Sex Differences in the Electrophysiological Characteristics of Pulmonary Veins and Left Atrium and Their Clinical Implication in Atrial Fibrillation

BACKGROUND: Sex and the autonomic nervous system play critical roles in the pathophysiology of atrial fibrillation (AF). Sex differences in electrophysiological characteristics of the pulmonary veins (PVs, AF initiator) and left atrium (LA, AF substrate) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record the action potential in isolated PV and LA tissue preparations from male and female (age, 8≈10 months) rabbits before and after drug administration (adenosine, acetylcholine, and isoproterenol). Male PVs (n = 7) had a higher spontaneous beating rate (1.7 ± 0.2 versus 1.2 ± 0.1 Hz, P = 0.021) and incidence of burst firing (72% versus 11%, P = 0.038) than female PVs (n = 9). Male PVs without spontaneous activity (n = 10) and the LA (n = 11) had longer action potential durations than female PVs (n = 9) and LA (n = 9). Additionally, male PVs had a more-positive resting membrane potential (79 ± 3 versus 84±2 mV, P=0.022). Isoproterenol (3 μmol/L) increased the delayed afterdepolarizations to a greater extent in male than in female PVs. In PVs without spontaneous activity or LA, isoproterenol (0.1 and 3 μmol/L) consistently shortened the action potential durations in females but not in males. Acetylcholine (5.5 μmol/L) decreased the spontaneous activity of PVs and shortened the action potential durations in both groups. Adenosine (10 μmol/L) also similarly decreased the spontaneous activity of PVs and delayed afterdepolarizations in both groups. CONCLUSIONS: There are significant sex differences in PV and LA action potential characteristics in rabbits. The higher amplitude of delayed afterdepolarizations after isoproterenol superfusion in male PVs may contribute to sex-related arrhythmogenesis.