Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, affects nearly 10 million adults in the United States. While males develop AF earlier, the overall lifetime prevalence is similar between sexes. However, females experience worse outcomes, including greater symptom burden, higher thromboembolic risk, and heightened sensitivity to drug toxicity. Recent studies have also revealed sex-specific mechanistic differences underlying AF, yet, current antiarrhythmic drugs are prescribed without consideration of sex, likely contributing to reduced efficacy in women. This underscores the need to develop sex-specific therapeutic strategies that directly address underlying mechanistic differences. Here, we present a computational pipeline to identify and evaluate sex-specific therapeutic strategies for AF. In this framework, sex-specific human atrial models of chronic AF were used to calculate regression coefficients linking ionic current and Ca 2+ handling perturbations to changes in action potential duration (APD), Ca 2+ transient amplitude, and arrhythmia vulnerability. We leveraged these sensitivity coefficients to identify strategies aimed at recovering AP and Ca 2+ transient characteristics and reversing sex-specific AF mechanisms to normal sinus rhythm. Recovery was defined as the restoration of these features across a graded scale, enabling quantification of both partial and complete restoration. To achieve these goals, the pipeline systematically evaluated combinations of ionic and Ca 2+ handling perturbations, iteratively expanding parameter sets until recovery thresholds were met. The analysis revealed that feasible polytherapy strategies differ between sexes, with males reaching restoration through fewer interventions, whereas females required broader modulation to achieve comparable outcomes. Forward simulations validated that polytherapy combinations can reduce arrhythmia susceptibility in a sex-specific manner. This work delivers the first systematic computational framework to define sex-specific therapeutic strategies for AF. By addressing mechanistic differences between sexes, this approach lays the foundation for safer, more effective, and equitable therapies.
Herrera et al. (Sun,) studied this question.