Predictors of Atrial Fibrillation Recurrence after Ablation

Abstract

Various treatment methods have been used for atrial fibrillation (AF), which has long been a cause of cerebral infarction and heart failure. Antiarrhythmic drug, the first developed treatment, was not effective in maintaining sinus rhythm and did not improve prognosis. In contrast, pulmonary vein (PV) isolation is effective in paroxysmal AF, expected to maintain sinus rhythm by 70–80% in the first session. Therefore, catheter ablation is the first-line treatment for patients with drug-resistant paroxysmal AF. For PV isolation, radiofrequency ablation was developed first, followed by cryoballoon ablation, which was shown to be not inferior to radiofrequency ablation. In contrast, for persistent AF, PV isolation alone has been found to result in a low rate of maintenance of sinus rhythm. However, there has been no impact of the additional radiofrequency application on AF recurrence rate. Recently, a number of the predictive factors of AF recurrence after AF ablation have been reported. Among them, AF duration, defibrillation threshold, left atrial volume are considered useful as predictors of atrial fibrillation recurrence after ablation. In order to improve the outcome of AF ablation, it is desirable to select patients with AF in consideration of the predictive factors of AF recurrence after AF ablation.

1. Introduction

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, causes cerebral infarction or heart failure. For this reason, treatment strategies for it have been studied for several years. The Atrial Fibrillation Follow-up Investigation of Rhythm Management study [1] published in 2002 reported that, compared with a rate control strategy, a rhythm control–induced strategy with medications does not help improve AF prognosis. In contrast, in catheter ablation, a nonpharmacological therapy for AF reported in 1998 by Haïssaguerre et al. [2], frequent ectopic beats arising from the pulmonary veins (PVs) contribute to AF development, while PV electrical isolation can maintain sinus rhythm. The Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial [3] showed that AF recurrence occurred less frequently in the ablation group than in the standard medical therapy group. The ablation group in the same trial showed improved quality of life among patients with AF compared with the standard medical therapy group. Furthermore, the Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial demonstrated that, among patients with congestive heart failure, ablation therapy prevented more events than medical therapy [4]. Based on the European Society of Cardiology Guidelines, catheter ablation is the first-line treatment for patients with drug-resistant paroxysmal AF. The FIRE AND ICE trial, which compared the efficacy and safety of radiofrequency ablation versus cryoballoon ablation for drug-resistant paroxysmal AF, determined that the cryoballoon ablation invented in recent years was not inferior to radiofrequency ablation [5]. However, compared with paroxysmal AF, persistent AF has a higher recurrence rate after ablation. To improve the prognosis of persistent AF, the ablation of atrial substrates, including linear ablation [6], complex fractionated atrial electrogram (CFAE) ablation [7], CARTOFINDER [8], ExTRa Mapping [9], and non-PV foci ablation [10], has been performed in addition to pulmonary vein isolation (PVI). A report of whether these procedures can further prevent AF recurrence is expected in the future.

AF development is orchestrated by many risk factors, including hypertension, overweight/obesity, dyslipidemia, diabetes, tobacco smoking, and excessive drinking [11, 12]. Thus, managing these risk factors is important for its prevention.

In addition, patient selection is considered important for improving treatment outcomes; therefore, it is necessary to identify a new index that correlates with patient prognosis.

2. Prognosis differs among ablation devices

2.1 AF recurrence rates for radiofrequency ablation versus cryoballoon ablation

Cryoballoon ablation is a procedure that involves inducing necrosis by exposing the myocardium to ultralow temperatures. PVI using cryoballoon ablation is currently performed in many medical facilities because cryoballoon ablation catheter is relatively easy to handle compared with a radiofrequency ablation catheter. Because the cryoballoon’s radius cannot be adjusted, electrical isolation is difficult in some cases; therefore, it is important to confirm the locations of the PV and left atrium using preoperative computed tomography. In the FIRE AND ICE trial, the effectiveness of cryoballoon ablation was not inferior to that of conventional radiofrequency ablation, while the operating time for cryoballoon ablation was significantly shorter.

2.2 Laser balloon ablation

Laser balloon ablation enables observation of the crimped myocardium through the endoscope following balloon occlusion of the PV. Furthermore, the laser balloon enables free adjustment of the balloon size, target ablation site, and output power. The flexibility of the laser balloon allows an operator to perform a personalized PVI. One previous study reported that treatment outcomes for paroxysmal AF vary widely among patients [13]. Other studies reported the high incidence of phrenic neuropathy.

The isolation success and complication rates involve a learning curve. Laser balloon ablation is expected to have safe and good treatment outcomes if used properly.

