The Clinical Usefulness of Virtual Ablation Guided Catheter Ablation of Atrial Fibrillation Targeting Restitution Parameter-Guided Catheter Ablation (CUVIA-REGAB) was a multi-center, prospective, single-blind randomized controlled trial including non-valvular AF patients who were scheduled for AFCA (ClinicalTrials.gov number NCT02558699). The study protocol was approved by the Institutional Review Board of each participating center (The Severance Clinical Research Center, IRB No.: 4-2015-0646) and complied with the principles of the 2013 Declaration of Helsinki. All participants provided written informed consent before the study enrollment. The trial enrollment began in March 2019.

Patients were eligible if they were i) aged 19–80 years and ii) had documented AF despite more than 6 weeks of antiarrhythmic drug (AAD) treatment or documented AF with intolerance to AADs. The major exclusion criteria were an estimated glomerular filtration rate <30 mL/min, contraindication to anticoagulants, cardiac structural abnormalities that were not suitable to a catheter-based AF ablation procedure, history of major bleeding complications, history of a recurrent ischemic stroke, prior AFCA or Maze surgery, or any other conditions that impeded a cardiac computed tomography (CT) scan.

The included patients were randomly assigned to either the virtual Smax simulation (V-Smax) group or empirical ablation (E-ABL) group in a 1:1 ratio. Randomization was performed by a central randomization service independent of the investigators. All patients received anticoagulation before the AFCA for at least 3 weeks. The AADs were discontinued for at least 5 half-lives prior to the procedure. A cardiac CT scan was performed before the procedure and the absence of any LA appendage thrombus was confirmed. During the ablation procedure, a circular mapping catheter and ablation catheter were advanced into the LA via a transseptal access. Three-dimensional (3D) electroanatomic mapping of the LA was performed in both groups using either an Ensite Navx (Abbott, St. Paul, MN, USA) or CARTO (Biosense Webster, Diamond Bar, CA, USA) system. In patients with ongoing AF at the beginning of AFCA procedure, intracardiac electrical cardioversion was performed and electroanatomic mapping was conducted during sinus rhythm or regular atrial pacing. If the cardioversion failed or AF recurred during the substrate mapping, a repeated cardioversion was attempted up to 3 times. If AF recurred before the completion of the substrate mapping despite electrical cardioversion, the patient was excluded from the analysis. A CPVI was conducted first in both groups, and the V-Smax group received additional ablation guided by the virtual Smax map (Figure 1). In patients in whom AF remained after the completion of the recommended high Smax site ablation, electrical cardioversion was conducted and the procedure was finished after sinus conversion. In the E-ABL group, further extra-PV ablation was conducted at the operator’s discretion. The ablation procedure was performed using radiofrequency energy with an open irrigated catheter with a power of up to 40W. In both groups, ablation of the cavo-tricuspid isthmus line was performed at each operator’s discretion.

The study process in the V-Smax group is shown in Figure 1. At the beginning of the computational modeling procedure, an on-site procedure team acquired the clinical electroanatomical map (voltage map and local activation time [LAT] map) and sent the spatiotemporal data to the core laboratory after integration of the patient’s heart CT imaging. The core laboratory team conducted the simulation study using the patient data obtained from the procedure team while the on-site operators started the CPVI. Merging of the LAT and voltage maps with the CT images were performed by 4 steps: geometry, trimming, field scaling, and alignment.16) The clinical electroanatomical map merged with CT was created to obtain the clinical LAT and voltage maps. We acquired the clinical voltage map that was recorded on the LA during sinus rhythm or regular atrial pacing based on bipolar electrograms. We merged the 3D LA modeling results with CT images of the patient’s heart and then adjusted them with the clinical map.

The detailed description of the 3D computational modeling is provided in the supplemental methods. The LA geometries were reconstructed from the 3D CT digital images and communication in medicine files.9) The virtual LAT and voltage map of the LA were generated and synchronized with the clinical maps using the CUVIA software (Model: SH01; Laonmed Inc., Seoul, Korea). To determine the Smax for each node, the APD of 90% (APD₉₀) and DI were measured during ramp pacing for the duration from the start of the pacing to 3 beats after AF induction. Then the APD restitution curve was determined by employing the relationship between the APD₉₀ and DI, and the Smax was calculated via the maximal slope of the restitution curve, defined at each node of the LA model. The generated Smax map was transmitted to the on-site procedure team for the V-Smax ablation. The region with the highest 10% Smax value was provided by a color-coded Smax map which was normalized between the minimum and maximum V-Smax values of overall nodes for each patient in the V-Smax group. Mean Smax value was 1.00±0.33. We ablated the highest 10% Smax area to minimize the critical mass reduction effects.

The primary study endpoint was a freedom from any atrial tachyarrhythmia recurrence for 12 months. The secondary study endpoints were periprocedural mortality, major bleeding, thromboembolic complications, then procedure time, and total ablation time. Major bleeding was defined as a cardiac tamponade requiring intervention or bleeding events that required a transfusion or resulted in more than a 4 g/dL decrease in the hemoglobin. Post-procedural AADs were used at each operator’s discretion for 3 months after the AFCA, then the AADs were discontinued when there was no recurrent AF. Patients were routinely scheduled to visit our outpatient clinic at 1, 3, 6, and 12 months after the AFCA and every 6 months thereafter. A 12-lead electrocardiogram (ECG) was recorded on every visit, and 24-hour Holter monitoring was performed at 3, 6, and 12 months. After a 3-month blanking period, any AF or atrial tachycardia (AT) recorded on the 12-lead ECG or lasting for more than 30 seconds on the Holter testing was considered a recurrence. All clinical outcomes of interest were confirmed and adjudicated by the central clinical events committee.

