Multicenter Study on the Safety of Pulsed Field Ablation in Over 40,000 Patients: MANIFEST-US

Background: Pulsed field ablation (PFA) is emerging as the preferred energy source for atrial fibrillation ablation, largely because of its promising safety profile, including lower risks of esophageal injury, pulmonary vein stenosis, and phrenic nerve injury. However, rare complications may only emerge after treating many thousands of patients. Objectives: This study sought to determine the real-world utilization and safety profile of the pentaspline PFA catheter in the United States. Methods: In this retrospective analysis, invitations were sent to U.S. centers performing PFA with the pentaspline catheter. Centers submitted data on patient demographics, procedural details, and adverse events (AEs). The main outcomes included the incidence of major and minor procedure-related AEs. Results: Of the 435 centers contacted, 102 participated, averaging 5.1 operators per center (range 1-16 operators per center). Each center treated a median of 412 patients (range 26-1,961 patients), totaling 41,968 patients between February 2024 and July 2025. The median patient age was 68 years (range 17-99 years), and 56% were male. Most patients underwent first-time ablation (73%), primarily for paroxysmal (54%) or persistent atrial fibrillation (37%). Pulmonary vein isolation was performed in 93% of patients, with extravenous lesions on the posterior wall (57%), cavotricuspid isthmus (31%), or mitral isthmus (14%). Major AEs occurred in only 0.63% of patients, including cardiac tamponade (0.16%), vascular injury requiring intervention (0.18%), and stroke (0.10%). Importantly, no cases of esophageal fistula, persistent phrenic nerve paralysis, or pulmonary vein stenosis occurred. Mortality at 30 days was rare (0.04%), but there was a potential signal for rare (0.019%) unexplained sudden death/cardiac arrest. Rare AEs included coronary spasm (0.10%) and acute renal failure requiring dialysis (0.02%). Minor complications were reported in 2.05%, mainly vascular issues (0.96%), pericarditis (0.52%), and self-limited esophageal dysmotility (0.04%). Conclusions: In a real-world setting of unselected U.S. patients, PFA demonstrated a safety profile consistent with preferentiality to functional myocardial tissue ablation, without evidence of esophageal fistula or pulmonary vein stenosis. The major complication rate was ∼0.6%—mostly vascular AEs and pericardial tamponade. Stroke (∼1 in 1,000) and death (∼1 in 2,000) were rare. These data indicate that the initial implementation of pentaspline PFA has been overall safe.