2.3 Hot balloon ablation

In a hot balloon catheter, a compliant balloon made of polyurethane is attached to the end of the catheter, while electrodes for radiofrequency energy and a temperature sensor are placed inside the catheter. In hot balloon ablation, the administration of a contrast–saline mixture causes the balloon to fully expand to the appropriate size and then press against the tissue surrounding the PV. The balloon is heated to 70°C by energizing of the radiofrequency current in the balloon electrode. Compared with cryoballoon, the major difference of hot balloon ablation is to change the balloon size. Furthermore, hot balloon ablation is considered a relatively safe method because the temperature for tissue heating is ≤70°C. For that reason, the steam pop phenomenon does not occur. We are awaiting the results of a multicenter study of its clinical performance [14].

2.4 Pulsed field ablation

Pores in cell membranes are made using electric pulses, through which substances can enter cells, a phenomenon called electroporation. This method has been used for transformation, by which Escherichia coli or animal cells deliver DNA into cells; however, irreversible electroporation, which kills cells via irreversible perforation, has also been developed. The electric pulse frequency that kills cells differs among tissues. When applying the frequency to ablation, it is possible to selectively ablate the atrial muscle without affecting the tissues surrounding the blood vessels, nerves, and esophagus. Although the number of cases is small, the effectiveness and safety of pulsed field ablation have been reported [15].

3. AF recurrence after persistent AF ablation

Along with the progress of catheter ablation, the proportion of patients cured of AF among those with paroxysmal AF is high in all medical facilities; however, in terms of the ablation of persistent AF, the proportion of patients cured of AF still shows great variability among medical facilities.

According to the CASTLE-AF trial, catheter ablation for AF complicated by heart failure significantly decreases the composite endpoint of hospitalization; thus, its use for persistent AF is becoming increasingly significant. Although persistent AF is associated with non-PV foci ectopy, degeneration of the atrial substrate also contributes greatly to persistent AF. To improve the outcomes of persistent AF, ablations other than PVI targeting the left atrial substrate published in recent reports are described below.

3.1 Complex fractionated atrial electrogram (CFAE)

Nademanee et al. defined local potentials (cycle length ≤ 120 ms) or continuously fractionated potentials as complex fractionated atrial electrogram (CFAE). According to Nademanee et al., CFAE during AF indicates regions of slow conduction and pivot points, within which ablation can terminate AF. However, CFAE does not always imply a reentry circuit that sustains AF; rather, it sometimes indicates the regions in which the excitable media that underlie fibrillation can be passively propagated or the etiology of AF is not connected. The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF II) trial [16] demonstrated that CFAE showed no significant difference when compared with PVI alone in terms of prevention of AF recurrence. Therefore, this method has not been used in recent years.

3.2 Linear ablation

Linear ablation has been used previously. The most common linear ablations consist of a “roof line” that creates an ablation line connecting the right and left superior PVs and a “mitral isthmus line” creating an ablation line connecting the posterolateral mitral annulus and the left inferior PV. However, because the linear ablation technique is difficult to perform in many cases, prolonged procedure time and complications occasionally occur. Additionally, residual conduction gaps may cause recurrent arrhythmias.

In the STAR AF II trial, no significant difference was reported between linear ablation and PVI alone in terms of preventing AF recurrence.

3.3 Non-PV foci

Ablation of PVI and non-PV foci is necessary to improve treatment outcomes. Non-PV foci arise from the superior vena cava, left atrial posterior wall, atrial septum, mitral annulus, ligament of Marshall, coronary sinus, and crista terminalis. Active induction is often required to identify non-PV foci. When AF lasts longer, cardioversion is used to restore sinus rhythm. When AF recurs, it is necessary to identify its triggers. During sinus rhythm, induction is attempted by isoproterenol loading, ATP loading, and atrial pacing. To enable wide mapping, multiple electrodes are placed at various locations, and the region originating from the non-PV foci, which act as AF triggers, is identified from the early electric potentials recorded.

3.4 Ganglionated plexus

Ganglionated plexuses (GPs), which are mainly embedded within fat pads distributed to the epicardial surface of the atrium, contain the same number of cholinergic and adrenergic neurons. The cell bodies of GP neurons are densely populated by the following five areas of left atrial GPs: superior left GP, Marshall tract GP, anterior right GP, inferior left GP, and inferior right GP. GP ablation makes it possible to inhibit and eliminate both PV firing and fractionated atrial potential. According to Nakagawa et al. [17], among 63 patients with paroxysmal AF who underwent GP ablation and PVI, 90% did not experience AF recurrence at 1 year of follow-up.

3.5 CARTOFINDER™

The CARTOFINDER™ mapping system for AF catheter ablation, which was developed in recent years, enables the generation of wavefront propagation maps acquired from bipolar and unipolar signals using a 64-pole basket catheter. After filtering the ventricular activation signals, the unipolar signal created between two neighboring bipolar signals is annotated, and the focal and rotational activities are recorded. Ablation is performed on these drivers that terminates AF. The effectiveness of this ablation was reported previously, and future reports on clinical outcomes are expected.