The sample size was estimated from the recurrence rate derived from the CUVIA-I trial.8) The AF recurrence rates were presumed to be 20% in the Smax simulation group and 40% in the empirical ablation group. An overall sample size of more than 172 was expected to have an 80% power to detect a statistical difference between the 2 groups at a 2-sided alpha of 0.05. For the baseline characteristics, the continuous variables are presented as the mean±standard deviation and were compared using Student’s t-tests. Categorical variables are presented as frequencies with percentages (%) and were compared by the χ² test or Fisher’s exact test. The cumulative incidence of the primary outcome was estimated by Kaplan-Meier survival curves and compared with the log-rank test. In the overall population, a multivariate Cox proportional hazard regression analysis was used to adjust the risk of the outcome of interest and to identify independent predictors. All variables with p values <0.2 in the univariate Cox regression analysis and other non-significant variables with a proven importance to predict AF recurrence were included in a multivariate Cox proportional hazards regression model. For all 2-tailed comparison, p values <0.05 were considered to indicate statistical significance. All the statistical analyses were performed using SPSS version 25.0 software (SPSS Inc., Chicago, IL, USA).

Among a total of 196 patients with AAD-resistant symptomatic PeAF undergoing catheter ablation, 18 (9.2%) were excluded due to a failed internal cardioversion or 3 episodes of recurrent AF re-initiated during paced atrial substrate mapping, which provided the mandatory electrophysiologic data for our realistic computation modeling (Figure 2). A total of 178 patients were included in the study, including 90 allocated to the V-Smax group and 88 to the E-ABL group. The mean age was 62.2±9.9 years and 131 (73.6%) were male (Table 1). The median AF duration was 31 (15–66) months and the mean CHA₂DS₂-Vasc score was 2.2±1.3. The mean LA dimension (antero-posterior diameter) was 43.0±6.1 mm, and the left ventricular ejection fraction was 56.6±8.7%. Both groups were well-balanced, and there was no significant difference in the baseline characteristics between the 2 groups.

The CPVI was completed in all patients and additional cavo-tricuspid isthmus ablation was performed in 159 (89.3%) patients (Table 2). The mean Smax values were 1.04±0.32 in the V-Smax group and 0.96±0.34 in the E-ABL group (p=0.108). The Smax for the E-ABL was calculated by a post hoc analysis. The high Smax area was located within the low voltage area in 93.5% of the patients and corresponded to the slow conduction zone in 72.3% of the patients. Among the total of 522 high Smax sites, 58.2% were in the areas of disorganized fiber orientation (septum, appendage base, roof of coronary sinus, or PV antrum). In the V-Smax group, additional extra-PV ablation targeting Smax sites was conducted on the roof area (36.7%), anterior wall (41.1%), antero-septum (41.1%), posterior wall (28.9%), and left lateral isthmus area (23.3%), respectively (Table 2, Supplementary Figure 1). In the E-ABL group, extra-PV ablation was conducted for roof line in 23.9%, anterior line in 18.2%, septal line in 5.7%, and posterior box in 8.0% of patients. The bidirectional block rates of the linear ablation were 66.7%, 75.0%, and 71.4% for the roof line, anterior line, and posterior box isolation, respectively. The total procedure time was significantly longer in the V-Smax group than E-ABL group (p=0.008). The major complication rates did not significantly differ between the 2 groups (p=0.498, Table 2). There were 4 cases of intraprocedural cardiac tamponade requiring emergent pericardiocentesis in the V-Smax group. Three of them were developed during CPVI, and the other one was developed during cavo-tricuspid isthmus ablation performed for previously documented atrial flutter. None of the cardiac tamponades were associated with virtual high Smax sites ablation, and all patients were fully recovered.

The mean follow-up duration was 12.3± 5.2 months. After the AFCA, AADs were prescribed in 49 patients (27.5%) after 3 months and 84 (47.2%) patients at the final follow-up, without a significant difference between the 2 groups (Table 3). Recurrence of atrial arrhythmias after the blanking period was observed in 23 (25.6%) patients in the V-Smax group and 21 (23.9%) in the empirical ablation group (log rank, p=0.880) (Figure 3A). According to the mode of recurrence, AT recurrences among the overall clinical recurrences were 43.5% in the V-Smax group and 23.8% in the E-ABL group (p=0.169, Table 3). However, the post-AFCA cardioversion rate was significantly higher in the V-Smax group (14.4%) than E-ABL group (5.7%, p=0.027). In patients who were not prescribed any AAD after 3 months, the AF freedom rate was 52/66 (78.7%) in the V-Smax group and 51/63 (80.9%) in the E-ABL group (p=0.776, Figure 3B). In the multivariate analysis, only AF duration and LA volume index were independent predictors for a clinical recurrence (Table 4). The computational modeling-guided Smax ablation was not associated with higher AF freedom. In a sub-group analysis according to the global average of Smax value, the rhythm outcome did not differ between the patients with an Smax ≥1.0 and those with an Smax <1.0 in either the V-Smax group (Log-rank p=0.796) or E-ABL group (p=0.504) (Figure 4A and B). Examples of Smax maps that represent patients with high (≥1) and low (<1) Smax values are shown in Figure 4C and D.