Evidence Supporting Atrial Remodelling
The concept of electrical remodelling was first introduced in 1995 simultaneously by Wijffels et al.1 and Morillo et al.2 who demonstrated that once sustained atrial fibrillation (AF) was induced in goats, or rapid atrial pacing was performed in dogs, physiological changes occurred that favoured the maintenance of AF.3 This led to the concept that ‘AF begets AF’.
Several aspects of the cellular and ion channel function changes that occur during persistent AF have been defined. These include:
- Reduced inward L-type Ca2+ current (ICaL) by up to 70 %, reducing action potential duration (APD) and effective refractory period (ERP).4,5
- Down-regulation of ICaL to prevent Ca2+ overload during rapid atrial rates.6
- Upregulation of acetylcholine-dependent potassium current (IKACh), which may contribute to shortening of the atrial ERP.
- Dysregulated connexin function, which plays an important role in electrical propagation during persistent AF.3,7
The rapid rates of AF induce shortening of both the atrial ERP and APD.2 Shortening of the ERP has been attributed to down-regulation of the L-type Ca2+ current (ICaL) caused by Ca2+ accumulation within atrial myocytes.3,6 Spatial heterogeneity of ERP and conduction velocity also contribute to the pro-arrhythmic electrical changes observed in AF.8 The effects of atrial remodelling have been correlated with measurement of the P-wave duration on surface electrocardiogram (ECG) recordings.9,10 The shortened ERP reduces the wavelength of atrial impulses that promotes wave break and multiple wavelet re-entry. Structural and mechanical atrial remodelling (which are beyond the scope of this review) along with electrical remodelling increase the frequency of ectopic and re-entrant arrhythmias and provide atrial tissue substrate that favours sustained re-entrant arrhythmias.6,11
Evidence of Reverse Remodelling
The electrical components of atrial remodelling have been demonstrated to be reversible. Soon after studies revealed that AF begets AF, a study from Wijffels et al. recorded complete recovery of atrial ERP one week after cardioversion (goat model, AF duration 24 hours prior to cardioversion).1,12
Animal experiments can directly measure various electrophysiological properties indicative of remodelling and reverse remodelling. This is more difficult in the clinical environment, especially without invasive procedures. However, surface ECG measurements of P-wave duration, including the maximum P-wave duration, P-wave dispersion, and highresolution signal-averaged P-wave (SAPW) have proved to be accurate non-invasive reflections of atrial electrical remodelling.9,10,13–16
For example, several studies have demonstrated that reverse electrical remodelling occurs in humans once sinus rhythm is restored. Using SAPW post-cardioversion, two studies revealed significant reduction in SAPW duration at one and three months post-cardioversion, but no reduction for patients who experienced recurrent AF.13,17 Another study demonstrated that patients who maintain sinus rhythm six months post-cardioversion have shorter P-wave duration compared with those with AF recurrence.18 Two studies evaluated invasive measures of electrical remodelling (ERP) four days and one week postcardioversion. 19,20 The studies revealed significantly decreased duration of SAPW and prolongation of atrial ERP, elegantly proving both the physiological phenomenon of atrial electrical reverse-remodelling and the fact that surface P-wave characteristics can be used as a noninvasive measure of atrial electrical remodelling.
Change in P-wave Duration
P-wave duration at baseline was significantly longer in the persistent AF group compared with the paroxysmal AF group (p < 0.001). Patients in the treatment group with persistent AF treated with dofetilide demonstrated a statistically significant reduction in the mean P-wave duration by the time they returned for PVI three months later (see Figure 2). In contrast, the cohort patients with paroxysmal AF who were not treated with AAD during the three months prior to PVI experienced no significant change in P-wave duration (see Figure 2). Patients with persistent AF who responded to PVI after pretreatment with dofetilide had a significantly greater decrease in P-wave duration in response to dofetilide (137.0 ± 23.1 to 116.7 ± 21.2 ms [20.3 ± 16.9 ms or 15 % decrease], P < 0.001) compared with nonresponders (132.9 ± 17.2 ms to 124.7 ± 16.6 ms [8.2 ± 12.4 ms or 6 % decrease], P = 0.014), (see Figures 3 and 4).
Predictors of Freedom from Recurrent AF Following Ablation
Age, gender, hypertension, left atrial size, duration of persistent AF episodes, duration of AF history, dose of dofetilide and clinical response (suppression vs. paroxysmal AF) to dofetilide all failed to predict a complete clinical response to PVI. A decrease in P-wave duration was the only significant predictor of clinical response to PVI (hazard ratio [HR] 0.94, confidence interval [CI] 0.90–0.98; P = 0.009) on univariate analysis. For each decrease in P-wave duration of 1 ms from baseline to ablation, there was a 6 % increase in the likelihood of a complete response to PVI. Similarly, on multivariate analysis a decrease in P-wave duration was again the only significant predictor of clinical response to PVI (HR 0.092, CI 0.86-0.98; P = 0.007).
