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Cardiovascular Research 2000 47(2):244-253; doi:10.1016/S0008-6363(00)00100-0
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence

Emmanuel G. Manios, Emmanuel M. Kanoupakis, Gregory I. Chlouverakis, Mihail D. Kaleboubas, Hercules E. Mavrakis and Panos E. Vardas*

Department of Cardiology, University Hospital of Heraklion, P.O. Box 1352 Stavrakia, Heraklion, Crete, Greece

* Corresponding author. Tel.: +30-81-392-706; fax: +30-81-542-055 cardio{at}med.uoc.gr

Received 15 November 1999; accepted 4 April 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Objective: To study the reversibility of atrial electrical remodeling and its relation with recurrence in post-conversion chronic atrial fibrillation (CAF) patients. Methods: In 28 drug-free CAF patients (mean AF duration 41±39 months) electrically converted to sinus rhythm effective refractory period (ERP) at 500 ms, monophasic action potential at 90% of repolarization (MAPd90) at five cycle lengths (CL, 350, 400, 450, 500, 600 ms), and P wave duration were measured three times: within the interval 5–20 min post-conversion, 24 h and 1 month later. Fifteen subjects with no history of AF and normal atrial structure served as a control group. Patients were followed up for recurrence for 1 month; 12 relapsed. Results: ERP changed from 205±20 to 243±31 to 241±24 ms (P<0.001), attaining a level comparable to that of the controls (238±21 ms) within 24 h. MAPd90 significantly (P<0.001) increased (from 175±11 to 190±19 to 191±10 ms at CL 350 ms and 201±12 to 234±20 and 233±23 ms at CL 600 ms) also reaching control levels within 24 h. MAPd90 exhibited an abnormal adaptation to rate only in the first evaluation. P wave duration was prolonged (137±33 ms) and exhibited a slower course of shortening (130±32 to 123±27 ms, P<0.001), reaching control levels within 1 month. Patients with higher values of MAPd90 at CL 350 in the immediate post-conversion period were more likely to relapse (P<0.005). Conclusions: ERP and repolarization shortening as a result of CAF are reversed within 24 h after conversion, while P wave duration reduces more slowly. Post-conversion MAPd90 values contain prognostic information for recurrence.

KEYWORDS Atrial function; Defibrillation; Remodeling; Supraventr. arrhythmia

This article is referred to in the Editorial by A. Bollmann (pages 207–209) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Data from recent animal and human studies have shown that atrial fibrillation (AF) results in a marked shortening of the atrial effective refractory period (ERP) and loss of its physiological ability to adapt to rate [1–14]. These effects, known as atrial electrical remodeling, have been implicated in the self-perpetuation of AF or its early recurrence [1,8,15]. Atrial electrical remodeling resolves with time after conversion to sinus rhythm [1,2,8,9,11–14].

There are a few studies dealing with changes in human atrial electrical behavior as a consequence of long periods of spontaneous AF [6,10,12–14]. These, however, do not adequately elucidate the time course of the resolution of atrial electrical remodeling after conversion to sinus rhythm and its relation to arrhythmia recurrences. Since data from experimental studies cannot necessarily be transferred to humans and existing human studies do not provide definitive data, there is a clear need for a further exploration of the time course of atrial electrical remodeling resulting from spontaneous chronic AF and its relation to arrhythmia recurrence.

The purpose of the present study was to explore the time course of changes in atrial ERP, repolarization and conduction time in drug-free, chronic AF patients following successful low energy atrioversion, and to investigate whether the atrial electrical remodeling differs between relapsed and non-relapsed patients.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 References
 
2.1 Patient selection
Patients with chronic AF (more than 3-months’ duration) were included in the study. The diagnosis of AF was made by means of the surface electrocardiogram (ECG), based on the following criteria: (a) fluctuation of the baseline without regular P or F waves, and (b) totally irregular RR intervals. Diagnosis had to be validated by intracardiac recordings showing irregular atrial activity not separated by an isoelectric line or discrete atrial electrograms with irregular intervals between them. AF was considered as chronic when it was repeatedly documented on sequential 12-lead ECGs, without any intervening periods of sinus rhythm. Duration of AF was assessed at entry into the study, based on medical records and existing ECGs.

