Effect of Verapamil and Procainamide on Atrial Fibrillation–Induced Electrical Remodeling in Humans
Background Atrial fibrillation (AF) shortens the atrial effective refractory period (ERP) and predisposes to further episodes of AF. The purpose of this study was to determine the effect of verapamil and procainamide on these manifestations of AF-induced electrical remodeling.
Methods and Results In adult patients without structural heart disease, the atrial ERP was measured before and after AF after pharmacological autonomic blockade and administration of verapamil (17 patients), procainamide (10 patients), or saline (20 patients). AF was then induced by rapid pacing. Immediately on AF conversion, the post-AF ERP was measured at alternating drive cycle lengths of 350 and 500 ms. In the saline group, the pre-AF and first post-AF ERPs at the 350-ms drive cycle length were 206±19 and 179±27 ms (P<.0001), respectively, and at the 500-ms drive cycle length, the values were 217±16 and 183±23 ms, respectively (P<.0001). There was a similar significant shortening of the first post-AF ERP in the procainamide group. In the verapamil group, however, there was no difference between the pre-AF and the first post-AF ERP at the 350-ms (226±15 versus 227±22 ms, P=.8) or 500-ms (230±17 versus 232±20 ms, P=.6) drive cycle length. During determinations of the post-AF ERP, 105 secondary episodes of AF were unintentionally induced in 12% of verapamil patients compared with 90% and 80% of saline and procainamide patients (P<.01 versus verapamil).
Conclusions Pretreatment with the calcium channel antagonist verapamil, but not the sodium channel antagonist procainamide, markedly attenuates acute, AF-induced changes in atrial electrophysiological properties. These data suggest that calcium loading during AF may be at least partially responsible for AF-induced electrical remodeling.
Experimental and clinical studies have demonstrated a progressive shortening of atrial refractoriness in response to brief or chronic episodes of pacing-induced atrial fibrillation (AF).1 2 3 4 A study in dogs demonstrated that the shortening of the atrial effective refractory period (ERP) induced by rapid atrial pacing can be blocked by verapamil and accentuated by hypercalcemia, suggesting that calcium loading may be responsible for this type of atrial electrical remodeling.3 However, no prior studies have assessed the effects of calcium channel blockade by verapamil or sodium channel blockade by procainamide on atrial electrical remodeling induced by AF. Therefore, the purpose of this study was to determine the effects of intravenous verapamil and procainamide on the atrial electrophysiological changes induced by AF in humans.
Characteristics of Study Population
The subjects of this study were 47 patients referred to the University of Michigan Hospital for electrophysiological testing and/or radiofrequency catheter ablation. Exclusion criteria included a baseline rhythm of AF, atrial flutter, or atrial tachycardia; current therapy with a calcium channel antagonist; a contraindication to the use of propranolol, atropine, verapamil, or procainamide; the presence of structural heart disease as determined by a transthoracic echocardiogram; the inability to achieve a stable electrode catheter position in the right atrial appendage throughout the study protocol; or the inability to induce AF by pacing. Among 58 patients who were screened, 47 patients did not have any of these exclusion criteria. There were 28 men and 19 women, and their mean age was 40±16 years (±SD). The mean left ventricular ejection fraction was 0.62±0.05. The electrophysiology procedure was performed to evaluate and treat paroxysmal supraventricular tachycardia in 46 patients and to evaluate syncope in 1 patient.
At the time of the electrophysiology procedure, three patients were being treated with a β-adrenergic antagonist. In the other 44 patients, all antiarrhythmic drug therapy was discontinued at least five half-lives before the procedure. After informed consent was obtained, three 7F sheaths (Daig Corp) were placed in a femoral vein, and three quadripolar electrode catheters that had an interelectrode spacing of 2-5-2 mm (Mansfield EP) were positioned in the high right atrium, His-bundle position, and right ventricular apex. Patients were sedated with intravenous midazolam and received 3000 U intravenous heparin. Leads V1, I, II, and III and the intracardiac electrograms were recorded (Mingograf 7; Siemens-Elema AB). Pacing was performed with a programmable stimulator (Bloom Associates).
