Early Recurrences of Atrial Fibrillation: How To Predict Them? G.L. B

G.L. B

, M. L

, F. R

, M.G. G

, G. F

Introduction

Atrial fibrillation (AF) is the most common sustained tachyarrhythmia encountered in clinical practice [1], causing the highest number of days of hospitalisation for arrhythmia admission in the United States [2]. It affects more than 2.2 million individuals in the USA: the overall prevalence in the adult population is 0.4%, and its incidence increases with age (up to 8–10%

of persons older than 80 years) and with the presence of heart disease [3–5].

The AFFIRM study demonstrated equivalent survival between patients treat- ed using rate control versus rhythm control strategy [6]; however, converting the rhythm electrically and preventing recurrences with drugs remains a standard approach to reducing symptoms [1]. With all of these options, embolic risk stratification and proper anticoagulation strategies are required for each patient [1, 6, 7].

Electrical cardioversion (ECV) is currently the most effective way to con- vert persistent AF to sinus rhythm (SR), with success rates of approximately 75–95% with the use respectively of monophasic or biphasic defibrillators [8–10]. Unfortunately, because of the high recurrence rate, no more than 40–50% of patients maintain SR for 6 months or more with anti-arrhythmic drug prophylaxis different from amiodarone [11]. Thus, the main limitation on cardioversion success is not ‘technical failure’ – impossibility of restoring SR – but recurrence of the arrhythmia, which may occur in different time frames following the procedure.

Department of Cardiology, Sant’ Anna Hospital, Como, Italy

Time Course and Definition of Recurrence of AF

The aetiology of reinitiation of AF after external ECV is obscure and its inci- dence is unknown. It can occur in a significant proportion of patients follow- ing successful ECV using either internal [12, 13] or external methods [14]. It is a phenomenon that was only described in the late 1990s, in part because the increasing use of internal ECV [11], the catheters for which enable recording of atrial electrograms, and the employment of atrial defibrillator devices [12], which make possible the analysis of stored atriograms, provide the motive and the means for its study. The recurrence phenomena have acquired their own acronyms: recurrence may occur in a very early phase (minutes) after electrical shock, and this is now called IRAF (immediate recurrence of AF); it may occur in an early phase (first 24–48 h to 5–7 days;

ERAF, or early recurrence of AF); or it may occur weeks to months after the successful procedure (LRAF, or late recurrence of AF).

In a retrospective study of 85 patients with AF, the functional and phar- macological variables which could possibly influence the long-term outcome after first ECV were analysed [15]. Multivariate analysis confirmed the dura- tion of the treated episode and age below 75 years as prognostic factors that predict persistence of SR 100 days after successful ECV, whereas echocardio- graphic parameters and the presence of organic heart disease played no role.

The phenomena of IRAF and ERAF are the most difficult to characterise because they would require continuous monitoring of an AF patient’s cardiac rhythm, and few studies are available concerning this. However, understand- ing these phenomena and the potential factors affecting them may improve the efficacy of maintaining SR in the long run. For instance, IRAF can occur within seconds after ECV and may be difficult to distinguish from shock fail- ure. In a small study, 27 patients who experienced unsuccessful ECV were treated with a 1-month load of amiodarone, after which ECV was repeated.

Of the patients in whom the initial ECV failed due to technical failure, only 31% were in SR at 1 month, compared with 91% for those with initial failure due to IRAF [16].

Early Recurrences of AF

The phenomenon of ERAF following successful ECV is a clinical setting in

which two important concepts are implicated and may strongly interact. The

first is that an increasingly recognised and growing number of patients have

AF initiated, and possibly maintained, by an ectopic focus of repetitive atrial

activity [17]. The second is that AF itself causes changes in cellular electro-

physiology that, at least in animal models, have the effect of further increas-

ing the tendency to fibrillation [18], and there is a reversal of this electro- physiological remodelling after a certain period of SR [19]. The first of these two concepts relates to the triggers for initiation of the arrhythmia and the second to the myocardial substrate predisposing to and maintaining the arrhythmia. However, the extent to which ERAF is due either to enhanced frequency of atrial ectopic activity as potential triggers or to enhanced vul- nerability of the remodelled, recently defibrillated atrium to the effects of the atrial ectopy remains uncertain.

Several authors have reported premature atrial beats causing ERAF.

Premature atrial beats initiated ERAF in 91% of cases after internal ECV [20], and a short interval predicted an early relapse in patients with AF recurrences [21]. A recurrence rate of up to 27% within the first minute after external ECV has been reported. An high incidence of premature atrial beats, with particular specific sequences such as long–short, were responsible for 70% of cases of ERAF after external ECV [22].

It has been demonstrated that prolonged atrial pacing in goats at rates sufficiently rapid to produce AF causes reversible electrophysiological and structural changes in the atria. Whereas during the control condition no sus- tained AF could be induced, after several days to weeks of rapid pacing in these animals, AF had become sustained.

