Abstract
Changes in ventricular refractoriness and repolarization after successful electrical cardioversion to sinus rhythm in persistent atrial fibrillation (AF) patients were studied.
In 33 AF patients with controlled ventricular response, right ventricular ERP (VERP) at three basic cycle lengths (600, 500, 400 ms), as well as monophasic action potential duration (MAPd90) at a drive cycle length of 500 ms, were measured just before, 20 min and 24 h after cardioversion.
VERP at 600 ms changed from 241 ± 19 ms to 249 ± 21 ms to 253 ± 24 ms (P < 0.001), VERP at 500 ms changed from 234 ± 19 ms to 242 ± 22 ms to 246 ± 23 ms (P < 0.001) and VERP at 400 ms changed from 224 ± 20 ms to 232 ± 23 ms to 236 ± 24 ms (P < 0.001). MAPd90 changed from 247 ± 16 ms preconversion to 252 ± 17 ms 20 min postconversion to 253 ± 19 ms after 24 h (P < 0.05).
Change in refractoriness at 500 ms was well correlated with change of mean RR interval before and 20 min after conversion (R = 0.616, P < 0.001). There was no correlation between RR variability and VERP before cardioversion.
Restoration of sinus rhythm in persistent AF patients is followed by significant effects on ventricular refractoriness and repolarization related to cycle length change. No AF related ventricular electrophysiological alterations were found.
Introduction
Rapid atrial rate during atrial fibrillation (AF) has an impact on atrial electrophysiology, a process known as atrial electrical remodelling [1–,5]. Apart from rapid atrial rates, AF may cause the ventricles to beat in an irregular and rapid rhythm. From the relevant literature it appears that very rapid ventricular rates in certain animal species and in humans can result in structural and electrophysiological remodelling [6–,11].
However, most patients with persistent or permanent AF have a controlled ventricular response at rest, although during exercise or normal daily activities they exhibit an inappropriate increase in ventricular rate while at the same time the RR intervals remain irregular. So far, it is largely unknown if these irregular and transient rapid ventricular rhythms can result in changes in ventricular electrical properties. It is possible that alterations in ventricular refractoriness and repolarization in persistent AF patients after restoration of sinus rhythm may be involved in the ventricular arrhythmogenic mechanisms that are responsible for the ventricular arrhythmias frequently present in AF patients [6,,12].
The aim of this study was to ascertain if restoration of sinus rhythm in persistent AF patients with a controlled ventricular response is associated with changes in ventricular electrophysiology, and to explore their time course.
Methods
Patient selection
We considered patients with persistent AF (AF lasting more than seven days) who had been referred to our department for cardioversion, as eligible. Exclusion criteria were age more than 80 years and pacemaker or defibrillator implantation. Patients who had received amiodarone in the previous three months were also excluded. Digitalis, other class I or III antiarrhythmic drugs had to be discontinued for at least one month before cardioversion. Diltiazem as well as beta-blockers were allowed for ventricular rate control.
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 persistent when it was repeatedly documented on sequential 12-lead ECGs, without any intervening periods of sinus rhythm.
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 [13,,14].
Signed written consent was obtained from all the 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.
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 2.0 and 3.0 for at least one month. Cardioversion was performed in the electrophysiology laboratory with a single 10 J intracardiac electrical shock (ALERT™, EP MedSystems, Inc., USA), under general anaesthesia with intravenous propofol as has been described elsewhere [15]. The ECG was monitored continuously during the procedure until stable sinus rhythm was established and the recordings were stored on an optical disk (EP Lab, Quinton, Inc, USA).
ERP assessment
A second catheter (MAP Pacing, EP Technologies, Inc, USA), capable of simultaneous pacing and monophasic action potential (MAP) recording, was inserted percutaneously and positioned in the right ventricular apex. 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, ventricular ERP (VERP) was assessed by the incremental method in steps of 2 ms at three basic cycle lengths (600, 500 and 400 ms) as has been described elsewhere [4]. A 2 min interval was allowed between ERP determinations at each cycle length.
MAP recordings and measurements
After assessment of ventricular ERP, MAP signals were recorded during pacing at the basic cycle length of 500 ms. MAP recordings and simultaneous external ECG were stored on an optical disk. Two independent observers analyzed signals manually for MAP repolarization at 90% (MAPd90), according to the standard method [16], at a paper speed of 200 mm/s. Mean MAPd90, derived from the last three signals, was evaluated. Intraobserver and interobserver variations were less than 5%.