Clinical Studies Using Cardioversion or Antiarrhythmic Drug Pre-ablation Another study, based upon the same concept of reverse atrial electrical remodelling as a potential tool to limit the extent of catheter ablation required for successful treatment of persistent AF, was published by Rivard et al. in 2012.22
This two-group cohort study was conducted from 2007 through 2009 and included patients undergoing a first catheter ablation procedure for persistent and long-standing persistent AF. The study group consisted of 40 consecutive patients from three European centres who underwent electrical cardioversion one month prior to ablation. Patients who did not remain in sinus rhythm were excluded from the study, and all patients were required to have left atrial diameters ≤55 mm. These patients were retrospectively matched 1:1 with contemporary controls (for age, gender, duration of AF) with persistent AF in whom no attempt to restore sinus rhythm was made prior to ablation.
Radiofrequency catheter ablation was performed one month after cardioversion (for the study group), and after four weeks of therapeutic anticoagulation for both study arms. AAD therapy was discontinued five half-lives before the ablation procedure, with the exception of amiodarone. Ablation was performed during AF in all patients according to a sequential stepwise approach previously described in detail.25 AF was induced by burst atrial pacing for patients who presented in sinus rhythm due to previous cardioversion. Briefly, left atrial antral PVI was performed using a 3.5 mm irrigated-tip catheter (ThermoCool™; Biosense Webster, Inc., CA, USA) and guided by a circular mapping catheter (LASSO; Biosense Webster, Inc., CA, USA). Next, electrogrambased ablation was performed at right atrial and/or left atrial sites demonstrating features of continuous electrical activity, complex rapid and fractionated electrograms, and a gradient of activation. If AF persisted after this step, linear ablation lesions were created across the left atrium roof between the superior pulmonary veins and then from the left inferior pulmonary vein to the mitral annulus. The endpoint was termination of AF during ablation. However, if AF persisted beyond these ablation lesions, electrical cardioversion was performed.
Patients were evaluated at one, three, six and 12 months postablation with 48-hour Holter monitoring performed at each visit. Success was defined as the absence of AF or atrial tachycardia lasting 30 seconds or longer off AAD therapy.
Eighty patients were included in the study (40 in each arm). Both groups were similar with the exception of a slightly lower ejection fraction among patients in the control arm (63.9 ± 11.7 vs. 55.7 ± 14.9, P<0.05). AF cycle length was greater among patients who presented for ablation in sinus rhythm (i.e. induced AF in the treatment arm). Termination of AF occurred more frequently during ablation of patients in the treatment arm, with less extensive application of ablation and with less fluoroscopic exposure (see Table 1).
Clinical success without the use of AAD therapy was similar in both groups up to 36 months following ablation (see Figure 5). The need for repeat ablation was similar in both groups, and after the last procedure success rates off AAD therapy were 80 % in the treatment arm vs. 70 % in the control group (P = 0.47). Noninvasive measures of reverse remodelling were not performed.
The authors concluded that cardioversion and maintenance of sinus rhythm one month prior to ablation decreased the extent of ablation required to restore and maintain sinus rhythm without compromising efficacy.
Findings from two other independent studies support the hypothesis that pretreatment of persistent AF with AAD therapy and restoration of sinus rhythm improves efficacy of catheter ablation or at least identifies a subset of patients who are more likely to respond favourably to catheter ablation and thus may limit the extent of ablation lesions required for success.23, 24 Igarashi et al. studied 51 consecutive patients with drug-resistant persistent AF who underwent combined AAD therapy with both a class I and III AAD for greater than three months prior to catheter ablation.23 AAD therapy consisted of a class III AAD (amiodarone or bepridil) plus a class I AAD (flecainide, aprindine, pilicainide or propafenone). Thirty three patients (65 %) converted to sinus rhythm during the three-month treatment period with dual AAD therapy (SR group). The sinus rhythm patients demonstrated evidence of mechanical remodelling such as improved left ventricular ejection fraction, reduced left atrial diameter, and reduced brain natriuretic peptide plasma levels. AAD therapy was discontinued five half-lives before the ablation, with the exception of amiodarone which was discontinued ≥2 weeks before catheter ablation.
All 51 patients underwent catheter ablation consisting of PVI and cavotricuspid isthmus ablation. Ten patients (28 %) from the sinus rhythm group and five patients (28 %) from the AF group (p = ns) required further ablation lesions including a left atrial roof line, superior vena cava isolation, and ablation of complex fractionated electrograms. Fourteen months following ablation, patients who converted to sinus rhythm during treatment with dual AAD therapy prior to ablation were significantly more likely to be in sinus rhythm following a single catheter ablation procedure (61 % vs 22 %; HR 2.62, 95 % CI 1.22–5.63; p = 0.013).