Exclusion criteria were age more than 75 years, previous cardiac surgery, and pacemaker or defibrillator implantation. No patient received any antiarrhythmic drug, digitalis or verapamil during the study. When it was necessary to control ventricular rate in the pre-cardioversion period, oral metoprolol and/or diltiazem were used. These drugs were discontinued at least five half-lives before cardioversion, while patients were hospitalized.

Fifteen subjects in sinus rhythm, with structurally normal atria and no known organic heart disease, served as a control group. These patients were evaluated in our laboratory for paroxysmal atrioventricular nodal reentrant tachycardia, atrioventricular tachycardia or syncope. None had a history of AF. They were also free of antiarrhythmic drugs for five half-lives before their entry into the study.

Thyroid dysfunction and abnormal electrolyte concentrations were ruled out in all subjects.

Maximal left atrial diameter and left ventricular ejection fraction were assessed in all subjects according to the standard methods [16,17].

Signed written consent was obtained from all subjects before their participation in the study. The study was approved by the Ethics Committee of our Institution. This investigation conforms with the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997;35:2–3).

2.2 Cardioversion
Electrical conversion to sinus rhythm was attempted while patients with AF were on an acenocoumarol regimen that resulted in an international normalized ratio between 2.5 and 3.5 for at least 1 month. Cardioversion was performed in the electrophysiology laboratory with an intracardiac electrical shock ranging from 6 to 15 J, under general anesthesia with intravenous propofol. For this purpose a specially designed balloon-guided catheter for energy delivery (ALERTTM, EP MedSystems, Inc., USA) was inserted via the right femoral vein and advanced to the right cardiac cavities. The ECG was monitored continuously during the procedure until a stable sinus rhythm was established and recordings were stored on an optical disk (EP Lab, Quinton, Inc, USA).

2.3 Measurements of P wave duration
After cardioversion, when a stable sinus rhythm was established, the P wave was validated as an indicator of atrial conduction time. Two independent observers measured P wave duration from the earliest onset to the end of atrial activity in ECG lead II at a paper speed of 100 mm/s. Gain was set at 20 mm/mV. Mean values derived from three consecutive good quality beats were assessed. Measurements were repeated in the same manner during the subsequent patient evaluations just before the stimulation protocol. Interobserver and intraobserver variation were less than 5%.

2.4 ERP assessment
After conversion to a stable sinus rhythm, a second catheter (MAP Pacing, EP Technologies, Inc, USA) capable of simultaneous pacing and monophasic action potential (MAP) recording was advanced within the right atrial appendage. After stable placement in a site where a satisfactory MAP signal was continuously recorded and a diastolic stimulation threshold less than 1.5 mA was found, atrial ERP was assessed by the incremental method at a basic cycle length of 500 ms. Eight-beat stimulation trains at twice the diastolic threshold were used, with a 2-s pause between them. A starting coupling interval of 150 ms was selected for the extrastimulus and was increased initially in 10-ms steps. When atrial capture was noted stimulation was repeated, starting from a coupling interval 20 ms lower than that where atrial capture occurred and increasing in steps of 2 ms. The ERP was defined as the longest S1–S2 coupling interval that failed to result in atrial capture.

2.5 MAP recordings and measurements
After assessment of atrial ERP, MAP signals were recorded during pacing at five basic cycle lengths: 600, 500, 450, 400 and 350 ms. To achieve a steady state, pacing was started at the longest cycle length (600 ms) and kept stable for 1 min. Then the cycle length was decreased, without interruption, to the next pre-selected cycle length for 1 min of regular pacing. This sequence was repeated until the cycle length of 350 ms was achieved. MAP signals were preamplified (MAP Preamplifier, EP Technologies, Inc, USA) and processed through a bandpass filter in the zone 0.005–400 Hz. (EP Express, Quinton, USA). MAP recordings and simultaneous external ECG were stored on an optical disk. Two independent observers analyzed signals manually for cycle length and MAP repolarization at 90% (MAPd90) according to the standard method [18], at a paper speed of 200 mm/s. Mean MAPd90, derived from the last three signals at each cycle length drive, was evaluated. Intraobserver and interobserver variations were less than 5%. MAP signals with amplitude less than 10 mV were excluded since they were considered unsatisfactory. An example of MAP recordings obtained from the right atrial appendage is given in Fig. 1.


Figure 1
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  		Fig. 1 Superimposed steady-state monophasic action potential (MAP) signals recorded in the same patient from within the right atrial appendage at three (400, 500, 600) paced cycle lengths. These signals were recorded within the interval 5–20 min after conversion to sinus rhythm and 24 h later. Note prolongation of MAP 24 h post-conversion.

