Conversion of atrial fibrillation to sinus rhythm during cryoballoon ablation: A favorable and not unusual phenomenon during second‐generation cryoballoon pulmonary vein isolation

Abstract Background The prevalence and the clinical impact of conversion of atrial fibrillation (AF) to sinus rhythm (SR) during cryoballoon ablation (CB‐A) are unknown. Objective The purpose of this study was to evaluate the prevalence of restoration of SR during CB‐A and the clinical impact of this phenomenon. Methods Between January 2012 and September 2018, all patients who experienced conversion of AF to SR during CB‐A were included. This group was subsequently matched for gender, age, type of AF, diagnosis‐to‐ablation time, and left atrial size with patients who underwent CB‐A and did not experienced conversion of AF to SR. After discharge, patients were scheduled for follow‐up visits at 1, 3, 6, and 12 months and 24 hours Holter recordings were obtained at each follow‐up visit. All documented AF episodes of >30 seconds were considered as recurrence. A 3 month post‐procedural blanking period (BP) was applied. Results A total of 1559 patients underwent pulmonary veins isolation by CB‐A between January 2012 and September 2018; among them, 58 patients (3.7%) experienced restoration of SR during CB‐A. In total, 53 patients (41 males [77.3%], mean age 61.4 ± 13.3 years) were included in the case group. During CB‐A, restoration of SR occurred more frequently during right‐side PVs applications (right inferior pulmonary vein 39.6%, right superior pulmonary vein 30.2%). If considering a BP, at 2 year follow‐up, freedom from recurrences was 86.5% in the case group and 68.0% in the control group (P = .036). Conclusion Conversion of AF to SR is a favorable and relatively frequent phenomenon during cryoballoon pulmonary vein isolation ablation.


| INTRODUC TI ON
Pulmonary veins isolation (PVI) is currently an establish and reliable treatment for patients with refractory symptomatic atrial fibrillation (AF). 1 Over the last decade, cryoballoon ablation (CB-A) has emerged as an effective alternate strategy to point-by-point radiofrequency (RF) ablation, showing similar outcomes in terms of freedom from AF when compared to traditional techniques 2,3 and also favorable data in terms of total procedural time 3 and reproducibility. 4 Both safety and effectiveness of the CB-A technology were firstly assessed in patients with documented symptomatic paroxysmal AF, 5 and then, its non-inferiority to other energy sources was confirmed also in the setting of persistent AF. 6,7 Although some differences have been described in terms of temperature behavior when CB-A has been performed in patients with ongoing AF compared to those in sinus rhythm (SR), 8 still this procedure can be performed regardless of the presenting cardiac rhythm, solely aimed at electrically isolating the pulmonary veins (PVs) from the left atrium (LA). Since in the stepwise RF ablation approach, 9,10 whose main goal is the intra-procedural AF termination achieved by different and sequential ablation approaches, conversion of AF to SR has then been demonstrated to be a strong predictor for single-procedure success, 11 restoration of SR during CB-A PVI might also correlate with the clinical outcome. The present study sought to focus on the mid-term outcomes in patients who experienced conversion to SR during PVI CB-A performed for drug-resistant AF.

| Study population
Between January 2012 and September 2018, all patients who experienced conversion of sustained (>30 seconds) AF to SR and no further intra-procedural documentation of atrial tachycardia (AT)/AF during CB-A performed for both paroxysmal and persistent AF were retrospectively analyzed and considered for our study. This group (case group) was subsequently matched for gender, age, type of AF, diagnosis-to-ablation time, and LA size with patients who underwent CB-A over the same period of time and did not experienced conversion of AF to SR with a 1:2 ratio (control group). During this time span, the second-generation Arctic Front Advance (AFA, Medtronic) 28 mm cryoballoon (CB) was the catheter of choice for this specific procedure. All procedures have been performed in our Center by electrophysiology fellows under the strict supervision of experienced operators. The exclusion criteria for the procedure were any contraindication for the procedure including the presence of an intracavitary thrombus, uncontrolled heart failure (HF), and contraindications to general anesthesia. This study was run in compliance with the principles outlined in the Declaration of Helsinki and approved by the institutional ethics committee of our institutions.