In the study of Wijffels et al. [18] the refractory period was measured at multiple sites by programmed electrical stimulation. AF was produced by burst pacing (1 s, 50 Hz). In the normal goat, electrically induced AF lasted only for a short time and terminated promptly within a few seconds. After the baseline study was completed, the animals were connected to an external automatic atrial fibrillator. The device detected spontaneous cardioversion of AF and delivered a burst of stimuli to promptly reinduce the arrhythmia.

Within the first 24 h of AF, both the duration and the rate of the arrhythmia increased significantly and AF cycle length shortened progressively until after about 4–6 days a new steady state was reached. The most important atrial parameter of AF-induced electrical remodelling is the refractory peri- od. During control, early premature beats did not induce any arrhythmia.

After few hours of AF, the atrial refractory period was shortened and a pre- mature stimulus was followed by a short run of rapid atrial responses.

Twenty-four hours of AF further shortened the atrial refractory period and

now early premature beats triggered paroxysms of AF. Moreover, during con-

trol, the refractory period showed a short-term rate adaptation to pacing

intervals. After hours of AF, the relationship between refractory period and

rate become reversed, so that instead of lengthening at slow rate, the refrac-

tory period actually shortens [18]. The loss of the physiological prolongation

of the refractory period in response to a sudden decrease in rate has also

been observed in other studies [23, 24].

In this condition, the physiological normalisation of atrial refractoriness after SR restoration was lost, and it was recovered only after several days of stable sinus rhythm [19]. Of note is the finding that the time course of elec- trical remodelling parallels the timing when likelihood of recurrence is highest [21].

Novel Techniques to Predict Recurrences of AF

Prediction of the outcome of electrical cardioversion is not perfect: clinical and laboratory variables have not always been predictive [15]. This consti- tutes the background of the need for new parameters that can identify patients who will have recurrence after successful ECV, and distinguish them from those that will not.

Changes in autonomic milieu probably play a role in the occurrence of relapse into AF. Lombardi et al. [25] demonstrated increased sympathetic tone and decreased vagal modulation of the sinus node in patients prone to ERAF. The authors analysed short-term heart rate variability in 93 patients with persistent AF and on chronic amiodarone treatment, after restoration of SR by ECV. Patients with ERAF (25/93, 27%) were characterised by a greater LF/HF ratio than those in SR. In univariate analysis no clinical parameters distinguished the two groups, and no correlation was observed between LF/HF ratio and late recurrences.

Bollmann et al. [26] analysed the meaning of AF frequency obtained from the surface ECG for prediction of early arrhythmia relapse in patients under- going internal ECV of persistent AF. AF relapse occurred in 11 out of 19 (58%) patients, but in 7 out of 8 (88%) patients with a high fibrillatory fre- quency (≥ 7 Hz). A high fibrillatory frequency reflects a high AF complexity (that is, the number of simultaneous wandering wavelets) [27] and correlates inversely to the refractory period [28].

AF is an irregularly irregular (random) heart beat [29], and the random-

ness of ventricular rhythm is primarily a consequence of the inherent ran-

domness of atrial activity. However, controversy exists as to whether the ven-

tricular rhythm in AF is truly random, and some investigators using a variety

of mathematical techniques have shown that a certain degree of clustering

may be present [30]. Everett et al. [31] confirmed in a dog model that AF is

characterised by varying degrees of organisation, and demonstrated that the

efficacy of electrical shock in restoring SR is increased when shocks are deliv-

ered during periods of high AF organisation. Based on this premise, Van den

Berg et al. [32] demonstrated in humans that ECV is more effective in restor-

ing SR in AF patients with clustering than in patients in whom no clustering is

apparent in plots obtained from Holter monitoring. In addition, the degree of

clustering appears to be predictive of the overall outcome of ECV: the higher the degree of clustering, the higher the likelihood of SR at follow-up.

Conclusions

The heterogeneous nature of AF dictates that a variety of treatment modali- ties should be used to manage this disease. Recent studies have shown that strategy of rate control is not inferior to a strategy of rhythm control in terms of mortality [6]. However, in highly symptomatic patients restoration of SR is still desirable, and selection of patients with a high likelihood of clinically effective ECV remains critical.

The therapeutic efficacy of this treatment modality is likely to be affected by early recurrences of AF noted soon after cardioversion. The mechanism underlying early recurrence of AF is unclear for the majority of patients, but is probably multifactorial. Contributing factors may include complex electro- physiological remodelling which strongly interacts with triggering factors such as atrial ectopic beats, both probably modulated by the autonomic ner- vous system.

Several clinical factors and laboratory variables that are predictive of poor arrhythmia outcome after ECV have been identified, but their efficacy in the clinical setting is not completely satisfactory [15]. Novel and simple techniques are expected to permit identification of patients likely to experi- ence a better outcome of ECV of AF.

Future larger studies are warranted to establish further the potential clin- ical role of these new techniques.

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