BPS2026 – Synergistic effects of sex-specific remodeling and T-tubule heterogeneity on triggered arrhythmias in atrial fibrillation

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.