| Aim of the study
The main aim of the study was to analyze the prevalence of restoration of SR during CB-A AF ablation and the clinical impact of this phenomenon in terms of mid-term outcome after ablation.

| Pre-procedural management
All patients provided written informed consent prior to the procedure. A transthoracic echocardiogram (TTE) was performed within 1 week prior to ablation. To exclude the presence of intracavitary thrombi, all patients underwent transesophageal echocardiography (TOE) the day before the procedure. The LA diameter was assessed by 2D transthoracic echocardiography as the LA anteroposterior diameter measured during parasternal long-axis M-mode recordings and indexed to body surface area. Moreover, prior to the procedure, detailed information on LA and PVs anatomy was achieved by computed tomographic (CT) scan. All antiarrhythmic drugs (AADs) were discontinued at least 5 half-lives prior to ablation (except for amiodarone). Exclusion criteria were the presence of LA thrombus, severe uncontrolled HF, and any contraindications to general anesthesia.

| CB-A procedure
The CB-A procedure has been described in detail previously. 12 Briefly, after obtaining LA access through a single trans-septal puncture, a steerable 15 Fr sheath (FlexCath Advance, Medtronic) was placed in the LA. Before introducing the CB in the sheath, the inner lumen mapping catheter (ILMC) was inserted in its lumen; both 2ACH20 20 mm and 2ACH25 25 mm Achieve mapping catheter (Achieve Advance, Medtronic) were used as ILMC during this time span. Afterwards, the 28 mm CB was advanced through the sheath into the LA, and it was then inflated and positioned close to each PV ostium. Before ablation, for each PVs, the ILMC was positioned at a proximal site in the PV ostium, in order to record baseline pulmonary vein potentials (PVPs). PVs occlusion was considered optimal when selective iodine contrast injection showed total contrast retention, without any backflow into the LA; once occlusion was documented, the cryo-application was started delivering initially two applications and then from April 2013 with a single freeze-thaw cycle of 240 first and 180 seconds then for each vein. 13 Our usual ablation sequence was treating the K E Y W O R D S atrial fibrillation, cardioversion, catheter ablation, cryoablation, pulmonary vein isolation left superior PV (LSPV) first, followed by the left inferior (LIPV), right inferior (RIPV), and right superior (RSPV). During ablation, if PVPs were visible during energy delivery, time to isolation was recorded when PVPs completely disappeared or were dissociated from LA activity. Further additional cryothermal applications were not considered necessary if the veins were isolated following the initial freeze. Based on the findings documented throughout this all period, a second freeze-thaw cycle was then delivered if, during the first application, PV isolation occurred after 60 seconds or if the temperature of −40°C was not reached during within the first 60 seconds of the cryo-application. 14 If no PVPs were detected before and during ablation, from 2017, the temperaturebased approach of −40°C within first 60 seconds was taken as a reference to define an effective cryo-application. 15 Durable PV isolation was then assessed for each PV at the end of the procedure. During the whole procedure, activated clotting time was maintained over 250 seconds by supplementing heparin infusion, as required. was immediately stopped, with immediate deflation of the CB, 16 in case of VPW decrease of more than 50% of the peak-to-peak initial value, and/or if weakening or loss of right diaphragmatic movement was noted. In case of phrenic nerve palsy (PNP), the eventual recovery of diaphragmatic contraction was carefully monitored for 15 minutes.

| Post-ablation management
All patients were discharged the day following the ablation if their clinical status was stable. Before hospital discharge, all patients underwent TTE and a chest X-ray in order to exclude pericardial effusion or any complications related to the procedure. Low-molecular-weight heparin was started the same day of the procedure and continued until target international normalized ratio was reached; in patients taking new oral anticoagulants therapy, the treatment was restarted the same day of the ablation. The decision to switch or restart AADs after the procedure, or to perform a repeat procedure, was taken in cases of a first episode of recurrence of AF according to both patient and physician's preferences.

