(Circulation. 1997;96:1542-1550.)
© 1997 American Heart Association, Inc.
Articles |
Effect of Verapamil and Procainamide on Atrial Fibrillation–Induced Electrical Remodeling in Humans
From the Division of Cardiology, Department of Internal Medicine, University of Michigan (Ann Arbor).
Correspondence to Emile Daoud, MD, University of Michigan Hospital, Division of Cardiology; B1-F245, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0022.
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Abstract |
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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.
Key Words: calcium • fibrillation • remodeling • electrophysiology
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Introduction |
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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.
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Methods |
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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.
Electrophysiological Testing
At the time of the electrophysiology procedure, three
patients were being treated with a ß-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).
Study Protocol
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.
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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).
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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).
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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.
Statistical Analysis
Continuous variables are expressed as mean±1 SD. Continuous
variables were compared with a paired t test, and
categorical variables were compared by 
2
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.
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Results |
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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).
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P<.01,
¥P<.05, P>.05 (NS) versus after drug or
saline.
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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).
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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).
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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).
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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.
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Discussion |
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Main Findings
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 velocityxrefractory
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
Autonomic Tone
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.
Previous Studies
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.
Study Limitations
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.
Conclusions
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.
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