Enhanced Ca-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 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.