(Circulation. 1997;95:1945-1953.)
© 1997 American Heart Association, Inc.
Articles |
Verapamil Reduces Tachycardia-Induced Electrical Remodeling of the Atria
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995, and published in abstract form (Circulation. 1995;92[suppl I]:I-754.).
From the Department of Cardiology, Thoraxcenter, University Hospital Groningen; the Department of Clinical Pharmacology, University of Groningen; and the Department of Physiology, University of Limburg, Netherlands.
Correspondence to R.G. Tieleman, MD, Department of Cardiology, Thoraxcenter, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, Netherlands.
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Abstract |
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Background Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time.
Methods and Results To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P<.001, P<.01, and P<.01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P=.03).
Conclusions Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.
Key Words: fibrillation • atrium • remodeling • calcium • electrophysiology
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Introduction |
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Atrial fibrillation is a common arrhythmia with an overall prevalence of 0.4% in the adult population. The prevalence increases with age, being 4% in patients >60 years old.1 2 3 AF has a tendency to become more persistent over time. This is illustrated by the fact that a large percentage of patients with paroxysmal fibrillation eventually will develop chronic AF,1 even in the absence of an underlying cardiovascular disease.4 Also, conversion of AF becomes more difficult with duration of the arrhythmia. Pharmacological cardioversion by intravenously administered antiarrhythmic drugs is less effective if AF has lasted for >24 to 72 hours.5 6 7 8 The success rate of electrical cardioversion9 10 11 and maintenance of sinus rhythm thereafter is also related to the duration of the arrhythmia.10 11 12 13 14
Progression of an underlying disease is one explanation for the relation between duration and intractability of the arrhythmia. Another possible explanation for this phenomenon was suggested recently by Wijffels et al.15 In that study, the concept of electrical remodeling of the atrium by repetitive induction of AF was described in normal, chronically instrumented goats. Artificial maintenance of AF led to a significant shortening of the atrial refractory period, with no major effects on the conduction velocity. The physiological rate-related shortening of atrial refractory periods was reversed and the inducibility and stability of AF increased. Wijffels et al postulated that because of a decreased wavelength of excitation in response to the arrhythmia, "AF begets AF."
The mechanism behind electrical remodeling of the atrium by AF has not yet been clarified. Reduction or prevention of AF-induced electrical remodeling may prevent paroxysmal AF from becoming chronic, and it may abolish or diminish the negative effect of time on the success rates of pharmacological and electrical cardioversion.
Rapid or irregular rhythms are known to be associated with increased intracellular calcium levels in cardiac myocytes.16 17 18 19 20 A recent study by Leistad et al21 showed that administration of verapamil during AF reduced postcardioversion atrial systolic dysfunctioning, whereas the calcium agonist BAY K8644 worsened postfibrillation atrial dysfunction. A relation may exist between postcardioversion atrial "stunning" and AF-induced electrical remodeling, because both processes show a comparable time course of recovery after restoration of sinus rhythm.15 22
The aim of the present study was to investigate whether an increase in intracellular calcium may play a role in the process of electrical remodeling and whether verapamil, by blocking calcium influx, could prevent or reduce electrical remodeling.
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Methods |
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Animal Preparation
All experiments were performed in accordance with the Guidelines for Animal Research and approved by the Ethics Committee on Animal Research of the University of Groningen.
For this study, we used five goats weighing 56±7 kg. With routine
anesthetic and surgical techniques, a right intercostal thoracotomy was
performed and the pericardium opened. A custom-made felt electrode
array (9.0x1.0 cm) containing 11 platinum electrodes (electrode
diameter, 1.5 mm; interelectrode distance, 8 mm) was guided
through the opening between the aortic root and the anterior transverse
sinus. The ends of the electrode strip were sutured to the left and
right atrial appendages (Fig 1
). A second strip
containing 5 platinum electrodes was sutured to the right atrial free
wall and a third strip with 3 electrodes to the right ventricle.
Subsequently, the pericardium was approximated and the thorax closed.