Serial stimulation studies – RR interval measurements
All subjects underwent the above described stimulation protocol three times: before cardioversion and 20 min and 24 h postconversion. The administration of heart rate control drugs was continued for 24 h after conversion, in order to ensure stable study conditions.
During the minute before VERP determination at the cycle length of 500 ms RR intervals were measured. Fifty consecutive RR intervals were used for mean RR (RRpre) determination during AF. For mean RR (RRpost) assessment during sinus rhythm 20 consecutive RR intervals were considered. Change of mean RR interval (δRR) was assessed (RRpost – RRpre). Change of VERP at the same interval was also determined (δERP).
All patients underwent continuous ambulatory Holter monitoring 3 h before cardioversion. Monitoring was performed using a 3-channel bipolar recorder and was automatically evaluated after digitization by an Elatec analyzer V3.03 (Ela Medical, Paris, France). Each 3 h recording was subjected to computerized analysis that provided the SD of the RR intervals (SD RR) and the root mean square SD of the RR intervals (RMSSD RR).
Statistical analysis
Continuous variables are summarized as mean ± SD. Temporal changes of ERP and MAPd90 were assessed with repeated ANOVA measures. Linear regression analysis methods were used to investigate the association of refractoriness, repolarization or δERP with cycle length change (δRR) or variation (SD RR, RMSSD RR).
All statistical tests were performed at the 5% level of significance.
Results
Of the 43 patients who fulfilled the inclusion criteria and underwent electrical conversion, 37 were successfully converted. In four patients the arrhythmia recurred within the study period. A complete set of refractoriness measurements was obtained in 33 subjects while satisfactory MAP recordings were obtained from 29 patients. Clinical and demographic characteristics of these patients are presented in Table 1.
Clinical and demographic characteristics of patients
| Age (y) | 64 ± 8 |
| Sex (m/f) | 19/14 |
| Left atrial diameter (mm) | 42 ± 4 |
| Left ventricular ejection fraction (%) | 58 ± 8 |
| AF duration (mo) | 16 ± 27 |
| Drugs for ventricular rate control | |
| Diltiazem | 12 |
| Beta-blocker | 9 |
| None | 12 |
| Heart disease | |
| Hypertension | 16 |
| Mitral valve disease | 5 |
| Ischaemic heart disease | 4 |
| None | 8 |
| Age (y) | 64 ± 8 |
| Sex (m/f) | 19/14 |
| Left atrial diameter (mm) | 42 ± 4 |
| Left ventricular ejection fraction (%) | 58 ± 8 |
| AF duration (mo) | 16 ± 27 |
| Drugs for ventricular rate control | |
| Diltiazem | 12 |
| Beta-blocker | 9 |
| None | 12 |
| Heart disease | |
| Hypertension | 16 |
| Mitral valve disease | 5 |
| Ischaemic heart disease | 4 |
| None | 8 |
Clinical and demographic characteristics of patients
| Age (y) | 64 ± 8 |
| Sex (m/f) | 19/14 |
| Left atrial diameter (mm) | 42 ± 4 |
| Left ventricular ejection fraction (%) | 58 ± 8 |
| AF duration (mo) | 16 ± 27 |
| Drugs for ventricular rate control | |
| Diltiazem | 12 |
| Beta-blocker | 9 |
| None | 12 |
| Heart disease | |
| Hypertension | 16 |
| Mitral valve disease | 5 |
| Ischaemic heart disease | 4 |
| None | 8 |
| Age (y) | 64 ± 8 |
| Sex (m/f) | 19/14 |
| Left atrial diameter (mm) | 42 ± 4 |
| Left ventricular ejection fraction (%) | 58 ± 8 |
| AF duration (mo) | 16 ± 27 |
| Drugs for ventricular rate control | |
| Diltiazem | 12 |
| Beta-blocker | 9 |
| None | 12 |
| Heart disease | |
| Hypertension | 16 |
| Mitral valve disease | 5 |
| Ischaemic heart disease | 4 |
| None | 8 |
Mean RR interval before cardioversion was 730 ± 112 ms (range 570–1002 ms) and 20 min after cardioversion it changed to 885 ± 108 ms (P < 0.001), (range 692–1132 ms). A further, non-significant increase to 902 ± 94 ms was observed 24 h later (P = 0.41).