The study protocol was approved by the Human Research Committee and was performed with the patients’ consent after completion of the clinically indicated portion of the electrophysiology procedure (Fig 1⇓). Quadripolar electrode catheters were positioned in the right atrial appendage and against the right atrial free wall. In the atrial appendage, the two distal electrodes were used for pacing, and the two proximal electrodes were used to record the local right atrial electrogram. Autonomic blockade was achieved by infusion of 0.04 mg/kg atropine and 0.2 mg/kg propranolol over ≈5 minutes.5 The mean patient weight was 79±18 kg, and the mean atropine and propranolol doses were 3.1±0.7 and 15.6±3.6 mg, respectively.
The initial 37 patients received saline or verapamil in a random order. The remaining 10 consecutive patients received intravenous procainamide. There were no differences in clinical characteristics among patients given verapamil, saline, or procainamide (Table 1⇓).
Verapamil was administered at a dose of 0.1 mg/kg over ≈3 minutes. An infusion of 0.005 mg · kg−1 · min−1 verapamil was started 5 minutes later and continued until the protocol was completed.6 7 The mean total verapamil dosage was 14.7±2.7 mg, administered over 27.8±4.9 minutes. Procainamide was infused at a rate of 50 mg/min until the atrial ERP increased by ≈10%; then, it was continued at a rate of 2 mg/min. The mean total procainamide dosage was 344±155 mg, administered over 25.4±5.6 minutes. The mean procainamide and N-acetylprocainamide plasma concentrations at the completion of the study protocol were 5.9±2.3 and 0.3±0.2 μg/mL, respectively. Saline was administered as a bolus of 0.1 mL/kg, followed by an infusion of 0.005 mL · kg−1 · min−1.
The mean atrial capture threshold was 0.9±0.2 mA. Pacing was performed at three times threshold. The atrial ERP was measured at the right atrial appendage using an incremental technique in 5-ms steps at basic drive cycle lengths of 350 and 500 ms for eight beats with a 1-second pause between pacing trains. The ERP was defined as the longest S1S2 coupling interval that failed to result in atrial capture. The pre-AF atrial ERP was measured after pharmacological autonomic blockade three times at each drive cycle length and averaged. The pre-AF ERP was then remeasured ≈3 minutes after the saline, verapamil, or procainamide bolus.
AF was induced by bursts of atrial pacing at cycle lengths of 160 to 190 ms. The mean duration of pacing required to induce sustained AF was 19±11 seconds. After ≥5 minutes of AF, the AF was allowed to spontaneously convert to sinus rhythm. If the AF did not spontaneously convert after ≥10 minutes, electrical cardioversion was performed. Blood pressure was measured by sphygmomanometry 1 minute after spontaneous or electrical conversion of AF. The pre- and post-AF right atrial pressure was measured in 22 patients (8 saline, 10 verapamil, and 4 procainamide). Twenty episodes of pacing-induced AF converted spontaneously, and 27 episodes required electrical cardioversion (Table 2⇓). Other than a longer sinus cycle length and atrial-His interval in the verapamil patients, there were no significant differences among the pacing and hemodynamic parameters in the verapamil, saline, and procainamide groups (Table 2⇓).
Immediately on conversion to sinus rhythm and until the atrial ERP returned to within 5 ms of the baseline atrial ERP or ≥20 measurements had been made, the post-AF atrial ERP was measured at alternating drive cycle lengths of 350 and 500 ms from the right atrial appendage. To assess the temporal changes in the ERPs, the time from conversion of AF to determination of each post-AF atrial ERP was measured to the nearest second. Whenever secondary episodes of AF were unintentionally induced during measurement of the post-AF ERP, the time at which the AF was induced was noted and the duration of the episode was measured to the nearest second. In 28 patients, a secondary episode of AF was persistent and did not revert to sinus rhythm until electrical cardioversion after 10 to 19 minutes. In these patients, only the data collected before the onset of the persistent secondary episode of AF were used for analysis.