The electrode leads were tunneled subcutaneously to the back of the
neck, where they were exteriorized by a 30-pin connector (OD, 10
mm). Three subcutaneous silver plates (diameter, 25 mm) served as
grounding and indifferent electrodes. A telemetric ECG transmitter
(TA10CTA-D70, Data Sciences Inc) was implanted in a subcutaneous pocket
below the right scapula. Telemetric leads were positioned
subcutaneously in a standard lead 2 configuration. The animals received
ampicillin 1000 mg prophylactically once before surgery and
once daily for 3 days after surgery.
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AV Sequential Pacing Model
Four weeks after surgery, the goats were placed in a cage
(1.5x0.7 m) in the electrophysiology laboratory. The animals had free
access to food and water. A cable from an external stimulator (Nihon
Kohden Cardiac Stimulator CES 3102) and a custom-built multichannel
recording unit (bandwidth, 50 to 400 Hz) was plugged into the
connector in the neck of the goat. The cable and the electrode lead
connector were fastened onto a leather collar. The cables were
connected to the ceiling with a balancing counterweight and a pulley to
allow the goats free movement in their cages. The atria and right
ventricle could be stimulated through any of the implanted atrial and
right ventricular electrodes. To mimic an atrial
tachycardia with 2:1 AV conduction, the atria were paced
with a cycle length of 200 ms and the ventricles with a cycle length of
400 ms, with an AV delay of 100 ms (Fig 2). This pacing
mode prevented both 1:1 AV conduction with rapid
ventricular rates and slowing of the
ventricular rate during verapamil infusion.
During AV pacing, no cannon waves were observed. Cessation of pacing
resulted in instant restoration of sinus rhythm. AV sequential pacing
was continued for 24 hours, interrupted at t=4, 8, and 16 hours for an
electrophysiological study lasting about 30
minutes. After 24 hours of rapid atrial pacing, sinus rhythm was
resumed, and the electrophysiological
measurements were repeated 0, 4, 8, 16, and 24 hours after cessation of
rapid atrial pacing to study the reversibility of the
electrophysiological changes (Fig 3).
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Electrophysiological Measurements
After the goats had recovered from surgery, the AERP was
measured at three different cycle lengths (430, 300, and 200 ms) at
multiple left and right atrial sites by programmed electrical
stimulation. Eight basic drive stimuli were followed by one single
premature stimulus, all of 4 times diastolic threshold,
with current pulses 2 ms in duration. The S1S2
coupling interval was increased in steps of 5 ms, starting from well
within the refractory period. The longest S1S2
coupling interval that failed to result in a propagated atrial response
was taken as the local AERP. Intra-atrial conduction velocity was
determined during regular pacing at intervals of 430, 300, and 200 ms
from either the left or right atrial appendage. The conduction velocity
was calculated from the conduction times recorded at the electrodes
positioned at Bachmann's bundle between the left and right atrial
appendages. The distance between the electrodes used for measurement of
the conduction velocity ranged from 16 to 32 mm (22±6 mm) in
different experiments. Inducibility of AF was defined as the relative
number of pacing sites at which episodes of rapid irregular atrial
activity lasting >1 second was induced by a single extrastimulus.
Inducibility of AF was determined at all basic drive cycle lengths of
430, 300, and 200 ms. The Wenckebach point was determined by continuous
atrial pacing while the cycle length was decreased in steps of 5 ms.
The longest pacing cycle length at which 1:1 AV nodal conduction failed
was taken as the Wenckebach point. QRS duration and PR, QT, and RR
intervals were measured from the telemetric surface ECG
recordings.
Verapamil Infusion
In each goat, the pacing protocol was performed both during
continuous verapamil infusion and during control saline
infusion through a 6F venous catheter in the left or right jugular
vein. Verapamil or saline infusion was started 4 hours
before rapid atrial pacing. Verapamil administration was
started with a loading dose of 0.1 mg/kg for the first 2 minutes,
followed by a continuous infusion of 5
µg·kg-1·min-1
during the rest of the experiment (52 hours). Verapamil
plasma levels were measured twice a day by venous sampling from the
contralateral jugular vein. An interval of at least 1 week was
maintained before the protocol was repeated. Verapamil and
control experiments were performed in random order.