 
2.6 Follow up studies
All subjects underwent the above described stimulation protocol. Measurements of all studied parameters in the immediate post-conversion period were made in the interval 5–20 min after conversion. The stimulation procedure was repeated 24 h and 1 month post-cardioversion only in the AF group. No antiarrhythmic medication, digitalis, verapamil or diltiazem was prescribed during this period. After discharge patients were monitored for AF recurrence on a daily basis up to the final evaluation using a transtelephonic monitoring system (Medtronic Inc., USA). As recurrence was considered the presence of AF in the patient's ECG at the time of contact. In the case of relapse, when necessary, the sinus rhythm was restored by internal cardioversion and antiarrhythmic medication was given according to the treating physician's preference. Relapsed patients were not evaluated in the next step of the study.

2.7 Data analysis
Continuous variables are summarized as mean±S.D. Comparisons of clinical characteristics between the groups were performed with t-tests for continuous and {chi}2-tests for categorical variables. To assess differences in the course of MAPd90 at the various cycle lengths, measured three times over a period of 1 month, between the patients and the normal subjects, a multivariate repeated measures analysis of variance was used, with two within-factors (cycle length, temporal) and one between-factor (group). Differences in ERP and P wave duration were also assessed with repeated measures ANOVA with one within-factor (temporal) and one between (group). Interactions among the factors were also assessed. Assessment of temporal changes of the studied parameters was based on data from patients who had a complete set of measurements throughout the study (i.e. non relapsed patients).

A separate sub-analysis with status (relapse or not) being the grouping factor was carried out to determine whether there were significant differences in MAPd90, ERP, P wave duration and clinical parameters between the patients who relapsed and those who did not. A stepwise logistic regression model was used to determine whether any of the variables that were measured on the first evaluation (age, AF duration, atrial dimension, P wave duration, ERP and MAPd90) contained independent prognostic information about relapse. A Kaplan–Meier product limit estimate curve was also constructed to show the progression of recurrences. All statistical tests were performed at the 5% level of significance.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 References
 
The stimulation protocol was successfully completed in all 15 subjects in the control group. Of the total of 39 patients with chronic AF who were initially recruited, internal cardioversion established sinus rhythm in 34 patients, but immediate reinitiation of arrhythmia occurred in three of these. In two patients it was not possible to record satisfactory MAP signals from within the right atrial appendage and these patients were excluded from the study. One additional patient was excluded from further analysis because of unwanted AF induction during ERP assessment at the first evaluation. Thus, at first stimulation the protocol was applied successfully to 28 patients. The second evaluation 24 h post-conversion was applied to 25 patients, since three patients had relapsed spontaneously in the meantime. Sixteen patients were included in the third evaluation, since AF recurred in nine additional patients during the follow up. In eight of these recurrence occurred during the first week post-conversion (Fig. 2).


Figure 2
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  		Fig. 2 Kaplan–Meier curve indicating progression to atrial fibrillation during the first post-conversion month.

 
The pertinent clinical features of the control subjects and of the patients who were studied are shown in Table 1.


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  		Table 1 Clinical characteristics of patients and control subjectsa

 
3.1 Changes in refractoriness and P wave duration
ERP measurements at a drive cycle length of 500 ms were significantly shorter in patients than in controls in the immediate post-conversion period (205±20 vs. 238±21 ms, P<0.001). Twenty-four hours later ERP had increased significantly (243±31 ms, P<0.001) to levels comparable to those of the controls. One month later ERP remained virtually unchanged (241±24 ms).

P wave duration showed an opposite time course, since it decreased gradually from 137±33 ms in the immediate post-conversion period to 130±32 and 123±27 ms in the subsequent studies (P<0.001). This last value was not significantly different from that of the control subjects (115±17 ms).

Fig. 3 depicts temporal changes in refractoriness and P wave duration.


Figure 3
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  		Fig. 3 Temporal changes of effective refractory period-ERP (A) and P wave duration (B). Data are derived from 16 patients who did not relapse during follow-up. The rightmost error bar of each graph represents control values (n=15). See text for more details.