| Follow-up
After discharge from the hospital, patients were scheduled for follow-up visits at 1, 3, 6, and 12 months and then according to the clinical preferences of the physician. Twenty-four hours Holter recordings were obtained at each follow-up visit. All reports of Holter monitoring or electrocardiogram recordings having been performed in referring centers were sent to the Heart Rhythm Management Centre, UZ Brussels for diagnosis confirmation during follow-up. All documented AF episodes of >30 seconds after the index procedure were considered as a recurrence. A 3 month post-procedural blanking period (BP) was applied. 1   Table 1.

| Procedural characteristics
All patients underwent CB-A performed with the second-generation AFA 28 mm CB. Mean procedure (ie, from the first groin puncture to complete sheath extraction) and fluoroscopy times in the case group were 66.4 ± 15.5 and 16.2 ± 4.7 minutes, respectively.
All PVs were successfully isolated with CB-A without the need for additional focal-tip ablation. There was no other statistically significant difference between the two groups in terms of anatomical variants of PVs, numbers of PVs that required more than one freeze or mean minimal temperatures achieved in each vein. There was no major complications in any patient of the study, while transient PNP occurred in four patients in the case group (7.5%) and in seven patients in the control group (6.6%). Procedural details are shown in Table 2.

| Outcome and repeat procedure
Mean follow-up in the case group was 27.9 ± 17.9 months. If considering a BP of 3 months, the freedom from AF at 24 month

| D ISCUSS I ON
To the best of our knowledge, this is the first study evaluating the prevalence and the mid-term clinical outcomes of patients experiencing restoration of SR during CB-A AF ablation using the second-generation 28 mm CB. The main finding of our study is that this phenomenon is associated with a low rate of AF recurrence over a 24 month follow-up, granting freedom from any atrial arrhythmia in 86.5% of individuals after a BP in this specific population, with significant difference in terms of outcome when compared to a matched population.
After the first description of the PV origin of the atrial ectopic beats initiating AF, 18 permanent PVI by modifying the LA-PV junction using various ablation techniques has gradually become the cornerstone of any AF ablation. 1 In particular, among all the different therapeutic options in the setting of patients with drug-refractory paroxysmal AF, PVI by CB-A has proven to be noninferior to PVI performed by RF ablation in terms of both efficacy and safety. 19,20 Subsequently, also in the context of persistent 21,22 and long-standing persistent 22 AF, CB-A has demonstrated to be safe and effective.
The overall comparability of these two different techniques, after being addressed by the FIRE and ICE trial, 19 was recently confirmed by an observational cluster cohort study by Hoffmann et al, 23 who showed no difference between CB-A and RF ablation in terms of atrial arrhythmia recurrence and, furthermore, significantly less rehospitalization due to re-ablations and adverse events during follow-up after CB-A.
As the target of the procedure is defined by effective and permanent PVI, the ablation can be carried out independently of the presenting rhythm, since the restoration of SR during the ablation is not In the context of RF AF ablation, termination of AF to SR or AT has been traditionally pursued as procedural endpoint within the stepwise ablation approach. 9,10 Ablation with the endpoint of AF termination was seeking to progressively target the multiple drivers sustaining AF, until most or all of the sources were eliminated 29 ; therefore, conversion to SR during ablation has been proposed as a

| LI M ITATI O N S
Our study has some important limitations. First, a major limitation of our study is its nature (ie, non-randomized, single-center, retrospective). Second, in our daily practice during CB-A, AF has not been regularly induced at the beginning of the procedure and most of the patients undergo this procedure in SR; therefore, the prevalence of the phenomenon described above might be deeply underestimated. Third, no patient has been implanted with an implantable loop recorder; therefore, asymptomatic episodes occurred during the follow-up might have occurred unnoticed and our success rate might have been overestimated. Fourth, since the number of events in the follow-up was relatively small, we did not evaluate the presence of predictors of arrhythmias recurrence. Future prospective studies are needed to better define the clinical impact of conversion of AF to SR during CB-A.

| CON CLUS IONS
Restoration of SR during AF ablation performed with second-generation CB is a favorable and quite frequent phenomenon; up to 86.5% of individuals showing this specific sign can be expected to be free of AF recurrence at a 2 year follow-up. fibrillation: executive summary. J Interv Card Electrophysiol.