Statistical Analysis
Analysis was performed with the individual electrodes
used as the experimental units. Only electrodes at which determination
of AERP was performed both during control and with
verapamil were used for statistical analysis. Data
are reported as mean±SD. A two-sided probability level of
P
.05 was considered to indicate a statistical difference.
For comparison of continuous variables, either Student's
t test or the Wilcoxon rank-sum test was used. To
evaluate differences between groups of discrete variables, a
two-tailed Fischer's exact test was used. Time series were
analyzed by repeated measurements with a random-coefficient
model. The analysis was performed by SAS statistical software
(SAS, version 6.11).
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Results |
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Electrophysiological Effects of Verapamil
Table 1
shows the effects of infusion of
verapamil on the
electrophysiological baseline
characteristics, ie, before rapid atrial pacing was started. The
average plasma level of verapamil was 190±91 mg/L. As
expected, verapamil increased the Wenckebach point from
244±34 to 388±50 ms (P<.001). This was paralleled by
an increase in the PR interval on the surface ECG.
Verapamil had no statistically significant effects on the
other ECG parameters, the mean AERP, the intra-atrial
conduction velocity, or the inducibility of AF.
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Table 2 lists the ECG parameters in response
to rapid atrial pacing and during the 24 hours after cessation of
pacing. In the control experiments, there were no consistent
changes during the course of the experiment. Continuous infusion
of verapamil maintained the prolongation of the PR
interval and resulted in a slight increase of the RR interval during
day 2 of the experiment.
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Effects of Verapamil on Electrical Remodeling
In the control experiments, 24 hours of rapid atrial pacing
shortened the AERP significantly at all three cycle lengths (Fig 4A). Shortening was most pronounced during the first 4
hours of pacing. Since shortening of AERP was larger at slower than
faster heart rates, in the remodeled state the
physiological rate adaptation of the AERP was
lost.
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During infusion of verapamil, shortening of the AERP still
occurred (Fig 4B
) but significantly less than control. After 8 hours of
rapid atrial pacing, the AERP no longer shortened significantly, and
the AERP after 8 hours was not significantly different from the value
at t=24 hours. Also, after 24 hours of rapid atrial pacing during
verapamil infusion, the physiological
shortening of the AERP was still present.
Reduction of electrical remodeling by verapamil was a
consistent finding. In Table 3, the data as
measured in all five goats are listed. There was no significant change
in intra-atrial conduction velocity or pacing thresholds before and
after rapid atrial pacing in either the control or the
verapamil experiments.
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Time Course of Remodeling
The time course of remodeling was calculated separately for
each pacing site, with the random-coefficient model used for repeated
measurements. It was characterized by the logarithmic function
AERPt=AERPt=0+
xln(t), where t is time
(hours), ln is natural logarithm, and is the time constant of
remodeling. Fig 5 shows the average time course of
remodeling at a BCL of 430 ms, when the time constants from all pacing
sites were taken together. Most of the remodeling occurred during the
first 4 hours of pacing, during infusion of both saline and
verapamil. In each individual goat, a time constant of
remodeling was calculated for every BCL at which the AERP was measured.
During rapid atrial pacing, verapamil reduced the time
constants of remodeling in all goats at all BCLs (Table 4).
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Recovery From Electrical Remodeling After Restoration of Sinus
Rhythm
After termination of rapid atrial pacing, the AERP gradually
prolonged again (Fig 6). In the control experiments, 24
hours after cessation of rapid atrial pacing, the AERP at drive cycle
lengths of 300 or 430 ms was still significantly shorter than baseline
values (P=.001 and P=.0001, respectively; Fig 6A).
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Recovery from electrical remodeling during verapamil
infusion was studied in three goats at a total of 31 atrial sites
(Table 3). During verapamil infusion, the AERP had returned
to its baseline value within <16 hours after cessation of rapid atrial
pacing (Fig 6B). In the verapamil experiments, however, the
AERP had shortened significantly less during rapid atrial pacing.