A retrospective case-control study of 82 patients with persistent AF examined outcomes according to those who underwent pretreatment with bepridil to restore sinus rhythm prior to ablation.24 Fifteen of the 22 patients (68 %) treated with bepridil for a maximum of four months prior to ablation achieved sinus rhythm prior to ablation. AAD therapy was discontinued at least three weeks prior to PVI ablation. Consecutive case-matched control patients (n = 60) underwent PVI ablation with the addition of left atrial linear ablation lesions if AF remained inducible. At the end of 18 ± 5 months off AAD therapy, the AF-free rate among patients successfully treated with bepridil who converted to sinus rhythm was 87 %, vs. 29 % for patients who failed to convert with AAD pretreatment. Seventy-two percent of case-matched control patients (not pretreated) remained in sinus rhythm (72 % vs 29 %, p=0.02). Conversion to sinus with bepridil identified a select group of patients with persistent AF who were more likely to respond to PVI. The question of whether restoration of sinus rhythm played a causative role (by reverse remodelling) in the long-term favourable outcome of this group was uncertain.
Together, these studies confirm that:
- Pretreatment of patients with persistent AF to restore sinus rhythm prior to catheter ablation, regardless of whether this is accomplished by drug or simple cardioversion, identifies a group of patients who are more likely to respond favourably to PVI catheter ablation.
- Electrical remodelling plays a role in the maintenance of persistent AF.
- Restoration of sinus rhythm facilitates pre-ablation reverse remodelling to occur.
- Catheter ablation for patients with persistent AF may at least be less complicated and prolonged if electrical remodelling is allowed to occur first, and is likely more effective.
The physiological evidence for reverse remodelling is demonstrated by the shortening of the P-wave duration and the longer AF cycle length among patients converted first to sinus rhythm. One potential explanation for the difference between studies is the difference duration of sinus rhythm prior to AF ablation. It is possible that one month is insufficient time to allow for full electrical remodelling. Whether three months is adequate remains unanswered.
The studies presented are non-randomised and relatively small. It is possible that by identifying patients who could remain in sinus rhythm (with dofetilide or after cardioversion alone or with other AAD therapy), a cohort of patients more likely to respond favourably to ablation was selected.26 A larger multicentre trial is needed to confirm these findings and the long-term benefits of this approach. And finally, a randomised clinical trial is needed to definitively establish the value of the clinical strategy described in these manuscripts with alternative ablation techniques for persistent AF.
This paper is not intended to include a comprehensive review of the phenomenon of atrial electrical remodelling associated with AF. Rather, we have focused on aspects that have been demonstrated to be relevant to ablation of persistent AF and for which some clinical data exists. Reverse electrical remodelling begins within minutes to hours following cardioversion, whether cardioversion is performed electrically or pharmacologically. Cardioversion during catheter ablation of AF is often performed to evaluate efficacy if ablation lesions. But we know of no data that evaluate whether restoration of sinus rhythm by cardioversion during ablation affects outcome of catheter ablation of persistent AF. The effect on ablation outcome of maintenance of sinus rhythm for less than one month prior to ablation of persistent AF remains unknown.
Practical Application of the Reverse Remodelling Concept
Catheter ablation for patients with symptomatic AF (paroxysmal or persistent) remains a long-term management strategy.Cardioversion with or without subsequent AAD therapy is often required acutely to alleviate severe symptoms and achieve adequate ventricular rate-control while a more definitive long-term treatment strategy is identified and then performed (e.g. linear lesion ablation strategy, ablation of autonomic ganglia, or rotor mapping/ablation). Even for patients with persistent AF who have only mild to moderate symptoms, elective cardioversion with or without AAD therapy may be viewed as a temporising intervention until a more definitive intervention such as catheter ablation may be viewed favourably by both the patient and physician. In addition to the benefits of atrial electrical remodelling, this period of time allows the patient time to consider the complex treatment options for persistent AF and confirm the symptom that was associated with AF. It also allows time for scheduling the catheter ablation which is resource-intensive and often must be scheduled weeks to months in advance.
Therefore, from a practical standpoint, many patients are already undergoing a period of reverse atrial electrical remodelling prior to catheter ablation of persistent AF, and the application of atrial reverse electrical remodelling may be considered a complementary tool to AF ablation strategies.
While our study utilised dofetilide to assist in maintenance of sinus rhythm prior to ablation of persistent AF, sinus rhythm is the essential component that allows electrical remodelling to occur, not the AAD.1,3,12,22 If dofetilide is not available or not appropriate for an individual patient, evidence suggests that the same benefit of preprocedural electrical remodelling would be achieved with other antiarrhythmic agents that effectively maintain predominant sinus rhythm.
AF, the most common heart rhythm disturbance, represents the end result of complex structural, electrical and mechanical changes of the atrial tissue. Early in the disease process, elimination of pulmonary vein triggers has been demonstrated to be effective therapy for many patients. However, as the disease process progresses, electrical and structural remodelling create conditions that favour continuation of AF.
Most ablation techniques for persistent AF are founded upon the theory that atrial tissue substrate modification, in addition to elimination of AF triggers, is required to improve ablation efficacy. Preprocedure electrical remodelling by restoration and maintenance of sinus rhythm one to three months prior to ablation for persistent AF offers an alternative strategy to improve ablation efficacy without extending the procedure duration and without exposing patients to the associated risks of prolonged procedures and extensive ablation lesions.
Randomised, controlled multicentre studies are needed to further characterise the effectiveness of preprocedure electrical remodelling prior to ablation of persistent AF and to clearly define the optimal duration of sinus rhythm required for electrical remodelling.