 
3.2 MAPd90 — temporal changes
Significant temporal (P<0.001), cycle (P<0.001) and interaction (P=0.003) effects were observed in the group of patients. MAPd90 increased significantly 24 h post-conversion and remained practically unchanged a month later. However, these changes were not the same at all studied cycle lengths; the increment was more pronounced at the higher cycle lengths. These data are plotted in Figs. 1 and 4Go.


Figure 4
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  		Fig. 4 Temporal changes in MAPd90 and comparisons of MAPd90 between patients and controls in the immediate post conversion period (A), 24 h (B) and 1 month later (C). The data plotted are derived from the 16 patients who did not relapse during follow-up.

 
3.3 MAPd90 — comparisons with control subjects
Significant cycle (P<0.001), group (P=0.001), and interaction (P<0.001) effects between control subjects and patients in the immediate post cardioversion period were found regarding MAPd90. In control subjects MAPd90 increased steadily with the paced cycle length, starting from mean values of 182±20 ms at cycle length 350 ms and reaching 242±21 ms at cycle length 600 ms. In contrast, AF patients in the immediate post cardioversion period had lower values of MAPd90 at all studied cycle lengths (range 175±11 ms at 350 ms to 201±12 ms at 600 ms). These differences between control subjects and AF patients were more pronounced at higher cycle lengths, demonstrating an abnormal adaptation of MAPd90 to rate in the AF patients.

In the subsequent stimulation studies 24 h and a month post-cardioversion the magnitude and the pattern of MAPd90 curves did not differ from those of normal subjects. Thus, the temporal changes in the AF patients that were described previously attenuated the group effect that was observed in the immediate post-conversion period. Data from these observations are presented in Fig. 4.

3.4 Atrial electrical remodeling in relapsed and non-relapsed patients
There were no significant differences in ERP (206±16 vs. 204±20 ms), P wave duration (136±9 vs. 137±32 ms) and the other studied clinical parameters between relapsed and non-relapsed patients (Table 2). In contrast, MAPd90 values at short cycle lengths (350, 400 ms) in the immediate post-conversion period in relapsed patients were significantly (P<0.05) longer than that of the non-relapsed patients. This difference was borderline non-significant (P=0.052) 24 h later in the same number of patients. Data from these comparisons were derived from relapsed and non-relapsed patients who had measurements in both observations (9 and 16, respectively) and are plotted in Fig. 5. Logistic regression analysis showed that, among the parameters that were measured on the first evaluation, only MAPd90 contained significant prognostic information about relapse. Furthermore, of the cycle lengths studied, MAPd90 at 350 ms was the sole independent prognostic variate (P=0.0049). A first estimation of the cut-off value, based on this sample, that best discriminated between the two groups was 195 ms. Indeed, only 8 out of the 24 patients with MAPd90 ≤195 ms relapsed within the time interval we studied, as opposed to four out of the four with MAPd90 >195 ms. This criterion had a sensitivity of 33%, a specificity of 100% and an overall accuracy of 71%.


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  		Table 2 Clinical characteristics of relapsed and non-relapsed patientsa

 

Figure 5
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  		Fig. 5 The significant difference (P<0.05) in MAPd90 between relapsed (circles) and non-relapsed patients (squares) in the immediate post-conversion period (A) became marginally non-significant (P=0.052) 24 h later (B). See text for details.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 References
 
The main findings of this study are as follows:
1. Spontaneous chronic AF in humans results in a shortening of atrial ERP and MAP duration, measured in situ within 5–20 min after electrical conversion to sinus rhythm. MAPd90 shortening is more pronounced at higher cycle lengths, suggesting an abnormal adaptation of repolarization to cycle length. Shortening of ERP and MAPd90 resolves during the next 24 h and exhibits a more or less normal adaptation curve. There is no further resolution of atrial electrical remodeling beyond 24 h, since no changes in refractoriness and repolarization time were found a month later.
2. Chronic AF in humans results in prolongation of P wave duration. This change exhibits a slower resolution course that extends beyond the first 24 h after restoration of sinus rhythm. This abnormality was restored within a month.
3. Most recurrences of AF were observed within the first week after conversion to sinus rhythm.
4. MAPd90 measured within 20 min post cardioversion was the sole variable among those studied to contain prognostic information about relapse. Relapsed patients exhibited longer duration of MAPd90 at short cycle lengths, when compared with the patients who did not relapse in the immediate post-conversion period.