Therefore, this faster return to baseline values was probably the
result of a different starting point of recovery, especially because
the time constant of recovery of the refractory period was
significantly higher in the control experiments (Fig 7).
Table 4 shows the mean time constants of recovery from electrical
remodeling in the individual goats.
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Inducibility of AF
The inducibility of AF was defined as the relative number of
atrial sites at which a single premature stimulus produced a fast,
irregular atrial response. The inducibility of AF was clearly
correlated with the duration of rapid atrial pacing both during control
and during the administration of verapamil (Fig 8A).
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Before rapid pacing was instituted (t=0), at about 14% of the atrial
sites tested, a short episode of AF was elicited. After 24 hours of
continuous rapid atrial pacing, the vulnerability of the atria to AF
was clearly increased, and now a premature stimulus induced AF in
58±21% (control) and 45±13% (verapamil) of the pacing
sites. After cessation of rapid pacing, during sinus rhythm the
vulnerability of the atria gradually returned to its baseline value
(Fig 8B).
The inducibility of AF at a certain moment of time appeared to be related to the duration of the AERP at that time. Remarkably, however, despite the reduction of electrical remodeling by verapamil, there was only a minimal reduction in the inducibility of AF. The cumulative percentage of atrial sites at which AF could be induced during the 48 hours of the experiment was only slightly reduced in the verapamil group (34% versus 39% during control, P=.03).
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Discussion |
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Main Results
This study demonstrated a reduction in electrical remodeling of the atria by verapamil. Because throughout the experimental protocol the ventricular rate was kept constant (at a cycle length of 400 ms), this effect of verapamil could not have been caused by changes in the ventricular rate.
Despite a significant reduction in electrical remodeling, the increase in inducibility of AF by prolonged atrial pacing was only slightly prevented by verapamil. The diminishment of electrical remodeling by verapamil suggests that the shortening of the AERP is at least in part mediated by an increased calcium influx in the atrial cells during prolonged rapid atrial pacing.
Electrical Remodeling of the Atria
Both animal and clinical studies in which the activation pattern
of AF was mapped23 24 25 26 27 28 29 30 have confirmed the hypothesis of Moe
et al31 32 33 that AF is based on multiple reentrant wavelets
wandering throughout the atria. The wavelength of these wavelets,
defined as the distance traveled by the depolarization wave during the
duration of its refractory period (wavelength=conduction
velocityxrefractory period),34 35 has been thought to be
of major importance for the induction of these reentrant
arrhythmias. The smaller the wavelength of the circulating
wavelets, the more easily AF was induced.26 27 36 37
It has recently been demonstrated that prolonged episodes of AF induced shortening of the atrial refractory period and loss of the physiological rate-related shortening in the absence of changes in conduction velocity.15 This electrical remodeling of the atria results in shorter wavelengths of the multiple wavelets during AF, which could explain the increased stability of AF. It may also play a role in the transition of paroxysmal AF to chronic AF and in the loss of efficacy of antiarrhythmic drugs or electrical shocks to cardiovert AF of longer duration.
The mechanisms behind electrical remodeling of the atria have not yet been clarified. In the present study, we showed that electrical remodeling of the atria can be influenced by the L-type calcium channel blocker verapamil. Although the exact mechanism by which this occurs is unknown, reduction of the electrical remodeling process might prevent or diminish the negative effects of the duration of AF on the success rate of cardioversion of AF. Pharmacological cardioversion in the presence of verapamil may have a higher efficacy, and verapamil might prevent paroxysmal AF from becoming chronic.
Evidence of Electrical Remodeling in Humans
Morillo et al38 showed that shortening of atrial
refractory periods after rapid atrial pacing in dogs for several weeks
could produce sustained AF. Wijffels et al15 showed
progressive shortening of the AERP during artificially maintained AF in
goats and a progressive increase in the duration of episodes of AF
until eventually they became chronic. So far, this has not been shown
in humans. However, as early as 1971, Olsson et al39
demonstrated short right atrial monophasic action potentials in 11
patients immediately after cardioversion of AF. The short duration of
the right atrial monophasic action potential seemed to be related to
the tendency of the arrhythmia to recur. These results were
confirmed by Cotoi et al,40 who repeated the experiments
in 45 patients with AF after conversion to sinus rhythm. They showed a
clear correlation between the duration of the monophasic action
potential and maintenance of sinus rhythm after cardioversion.
