Predictors of Atrial Fibrillation Recurrence after Catheter Ablation
Gianluca Epicoco MD, Antonio Sorgente MD, PhD
Electrophysiology and Arrhythmia Center
IRCCS Policlinico San Donato
Via Morandi 30 20097 San Donato Milanese, Milan, Italy.
Atrial fibrillation (AF) catheter ablation is a well-known treatment option for patients with drug refractory AF. The increasing number of electrophysiology laboratories able to perform this procedure will create in the next years an economic issue, which each cardiac electrophysiologist will have to face with. Identification of predictors of recurrence of AF after catheter ablation is therefore of primary importance to reduce health costs and improve long-term results of this intervention. The aim of this review is to give a brief overview on what have been published already in the literature on the topic and henceforth to increase the awareness of cardiac electrophysiophysiologists on the importance of selection of the right candidates to this intervention.
Corresponding Address : Antonio Sorgente
Electrophysiology and Arrhythmia Center,
IRCCS Policlinico San Donato
Via Morandi 30,
20097 San Donato Milanese, Milan, Italy.
Since its introduction into clinical practice in the late ninenties,1 catheter ablation of atrial fibrillation (AF) has become a well-established therapeutic option for the treatment of patients with symptomatic drug refractory AF.Nevertheless, the great interest of cardiac electrophysiologists in this new treatment option is facing a crisis after the publication of medium and long term efficacy data.2,3 Indeed, a recent meta-analysis4 which included 63 studies on the topic, evidenced a single-procedure success rate of ablation with no antiarrhythmic drug therapy after 12 months follow-up of 57%, significantly more than the sole antiarrhythmic therapy, which resulted in a 52% freedom from arrhythmias at one year. Only adding multiple procedures, success rate was 71% in absence of antiarrhythmic drugs and 77% with antiarrhythmic drugs.
According to the Heart Rhythm Society's consensus document5, catheter ablation’s success should be defined as freedom from symptomatic or asymptomatic AF, atrial tachycardia, or atrial flutter lasting ≥ 30 seconds after AF ablation. One year success is defined as freedom from arrhythmic events without antiarrhythmic drugs documented from the end of the blanking period (usually lasting three months after ablation) to 12 months of follow-up. Long-term success is considered as freedom from arrhythmic events from the end of the blanking period to at least 36 months follow-up following the ablation procedure off of antiarrhythmic drugs. AF ablation guidelines included also the definition of clinical or partial success as reduction (≥ 75%) of AF burden assessed with a device able to record ECG tracings or intracardiac electrograms in the presence or absence of antiarrhythmic drugs.
Certainly, success rate is affected by patient characteristics because AF includes different subtypes and occurs in different clinical subsets. The identification of the predictors of maintenance of sinus rhythm after catheter ablation is high desirable since it would certainly help all the community of cardiac electrophysiologists in reducing unnecessary procedures, in limiting complications and in reducing health care costs. The main scope of this manuscript is to give a brief overview of these predictors on the basis of what has been already published in the literature.
Types and Mechanisms of AF Recurrences
It is now widely recognized that there are different types of recurrence of AF.5 Early recurrence (ER) is defined as a recurrence of AF within three months of ablation, whereas recurrence post ablation is defined as an atrial fibrillation relapse more than 3 months following the intervention. Late recurrences (LR) of AF occurs 12 months or more after ablation. Since in a significant proportion of cases, relapse consists of atrial flutter or atrial tachycardia, the occurrence of these arrhythmias should also be considered as a recurrence. This classification has a clinical significance since there are various mechanisms behind different types of recurrences and not all recurrences will lead to later relapses. Recent studies have widened significantly the follow-up (over five years), introducing in the clinical setting a new subtype of AF relapse, regarded as very late recurrences (VLR).
