Procedural performance between two cryoballoon systems for ablation of atrial fibrillation depends on pulmonary vein anatomy

Abstract Background Cryoballoon ablation is a first‐line therapy for atrial fibrillation. We compared the efficacy and safety of two ablation systems and addressed the influence of pulmonary vein (PV) anatomy on performance and outcome. Methods We consecutively enrolled 122 patients who were planned for first‐time cryoballoon ablation. Patients were assigned 1:1 for ablation with the POLARx or the Arctic Front Advance Pro (AFAP) system and followed‐up for 12 months. Procedural parameters were recorded during the ablation. Before the procedure, a magnetic resonance angiography (MRA) of the PVs was generated and diameter, area, and shape of each PV ostium were assessed. We applied an evaluated PV anatomical scoring system on our MRA measurement data ranging from 0 (best anatomical combination) to 5. Results Procedures performed with POLARx were associated with shorter time to balloon temperature −30°C (p < .001), lower balloon nadir temperature (p < .001), and longer thawing time till 0°C (p < .001) in all PVs, however, time to isolation was similar. We observed a decreasing performance with each increase in the score for the AFAP, whereas the POLARx performed constant regardless of the score. At 1 year, AF recurred in 14 of 44 patients treated with AFAP (31.8%) and in 10 of 45 patients treated with POLARx (22.2%) (hazard ratio, 0.61; 95% CI 0.28 to 1.37; p = .225). There was no significant correlation between PV anatomy and clinical outcome. Conclusion We found significant differences in cooling kinetics, especially when anatomical conditions are difficult. However, both systems have a comparable outcome and safety profile.


| INTRODUC TI ON
Cryoballoon (CB) ablation for pulmonary vein isolation (PVI) as the first-line therapy is superior to antiarrhythmic drugs for maintaining sinus rhythm in patients with symptomatic, paroxysmal atrial fibrillation (AF). 1,2 Moreover, CB ablation is a reasonable first-line therapy in patients with persistent AF and has proven to be a safe and effective treatment option. 3,4 Recently, a new cryoablation system (POLARx™, Boston Scientific) has entered the market.
Recent studies have associated POLARx with shorter time to balloon temperature − 30 °C (T-30), lower balloon nadir temperatures (NT), and longer balloon thawing time till 0 °C (TT0); however, time to isolation (TTI) was similar to AFAP. 5,6 Furthermore, POLARx appeared to be safe, efficacious, and demonstrated a comparable 1-year outcome. [7][8][9][10] Biophysical parameters such as balloon NT and TT0 have been associated with durability of PVI after CB ablation. [11][12][13] The aim of the present study was to compare the biophysical parameters as well as complications and outcome to the established Arctic Front Advance Pro™ (AFAP, Medtronic) ablation system. Pulmonary vein (PV) anatomy can affect cooling kinetics and CB ablation outcome. [14][15][16][17] A recent study demonstrated an association between cross-sectional orifice area of the superior PVs and outcome after CB ablation in patients with paroxysmal AF. 9 Normal PV anatomy was associated with a significantly improved outcome for both catheter systems. 9 We addressed the influence of various PV anatomical characteristics on the cooling kinetics of both cryoablation systems by applying an established PV anatomy scoring system to preprocedural magnetic resonance (MR) angiography data. 14

| ME THODS
This study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. The authors had full access to and take responsibility for the integrity of the data and have read and agree with the manuscript as written.

| Study design
This was a non-randomized prospective single-center study. We enrolled 122 consecutive patients who underwent a CB ablation for symptomatic AF in our center from November 2020 to May 2021.
For the first 61 patients, the AFAP CB (Medtronic) was used. The following 61 procedures were performed by using the POLARx cryoablation system (Boston Scientific). The day before the ablation, a MR angiography of the pulmonary veins was generated and PV anatomy was evaluated. Procedural parameters (balloon NT, total freeze duration, T-30, TTI, TT0, body time and fluoroscopy time), as well as acute safety and efficacy outcomes were recorded during the ablation.

| Patient enrollment criteria
Briefly, we enrolled adults (>18 years of age) who underwent a firstever ablation for symptomatic paroxysmal or persistent AF. All patients provided written informed consent.