Attuel et al41 42 43 demonstrated loss of rate-related
shortening of the atrial refractory period together with a shortening
of the AERP in patients immediately after electrical cardioversion for
AF. These findings of a short atrial refractory period with loss of the
physiological rate adaptation in patients with AF
closely resemble the electrical substrate of the remodeled atria in
animal studies. This suggests that a similar process of electrical
remodeling takes place during AF in humans. It remains to be seen
whether verapamil can also reduce the amount of electrical
remodeling in humans.
Increased Intracellular Calcium and Electrical Remodeling
It is well known that rapid and irregular depolarizations can
increase free intracellular calcium in cardiac myocytes of many
different species.17 44 45 46 47 48 49 A recent article by Piot et
al50 demonstrated that high frequencies of depolarization
in human atrial myocytes induced upregulation of cardiac calcium
currents, resulting in up to 80% increases in calcium influx. These
increased levels of intracellular calcium could shorten the action
potential by opening of calcium-dependent potassium51 or
chloride channels.52 53
An increased intracellular calcium concentration will initially increase contractility.44 54 55 56 Together with the high rate of activation during AF, this explains the increased energy consumption that has been demonstrated.57 However, as shown by Leistad et al,58 after even a few minutes of AF, contractility decreases again, possibly as a result of adaptive mechanisms to prevent excessive energy consumption or calcium overload–induced cell deterioration. One of these mechanisms could be the opening of ATP-dependent potassium channels. These channels, which are normally closed, open under conditions of ATP depletion, such as acute myocardial infarction.59 60 This results in shortening of the action potential and a decrease in contractility, thereby reducing energy consumption. A recent study showed that these ATP-dependent potassium channels can also be opened in response to high heart rates.61 Rapid ventricular pacing immediately before experimentally induced coronary occlusion reduced infarct size by nonischemic activation of ATP-dependent potassium channels. If a similar process takes place in the atria, this may result in tachycardia-induced electrical remodeling. However, recent studies investigating this mechanism did not find any effect of the ATP-dependent potassium channel blocker glibenclamide on fibrillation-induced electrical remodeling of the atria.62 63
Role of Intracellular Calcium During AF
Leistad et al21 suggested that increased
intracellular calcium was related to the postcardioversion atrial
systolic dysfunction after electrical or chemical
cardioversion. They showed that infusion of verapamil
during short episodes of AF significantly reduced the duration of
postcardioversion atrial systolic dysfunction. Thus,
paradoxically, whereas verapamil normally exerted a
negative effect on contractility, during AF it seemed
to help preserve normal contractile function of the atria. Because
myocardial contractility is related to the duration of
the plateau phase of the action potential,56
postcardioversion systolic dysfunction may well be related to
electrical remodeling of the atria. Therefore, the preservation of
contractile function by verapamil during AF may be mediated
by prevention of the tachycardia-induced
electrophysiological changes.
Although in our study verapamil limited the extent of remodeling significantly, it was not completely prevented, suggesting that other mechanisms also might be involved in the process of electrical remodeling of the atrium.
Antiarrhythmic Effects of Verapamil During AF
Verapamil is widely used for control of the
ventricular rate during AF.64 65 66 67 68 69 70 However,
verapamil has no major
electrophysiological effects on the atrial
myocardium.71 72 Therefore, the empirical
finding that in some cases verapamil may convert
paroxysmal68 69 71 or chronic AF73 74 75 has
been thought to be coincidental rather than representing a
real drug effect. An increase in the duration of electrically induced
episodes of AF by verapamil has also been
reported.70 76 In all these studies, verapamil
was administered after onset of the arrhythmia, ie, after
electrical remodeling had already occurred.
The findings of the present study indicate a potential antiarrhythmic effect of verapamil during AF, when it is initiated before onset of the arrhythmia, because it reduces electrical remodeling of the atria.