To confirm a stable catheter position, the right atrial pacing threshold was remeasured after each electrical cardioversion and on completion of the study protocol. The capture threshold changed after cardioversion of the initial pacing-induced AF in 4 patients (2 saline, 2 verapamil), and these patients were therefore excluded from the study. To confirm a stable degree of autonomic blockade, the sinus cycle length and atrial-His intervals were remeasured on completion of the study.
Control Subjects in Whom AF Was Not Induced
To control for the possible effects of repeated refractory period determinations on the atrial ERP and to assess for a steady state verapamil effect, the atrial ERP was measured repeatedly after autonomic blockade with and without intravenous verapamil in a separate group of 10 subjects. This control group included patients referred to the University of Michigan Hospital for electrophysiological testing and/or radiofrequency catheter ablation. There were 4 men and 6 women, and their mean age was 52±15 years. The mean left ventricular ejection fraction was 0.61±0.09. The study protocol was performed after the clinically indicated electrophysiology procedure. The atrial ERP was measured at alternating basic drive cycle lengths of 350 and 500 ms, in a manner identical to the study population, for a total of 20 determinations.
Continuous variables are expressed as mean±1 SD. Continuous variables were compared with a paired t test, and categorical variables were compared by χ2 analysis. Serial measurements of the post-AF atrial ERP were analyzed by ANOVA with repeated measures. Linear interpolation of the plotted serial measurement data was used to generate data for analysis of temporal changes of the atrial ERP, in both the control and study patients.8 9 Nonlinear regression analysis was used to correlate the duration of secondary episodes of AF to the logarithm of the time to induction of secondary AF. A value of P<.05 was considered significant.
Pre-AF Atrial ERPs
After autonomic blockade, there was no significant difference in the right atrial ERP among the verapamil, procainamide, and saline groups at a drive cycle length of 350 ms (verapamil, 210±10 ms; procainamide, 201±16 ms, saline, 207±11 ms; P=NS) or at a drive cycle length of 500 ms (verapamil, 213±19 ms; procainamide, 210±21 ms; saline, 218±17 ms; P=NS). After drug or saline administration, the atrial ERP at a drive cycle length of 350 ms was 226±15 ms in the verapamil group (P<.0001 versus before verapamil), 226±18 ms in the procainamide group (P<.001 versus before procainamide), and 206±19 ms in the saline group (P=.9 versus before saline). At a drive cycle length of 500 ms, the atrial ERP was 230±17 ms after verapamil (P=.01 versus before verapamil), 233±20 ms after procainamide (P<.001 versus before procainamide), and 217±16 ms after saline (P=.8 versus before saline) (Figs 2⇓ and 3⇓).
Before induction of AF, the right atrial ERP at a drive cycle length of 350 ms was significantly longer after verapamil (226±15 ms) and procainamide (226±18 ms) than after saline (206±19 ms, P<.001 versus verapamil/procainamide groups). A similar relationship in the atrial ERP was found at a drive cycle length of 500 ms (verapamil, 230±17 ms; procainamide, 233±20 ms; saline, 217±16 ms; P<.001 versus verapamil/procainamide groups). Before induction of AF, the atrial ERPs in the verapamil and procainamide groups did not differ significantly (P=.8).
Changes in the Post-AF Atrial ERPs
There was no difference in the duration of induced AF, inclusive of the time required for atrial pacing, among the verapamil (12.9±6.4 minutes), procainamide (12.7±4.7 minutes), and saline (10.1±5.2 minutes) groups (P=NS). At drive cycle lengths of 350 and 500 ms, the post-AF atrial ERP was measured 216 times in the verapamil group (12±5 times per patient), 103 times in the procainamide group (10±7 times per patient), and 197 times in the saline group (10±7 times per patient).
