Enhanced Ca²⁺-Driven Arrhythmogenic Events in Female Patients With Atrial Fibrillation: Insights From Computational Modeling

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 Ca²⁺-handling disturbances and Ca²⁺-driven arrhythmogenic events in male vs female atrial cardiomyocytes and establish their responses to Ca²⁺-targeted interventions.

Methods: We integrated reported sex differences and AF-associated changes (ie, expression and phosphorylation of Ca²⁺-handling proteins, cardiomyocyte ultrastructural characteristics, and dimensions) into our human atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca²⁺-handling processes. Sex-specific responses of atrial cardiomyocytes to arrhythmia-provoking protocols and Ca²⁺-targeted interventions were evaluated.

Results: Simulated quiescent cardiomyocytes showed increased incidence of Ca²⁺ 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 Ca²⁺ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca²⁺ 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 Ca²⁺ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulated Ca²⁺-targeted interventions identified potential strategies (eg, t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) to attenuate Ca²⁺-driven arrhythmogenic events in women, and revealed enhanced efficacy when applied in combination.

Conclusions: Sex-specific modeling uncovers increased Ca²⁺-driven arrhythmogenic events in female vs male atria in AF, and suggests combined Ca²⁺-targeted interventions are promising therapeutic approaches in women.