Despite a reduction in electrical remodeling, only a slight decrease in the inducibility of AF was observed. However, verapamil might increase the success rates of class I and class III drugs in cardioverting AF. This hypothesis is supported by a recent study in which the determinants for pharmacological cardioversion by oral amiodarone were investigated. Concomitant administration of verapamil during amiodarone treatment appeared to be an independent factor that determined the likelihood of cardioversion.77
Limitations of the Study
Rapid AV sequential pacing was performed for only 24 hours. One
cannot extrapolate these results to a longer duration of rapid atrial
rhythms. Experiments in which a high atrial rate is maintained for a
longer period of time are necessary to find out whether
verapamil only delays or can really diminish the
amount of tachycardia-induced electrical remodeling of the
atria.
In the present study, electrical remodeling was induced by rapid atrial pacing at approximately half the depolarization rate of that during AF. Although this resulted in a rate of remodeling similar to that during AF,15 the possibility cannot be excluded that during AF, verapamil has a different effect. Reduction in the rate of remodeling by verapamil administered during AF may be even more pronounced, especially in light of the use-dependent effects of verapamil.78 However, although it is plausible, our results do not predict whether verapamil will exert the same reduction of electrical remodeling during AF.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Van Gelder is supported by grant 94.014 from the Dutch Heart Foundation.
Received August 12, 1996; revision received October 24, 1996; accepted November 12, 1996.
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C. Pandozi, L. Bianconi, L. Calo, A. Castro, F. Lamberti, M. C. Scianaro, G. Gentilucci, and M. Santini Postcardioversion atrial electrophysiologic changes induced by oral verapamil in patients with persistent atrial fibrillation J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2234 - 2241. [Abstract] [Full Text] [PDF]
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C. Sticherling, H. Oral, J. Horrocks, S. P. Chough, R. L. Baker, M. H. Kim, K. Wasmer, F. Pelosi, B. P. Knight, G. F. Michaud, et al. Effects of Digoxin on Acute, Atrial Fibrillation-Induced Changes in Atrial Refractoriness Circulation, November 14, 2000; 102(20): 2503 - 2508. [Abstract] [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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E. G. Manios, E. M. Kanoupakis, G. I. Chlouverakis, M. D. Kaleboubas, H. E. Mavrakis, and P. E. Vardas Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence Cardiovasc Res, August 1, 2000; 47(2): 244 - 253. [Abstract] [Full Text] [PDF]
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H. Nakashima, K. Kumagai, H. Urata, N. Gondo, M. Ideishi, and K. Arakawa Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation Circulation, June 6, 2000; 101(22): 2612 - 2617. [Abstract] [Full Text] [PDF]
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T. Yamashita, Y. Murakawa, N. Hayami, E.-i. Fukui, Y. Kasaoka, M. Inoue, and M. Omata Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium : Electrical Remodeling in Paroxysmal Atrial Tachycardia Circulation, April 25, 2000; 101(16): 2007 - 2014. [Abstract] [Full Text] [PDF]
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J. V. Jayachandran, D. P. Zipes, J. Weksler, and J. E. Olgin Role of the Na+/H+ Exchanger in Short-Term Atrial Electrophysiological Remodeling Circulation, April 18, 2000; 101(15): 1861 - 1866. [Abstract] [Full Text] [PDF]
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W. J. C. Hobbs, S. Fynn, D. M. Todd, P. Wolfson, M. Galloway, and C. J. Garratt Reversal of Atrial Electrical Remodeling After Cardioversion of Persistent Atrial Fibrillation in Humans Circulation, March 14, 2000; 101(10): 1145 - 1151. [Abstract] [Full Text] [PDF]
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A Capucci, G.Q Villani, D Aschieri, A Rosi, and M.F Piepoli Oral amiodarone increases the efficacy of direct-current cardioversion in restoration of sinus rhythm in patients with chronic atrial fibrillation Eur. Heart J., January 1, 2000; 21(1): 66 - 73. [Abstract] [PDF]
