First‐Line PVI‐Linear Plan With Pulsed Field Ablation and Vein of Marshall Ethanol Infusion in Persistent Atrial Fibrillation: Safety, Feasibility, and Mitral Isthmus Workflow Optimization

Introduction Different ablation strategies and energy sources have been developed for the treatment of persistent atrial fibrillation (PeAF), but the optimal early management remains controversial. In patients with PeAF, the safety and efficacy of an early linear strategy combining pulsed field ablation (PFA) with vein of Marshall ethanol infusion (VOMEI) have not yet been evaluated. Objective This prospective cohort study aimed to: (1) assess the safety and feasibility of a pulmonary vein isolation plus linear plan (PVI‐LP) combined with VOMEI as a first‐line therapy in patients with PeAF; and (2) evaluate the most effective PFA workflow for mitral isthmus (MI) ablation, comparing a flower‐only approach with a basket + flower strategy integrated with the Faraview system. Methods Between April 2024 and September 2025, 87 consecutive patients with PeAF were referred for PFA using a PVI‐LP strategy combined with VOMEI. The procedural workflow consisted of VOMEI first, followed by left PVI, MI line ablation, roof line ablation, and finally right PVI. At the end of the procedure, both the roof line and the MI line were reassessed after a 15‐min waiting period. All procedures were performed using the Farapulse system. Results Eighty‐seven patients undergoing a PVI‐LP plus VOMEI approach as first‐line therapy were initially included. Marshall vein cannulation or infusion failure occurred in 9/87 patients (10.3%). Thus, 78 patients (89.7%) successfully underwent PFA with the PVI‐LP plus VOMEI approach and were included in the final analysis. Baseline clinical and echocardiographic characteristics were as follows: mean age 70.3 ± 8.9 years, 30.8% women, mean CHA 2 DS 2 ‐VASc score 3.0 ± 1.6, mean left ventricular ejection fraction 59 ± 12%, mean left atrial surface area 26.3 ± 4.5 cm 2 , and mean indexed left atrial volume 51 ± 23 mL/m 2 . Procedural time and fluoroscopy time were 51.9 ± 9 and 12.7 ± 4.5 min for the overall procedure, 9.4 ± 2.9 and 3.3 ± 2.2 min for VOMEI, 4.8 ± 4.7 and 2.7 ± 2.9 min for transseptal puncture, and 22.7 ± 7 and 6.7 ± 2.3 min for PFA, respectively. The rate of 15‐min MI reconnection despite VOMEI decreased from 15/39 (38.5%) in the mitral flower group to 6/39 (15.4%) in the basket + flower + Faraview group, corresponding to an absolute risk reduction of 23.1% (95% CI: 4.1%–42.1%), a relative risk of 0.40 (95% CI: 0.17–0.92), and an unadjusted OR of 0.29 (95% CI: 0.10–0.86). Additional applications were delivered whenever MI conduction recovered, until durable bidirectional block was re‐established. At the end of the procedure, the mean total number of PFA applications was 60.3 ± 9.3: 34.4 ± 3.5 for PVI, 8.7 ± 2.9 for the roof line, and 17.1 ± 6.4 for the mitral line. Acute complications included one nitrate‐reversible coronary spasm during the early phase and one acute pericardial tamponade requiring pericardiocentesis. At mid‐term follow‐up (11 ± 3 months), freedom from any atrial arrhythmia after the blanking period was 80.7%. Recurrences included PeAF in six patients, pAF in four, left atrial flutter in four, and right atrial flutter in one. Conclusion This real‐world prospective cohort study shows that de novo PFA using the PVI‐LP plus VOMEI approach is feasible and safe, with a notably short procedural duration. Acute MI reconnection appears to depend on the specific PFA workflow strategy.