ER after catheter ablation of AF is fairly common: Bertaglia found 46% of atrial tachy-arrhythmias relapse during the first three months of follow-up.6 Moreover the incidence of ER is maximum soon after the procedure while decreases in the following days.7 Although prevalence of ER is not negligible, it has been widely recognized that a good proportion of patients experiencing ER are free of significant atrial arrhythmias at prolonged observation. Nevertheless, the occurrence of LR is more frequent in the subgroup with ER.8 These data suggest that ER is probably linked to the procedure, even if the mechanisms involved in determining it have not completely been understood. The application of radiofrequency energy provokes a thermal injury followed by a flogistic response in myocardial tissue.9 Furthermore a transient imbalance between sympathetic and parasympathetic tone has been reported after ablation and may potentially contribute to arrhythmic recurrences in this phase.10,11 Several studies have demonstrated a progressive growth of ablation lesions over the procedure: thus the lack of a complete scar across the atrial wall in the first days after the ablation can cause ER, while lesion maturation accounts for persistence of sinus rhythm.11,12 Another possible explanation for the uncertain clinical impact of ER is the occurrence of atrial reverse structural and electrical remodeling after ablation: indeed maintenance of sinus rhythm affects positively conduction velocities and effective refractory periods of the atria, which result less susceptible to initiation and perpetuation of atrial arrhythmias.13
Several studies have shown that recurrences after more than 6-12 months from the index procedure are the result of the “reconnection” of the pulmonary veins: the recovery of the electrical conduction between pulmonary veins and left atrium14 favors the AF relapse. Another type of recurrence is represented by atrial flutter: at the basis of this arrhythmia there is an incomplete linear lesion drawn during the ablation procedure,15 to avoid this circumstance is essential to achieve complete block across ablation lines. Moreover non-pulmonary veins foci, which are localized outside from the circumferential ablation lines, could also contribute to the initiation of AF.16
Very Late Recurrences (VLR)
Relapses of AF long after the ablation are the result of the deterioration of the atrial tissue: progression of atrial fibrosis, enlargment of left atrium and the adverse electrical and molecular remodeling of myocardial tissue are involved in this type of recurrences.17 Thus very late recurrence accounts for the final stage of the atrial electrical disease, even though further investigation on the topic is warranted.
To date, several predictors of recurrence have been identified in various studies. Among all the published manuscripts, the systematic review by Balk et al.18 on predictors of AF recurrence after radiofrequency catheter ablation surely represents one of the most significant original contributions in this field. The Authors have made a huge effort to synthesize all the data reported in 2.169 different citations, focusing their attention on the most significant pre-procedural patient characteristics such as AF type, AF duration, left ventricular ejection fraction, left atrial diameter, gender, age, presence of structural heart disease and presence of hypertension. Their meta-analysis showed that no one of these clinical parameters is able to predict arrhythmia recurrences at a high level of evidence. The only clinical parameter which demonstrated a potential link to AF recurrence was AF type and more in detail non-paroxysmal AF, even if only at the univariable analysis and not at multivariable level. This lack of real predictors of AF recurrence is surely related more to the quality and the limitations of the existing literature than to a true absence of association. The studies on AF ablation are extremely heterogeneous with respect of patient characteristics, procedural features and follow-up modalities and this renders any attempt of synthesis very challenging. Furthermore patients undergoing AF ablation have a limited range of variation in the majority of the clinical variables: it’s rare that they are younger than 40 years old or older than 70 years old, females represent a minority and left atrial diameters and/or left ventricular ejection fractions are usually aligned on a narrow range of values. Finally, some of these clinical variables are related and this implies that they are not statistically independent and that the simple Cox or logistic regression are too simplified models to account for the complex relationships among factors.
Taking all this in mind, let’s give anyway a brief overview of which clinical, procedural and post-procedural predictors have been identified by the most significant single studies for each type of AF recurrence after catheter ablation.