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M.P. Ingemansson, B. Smideberg, and S.B. Olsson Intravenous MgSO4alone and in combination with glucose, insulin and potassium (GIK) prolong the atrial cycle length in chronic atrial fibrillation Europace, January 1, 2000; 2(2): 106 - 114. [Abstract] [PDF]
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A. A. Grace and A.J. Camm Voltage-gated calcium-channels and antiarrhythmic drug action Cardiovasc Res, January 1, 2000; 45(1): 43 - 51. [Full Text] [PDF]
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S. Fareh, A. Benardeau, B. Thibault, and S. Nattel The T-Type Ca2+ Channel Blocker Mibefradil Prevents the Development of a Substrate for Atrial Fibrillation by Tachycardia-Induced Atrial Remodeling in Dogs Circulation, November 23, 1999; 100(21): 2191 - 2197. [Abstract] [Full Text] [PDF]
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R. G. Tieleman, Y. Blaauw, I. C. Van Gelder, C. D. J. De Langen, P. J. de Kam, J. G. Grandjean, K. W. Patberg, K. J. Bel, M. A. Allessie, and H. J. G. M. Crijns Digoxin Delays Recovery From Tachycardia-Induced Electrical Remodeling of the Atria Circulation, October 26, 1999; 100(17): 1836 - 1842. [Abstract] [Full Text] [PDF]
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A. De Simone, G. Stabile, D. F. Vitale, P. Turco, M. Di Stasio, F. Petrazzuoli, M. Gasparini, C. De Matteis, R. Rotunno, and T. Di Napoli Pretreatment with verapamil in patients with persistent or chronic atrial fibrillation who underwent electrical cardioversion J. Am. Coll. Cardiol., September 1, 1999; 34(3): 810 - 814. [Abstract] [Full Text] [PDF]
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E. G. Daoud, P. Marcovitz, B. P. Knight, R. Goyal, K. C. Man, S. A. Strickberger, W. F. Armstrong, and F. Morady Short-Term Effect of Atrial Fibrillation on Atrial Contractile Function in Humans Circulation, June 15, 1999; 99(23): 3024 - 3027. [Abstract] [Full Text] [PDF]
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S. Zhang, Z. Zhou, Q. Gong, J. C. Makielski, and C. T. January Mechanism of Block and Identification of the Verapamil Binding Domain to HERG Potassium Channels Circ. Res., May 14, 1999; 84(9): 989 - 998. [Abstract] [Full Text] [PDF]
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S. Nattel Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation Cardiovasc Res, May 1, 1999; 42(2): 298 - 308. [Abstract] [Full Text] [PDF]
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M. Hara, A. Shvilkin, M. R Rosen, P. Danilo Jr., and P. A Boyden Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms Cardiovasc Res, May 1, 1999; 42(2): 455 - 469. [Abstract] [Full Text] [PDF]
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M. Courtemanche, R. J Ramirez, and S. Nattel Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model Cardiovasc Res, May 1, 1999; 42(2): 477 - 489. [Abstract] [Full Text] [PDF]
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L. Yue, P. Melnyk, R. Gaspo, Z. Wang, and S. Nattel Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation Circ. Res., April 16, 1999; 84(7): 776 - 784. [Abstract] [Full Text] [PDF]
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L.-P. Lai, M.-J. Su, J.-L. Lin, F.-Y. Lin, C.-H. Tsai, Y.-S. Chen, S. K. S. Huang, Y.-Z. Tseng, and W.-P. Lien Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca2+-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: An insight into the mechanism of atrial electrical remodeling J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1231 - 1237. [Abstract] [Full Text] [PDF]
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S.-H. Lee, F.-Y. Lin, W.-C. Yu, J.-J. Cheng, P. Kuan, C.-R. Hung, M.-S. Chang, and S.-A. Chen Regional Differences in the Recovery Course of Tachycardia-Induced Changes of Atrial Electrophysiological Properties Circulation, March 9, 1999; 99(9): 1255 - 1264. [Abstract] [Full Text] [PDF]
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S. Nattel, L. Liu, and D. St-Georges Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties Cardiovasc Res, March 1, 1998; 37(3): 627 - 635. [Abstract] [Full Text] [PDF]
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