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Background: Durable pulmonary vein isolation (PVI) is recommended for symptomatic paroxysmal atrial fibrillation (AF) treatment, but it has been demonstrated that it may not be enough to treat persistent AF (Pe-AF). Therefore, posterior wall isolation (PWI) is among the strategies adopted on top of PVI to treat Pe-AF patients. However, PWI using contiguous and optimized radiofrequency lesions remains challenging, and few studies have evaluated the impact of the Ablation Index (AI) on the efficacy of PWI. Moreover, previous papers did not evaluate arrhythmia recurrences using continuous monitoring. Methods: This is a prospective, observational, single-center study on patients affected by Pe-AF undergoing treated PVI plus AI-guided PWI. Procedures were performed using the CARTO mapping system, SmartTouch SF ablation catheter, and PentaRay multipolar mapping catheter. The AI settings were 500–550 for the anterior PV aspect and roofline, while the settings were 450–500 for the posterior PV aspect, bottom line, and/or PW lesions. All patients received an implantable loop recorder (ILR). All patients underwent clinical evaluation in the outpatient clinic at 1, 3, 6, 12, 18, and 24 months. A standard 12-lead ECG was performed at each visit, and device data from the ILR were reviewed to assess for arrhythmia recurrence. Results: Between January 2021 and December 2021, forty-one consecutive patients underwent PVI plus PWI guided by AI at our center and were prospectively enrolled in the study. PVI was achieved in all patients, first-pass roofline block was obtained in 82.9% of the patients, and first-pass block of the bottom line was achieved in 36.5% of the patients. In 39% of the patients, PWI was not performed with a "box-only" lesion set, but with scattered lesions across the PW to achieve PWI. AI on the anterior aspect of the left PVs was 528 ± 22, while on the posterior aspect of the left PVs, it was 474 ± 18; on the anterior aspect of the right PVs, it was 532 ± 27, while on the posterior aspect of the right PVs, it was 477 ± 16; on the PW, AI was 468 ± 19. No acute complications occurred at the end of the procedure. After the blanking period, 70.7% of the patients reported no arrhythmia recurrence during the 12-month follow-up period. Conclusions: In patients with Pe-AF undergoing catheter ablation, PWI guided by AI seems to be an effective and feasible strategy in addition to standard PVI. [ABSTRACT FROM AUTHOR]