BACKGROUND: Transseptal puncture (TSP) for left atrial access is routinely used during various cardiac interventions, including ablation for atrial tachyarrhythmia. However, in selected patients, subsequent iatrogenic atrial septal defects (iASD) persist. This study determines whether fibrotic atrial cardiomyopathy (FACM) or mitral valve regurgitation (MR) are predictors of persistent iASD development post-TSP. METHODS: We analyzed data from patients undergoing radiofrequency ablation with high-density electroanatomical mapping for recurrent atrial tachyarrhythmias after a primary pulmonary vein isolation using either cryo or RF technologies. Patients were categorized based on transesophageal echocardiography findings: (1) competent atrial septum (cAS) (2), iASD, or (3) a patent foramen ovale (PFO). Differences in FACM and MR were assessed across these groups. RESULTS: Of 149 patients (age 67.7 ± 9.7 years), 125 (83.9%) had cAS, 8 (5.4%) iASD, and 16 (10.7%) PFO. No significant differences were observed in age (p = 0.932), BMI (p = 0.612), or LVEF (p = 0.581). The TSP sheath size was not associated with iASD occurrence (p = 0.857). Common surrogates of FACM, i.e., LAVI (p = 0.114), LA area (p = 0.156), mean left atrial pressure (LAP
p = 0.459), or total low-voltage area burden (p = 0.058) did not differ significantly among groups. MR was not linked to increased LAP (at first (p = 0.290) and second procedure (p = 0.212)) or a higher incidence of iASD (at first (p = 0.155) and second procedure (p = 0.917)). Mean LAP did not correlate with LA size (p = 0.471) or low-voltage extent (p = 0.084). CONCLUSION: Our findings underscore that iASDs post-TSP for left atrial ablation are uncommon and unrelated to TSP sheath size, FACM, or MR, further minimizing concerns for routine interventions in patients with more advanced arrhythmia substrate or valvular disease.