予測的房室細動に対する性別特異的抗不整脈戦略：回帰誘導型計算モデリングパイプライン

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a major contributor to stroke, heart failure, and mortality worldwide. Although AF affects both men and women at a similar rate, accumulating experimental and clinical evidence indicates that its underlying mechanisms, disease progression, and treatment responses differ by sex. However, current antiarrhythmic drug development and clinical management of AF remains largely sex neutral, likely contributing to limited efficacy and increased adverse effects. To address this gap, we developed a computational drug-screening pipeline based on experimentally constrained, sex-specific human atrial cardiomyocyte models to predict and evaluate sex-specific pharmacological strategies for AF. The pipeline integrates multivariable regression with mechanistic modeling to systematically test multi-target combinations of ion channel inhibitors and Ca ²⁺ handling modulators and identify interventions that reduce arrhythmia vulnerability by restoring sex-specific electrophysiological and Ca ²⁺ handling properties toward normal sinus rhythm (nSR). Application of this approach revealed a greater number of successful inhibitory drug combinations in males than in females. In males, optimal recovery to nSR primarily required inhibition of Na ⁺ and K ⁺ channels to prolong repolarization and refractoriness, increase Ca ²⁺ transient amplitude (CaT _Amp ), and reduce susceptibility to action potential duration (APD) alternans. In females, modulation of Ca ²⁺ -related pathways was additionally required to suppress delayed afterdepolarizations (DADs). Forward single-cell simulations confirmed the predictions of the drug-analysis pipeline, demonstrating recovery of APD, CaT _Amp , and arrhythmia vulnerability indices without introducing instabilities. Importantly, extension of these interventions to two-dimensional atrial tissue simulations demonstrated that sex-specific drug strategies reduce vulnerability to triggered activity, while suppression of reentry was most effective when combined with partial recovery of cell-cell coupling. Our results establish a multiscale computational pipeline for identifying sex-informed, multi-target antiarrhythmic therapies, amenable to experimental validation and translation to the clinic.

What is Known: Atrial fibrillation arises from multiple interacting multiscale mechanisms, which limit the effectiveness of single-target therapies.Current single-target antiarrhythmic drugs for atrial fibrillation show more limited efficacy and higher adverse event rates in women than in menWhat the Study Adds: This study demonstrates that effective pharmacologic strategies require different combinations of ion channel and calcium handling modulation in males versus females with persistent (chronic) atrial fibrillation. In males, coordinated Na ⁺ and K ⁺ channel inhibition most effectively improves electrical stability, whereas in females additional targeting of Ca ²⁺ handling is required to suppress triggered activity. Sex-specific multi-target drug strategies including partial recovery of intercellular coupling suppress triggered activity and reentry in atrial tissue while preserving conduction.