The effect of left atrial remodeling after cryoballoon ablation and radiofrequency ablation for paroxysmal atrial fibrillation

Abstract Background Cryoballoon ablation (CBA) and radiofrequency ablation (RFA) are the most common procedures used to treat refractory atrial fibrillation (AF) and are performed through pulmonary vein isolation (PVI). Studies have shown that CBA can approximately match the therapeutic effects of RFA against AF. However, few studies have investigated the difference between CBA and RFA of the effects on left atrial remodeling for paroxysmal AF. Objective Atrial remodeling is considered pivotal to the occurrence and development of AF, therefore we sought to assess the influence of atrial remodeling in patients with paroxysmal AF after CBA and RFA in this study. Methods In this nonrandomized retrospective observational study, we enrolled 328 consecutive patients who underwent CBA or RFA for refractory paroxysmal AF in May 2014 to May 2017 in our hospital. After propensity score matching, 96 patients were included in the CBA group, and 96 were included in the RFA group. Patients were asked to undergo a 12‐lead electrocardiogram, a 24‐h Holter monitor, and an echocardiogram and to provide their clinical history and symptoms at 6 months and 1, 2, and 3 years postprocedurally. Electrical remodeling of the left atrium was assessed by P wave dispersion (Pdis); structural remodeling was assessed by the left atrium diameter (LAD) and left atrial volume index (LAVI) during scheduled visits. Results As of January 2020, compared with baseline, at 1 year, 2 years, and 3 years after ablation, the average changes in Pdis (∆Pdis), LAD (∆LAD), and LAVI (∆LAVI) were significant in both the CBA and RFA groups. Six months after ablation, ∆Pdis, ∆LAD, and ∆LAVI were greater in the CBA group than in the RFA group. There was no significant difference between the two groups in AF/flutter recurrence, but the AF/flutter‐free survival time of CBA group may be longer than RFA group after 2 years after ablation. A higher ∆Pdis, ∆LAD, or ∆LAVI at 1 year after ablation may increase AF/flutter‐free survival. Conclusions Although CBA and RFA are both effective in left atrial electrical and structural reverse‐remodeling in paroxysmal AF, CBA may outperform RFA for both purposes 6 months after ablation. However, during long‐term follow‐up, there was no significant intergroup difference.

Conclusions: Although CBA and RFA are both effective in left atrial electrical and structural reverse-remodeling in paroxysmal AF, CBA may outperform RFA for both purposes 6 months after ablation. However, during long-term follow-up, there was no significant intergroup difference.

| INTRODUCTION
Previous studies have shown that the occurrence and development of AF are closely related to atrial remodeling, which includes neural remodeling, electrical remodeling and structural remodeling. [1][2][3] In recent years, as catheter ablation based on pulmonary vein isolation (PVI) has become accepted as the cornerstone of all AF ablation procedures to maintain sinus rhythm, studies have been performed to observe the clinical outcomes of both cryoballoon ablation (CBA) and radiofrequency ablation (RFA). Evaluations of the differences in the safety and effectiveness of these two procedures have shown that CBA can achieve therapeutic effects similar to those of RFA in the treatment of paroxysmal AF. [4][5][6][7] Several studies have explored the effects of catheter ablation on left atrial size [8][9][10][11] and electrical conduction [12][13][14][15] in patients with AF, but no one has compared the influence of atrial remodeling caused by CBA and RFA in paroxysmal AF.

| Patients
We searched for patients who underwent CBA or RFA for paroxysmal AF in May 2014 to January 2017 at the First Affiliated Hospital of Zhengzhou University. Patients were selected according to the inclusion and exclusion criteria. All patients were required to have complete medical records, including age, sex, height, weight, and history of AF and comorbidities, as well as a preprocedural transesophageal echocardiogram to verify the absence of intracardiac thrombus and a computed tomography angiography (CTA) imaging to review the anatomy of the left atrium and PVs before the procedure. The management of oral anticoagulation during the perioperative period was determined by the physician according to the CHA2DS2-VASc score.
We enrolled patients according to the following criteria: patients aged 18 to 75 years with paroxysmal AF who had undergone RFA or CBA.
Exclusion criteria included a previous history of catheter ablation for AF, complicated with valvular heart disease, hepatic and renal insufficiency, hyperthyroidism, cardiomyopathy, and implanted pacemakers or defibrillators.

| Follow-up
Patients were followed up by WeChat platform and outpatient service at 6 months and 1, 2, and 3 years after ablation, assessed for clinical history and symptoms, and asked for a 12-lead electrocardiogram, a 24-h Holter monitor, and an echocardiogram. Patients who presented with symptoms such as palpitations and chest tightness were asked to undergo a 12-lead electrocardiogram or a 24-h Holter monitor immediately and to transmit the ECGs to us. Atrial fibrillation (AF)/flutter-free survival was defined as the absence of AF and atrial flutter recurrence ≥30 seconds following a 3-month blanking period. AF/flutter recurrence was defined as documented recurrence of AF or atrial flutter (lasting more than 30 s) after the 90-day blanking period or repeat ablation. 6 Electrical remodeling of the left atrium was assessed by P wave dispersion (Pdis) [16][17][18] as measured by a 12-lead electrocardiogram, while structural remodeling was assessed by the left atrium diameter (LAD) and left atrial volume index (LAVI) as measured by echocardiogram during scheduled visits. [19][20][21] Pdis was defined as the difference between the maximum and minimum P-wave durations recorded by the 12 ECG leads. 17,22 Minimum three consecutive beats were measured in all simultaneous 12 leads to calculate P-wave duration. LAD and left atrial volume (LAV) were measured using real-time three-dimensional echocardiography technology, then, the LAV was converted to LAVI by dividing by body surface area. Evaluation of each measurement was repeated three times to obtain the mean value for analysis. The postprocedural Pdis, LAD, and LAVI of each patient were subtracted from the Pdis, LAD, and LAVI at baseline to obtain the changes in Pdis, LAD, and LAVI of each patient, and then we could obtain the mean values of the changes in Pdis, LAD, and LAVI, that is, ΔPdis, ΔLAD, and ΔLAVI, in the CBA group and the RFA group. Follow-up was ended once the patient underwent a repeat ablation after AF/flutter recurrence.

