Sex differences in atrial fibrillation (AF) mechanisms are increasingly recognized but remain poorly understood, in part due to the underrepresentation of females in preclinical and clinical studies. Spontaneous Ca 2+ release (SCR) events are a known arrhythmogenic trigger, and our recent studies using single atrial cardiomyocyte models revealed a higher susceptibility to SCR-induced delayed after depolarizations in female AF myocytes, arising from sex- and AF-specific remodeling such as increased RyR2 phosphorylation and reduced T-tubule density. Here, we aimed to determine how sex-specific AF remodeling components, including subcellular structural organization (T-tubule density/heterogeneity), interact to influence the initiation of triggered arrhythmias in human atrial tissue. We developed reduced-order models that captured sex- and AF-specific SCR dynamics to assess the likelihood of SCRs triggering full action potentials (TAs) in response to beta-adrenergic stimulation. We simulated the model within a 2D atrial tissue framework to investigate how these cellular events overcome electrotonic load and initiate triggered activity at the tissue level. Simulations demonstrated that female AF tissue exhibits a markedly greater propensity for TAs compared with male, driven by reduced source-sink mismatch and enhanced excitability. To probe the role of structural organization, we simulated tissues with transmural epi- to endocardial gradients in T-tubule density and found that heterogeneous T-tubule organization modulates SCR synchrony and arrhythmia initiation, with sparsely tubulated regions amplifying focal excitation. Together, our findings identify a synergistic interaction between sex- and AF-associated functional and ultrastructural remodeling in shaping triggered arrhythmias in human atria. This computational framework advances mechanistic understanding of sex-specific arrhythmogenesis and may inform future development of targeted AF therapies.
Wu et al. (Sun,) studied this question.