Mechanistic Insights into Sex Differences in Atrial Electrophysiology and Arrhythmia Vulnerability through Sex-specific Computational Models

作者：Nathaniel T Herrera, Haibo Ni, Charlotte Smith, Yixuan Wu, Dobromir Dobrev, Stefano Morotti, Eleonora Grandi · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.08.18.670886 · 被引用次数：4 · 研究领域：Cardiac electrophysiology and arrhythmias

Abstract Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterized by notable sex differences in clinical presentation, treatment response, and outcomes. Although prevalence is similar between sexes, women often experience more severe symptoms, higher rates of adverse drug effects, and reduced treatment efficacy. To investigate the underlying sex-specific AF mechanisms, we developed and validated male and female human atrial cardiomyocyte models that integrate known sex-based differences in electrophysiology and calcium (Ca 2+ ) handling under normal sinus rhythm (nSR) and chronic AF (cAF) conditions. While the model parameterizations were based on limited human data, and the assumptions may not capture the full spectrum of clinical variability, the models reproduced key reported sex-dependent differences in human atrial cardiomyocyte action potential (AP) and Ca 2+ transient (CaT) dynamics. Simulations revealed that both sexes exhibited shortened effective refractory periods and wavelengths in cAF vs. nSR. However, females were more prone to delayed afterdepolarizations (DADs), while males were more susceptible to AP duration (APD) and CaT amplitude (CaT Amp ) alternans. Population-based modeling identified distinct parameter associations with arrhythmia mechanisms, whereby DAD vulnerability was associated with enhanced ryanodine receptor sensitivity to Ca 2+ (in females), and alternans in males correlated with reduced L-type Ca 2+ current maximal conduc...