Mechanistic insights into sex differences in atrial electrophysiology and arrhythmia vulnerability through sex-specific computational models.

Atrial fibrillation (AF), the most common cardiac arrhythmia, shows marked sex differences in clinical presentation, treatment response and outcomes. Although prevalence is similar, 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 sex-based differences in electrophysiology and calcium (Ca²⁺) handling under normal sinus rhythm (nSR) and chronic AF (cAF) conditions. Although the model parameterizations and assumptions (based on limited human data) 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 Ca²⁺ transient (CaT) dynamics. Simulations revealed that both sexes exhibited shortened effective refractory periods and wavelengths in cAF vs. nSR. Females were more prone to delayed afterdepolarizations (DADs), whereas males were more susceptible to AP duration (APD) and CaT amplitude (CaT_Amp) alternans. Population-based modelling identified distinct parameter associations with arrhythmia mechanisms: DAD vulnerability was associated with enhanced ryanodine receptor Ca²⁺ sensitivity in females, and alternans in males correlated with reduced L-type Ca²⁺ current maximal conductance. Pharmacological simulations revealed sex-specific responses to antiarrhythmic therapies. In males, multiple drug combinations restored APD at 90% repolarization (APD₉₀), CaT_Amp and reduced alternans susceptibility, whereas females responded to only one combination improving APD₉₀ and CaT_Amp but with minimal impact on DAD risk. These findings underscore the need for sex-specific therapeutic strategies and support use of computational modelling in guiding precision medicine against AF. KEY POINTS: Atrial fibrillation (AF) is a common heart rhythm disorder that presents differently in males and females, but how the underlying mechanisms differ in males and females is not fully understood. We developed and validated computer models of male and female human atrial cardiomyocytes that incorporate known sex differences in ion channels and calcium handling under normal sinus rhythm and AF conditions. Under normal rhythm, males and females showed distinct electrical activity, which became less pronounced in AF. In AF, both sexes showed reduced effective refractory period and wavelength and depressed calcium transients. Males were more susceptible to electrical alternans, whereas females showed a greater tendency for calcium-driven delayed afterdepolarizations. Simulated drug treatments showed greater benefit in male models, particularly with combinations targeting multiple potassium channels, whereas female models showed limited response. These results highlight the need for sex-specific approaches to treating AF and may help guide future drug development.