4.1 Atrial electrical properties following cardioversion of chronic atrial fibrillation
Several previous studies have shown that sustained rapid atrial rates, such as those found in AF, result in significant shortening of refractoriness and repolarization and loss of their physiological ability to adapt to rate [1–14]. Changes in refractoriness have been shown to be reversible in animal models [1–3,5,19]. In goats, electrical remodeling of the atria was completely reversed within 1 week after restoration of sinus rhythm [1]. However, animal data cannot accurately be transferred to humans. So far, not many studies have examined the effects of chronic AF on human atrial electrical properties and the available data are conflicting [10,12–14]. In a study [10] involving patients with chronic AF or atrial flutter 15–30 min after conversion to sinus rhythm, shortening and maladaptation of MAPd90 at cycle lengths from 400 to 800 ms were found. These researchers did not study the time course of these abnormalities. Significant shortening of MAPd90 was not confirmed in a recent study [13] including post-cardioversion chronic AF patients. In the same study the ‘normal’ pattern of atrial refractoriness dispersion was not present, while a marked shortening of right atrial appendage ERP was observed. In our opinion, that study did not have the statistical power to detect the probable effect of atrial remodeling on the repolarization because of the small number of patients studied (n=13) and the observed wide variation of MAP duration. Pandozi et al. [12] recently studied refractoriness in patients with persistent AF after electrical low energy conversion to sinus rhythm. They evaluated their patients 5 min after conversion and 4 weeks later and showed a significant increase in atrial ERP during this interval, with a normal or nearly normal adaptation of refractoriness to rate in the majority of patients. However, the rate and the extent of atrial electrical remodeling resolution were not adequately assessed in that study, since it lacked a control group and the interval between evaluations was long. In a recent study including 19 chronic AF patients, Yu et al. [14] found impaired adaptation to rate and significant shortening of refractoriness. ERP changes reached a stable level on the third day after cardioversion in that study.

The data from the present study are based on observations of MAPd90 and ERP changes derived from three serial stimulation procedures within a 1-month period and comparisons with control subjects. They show that chronic AF shortens atrial refractoriness and repolarization. Although shortening of MAPd90 and its abnormal adaptation to rate as a result of chronic AF have been previously described in humans [6,10], the present study provides new data about the reversal of these abnormalities and its parallel course with changes in refractoriness. This finding is consistent with the concept that alterations in refractoriness are due to changes in action potential duration [20]. Our data indicate that, even in chronic AF patients, changes in refractoriness and repolarization are reversible within 24 h post-cardioversion. This finding is not consistent with that of a smaller study by Yu et al. [14], who observed that full reversal of refractoriness changes occurred later in the third post-conversion day. However, they used repeated high-energy external direct current shocks to convert AF and only 25% of the initially recruited patients were able to enter the study.

P wave duration reflects the global conduction time within the atria. Previous studies showed prolongation of atrial conduction time as a result of atrial electrical remodeling [14,21–24]. In animal models Gaspo et al. [22] reported conduction slowing with remodeling and showed that it developed more slowly than ERP changes. In a recent human study [24] Tse et al. demonstrated prolongation of P wave duration in humans after paroxysmal or chronic AF. These authors did not investigate the reversibility of this effect. Yu et al. [14] found a greater P wave duration and intraatrial conduction times in post cardioversion chronic AF patients when these parameters were compared with those of a control group. Although they observed a significant reduction in P wave duration they were unable to rule out a late recovery to control levels. Our data also show that conduction time within the atrium, as represented by the P wave, is involved in the electrical remodeling induced by chronic AF. Furthermore they show that P wave duration returns to levels not different from those of controls within a month. To our knowledge, this is the first human study to provide evidence that some of the P wave prolongation associated with AF is due to arrhythmia and is therefore a reversible feature.

4.2 Atrial electrical remodeling in relapsed and non-relapsed patients
Since some of our patients had a recurrence of AF we were able to examine whether the features of atrial electrical remodeling differed between relapsed and non-relapsed patients and to look for electrophysiological parameters with prognostic significance, a possibility that has been discussed by other researchers. A small early study by Olsson et al. [6] suggested that AF patients in whom post-conversion MAPd90 was shorter than 207 ms were likely to relapse, while two recent preliminary reports [25,26] related fibrillatory cycle length (an indirect indicator of atrial refractoriness) to AF recurrence. Our findings showed that MAPd90 in the immediate post-conversion period contained prognostic information. At short cycle lengths relapsed patients had significantly longer MAPd90 values compared with those who did not relapse. In particular, we found that patients who failed to shorten steady state MAPd90 at the cycle length of 350 ms to values less than 195 ms were more likely to relapse.

