Higher Na⁺-Ca²⁺ Exchanger Function and Triggered Activity Contribute to Male Predisposition to Atrial Fibrillation

Male sex is one of the most important risk factors of atrial fibrillation (AF), with the incidence in men being almost double that in women. However, the reasons for this sex difference are unknown. Accordingly, in this study, we sought to determine whether there are sex differences in intracellular Ca²⁺ homeostasis in mouse atrial myocytes that might help explain male predisposition to AF. AF susceptibility was assessed in male (M) and female (F) mice (4-5 months old) using programmed electrical stimulation (EPS) protocols. Males were 50% more likely to develop AF. The Ca²⁺ transient amplitude was 28% higher in male atrial myocytes. Spontaneous systolic and diastolic Ca²⁺ releases, which are known sources of triggered activity, were significantly more frequent in males than females. The time to 90% decay of Ca²⁺ transient was faster in males. Males had 54% higher Na⁺-Ca²⁺ exchanger (NCX1) current density, and its expression was also more abundant. L-type Ca²⁺ current (I_CaL) was recorded with and without BAPTA, a Ca²⁺ chelator. I_CaL density was lower in males only in the absence of BAPTA, suggesting stronger Ca²⁺-dependent inactivation in males. Ca_V1.2 expression was similar between sexes. This study reports major sex differences in Ca²⁺ homeostasis in mouse atria, with larger Ca²⁺ transients and enhanced NCX1 function and expression in males resulting in more spontaneous Ca²⁺ releases. These sex differences may contribute to male susceptibility to AF by promoting triggered activity.