Substantial sex-based differences have been reported in atrial fibrillation (AF), but the underlying mechanisms are poorly understood. 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. 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. Simulated quiescent cardiomyocytes showed increased incidence of Ca2+ sparks in female vs male myocytes inAF, 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. Sex-specific modeling uncovers increased Ca2+-driven arrhythmogenic events in female vs male atria inAF, and suggests combined Ca2+-targeted interventions are promising therapeutic approaches in women.
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