| Ablation procedure
During CBA, a second-generation cryoablation catheter and Achieve electrodes were advanced to the orifice of the PV. Once or twice cryoballoon freezes (each with a duration of 180 seconds) was performed to achieve PV isolation in each pulmonary vein. For RFA, after a three-dimensional reconstruction of the left atrium, salineirrigated electrode was used to perform pulmonary vein antrum isolation (PAVI) until complete PVI is obtained.

| Structural and electrical remodeling
In the per-protocol analysis, as shown in Table 2, compared with baseline, at 1, 2, and 3 years after ablation, the changes in Pdis, LAD, and LAVI were significant in both the CBA and RFA groups. At 6 months after ablation, the average changes in Pdis, LAD, and LAVI were larger in the CBA group than in the RFA group (shown in Table 3). However, there were no significant group differences in the other indices.

| Atrial fibrillation/flutter recurrence and atrial fibrillation/flutter-free survival time
As of January 2020, AF/flutter recurrence had recurred in 33(34.4%) patients in the CBA group and 39(40.6%) in the RFA group, but there was no significant difference between the two groups (Chisquare = 1.047, P = .592).
The Kaplan-Meier method was used to compare the AF/flutterfree survival time between the two groups (shown in Figure 1). The mean AF/flutter-free survival times of the two groups are shown in Note: LAD, left atrial diameter; ΔLAD, the mean value of the change in LAD; LAVI, left atrial volume index; ΔLAVI, the mean value of the change in LAVI; Pdis, P-wave dispersion; ΔPdis, the mean value of the change in Pdis. *P < 0.05: the difference between the CBA group and the RFA group was significant.
between the two groups (Chi-square = 0.164, P = .685). Then, we compared the AF/flutter-free survival times in cases with recurrence within 2 years and after 2 years between the CBA and RFA groups and found that the survival time of CBA group may be longer than RFA group after 2 years after ablation (shown in Figure 1 and

| Structural and electrical remodeling
The mechanism of occurrence and maintenance of AF remains unclear, but evidence indicates that rapid focal activation originating from the pulmonary veins may play a pivotal role. However, catheter ablation for AF remains challenging, with a low success rate over long-term follow-up. 5,19 Previous studies have shown that RFA can reduce left atrium size and volume in patients without recurrence. 9,10 Similarly, Canpolat et al 12  hence, CBA could potentially be noninferior to RFA with regard for safety and efficacy, as the FIRE AND ICE Trial showed over a 1.5-year follow-up duration. 6 In terms of long-term follow-up, the STOP AF Trial obtained a ratio of 64.1% for freedom from AF and symptomatic atrial flutter/atrial tachycardia at 36 months after CBA in patients with paroxysmal AF. 5 Another study reported a ratio of 41% freedom from atrial tachyarrhythmia recurrence after 31 ± 16 months of follow-up following a single RFA procedure in nonparoxysmal AF. 26 Our study compared the difference in the AF/flutter-free survival rate between CBA and RFA during a three-years-follow-up but did not show a significant difference. An important difference between our study and the aforementioned studies is that we evaluated clinical benefits according to the AF/flutter-free survival time and sought to explore the relationship between reverse left atrial remodeling and clinical benefits. In our study, the AF/flutter recurrence rates and AF/flutter-free survival times were not significantly different between the CBA and RFA groups, but the CBA group may have a longer survival time over 2 years after ablation.

| Associations of ΔPdis, ΔLAD, and ΔLAVI with atrial fibrillation/flutter-free survival
The DECAAF study found that progressive remodeling of the left atrium might be responsible for failure after ablation 27 ; hence, we sought to explore whether AF/flutter-free survival after ablation is associated with left atrial reverse-remodeling. We found that ΔPdis, ΔLAD, and ΔLAVI at 1 year after ablation were positively correlated with AF/flutter-free survival, indicating that left atrial electrical and structural reverse-remodeling may have a positive effect on AF/flutter-free survival after ablation.

| LIMITATIONS
This study is a single-center study with a small sample size, and large randomized studies are needed to confirm these data. Regrettably, we did not require long-term continuous electrocardiographic monitoring after ablation, and the effects of ablation on the AF/flutter recurrence rate and AF/flutter-free survival time may have been exaggerated. A more obvious difference may be found if a longer follow-up time and a larger sample size are used to explore the difference in long-term AF/flutter-free survival time using these two methods.

| CONCLUSIONS
Our results show that both CBA and RFA are effective in left atrial electrical and structural reverse-remodeling in AF, and CBA may perform better in electrical and structural reverse-remodeling at 6 months after ablation. However, over the long-term follow-up period, there was no significant difference between the two groups.

ACKNOWLEGMENTS
This study was supported by the National Natural Science Foundation of China (81600271).

CONFLICT OF INTEREST
The authors declare no potential conflict of interests.

DATA AVAILABILITY STATEMENT
Research data are not shared.

ETHICS STATEMENT
Informed written consent was signed by all patients. This study was approved by the ethics review committee of the First Affiliated Hospital of Zhengzhou University. Note: CBA, cryoballoon ablation; RFA, radiofrequency ablation.