There was a significant shortening of the first atrial ERP measured at a drive cycle length of 350 ms immediately after conversion of AF in the procainamide group (13±10%) and in the saline group (13±9%, P=.9 versus procainamide) but not in the verapamil group (Table 3⇓). A similar degree of shortening of the first post-AF atrial ERP was observed at a drive cycle length of 500 ms in the procainamide (9±7%) and saline (16±10%, P=.2 versus procainamide) groups but not in the verapamil group (Table 4⇓). A significant reduction in the atrial ERP persisted until the fourth measurement of the post-AF atrial ERP in the procainamide group and until the fifth measurement in the saline group at a drive cycle length of 350 ms (Table 3⇓). A similar significant reduction persisted in the procainamide and saline groups until the seventh measurement at a drive cycle length of 500 ms (Table 4⇓).
Within the verapamil, procainamide, and saline groups, there were no differences in the post-AF atrial ERPs at drive cycle lengths of 350 or 500 ms between patients requiring electrical cardioversion of the pacing-induced AF compared with patients in whom AF converted spontaneously.
Temporal Recovery of the Atrial ERP
The temporal recovery of the atrial ERP at a drive cycle length of 350 ms and 500 ms in the verapamil, procainamide, and saline patients is described in Figs 2⇑ and 3⇑. A significant reduction in the post-AF atrial ERP compared with the pre-AF atrial ERP persisted for 4.0 and 3.0 minutes at a drive cycle length of 350 ms in the procainamide and saline patients, respectively (P=.8), and for 5.0 and 6.0 minutes, respectively, at a drive cycle length of 500 ms (P=.8). In the verapamil group, there was no significant change in the atrial ERP at drive cycle lengths of 350 or 500 ms after conversion of pacing-induced AF. There was no significant difference in the pattern of temporal recovery of the post-AF atrial ERP between the basic drive cycle lengths of 350 and 500 ms in the verapamil, procainamide, and saline groups.
Induction of Secondary Episodes of AF
During the measurement of the post-AF atrial ERP in the verapamil, procainamide, and saline groups, 105 secondary episodes of AF unintentionally were induced in 28 patients. Secondary episodes of AF occurred in 2 of 17 (12%) verapamil patients, in 8 of 10 (80%) procainamide patients (P<.001 versus verapamil), and 18 of 20 (90%) saline patients (P=.7 versus procainamide, P=.001 versus verapamil). Three (0.3±0.7 episodes per patient), 28 (3.1±3.2 episodes per patient), and 74 (3.0±3.0 episodes per patient) episodes of secondary AF were induced in the verapamil, procainamide, and saline patients, respectively (P<.005 for verapamil versus saline and procainamide; P=.7 for saline versus procainamide).
Among 38 measurements of the first post-AF atrial ERP at the two drive cycle lengths of 350 and 500 ms in the saline group, 24 determinations (63%) resulted in a secondary episode of AF at a mean interval of 55±18 seconds after conversion of the primary episode of AF. For the second to the ninth measurements of the post-AF ERP in the saline group, 13 of 30 (43%), 10 of 26 (38%), 11 of 24 (46%), 7 of 20 (35%), 4 of 20 (20%), 3 of 18 (17%), 1 of 14 (7%) and 1 of 7 (14%) determinations resulted in secondary episodes of AF at 138±91, 225±98, 260±106, 293±103, 332±104, 377±112, 392±108, and 396±62 seconds after conversion of the primary episode of AF, respectively (P<.001, r=.9; Fig 4⇓). A similar inverse relationship between the time interval to induction of secondary episodes of AF and the frequency of secondary episodes was noted in verapamil (P=.001, r=.9) and procainamide (P<.001, r=.9) patients (Fig 4⇓).
Secondary episodes of AF lasted 2.3±3.7 minutes, with a range of 2 seconds to 19 minutes. The mean duration of secondary episodes of AF in verapamil, procainamide, and saline patients was 5.6±3.9, 5.5±4.5, and 3.8±4.2 minutes, respectively (P=NS). There were no significant differences in the percentage of episodes of secondary AF requiring electrical cardioversion (verapamil, 44%; procainamide, 14%; saline, 16%; P=NS).