Bertaglia et al.19 observed that the presence of structural heart disease and the lack of successful isolation of all targeted pulmonary veins (PV) are predictors of early atrial tachyarrhythmias recurrence. Other studies.20 have indicated hypertension, left atrial enlargement, permanent AF, and lack of superior vena cava isolation as predictors of early relapse of AF after ablation. Otherwise, the termination of AF during the ablation procedure, when compared to failure to terminate the arrhythmia with the necessity of an electrical cardioversion, predicts early and late success.21 A longer cycle length of AF is associated also with termination of AF and with overall success as well.22 These data suggest that the presence of structural heart disease or of significant risks factors for heart disease which lead to a higher degree of adverse left atrial remodeling and enlargement might be involved in the complex mechanisms which lead to early recurrence. A different meaning should be assigned to very early recurrence, which occurs within 48 hours from the ablation procedure. Chang et al.23 found 19% of very early AF recurrences: longer procedural time and lower LA voltage were independent predictors of very early AF recurrences. Koyama.24 reported also that an increase in body temperature and C-reactive protein associated with signs of pericarditis in patients with very early recurrence, hypothesizing an inflammatory mechanism as a potential causative factor.
Recurrence of AF 6 months after the ablation is the expression of pulmonary veins reconnection or incomplete transmural injury of the radiofrequency energy.25 One study26 underlined that overweight/obesity, metabolic syndrome and ER are independent predictors of AF relapse. Interestingly, the relationship between early and late recurrence has been put under observation in several studies. A prolonged procedure time and inducibility of AF or AT immediately after ablation has been found to predict independently late recurrence in patients with early recurrences of atrial tachycardia.27
Koyama 24 found a lower rate of late recurrence among patients that experienced a very early recurrence after ablation, whereas patients that had a relapse after the first 48 hours, had an higher rate of recurrence after 6 months. Similar results were obtained by Themistoclakis20 et al.: very early relapse was associated to a better final outcome when compared to recurrence within one month. These data have been confirmed by a recent meta-analysis28 that demonstrated recurrence within the first 30 days as the strongest predictor of future relapse.
ECG features have also been analyzed and related with AF recurrences. Low amplitude F waves in lead aVF and V1, for example, have demonstrated to be associated with late AF recurrence after ablation.29 Right atrium enlargement, more than 2 procedural attempts, AF duration and left atrial enlargement (> 43 mm) have also been included in the variegate and heterogeneous list of atrial arrhythmia recurrence after ablation.30,31 As stated already above, AF type may predict the outcome of the ablation, since nonparoxysmal AF is associated to 60% higher risk to relapse when compared to paroxysmal AF.18 These data suggest that the failure to maintain sinus rhythm after more than 6 months from the procedure is strongly associated to an ineffective ablation procedure since in the majority of cases it is possible to demonstrate pulmonary veins reconnection or development of atrial tachycardia around incomplete ablation lines. Furthermore, when PV reconnection is not present, the relapse is the consequence of the adverse electrical and anatomical remodeling associated with AF: repeated ablation attempts, low amplitude ECG waves and atrial enlargement are strictly linked to myocardial fibrosis and lack of viable myocardial tissue. Thereby, since AF type is a hallmark of the underlying substrate, indication to catheter ablation in patients with non-paroxysmal AF should be well balanced by cardiac electrophysiologists since these patients have undoubtedly a worse outcome.
Predictors of Very Late Recurrence
Very late recurrence has not been deeply evaluated in scientific studies. Just few scientists have performed long term follow up after ablation.Recurrence occurring more than 12 months from the procedure, is not excessively frequent and has been related to hypertension and left atrial enlargment.32 Mainigi found that the only predictors of very late recurrence were weight > 200 lbs and the presence of non-PV triggers in case of a repeated ablation,33 whereas other studies have underlined the role of right atrial foci.16 In one of the studies with the longest follow-up, Weerasooriya et al.34 found that valvular heart disease and non-ischemic cardiomyopathy were predictors of very late recurrence. On the basis of these data, very late recurrence can be considered a new type of AF, not depending on earlier triggers (e.g. PV foci), but originating from other areas of atrium with a more advanced degree of adverse remodeling.
Identification of predictors of recurrence of AF after catheter ablation is a challenging task due to the extreme heterogeneity of the data published in the literature. More research on the topic is warranted together with a combined effort to uniform AF catheter ablation procedures and to adhere stricter to the international guidelines available nowadays on this type of intervention.