2.1 Study Population

The study enrolled 900 consecutive patients who underwent cryoballoon pulmonary vein isolation for drug-resistant symptomatic AF at the Heart and Diabetes Center North Rhine-Westphalia, Germany, and the Klinikum Osnabrück, Osnabrück, Germany. This retrospective observational study followed patients who underwent an initial CB-PVI procedure between 2016 and 2023. Patients in the intervention group who underwent treatment with the new technique were enrolled from 2019. The study collected baseline, procedural, and follow-up data. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and approved by our local institutional ethics committee. The procedure in both groups was performed by three operators. Another two electrophysiologists had only performed procedures for the control group. All operators had experience of more than 100 procedures.

2.2 Procedural management

Prior to the procedure, intracardiac thrombus was excluded by preprocedural transesophageal echocardiography (TEE). The majority of patients underwent computed tomography (CT) or cardiac magnetic resonance imaging to visualize detailed anatomy of the left atrium (LA) and pulmonary veins (PVs). Patients who were treated with Vitamin-K-antagonists maintained their daily anticoagulation adjusted to the procedure with a target International Normalized Ratio of between 2.0 and 3.0. In contrast, patients treated with novel oral anticoagulants (NOACs) discontinued medication uptake one half-life prior to the ablation procedure and resumed after a 4-h time interval. Exclusion criteria included any contraindications to the procedure, uncontrolled heart failure, and contraindications to anesthesia.

2.3 Cryoballoon-based pulmonary vein isolation

The procedures were conducted under conscious sedation using propofol and analgesia with fentanyl as needed. Intravenous heparin was administered to maintain an activated clotting time (ACT) of > 300 s throughout the procedure.

Two right femoral vein punctures were performed. A 10-pole steerable diagnostic catheter (Inquiry™, Abbott, USA) was used for coronary sinus intubation, right ventricular rapid pacing, and phrenic nerve (PN) pacing. The procedure utilized a 28 mm 2nd generation CB (Arctic Front Advance, Medtronic, Minneapolis, MN, USA). After transseptal puncture, the balloon catheter was advanced into the LA through a steerable sheath (12-F FlexCath advance Medtronic, Minneapolis, MN, USA). PV mapping was performed using a multipolar mapping catheter (Achieve Advance Mapping Catheter, Medtronic, Minneapolis, MN, USA).

The transseptal puncture (TSP) was performed under fluoroscopy or intracardiac echocardiography (ICE) guidance in the control group until 2019. In the intervention group, TSP was guided solely by fluoroscopy.

After fluoroscopy-guided TSP, the control group underwent pulmonary vein angiography using the standard method or angiography under rapid pacing of the right ventricle. In all patients in the intervention group, angiography was performed under rapid pacing of the right ventricle, as previously reported [6]. Pulmonary vein occlusion was confirmed by PV angiography with the balloon inflated and placed at the PV ostia prior to each freezing cycle. The interventional group used the algorithm of time to isolation (TTI) plus 120 s, while the control group conducted a full freeze of 180 or 240 s. Permanent PVI (entry and exit block) was confirmed after a 20-min waiting period. Prior to ablating the septal PVs, a diagnostic catheter was inserted into the superior vena cava to stimulate the phrenic nerve. Compound motor action potentials (CMAP) from the right diaphragm were recorded along the abdominal palpation as described previously [7]. If the CMAP amplitude decreased by more than 30%, the cryoapplication was immediately stopped. To ensure proper phrenic nerve capture, we also observed diaphragmatic contraction under fluoroscopy.

2.4 Definition of the phrenic nerve injury

We defined any PNI resulting in cessation of cryo application as an event, this included a decrease in CMAP. We defined PNI as transient if it recovered before the end of the procedure or before discharge. If PNI was sustained at discharge, we defined it as persistent.

2.5 New Steps to Prevent PNI

In the intervention group, additional safety measures were taken during the ablation of the right pulmonary veins. Unlike the control group, the intervention group initially targeted the septal veins and the following steps were performed:

Step 1—Decrease PN stimulation output

The PN stimulation threshold was detected for all patients in the intervention group. Instead of continuous pacing with an amplitude of 10 V, we stimulated the phrenic nerve close to the pacing threshold with double output (Fig. 1).

Step 2—Pre-freezing for RSPV

Fig. 1

The consecutive steps of a new approach. All fluoroscopy pictures are presented in RAO 10° angulation, which is preferred over AP angulation because it provides better view of RIPV ostia. A Angiography of the PVs under rapid pacing from RV. Pre-freezing of the balloon close to the RSPV ostia (B) and pushing the balloon towards the ostia with simultaneous contrast injection until occlusion of the vein is verified (C). D After achieving −40 °C or isolating the vein, the pull-away maneuver (and hold until the end of the application) was performed. E The significance of PN stimulation with lower output, closer to the PN stimulation threshold, is demonstrated. The CMAP potential (colored blocks) decreases gradually when stimulated with 6 V/2.0 ms output (in this case, the PN stimulation threshold was 3 V/2.0 ms). Increasing the output to 10 V/2.0 ms immediately results in a higher CMAP potential, even higher than the initial potential under output with 6 V/2.0 ms. The application was immediately stopped despite high CMAP amplitude during stimulation with maximum output

The pre-freezing technique was used to occlude and ablate the right superior pulmonary vein (RSPV). The approach involved inflating the cryoballoon in close proximity to the RSPV ostia, initiating the cryotherapy and then advancing the balloon towards the ostium under simultaneous angiography until occlusion was confirmed (Fig. 1).

Step 3—Pull away for septal PVs

Once the temperature reached − 40 °C and/or the PV was isolated, a “pull-away” maneuver was performed on both right-sided PVs under continuous freezing. This maneuver is similar to the pull-back maneuver, but the position is held until the end of the procedure (see Fig. 1).

2.6 Postprocedural care and follow-up

After PNI was detected, each affected patient underwent a chest x-ray to determine the recovery status of the phrenic nerve before hospital discharge. Additionally, all patients underwent transthoracic echocardiography to exclude any possibility of fluid accumulation in the pericardium. Typically, patients were discharged the day after the procedure.

Anticoagulants were prescribed for a minimum of 3 months after the CB-PVI procedure. Lifelong anticoagulation was recommended according to the individual CHA2DS2-VASC scores. All patients were scheduled for follow-up visits after 3, 6, and 12 months.

2.7 Statistical analysis

Statistical analyses were performed using IBM SPSS V29 (IBM Corporation, Armonk, NY, USA). Data are expressed as percentages for categorical variables and as mean ± standard deviation (SD) or median ± interquartile range (IQR) for continuous variables. We compared continuous variables using Student’s t-test and Mann–Whitney U test as appropriate. Comparisons of categorical variables between groups were performed by Pearson’s X2 test, for expected frequencies < 5 by two-sided Fisher’s exact test. Logistic regression analysis was implemented to adjust for other covariates. Univariate analyses were initially performed and all parameters with p < 0.1 were then included in multivariate analysis. All p-values were two-sided, and statistical significance was assumed at a p-value of 0.05.