There was a significant inverse logarithmic relationship between the time to induction of secondary episodes of AF and the duration of these episodes in the procainamide (P=.04, r=.5) and saline (P<.001, r=.5; Fig 5⇓) patients. This relationship was not present in the verapamil patients (P=.5, r=.1).
Repeated Measurement of the Atrial ERP in the Absence of AF
In control patients in whom AF was not induced, the atrial ERP was measured 20 times in 10 patients, at alternating drive cycle lengths of 350 and 500 ms, after autonomic blockade and before and after the administration of verapamil. The serial atrial ERP measurements with and without verapamil at drive cycle lengths of 350 and 500 ms are summarized in Figs 6⇓ and 7⇓. There were no significant changes in the atrial ERP at a basic drive cycle length of 350 or 500 ms in the absence of verapamil. After verapamil, the atrial ERP at a drive cycle length of 350 ms increased from 213±12 to 220±11 ms (P<.001), and from 239±27 to 251±22 ms (P<.001) at a drive cycle length of 500 ms. Subsequent postverapamil measurements of the ERP did not differ significantly from the ERP measured immediately after the initial verapamil dosage at a drive cycle length of 350 or 500 ms.
The main finding of this study was that the acute changes in atrial electrophysiological properties that occur after a brief episode of pacing-induced AF are markedly attenuated by calcium channel blockade with verapamil but are unaffected by sodium channel blockade with procainamide. Pretreatment with intravenous verapamil completely prevents shortening of the atrial ERP in response to pacing-induced AF and markedly reduces the likelihood of inducing secondary episodes of AF. Although procainamide lengthened the atrial ERP, as would be expected with blockade of sodium channels,10 it did not attenuate the shortening of atrial refractoriness that occurs after AF. The divergent effects of calcium channel and sodium channel blockade on AF-induced shortening of the atrial ERP, despite a similar degree of lengthening of the atrial ERP, demonstrate that prevention of the acute changes in atrial electrophysiological properties after AF by verapamil is not attributable simply to a nonspecific prolongation in atrial refractoriness. These findings suggest that AF-induced atrial electrical may be at least in part caused by calcium loading in response to AF.
Atrial Wavelength and Propensity for Secondary Episodes of AF
High-density mapping studies of AF in humans suggest that a determinant of AF is the presence of a critical number of wandering reentrant atrial wavelets.11 12 Wavelength has been defined as the distance traveled by the depolarizing wave front during the refractory period (wavelength=conduction velocity×refractory period).13 If the atrial wavelength is relatively short, then a greater number of wave fronts can circulate through the atria and AF may be sustained.14 15 The findings of this study confirm the results of a prior study that demonstrated that a brief episode of AF shortens the atrial refractory period, thereby shortening the wavelength and increasing the propensity for the induction of secondary episodes of AF.4 Pretreatment with verapamil prevented AF-induced shortening of the atrial ERP, thereby preventing shortening of the atrial wavelength in response to AF and dampening the propensity of AF to facilitate additional episodes of AF.
Temporal Recovery of Atrial Properties
After spontaneous or electrical conversion to sinus rhythm, the electrophysiological effects of AF persisted for several minutes. The temporal recovery of AF-induced changes in atrial electrophysiological properties was manifest as a progressive increase in the atrial ERP, a progressive decrease in vulnerability to the reinduction of AF, and a progressive shortening of episodes of reinduced AF. In patients pretreated with verapamil, but not procainamide, these AF-induced changes in electrophysiological properties were blunted. These data imply that pacing-induced AF transiently alters atrial properties and that this effect persists after conversion to sinus rhythm, diminishes with time, is attenuated by calcium channel blockade, and is unaffected by sodium channel blockade.