3.6 ExTRa Mapping™

To completely cure patients with persistent AF using catheter ablation, it is necessary to determine the location of AF drivers in the atria. Ashihara et al. developed the first online real-time clinical arrhythmia visualization system, the ExTRa Mapping™. This system includes specialized artificial intelligence based on intracardiac electrocardiography signals recorded by a 20-pole spiral-shaped catheter inserted into the atrium and visualizes arrhythmia by combining the action potential waveform of the human atrial muscle calculated by computer simulation. Highly intensified rotor sites in the visualized areas are ablated.

3.7 Low-voltage area ablation

This ablation procedure targets the low-voltage area in AF. However, it has limitations; for example, the definition of low-voltage areas is inconsistent, the low-voltage area can be influenced by map density or mapping catheter, and mapping during AF may overestimate the low-voltage area [18].

3.8 Left atrial appendage isolation

The left atrial appendage, a known frequent origin of non-PV triggers [19], is likely involved in the sustained form of AF. Left atrial appendage isolation carries the risk of cardiac perforation. Furthermore, patients who undergo isolation must be placed on lifelong anticoagulation therapy or undergo left atrial appendage closure; therefore, indications for this procedure must be carefully considered [20].

4. Predictive factors of AF recurrence after ablation

Advances in ablation techniques have improved the prognosis for paroxysmal AF. However, the prognosis remains inadequate. To identify patients with a good prognosis, it is necessary to use a new index.

4.1 AF duration

Our study [21] enrolled 82 consecutive patients (mean age, 65.0 ± 12.4 years), including 45 with persistent AF and 37 with long-standing persistent AF. The recurrence rate after ablation was high among patients with long-standing persistent AF. According to Watanabe et al. [22], compared with paroxysmal AF, persistent AF showed a higher recurrence rate after ablation but a lower rate of long-standing persistent AF. Generally, the longer the AF duration, the higher the AF recurrence rate.

4.2 Defibrillation threshold

We studied postprocedural ablation predictors of AF recurrence after univariate and multivariate analyses in 82 patients.10 J was considered the average DFT for persistent AF and set as the cutoff value, as a review article [23] reported that the average DFT for intracardiac cardioversion (IC) of 25 patients with persistent AF was 9.1 ± 7.4 J. In patients with persistent AF, the AF recurrence rate increased with DFT for IC despite the addition of radiofrequency applications after PVI (such as box isolation). We demonstrated that the high DFT was the strongest prognostic factor for AF recurrence after the ablation procedure. Therefore, we speculate that the high DFT is correlated with atrial remodeling, which gradually decreases the success rate of catheter ablation in AF.

4.3 Left atrial diameter, left atrial volume

Liu et al. reported that left atrial diameter (LAD) contributes to the prognosis of patients with AF after catheter ablation [24]. Moreover, Pinto et al. reported that left atrial appendage volume contributes to AF recurrence [25]. In contrast, Masuda et al. [26] reported that LAD and AF recurrence are not correlated; thus, whether they are related remains controversial. In contrast, a review article of a meta-analysis reported that left atrial volume is a predictor of atrial fibrillation recurrence [27].

4.4 Brain natriuretic peptide

Zyng et al. reported that high brain natriuretic peptide (BNP) levels were associated with AF recurrence after catheter ablation [28]. In contrast, we studied postprocedural ablation predictors of AF recurrence after univariate and multivariate analyses in 82 patients, which found no relationship between BNP level and AF recurrence. This might be attributed to the policy of the institute, in which AF ablation is performed after adequate medical treatment for heart failure is administered. Thus, the relationship between BNP level and AF recurrence after catheter ablation requires further investigation.

4.5 Ejection fraction

Our 82-patient study on postprocedural ablation predictors of AF recurrence demonstrated no correlation between ejection fraction (EF) and AF recurrence after ablation. Watanabe et al. reported similar results, indicating that EF is not a prognostic or predictive factor for AF recurrence after ablation.

4.6 Serum creatinine levels

Our 82-patient study on postprocedural ablation predictors of AF recurrence showed no correlation between serum creatinine levels and AF recurrence after ablation. Watanabe et al. similarly stated that creatinine clearance <50 mL/min was not a predictive factor for AF recurrence. Therefore, serum creatinine level is not a prognostic or predictive factor for AF recurrence.

5. Conclusion

Patients with paroxysmal AF who underwent PVI alone had a good prognosis, suggesting that ablation is an established treatment for paroxysmal AF. However, PVI alone for persistent AF may not prevent AF recurrence; thus, additional ablation approaches combined with PVI have been developed. No current procedure clearly shows a preventive effect on AF recurrence; therefore, this issue remains controversial. To improve treatment outcomes of the ablation of persistent AF, it is necessary to identify patients who are most likely to experience the maximum therapeutic effect. Therefore, AF duration and DFT and left atrial volume could be indicators. Future large-scale studies are necessary.

Acknowledgments

The author thanks EDITAGE for providing English language editing.

Conflict of interest

The author declares no conflicts of interest.