Although this finding looks rather paradoxical it can be explained, at least in part, as a consequence of the inability of chronic AF patients to adapt MAPd90 to rate. The loss of rate adaptation is such that MAPd90 decreases caused by chronic AF are maximal at higher cycle lengths and less at shorter cycle lengths [10,18]. Probably our relapsed patients exhibited a more abnormal adaptation curve, in that they were unable to shorten MAPd90 at short cycle lengths to levels comparable to those of non-relapsed patients. Since this difference was only borderline non-significant 24 h later we can speculate that these patients may also exhibit a slower resolution course regarding this abnormality. The number of our patients was not large enough to allow us a definitive conclusion. In addition, these findings are derived from a single atrial site and they may not be representative of the whole atrial tissue. Thus, further investigation is required to confirm this point.

4.3 Recurrence of AF and the role of atrial electrical remodeling
Conventionally, the presence of a critical number of wandering reentrant atrial circuits has been suggested as a determinant for AF [27–30]. The wavelength of the reentrant circuit has been defined as the distance traveled by the depolarizing wavefront during the refractory period: (wavelength=conduction velocityxrefractory period) [27]. If the wavelength is short, then a greater number of wandering circuits can arise in a given mass of atrium and AF may be sustained, since the critical number of circuits is likely to be achieved. Patients with longer refractoriness and repolarization time are less likely to develop the critical number of reentrant circuits, since the wavelength they develop at a similar conduction velocity is longer. In contrast, when atrial refractoriness is markedly shortened and atrial conduction time is prolonged, susceptibility to AF recurrence is high [29,30]. However, other factors, such as spatial heterogeneity of electrophysiological properties, abnormal adaptation to rate or others still undefined, may play a role [20].

Atrial electrical remodeling, manifested as shortening of atrial refractoriness and loss of its ability to adapt to rate, has attracted research interest because it has been suggested as one of the mechanisms responsible for the self-perpetuation of AF or its early recurrences [1,8,15]. Tieleman et al. [31] followed up 61 patients and evaluated the daily incidence of AF recurrence. They found a peak of incidence within the first 5 days after cardioversion. These researchers had hypothesized the relationship between recurrence and remodeling, but they did not study the changes in the electrophysiological parameters of their patients and how they were related with recurrence.

In this study, we similarly observed most recurrences of AF within the first week post-conversion. In addition, we studied the resolution course of atrial electrical remodeling and found that abnormalities in atrial refractoriness and repolarization in the right atrial appendage were reversed within 24 h post-conversion. Only 11% of our patients relapsed within this interval, as compared with the 32% who relapsed later. Thus, our findings suggest that the absolute shortening of refractoriness contributes to the mechanisms that are responsible for the early recurrence of AF only during the first day after conversion. We cannot rule out the possibility that the reversal of refractoriness and repolarization remodeling is slower in other atrial sites, as some studies have suggested [5,19]. However, in humans Yu et al. [14] found a similar resolution course from a study of the distal coronary sinus and right atrial appendage sites.

Abnormal adaptation to rate has been suggested as a factor that facilitates recurrence. This abnormality, which decreases ERP or MAPd90 at slower rates, may favor induction of AF by premature beats during sinus rhythm [20]. We found abnormal adaptation to rate of MAPd90 in the immediate post-conversion period but this abnormality was not present 24 h later in the non-relapsed patients. Relapsed patients in the immediate post-conversion period exhibited less shortening of MAPd90, especially at shorter cycle lengths. Since this finding became statistically non-significant 24 h later, we could speculate that relapsed patients exhibit a more abnormal and probably slowly normalizing adaptation curve. Although it is not clear whether the prognostic significance of this criterion is of clinical value, it can serve as an argument supporting the hypothesis that abnormal adaptation to rate is related with early AF recurrence.

More importantly, in this study we found that atrial conduction time is prolonged by chronic AF and exhibits a slower recovery course. We did not find P wave duration to be an independent prognostic factor for recurrence. However, since P wave prolongation coincided with recurrence in most of our patients we believe that our data suggest an important contribution of conduction abnormalities to early recurrences.