Changes in refractoriness and repolarization
A statistically significant change in refractoriness at all studied cycle lengths was noted when preconversion VERP was compared with that measured 20 min following successful cardioversion. A further insignificant change was observed within the next 24 h (Table 2, Fig. 1).
Monophasic action potential recordings obtained from the right ventricular apex during determination of effective refractory period (VERP) at a drive cycle length of 500 ms. Panel A: During atrial fibrillation monophasic action potential duration at 90% of repolarization (MAPd90) was 221 ms and VERP 208 ms with evidence of capture at a coupling interval equal to 210 ms. Panel B: Twenty minutes after sinus rhythm restoration MAPd90 increased to 253 ms and a premature stimulus delivered at a coupling interval of 222 ms failed to capture. VERP increased to 222 ms postcardioversion. Panel C: Twenty-four hours later MAPd90 (250 ms) and VERP (220 ms) remained virtually unchanged.
Temporal changes in right ventricular refractory periods at the three studied cycle lengths
| ERP | CL | ||
|---|---|---|---|
| 400 ms | 500 ms | 600 msa | |
| Precardioversion (ms) | 224 ± 20 | 234 ± 19 | 241 ± 19 |
| 20 min postcardioversion (ms) | 232 ± 23* | 242 ± 22* | 249 ± 21* |
| 24 h postcardioversion (ms) | 236 ± 24* | 246 ± 23* | 253 ± 24* |
| ERP | CL | ||
|---|---|---|---|
| 400 ms | 500 ms | 600 msa | |
| Precardioversion (ms) | 224 ± 20 | 234 ± 19 | 241 ± 19 |
| 20 min postcardioversion (ms) | 232 ± 23* | 242 ± 22* | 249 ± 21* |
| 24 h postcardioversion (ms) | 236 ± 24* | 246 ± 23* | 253 ± 24* |
ERP = effective refractory period, CL = cycle length
*P < 0.01 compared to precardioversion values.
aWe did not measure ERP at 600 ms in seven patients, because of competition between ventricular cycle length during AF and pacing cycle length of 600 ms.
Temporal changes in right ventricular refractory periods at the three studied cycle lengths
| ERP | CL | ||
|---|---|---|---|
| 400 ms | 500 ms | 600 msa | |
| Precardioversion (ms) | 224 ± 20 | 234 ± 19 | 241 ± 19 |
| 20 min postcardioversion (ms) | 232 ± 23* | 242 ± 22* | 249 ± 21* |
| 24 h postcardioversion (ms) | 236 ± 24* | 246 ± 23* | 253 ± 24* |
| ERP | CL | ||
|---|---|---|---|
| 400 ms | 500 ms | 600 msa | |
| Precardioversion (ms) | 224 ± 20 | 234 ± 19 | 241 ± 19 |
| 20 min postcardioversion (ms) | 232 ± 23* | 242 ± 22* | 249 ± 21* |
| 24 h postcardioversion (ms) | 236 ± 24* | 246 ± 23* | 253 ± 24* |
ERP = effective refractory period, CL = cycle length
*P < 0.01 compared to precardioversion values.
aWe did not measure ERP at 600 ms in seven patients, because of competition between ventricular cycle length during AF and pacing cycle length of 600 ms.
This change in refractoriness was not uniform in all patients: although most exhibited prolongation. There were some patients in whom an opposite change (shortening) of refractoriness was observed (Fig. 2).
Change in ventricular refractory period at the drive cycle length of 500 ms (δERP). Values were obtained just before (ERP_Pre) and 20 min after cardioversion (ERP_Post).
In general there was a significant and strong correlation (R = 0.616, P < 0.01) between the change in mean RR (δRR) after successful conversion and the change in refractoriness (δERP) at a cycle length of 500 ms, suggesting that those patients in whom sinus mean RR after conversion was longer than that of AF exhibit prolongation of refractoriness, whereas those in whom sinus RR was shorter responded with a shortening of refractoriness (Fig. 3).
Significant correlation of δERP with change in mean RR interval (δRR) 20 min after conversion to sinus rhythm (P < 0.01, R = 0.616).
The rhythm irregularity, as measured by SD RR (180 ± 29 ms) and RMSSD RR (217 ± 36 ms), showed no significant correlation with any VERP during AF at the three studied cycle lengths.
Changes in repolarization followed a pattern similar to that of refractoriness, since steady state MAPd90 measured at the cycle length of 500 ms changed from 247 ± 16 ms preconversion to 252 ± 17 ms 20 min postconversion (P < 0.01). A further increase to 253 ± 19 ms after 24 h was not statistically significant (Fig. 1), nor was there any significant correlation of SD RR and RMSSD RR with MAPd90 during AF at the cycle length of 500 ms.
