Sex differences in atrial electrical properties

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss Heart Foundation Background Pronounced sex differences are known in the incidence and recurrence rates of atrial fibrillation (AF). In general, men carry a higher risk for AF - particularly at younger age - during which women are protected. Purpose In this project, we aimed to investigate electrophysiological properties of the atria that may underlie sex differences in AF development in the younger population. Methods First, we assessed sex differences in P-wave morphology (duration: PWD; area: PWA, amplitude) in 12-lead ECG in healthy volunteers (men 31.3±1.6 y, n=10; women 29.8±1.6 y, n=10) and wildtype (WT) rabbits (3-6 months, males n=12, females n=15). We investigated sex differences in atrial action potential (AP) in WT rabbits of both sexes using sharp electrode recording technique (males n=5, females n=6). To elucidate underlying mechanisms, sex differences on atrial inwardly rectifying potassium current IK1 at 37°C were evaluated using whole-cell patch-clamp technique in isolated atrial rabbit cardiomyocytes; to evaluate the long-term effect of sex hormones on IK1, we incubated the isolated cardiomyocytes for 24h with 3 or 10µM of 17β-estradiol (EST) or of dihydrotestosterone (DHT). Results Analyzing ECG parameters (figure 1), we observed a prolonged PWD and an increased PWA both in healthy men (p<0.0001) and in male rabbits (p<0.0001) as compared to healthy women or female rabbits, which may theoretically be due to a slower conduction velocity or longer AP duration in males. Intracellular AP recordings (figure 2A) showed a more negative atrial resting membrane potential (RMP, males -83.07±0.3mV vs. females -74.33±2.6mV, p<0.05) and a prolonged atrial AP duration (APD10, 18.20±3.6ms vs. 10.06±1.9ms, p=0.06; APD50, 36.60±6.6ms vs. 20.06±1.9ms, p<0.05; APD90, 91.00±10.3ms vs. 74.00±4.0ms, p=0.13) in males as compared to females. As highlighted in figure 2B, male atrial cardiomoycytes had smaller IK1 current densities, which could be due to high DHT concentration; in line with these findings (figure 2C) 24h DHT incubation of atrial cardiomyocytes from females reduced IK1, mimicking the sex differences observed. Conclusions Sex impacts on atrial electrophysiology, resulting in sex differences in P-wave morphology, AP parameters and ionic current densities. Delayed (early) repolarization in males may be causatively linked to the observed changes in P-wave morphology. The reduction of IK1 observed in males may be due to testosterone, since this reduction was observed even in female cardiomyocytes when incubated with DHT.