Apart from the above evidence, our data in conjunction with those of other studies may be helpful in explaining the actions of calcium blockers (verapamil or diltiazem) in preventing recurrence. In their study, Tieleman et al. [31] showed that pretreatment with calcium-lowering agents reduced recurrence rates in their patients during the first post-conversion month. These authors speculated that these drugs act by reducing or rapidly reversing the remodeling that results from chronic AF. Our data do not support such an explanation, since they show that most remodeling features are reversed within the first post-conversion day and that only 11% of our patients recurred during this interval. Furthermore, the more slowly reversible conduction abnormality has been related with down regulation of sodium channels [32] and verapamil was not found to have any effect on atrial conduction properties [33]. Existing data suggest that pretreatment with verapamil attenuates remodeling effects on refractoriness as a result of short periods of rapid atrial pacing or induced AF [2,9,33,34]. So far, there is no clear proof that this drug attenuates these electrophysiological abnormalities when it is administered in patients with established long standing AF. Two recent reports [35,36] indicate that administration of verapamil attenuates remodeling effects in patients with long standing AF. In contrast, Lee et al., in a dog model study [33], found that verapamil did not prevent long-term tachycardia induced changes of electrophysiological parameters. But even if verapamil is effective under these circumstances, our data suggest that it could prevent only a rather small percentage of very early recurrences. A closer inspection of the Tieleman's findings reveals similar recurrence rates in both of their treatment groups during the first week and shows that the effect of calcium blockers becomes evident in the second post-conversion week. In our opinion this finding could be explained by the documented action of verapamil in preventing the remodeling of atrial tissue by single or accumulated atrial premature beats that are encountered in most of these post-conversion patients.

It is possible that our data could contribute to the development of strategies for properly timed modifications of the electrophysiological parameters involved in the remodeling process with a view to reducing early AF recurrence. For example, an electrical intervention such as temporary multisite atrial pacing, which can attenuate conduction abnormalities, might prove clinically useful if used during the first post-conversion week. Furthermore, our data underline the need to reassess the use of other antiarrhythmic drugs, especially those which affect atrial conduction, during the post-conversion period and to examine how they interact with the course of the remodeling resolution.

4.4 Study limitations
In order to have a reproducible site for the serial stimulation studies, we restricted our observations to a single right atrial appendage site. Since the primary endpoint of this study was to investigate the possible relation between changing atrial electrical properties and the spontaneous recurrence of AF, we had to avoid unwanted induction of AF that could disturb steady-state conditions and bias our study population. Thus, we assessed refractoriness only at the cycle length of 500 ms. Data about effects of propofol on atrial electrical properties are insufficient. However, some studies did not find any significant effect on atrial refractoriness [37–39]. The MAP recordings used in this study were subject to the usual limitations of that technique [18,40]. Dispersion of refractoriness and repolarization, as well as anisotropy, have been described when many atrial structures were studied [5,12,19]. These issues were beyond the scope of this study. The ideal control group for this study would have been the patients themselves, if it had been possible to obtain measurements of the studied parameters before the onset of AF. Instead, we used subjects with normal atrial structure and no history of atrial fibrillation, as did most of the similar studies that have been published [10,13,14,24].

However, we believe that this study could still provide a clear insight into the relation between AF and refractoriness, repolarization, and their changes over time.


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
References
 
This study, which sought a relation between early recurrence and atrial electrical remodeling, provides data confirming that spontaneous chronic AF in humans results in significant shortening of refractoriness and repolarization and in an abnormal adaptation of repolarization to rate. These abnormalities are reversible within 24 h after restoration of sinus rhythm. Repolarization shortening at short cycle lengths is less in patients who relapse and is probably a predictor for recurrence. More importantly, AF prolongs conduction time in the atria and remodeling of atrial conduction is slowly reversible. Our observations may have an impact on the therapeutic strategy to avoid early AF recurrences. They imply that the first post-conversion days are critical for sinus rhythm preservation in AF patients. Furthermore, they indicate that, apart from the absolute refractoriness shortening, other remodeling features, such as abnormal adaptation to rate and conduction slowing, may be of greater importance for arrhythmia recurrence. Attenuation of these abnormalities by either pharmacological or electrical interventions (e.g. multisite atrial pacing) during the first days of the post-conversion period may prevent the immediate or early recurrence of AF.

Time for primary review 28 days.


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

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G. Michael, L. Xiao, X.-Y. Qi, D. Dobrev, and S. Nattel
Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis
Cardiovasc Res, February 15, 2009; 81(3): 491 - 499.
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