Sex-specific differences in left atrial fibrotic, structural and electrical remodeling in atrial fibrillation: P-wave duration enables sex-specific outcome prediction after pulmonary vein isolation

Abstract Background and aims Success rates of pulmonary vein isolation (PVI) differ significantly between female vs. male AF patients. We sought to assess differences in left atrial (LA) substrate and identify sex-specific predictors of arrhythmia outcome following circumferential PVI in females vs. males. Methods A total of 278 consecutive AF patients undergoing their first PVI procedure were included (100 female and 178 male, 45% paroxysmal AF). All patients underwent high-density (>2000 mapped sites per LA) voltage mapping during sinus rhythm (SR). LA global mean bipolar voltage (GMV), LA volume (LAV), extent of low voltage substrate (LVS) at 0.5mV and at 1.0mV thresholds were quantified. Biatrial conduction time was non-invasively determined measuring the „duration of amplified digital p-wave in SR (APWD)". All patients completed rhythm follow-up visits with 72-hour Holter recordings at 3, 6, 12, 18 and 24 months. Results Important sex-specific differences in LA remodeling were observed between female vs male AF patients: While a more advanced LA dilation was present in males (LAV: 99.3±27.8 ml vs. 91.0±23.5 ml, p=0.012), the extent of the LVS area (as electrical marker of fibrosis) was significantly smaller in males than in females at both bipolar thresholds: at 0.5 mV (1.1 cm2 [0.3-6.1 cm2] vs. 0.1 cm2 [0-1.7 cm2], p<0.001) and at 1.0 mV (9.2 cm2 [3.6-24.1 cm2) vs. 2.1 cm2 [0.7-7.6 cm2], p<0.001). GMV was significantly lower in females (1.7 ± 0.6 mV vs. 2.5 ± 0.9 mV, p<0.001). In contrast, biatrial conduction time (APWD) - which is influenced by both dilation and fibrotic remodeling with conduction slowing - was not significantly different (150 ± 23 ms vs. 148 ± 20 ms, p=0.321). Multivariate analysis revealed LVS <1.0mV and APWD as arrhythmia predictors in female patients, whereas in male patients LAV, LVS <1.0mV and APWD were the three significant arrhythmia predictors. In male patients, the LAV threshold of 98ml and the LVS threshold of 2.7cm2 (at 1.0mV) were associated with 81.0% vs. 48.7% and 76.1% vs.55.3% arrhythmia freedom rates at 24 months. The APWD threshold of 153ms was associated with 81.9% vs. 40.1% arrhythmia freedom rates at 24 months. In female patients, The LVS threshold 13cm2 (at 1.0mV) was associated with 67.3% vs. 35.7% arrhythmia freedom rates at 24months and below/above the APWD threshold of 141ms with 71.1% vs 47.5% at 24 months of FU. Conclusions LA remodeling differs between male and female patients. While LA dilation and to lesser extent fibrosis governs atrial remodeling in males, predominant fibrotic remodeling occurs in females. APWD depicts both remodeling processes (dilation and fibrotic remodeling) and is a potent predictor of arrhythmia outcome after PVI in both sexes.sex difference in atrial remodeling KM curves of atrial remodeling