrial fibrillation in the goat by class IA, IC, and III drugs: a comparison between hydroquinidine, cibenzoline, flecainide, and d-sotalol. J Cardiovasc Electrophysiol (1999) 10:178–193.[Web of Science][Medline]
  28. Tse H.F., Lau C.P., Ayers G.M. Incidence and modes of onset of early reinitiation of atrial fibrillation after successful internal cardioversion, and its prevention by intravenous sotalol. Heart (1999) 82:319–324.[Abstract/Free Full Text]
  29. Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol (1996) 7:999–1007.[Web of Science][Medline]
  30. Nattel S., Bourne G., Talajic M. Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation. J Cardiovasc Electrophysiol (1997) 8:469–480.[Web of Science][Medline]
  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.[Abstract/Free Full Text]
  32. Yesil M., Bayata S., Postaci N., Yucel O., Aslan O. Cardioversion with sotalol in selected patients with vagally and adrenergically mediated paroxysmal atrial fibrillation. Angiology (1999) 50:729–733.[Web of Science][Medline]
  33. Vos M.A., Golitsyn S.R., Stangl K., et al. Superiority of ibutilide (a new class III agent) over dl-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart (1998) 79:568–575.[Abstract/Free Full Text]
  34. Volgman A.S., Carberry P.A., Stambler B., et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol (1998) 31:1414–1419.[Abstract/Free Full Text]
  35. Oral H., Souza J.J., Michaud G.F., et al. Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. New Engl J Med (1999) 340:1849–1854.[Abstract/Free Full Text]
  36. Lee K.S., Lee E.W. Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel. J Pharmacol Exp Ther (1998) 286:9–22.[Abstract/Free Full Text]
  37. Yang T., Snyders D.J., Roden D.M. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (Ikr) in AT-1 cells, concentration-, time-, voltage-, and use-dependent effects. Circulation (1995) 91:1799–1806.[Abstract/Free Full Text]
  38. Chemnitius J.M., Schahmirzadi F., Gonska B.D., Kreuzer H., Zech R. Indirect parasympathomimetic activity of the class III antiarrhythmic substance d/l-sotalol in vitro: reversible inhibition of cholinesterase isoenzymes from blood and the human central nervous system. Pharmacol Res (1996) 34:193–200.[CrossRef][Web of Science][Medline]
  39. Mori K., Hara Y., Saito T., Masuda Y., Nakaya H. Anticholinergic effects of class III antiarrhythmic drugs in guinea pig atrial cells. Circulation (1995) 91:2834–2843.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
L. Rivard, H. Sinno, A. Shiroshita-Takeshita, G. Schram, T.-K. Leung, and S. Nattel
The pharmacological response of ischemia-related atrial fibrillation in dogs: Evidence for substrate-specific efficacy
Cardiovasc Res, April 1, 2007; 74(1): 104 - 113.
[Abstract] [Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
S. Nattel
Atrial Electrophysiology and Mechanisms of Atrial Fibrillation
Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1_suppl): S5 - S11.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
H.-F. Tse and C.-P. Lau
Electrophysiologic actions of dl-sotalolin patients with persistent atrial fibrillation
J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2150 - 2155.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. Becker, J. C Senges, A. Bauer, K. D Schreiner, F. Voss, W. Kuebler, and W. Schoels
Suppression of atrial fibrillation by multisite and septal pacing in a novel experimental model
Cardiovasc Res, May 1, 2002; 54(2): 476 - 481.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Derakhchan, K.
Right arrow Articles by Nattel, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Derakhchan, K.
Right arrow Articles by Nattel, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?