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Background: High-power short-duration (HPSD) radiofrequency (RF) ablation has been adopted to improve atrial fibrillation (AF) ablation. Although the role of HPSD is well-established in pulmonary vein isolation (PVI), fewer data have assessed the impact of HPSD when addressing extra-pulmonary veins (PVs) targets. Therefore, this study aims to determine the safety, effectiveness, and acute outcomes of HPSD lesion index (LSI)-guided posterior wall isolation (PWI) in addition to PVI as an initial strategy in persistent atrial fibrillation (Pe-AF). Methods: Consecutive patients who underwent ablation of Pe-AF in our center between August 2021 and January 2022 were retrospectively enrolled. All patients' ablation strategy was PVI plus PWI using HPSD LSI-guided isolation. RF parameters included 50 W targeting LSI values of ≥5 on the anterior part of the PVs and anterior roofline and ≥4 for the posterior PVs aspect, bottom line, and within the posterior wall (PW). We compared the LSI values with and without acute conduction gaps after the initial first-pass PWI. Left atrial mapping was performed with the EnSite X mapping system and a high-density multipolar Grid-shaped mapping catheter. We compared the procedural characteristics using HPSD (n = 35) vs. a control group (n = 46). Results: Thirty-five consecutive patients were included in the study. PWI on top of PVI was achieved in all cases in the HPSD group. First-pass PVI was achieved in 93.3% of PVs (n = 126/135). First-pass roofline block was obtained in most patients (n = 31, 88.5%), while first-pass block of the bottom line was only achieved in 51.4% (n = 18). There were no significant differences compared to the control group; first-pass PVI was achieved in 94.9% of PVs (n = 169/178), first-pass roofline block in 89.1%, and bottom-line in 45.6% of patients. To achieve complete PWI with HPSD, scattered RF applications within the PW were necessary. No electrical reconnection of the PW was found after adenosine administration and the waiting period. The procedure and RF times were significantly shorter in the HPSD group compared to the control group, with values of 116.2 ± 10.9 vs. 144.5 ± 11.3 min, and 19.8 ± 3.6 vs. 26.3 ± 6.4 min, respectively, p < 0.001. Fluoroscopy time was comparable between both groups. No procedural complications were observed. At the 12-month follow-up, 71.4% of patients remained free from AF, with no differences between the groups. Conclusions: HPSD LSI-guided PWI on top of PVI seems effective and safe. Compared to a control group, HPSD is associated with similar rates of first-pass PWI and PVI but with a shorter procedural and RF time. [ABSTRACT FROM AUTHOR]