| Cryoablation systems
The POLARx (Boston Scientific, Marlborough, MA, USA) is an upcoming cryoablation system, which largely resembles the wellestablished AFAP (Medtronic, Minneapolis, Minnesota). Both systems consist of a CB catheter (POLARx™ / AFAP™), a steerable sheath (POLARSHEATH™ / FlexCath Advance™), a mapping catheter (POLARMAP™ / Achieve Advance™) and a console (SMARTFREEZE™ / CryoConsole™). Differences to the AFAP are mainly found in the steerable sheath, which offers a slightly greater angle of maximal deflection (155° in POLARSHEATH™ vs. 135° in FlexCath Advance™). 18 The POLARx was designed to maintain stable pressure during all ablation phases aiming to prevent dislodgement of the CB. 18 Furthermore, the SMARTFREEZE console offers the possibility to directly display esophageal temperature and diaphragm movement monitoring.

| Cryoballoon ablation
Cryoablation was performed as described earlier. 19 Briefly, the ablation was performed under deep sedation and right-sided PVs were treated under phrenic nerve pacing. Introducing the 28-mm CB via a steerable sheath (FlexCath Advance™, Medtronic/POLARSHEATH™, Boston Scientific), the mapping catheter (Achieve Advance™, Medtronic/ PolarMap™, Boston Scientific) was used as a guidewire to position the CB proximal to the PV ostium. After inflation of the CB, occlusion was verified for each PV by injecting contrast medium through the inner lumen of the CB. We assessed TTI rigorously by two experienced operators during the ablations. The procedural end point was defined as persistent isolation (entry and exit block) of all PVs verified by the mapping catheter. 19 For safety reasons, a maximum of three CB applications per PV were performed. The standard freeze duration was 180 s.
In case of late TTI or unsatisfactory temperatures, the examiners were allowed to freeze up to 240 s. If PV isolation was not possible but the patients were in sinus rhythm in the follow-up examination, no further interventions were performed. If patients were diagnosed with symptomatic recurrence of AF after a blanking period of 90 days , a second ablation was scheduled using a 3D mapping system and RF energy. At this point, however, the patients were no longer part of the study, as recurrence of AF was considered as therapy failure.

| Thermal imaging
Aiming to prove correctness of the indicated balloon NTs, we measured the balloon surface temperature by thermal imaging. The experiment set up is shown in Figure 1

| MR image analysis
All MR Images were first viewed in the axial, coronal, and transversal plane. Then, a multiplanar reconstruction software (Philipps IntelliSpace PACS, Philips Healthcare, Best, The Netherlands) was used to obtain the oblique view of each PV ostium. PV ostium was defined as the point of maximal inflection between LA-wall and PV. PV ostial area, maximal (PVd max), and minimal diameters (PVd min) were measured. The ovality index was calculated as the ratio between the maximal and minimal diameter. The distance to branching was measured in reconstructed 2D-Images as shown in Figure 2. It was defined as the distance between PV ostium and the first branch leaving the vein and was expressed in millimeter. Using these parameters, an anatomical performance score was evaluated for each vein as described earlier. 14

| Follow-up
After the procedure, patients were typically observed overnight and discharged the following day. All patients received 72-h Holter monitoring at 3-, 6-, and 12-months post-ablation. The first 90 days after procedure were considered as a blanking period for all subjects. The documented recurrence of AF lasting longer than 30 s was considered as therapy failure.

| Patients
Between November 2020 and May 2021, a total of 122 patients were enrolled in this study. All patients were undergoing their first PVI procedure. The first 61 patients received treatment with the AFAP CB. The following 61 procedures were performed using the POLARx cryoablation system. The AFAP group had a higher proportion of patients using ACE inhibitors and a higher proportion of patients suffering from diabetes mellitus compared with the POLARx group. Other baseline characteristics were balanced in the two groups (

| Procedural performance parameters
We compared 61 procedures performed with the POLARx CB with the previous 61 consecutive PVI cases performed with the AFAP.
There was no significant difference for total freeze duration in all veins ( Table 2). Procedures performed with POLARx were associated with lower balloon NTs, shorter T-30 and longer TT0; however, no differences for TTI could be observed (Table 2). Detailed information of procedural and biophysical parameters associated with cryoablation is presented in Table 2 for each PV.

