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BACKGROUND

Substantial sex-based differences have been reported in atrial fibrillation (AF), but the underlying mechanisms are poorly understood.

OBJECTIVES

This study sought to gain a mechanistic understanding of Ca-handling disturbances and Ca-driven arrhythmogenic events in male vs female atrial cardiomyocytes and establish their responses to Ca-targeted interventions.

METHODS

We integrated reported sex differences and AF-associated changes (ie, expression and phosphorylation of Ca-handling proteins, cardiomyocyte ultrastructural characteristics, and dimensions) into our human atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca-handling processes. Sex-specific responses of atrial cardiomyocytes to arrhythmia-provoking protocols and Ca-targeted interventions were evaluated.

RESULTS

Simulated quiescent cardiomyocytes showed increased incidence of Ca sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca transients compared with the male model. Sensitivity analysis uncovered distinct arrhythmogenic contributions of each component involved in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation emerged as the major SCR contributor in female AF cardiomyocytes, whereas reduced L-type Ca current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulated Ca-targeted interventions identified potential strategies (eg, t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca⁺-ATPase) to attenuate Ca-driven arrhythmogenic events in women, and revealed enhanced efficacy when applied in combination.

CONCLUSIONS

Sex-specific modeling uncovers increased Ca-driven arrhythmogenic events in female vs male atria in AF, and suggests combined Ca-targeted interventions are promising therapeutic approaches in women.

背景

心房颤动（AF）中已报道存在显著的性别差异，但其潜在机制尚不清楚。

目的

本研究旨在深入了解男性与女性心房心肌细胞中钙处理紊乱及钙驱动的致心律失常事件的机制，并确定它们对钙靶向干预的反应。

方法

我们将已报道的性别差异和AF相关变化（即钙处理蛋白的表达和磷酸化、心肌细胞超微结构特征及尺寸）整合到我们的人类心房心肌细胞模型中，该模型将电生理学与空间详细的钙处理过程相结合。评估了心房心肌细胞对致心律失常方案和钙靶向干预的性别特异性反应。

结果

模拟的静息心肌细胞显示，与男性心肌细胞相比，AF女性心肌细胞中钙火花的发生率增加，这与先前的实验报告一致。此外，与男性模型相比，我们的女性模型表现出更高的发生起搏诱导的自发性钙释放（SCRs）的倾向，并且在动作电位（AP）诱发的钙瞬变中逐搏变异性增加。敏感性分析揭示了性别和/或AF改变中涉及的每个成分的不同致心律失常作用。具体而言，兰尼碱受体磷酸化增加是女性AF心肌细胞中主要的SCR促成因素，而L型钙电流降低对男性AF心肌细胞的SCR具有保护作用。此外，模拟的钙靶向干预确定了潜在策略（如横管修复、抑制兰尼碱受体和肌浆网/内质网Ca⁺-ATP酶）以减轻女性中钙驱动的致心律失常事件，并显示联合应用时疗效增强。