Sex differences in electrophysiology of the intact atria.

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with electrophysiological and calcium (Ca) handling remodeling. Though AF affects both sexes, there is disparity in the onset, presentation, treatment efficacy and outcomes of the disease: males develop AF earlier, but females experience abnormal symptoms, treatment side effects, and increased risk of mortality. Treatment success likely depends on the underlying arrhythmogenic substrate. However, sex-related differences in AF pathophysiology are currently unclear, complicated by sparse knowledge about how even the healthy atria differs between males and females. As such, this study aims to investigate sex differences in electrophysiology, Ca handling and arrhythmia susceptibility in the intact atria. Hearts were extracted from young (3-4 month) rabbits and optically mapped using voltage (RH237) and Ca-sensitive (Rhod-2 AM) indicators. Signals from the atria were isolated with minimal ventricular interference by covering all tissue beneath the coronary sulcus. Electrical stimulation was performed via a pacing electrode on the right atrium. Rapid pacing and premature stimuli protocols were performed to examine baseline electrophysiology and arrhythmia susceptibility that was further tested with pharmacological intervention with carbachol (0.5 µM). Females had longer action potential duration at 25% repolarization (APD25) but no difference in APD50, APD80 or Ca transient duration (CaTD50 or CaTD80) vs. males. There was similarly no difference in the pacing thresholds for emergence of alternans between sexes; however, females had steeper APD and CaTD restitution. Despite this, arrhythmia vulnerability was greater in males, with sustained reentry observed following application of carbachol and rapid pacing in 66% of animals. Our data suggests that males are more susceptible to reentrant arrhythmias due to innate differences in electrophysiology that may include autonomic modulation. Future work will focus on potential sex differences in the age-associated remodeling that predisposes to AF.