| In vitro performance parameters
Aiming to confirm correctness of indicated NTs, we performed in vitro measurements of surface temperatures of the distal hemisphere of both CBs. Most of our results on the bench match with our findings from procedure data. POLARx is associated with lower indicated balloon NT and longer TT0 (Table 3). However, we found differences for T-30. In our in vitro experiment, the T-30 was significantly shorter for AFAP™ (n = 61) mean ± SD/n (%) POLARx™ (n = 61) mean ± SD/n (%) AFAP (p < .001) ( Table 3), which stands in contrast to our in vivo findings (Table 2). Balloon surface temperature measured by thermal imaging was significantly lower for POLARx (p < .001) ( Table 3). Figure 1 demonstrates temperature profiles and thermal images of both CBs for a freeze duration of 120 s. Detailed information of all in vitro performance parameters is shown in Table 3. Based on our results, there is no indication for incorrect indicated balloon NTs.

| MR imaging
A total of 93 PVI procedures (AFAP: n = 44, POLARx: n = 49) with complete MR scan data were analyzed. Using multiplanar reconstruction software, ostial area, maximal and minimal diameter, ovality index and distance to first branching were calculated for each PV. Detailed information of PV anatomical features is presented in Table S1. In the AFAP group, ostial area as well as maximal and minimal diameter were significantly smaller for RIPV (Table S1).
Additionally, PV ovality index was slightly higher for the RSPV in the AFAP group. Other pulmonary vein anatomical conditions were balanced for both groups (Table S1).

| Anatomical performance score
Based on our results presented in Table S1, we calculated anatomical performance score as described by Borio et al. 14   PVs in reaching the required temperature (p = .001) (Figure 3). The data suggest that the POLARx is much less affected by difficult anatomic conditions. Figure 4

presents reached balloon NTs and TT0
for both groups depending on the anatomical score and for each PV. The results of the Cox-hazard regression analysis are shown in Table S2. Left atrial size was associated with recurrence of AF for patients treated with AFAP (p = .005) (Table S2). In total, 36 patients  (Table S2).

| Safety
There was an overall low incidence of complications in both groups.
Two transient phrenic nerve palsies were recognized in both groups, which recovered within the procedure (Table S3). One patient in the POLARx group suffered a persistent phrenic nerve palsy, which did recover before hospital discharge (Table S3). There were no cases of serious procedure-related adverse events.

| DISCUSS ION
This clinical study compared safety, outcome, and acute procedural parameters of two competing cryoablation systems under consideration of PV anatomical conditions.
Main findings: 1. Both cryoablation systems appeared to be safe and effective.
2. Procedures performed with the POLARx were associated with shorter T-30, longer TT0, and lower indicated NTs; however, TTI was similar. several studies have shown that early TTI is the most powerful predictor of durable PVI. 11,22,23 In both treatment groups, the TTI was longer than that in previous studies. Nevertheless, based on our long-term outcome data, it can be seen that a good treatment success was achieved. Thus, we can only explain the discrepancy in TTI by the fact that we were very strict in our assessment of TTI. Balloon cooling rates and NTs were found to be weak predictors for durable PVI for the second-generation CB (Arctic Front Advance, Medtronic) but a NT of −56°C was the best predictor for acute PVI for the POLARx in a recent study. 11,13,24 As described previously, the data from our in vitro experiment widely match with our gathered procedural data. However, we found a significant difference for T-30.

Based on our in vitro measurements
Procedures performed with the POLARx were associated with significantly shorter T-30. In our in vitro experiment, the AFAP demon-

| Limitations
The validity of the study is mainly restricted by the study design as a nonrandomized single-center study. We performed all procedures without using an esophageal temperature probe. Therefore, the effect of lower balloon NTs of the POLARx on esophageal temperature remains unclear. 5 However, lower NTs in the POLARx group did not result in a higher rate of complications and no symptoms of esophageal irritation were described by subjects in the followup examinations. Moreover, we applied an evaluated PV anatomical scoring system on our MR angiography measurement data but had slightly different measurement methods. While the cut-off in the score was evaluated for PV trunk length, we measured distance

FU N D I N G I N FO R M ATI O N
The work was supported by internal funds of the university RWTH Aachen.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors have no relevant financial or nonfinancial interests to disclose.

DATA AVA I L A B I L I T Y S TAT E M E N T
The authors had full access to and take responsibility for the integrity of the data and have read and agree with the manuscript as written. The data supporting the results of this study are available to reviewers upon request from the corresponding author. The data are not publicly available for privacy or ethical reasons.

E TH I C S A PPROVA L S TATE M E NT
This study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee.

PATI ENT CO N S ENT S TATEM ENT
All patients provided written informed consent.