Discussion
The main findings of this study were as follows:
Successful conversion of persistent AF in humans results in alterations of ventricular refractoriness and repolarization. In general there is a prolongation of these parameters. Interestingly, not all the patients exhibit this response, since in a minority of them shortening of ERP or MAPd90 is observed.
Our data relate the observed changes in refractoriness and repolarization with the change in mean RR interval, suggesting that they are dependent on the ventricular cycle length during AF and sinus rhythm. No relation of RR variation with VERP or MAPd90 during AF was documented.
Changes in ventricular electrical properties become overt soon after conversion and no further significant change was observed within the day following successful cardioversion.
Impact of atrial fibrillation on ventricular electrical properties
So far, the effects of rapid or irregular rhythms on ventricular electrophysiological properties are not well established. Existing data are rare and conflicting. In a canine study [6] both transient and prolonged rapid ventricular pacing resulted in prolongation of ventricular action potential duration and refractoriness. However, a goat study [9] showed no changes in VERP during prolonged AF with rapid ventricular rates.
Human data are also obscure. In their study Krebs et al. found that VERP lengthens after the termination of short-term sustained rapid ventricular pacing [8]. This prolongation does not occur until 15 min after cessation of pacing. On the other hand, Hamdan et al. [11] demonstrated an increase in right ventricular action potential duration and refractoriness after successful atrioventricular junctional ablation and slowing of ventricular heart rate in patients with drug-refractory AF.
In the present study we found prolongation of refractoriness and MAPd90 in those patients who had a slower rate after sinus rhythm restoration than during AF. This finding is very consistent with that of Hamdan et al. On the other hand, it is not inconsistent with that of Krebs, since in the latter study pacing was of short duration and resulted in more rapid ventricular rates.
In addition, we observed a shortening of ERP and MAPd90 in patients who had a faster ventricular rate after their conversion to sinus rhythm. The significant and strong correlation of ERP change with the change in RR interval found in the present study suggests that repolarization and refractoriness are dependent on the mean ventricular cycle length during AF or sinus rhythm. Changes in autonomic tone after conversion could be the underlying mechanism for either rate or electrophysiological alterations, as Hamdan et al. have suggested [11]. In our patients there was no reason to suspect any change in cardiac innervation. However, regularization of cardiac rhythm and changes in haemodynamics could interact with autonomic tone.
Our data suggest that RR variability (SD RR, RMSSD RR) does not affect ERP or MAPd90 during AF and do not implicate rhythm irregularity as a cause of the observed changes. The absence of such a correlation does not preclude the effect of RR variation on ventricular electrophysiology, since 12 of our patients received diltiazem, which may lead to more regular RR intervals during AF [17].
Most importantly the time course of the alterations we observed in ventricular electrical properties excludes reverse ventricular remodelling and allows us to suggest that AF does not result in any ventricular remodelling analogous to that induced in the atria. This observation can be explained by the fact that the controlled ventricular response at relatively low rates does not result in intracellular calcium overload, considered the cause of atrial remodelling [1,,3]. Furthermore, these findings may explain the low incidence of malignant ventricular arrhythmias in patients included in rate control arms in studies like AFFIRM or RACE and offer an electrophysiological support for their results [18,,19].
Limitations
Electrical shock or anaesthesia may affect ventricular electrophysiology. However, in this study a single 10 J shock was delivered and measurements were obtained 20 min after cardioversion.
Control of ventricular rate response during the study was necessary for ethical reasons. Also, discontinuation of other necessary treatments would have been unethical. However, we believe that since the drug regimen was unchanged throughout the study, the observed changes have to be attributed to the restoration of sinus rhythm. No relation of postconversion electrophysiological changes with any particular treatment was observed.
Successful rate control in most of our patients prevented exploration of ventricular electrophysiology during very rapid rates. Further studies are needed to elucidate this issue.
Conclusions
In patients with persistent AF, sinus rhythm restoration leads to alterations in ventricular refractoriness and repolarization. The changes in these electrical properties do not seem to express reverse remodelling of the ventricles due to AF, but rather changes in heart rate. Given that recent large-scale studies [18,,19] have shown low rates of ventricular arrhythmogenesis in patients with well-controlled ventricular response to AF, our findings may serve partly to explain this observation.