Mechanisms by Which Verapamil May Prevent Atrial Electrical Remodeling
Verapamil may prevent atrial electrical remodeling by minimizing AF-induced changes in atrial structural and electrophysiological properties. Verapamil may prevent acute AF-induced shortening of the atrial ERP by directly or indirectly inhibiting the delayed rectifier current (IK),16 17 the transient brief outward potassium current (Ibo),18 19 the inward rectifier channel (IK1),20 and the ATP-sensitive outward potassium channel (IK-ATP).21 22 Also, by limiting rate-related cellular calcium loading, verapamil may prevent structural changes in atrial myocytes that may contribute to electrical remodeling.3
In this study, propranolol and atropine were administered to minimize the possibility that the measured changes in atrial refractoriness were caused by changes in vagal or adrenergic tone.23 24 A constant degree of autonomic tone was confirmed by the absence of any significant differences in the sinus cycle length or atrial-His interval before and after completion of the study protocol in saline patients in whom AF was induced.
Effects of Verapamil on Atrial Refractoriness
In the control patients in whom AF was not induced, the atrial ERP was repeatedly measured during the infusion of verapamil. After the 0.1 mg/kg bolus of verapamil, there was a significant lengthening of the atrial ERP of ≈4%, with no further significant changes in the subsequently measured ERPs. These results confirm a steady state effect of verapamil on the atrial ERP. In addition, in the verapamil patients in whom AF was induced, there were no significant changes in the sinus cycle length or the atrial-His interval before and after completion of the protocol, providing further confirmation that the electrophysiological effects of verapamil were stable during the study protocol.
In an experimental study, Goette et al3 assessed the effect of 7 hours of pacing at 800 bpm on the atrial ERP in dogs after pharmacological autonomic blockade. The atrial ERP was measured at 30-minute intervals during the period of rapid pacing in control animals and after pretreatment with glibenclamide, an IK-ATP channel blocker, and after pretreatment with verapamil and calcium gluconate. In the control, calcium gluconate, and glibenclamide animals, rapid pacing significantly shortened the atrial ERP by ≈12%, which is similar to the results of the present study. In animals pretreated with verapamil, there was no significant change in the atrial ERP after rapid pacing. The results of the present study extend these experimental findings to the setting of pacing-induced AF in humans and also demonstrate a significant reduction in the propensity for secondary episodes of AF by verapamil.
A limitation of this study is that the findings may be specific to pacing-induced AF in subjects with structurally normal atria and may not apply to spontaneous episodes of AF or to episodes of AF occurring in patients with heart disease. A second limitation is that only the right atrial ERP was measured, and therefore the responses of other areas of the atrium to pacing-induced AF and verapamil are unknown. A third limitation is that the possibility of a synergistic interaction between verapamil and propranolol and/or atropine cannot be ruled out. A fourth limitation is that divergent hemodynamic responses during AF in the saline and procainamide groups may have contributed to shortening of the post-AF atrial ERP. A fifth limitation is that despite pharmacological autonomic blockade and the absence of a significant change in the sinus cycle length or atrial-His interval, the sudden onset of pacing-induced AF may increase circulating catecholamines, which may have contributed to shortening of atrial refractoriness in the saline and procainamide groups. Finally, conditioning pacing trains, which have been demonstrated to be useful in improving the reproducibility of ventricular refractory period determination,25 were not used in this study. The use of conditioning pacing trains would have precluded the frequent measurements of refractoriness needed to detect temporal changes.
In conclusion, AF-induced electrical remodeling in humans is manifest by a shortening of atrial refractoriness and a heightened propensity for the reinduction of AF after conversion to sinus rhythm. AF-induced shortening of the atrial ERP may be at least in part mediated by calcium loading and the interaction between an elevated cytosolic calcium concentration and potassium channel activity. Frequent26 27 and irregular28 depolarization of atrial myocytes during AF may result in cytosolic calcium loading. Blockade of the L-type calcium channel by verapamil, but not sodium channel blockade by procainamide, may reduce calcium loading during AF, minimize potassium channel activity, and, as demonstrated in this study, blunt AF-induced atrial electrical remodeling. Whether verapamil might be clinically effective in preventing immediate recurrence of AF after conversion of AF remains to be determined. In addition, the effects of potassium channel blockade on AF-induced electrical remodeling remain to be determined.
- Received February 6, 1997.
- Revision received April 8, 1997.
- Accepted April 18, 1997.
- Copyright © 1997 by American Heart Association
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