Abstract Mo057: Computational Modeling Reveals Enhanced Ca 2+ -Driven Arrhythmias in Female Patients with Atrial Fibrillation

Abstract

Background and Aim: Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, more complications from treatment, and greater risk of stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca 2+ dysregulation, whereby female myocytes more frequently exhibit proarrhythmic Ca 2+ -driven instabilities compared to male myocytes. Here, we aim to obtain a mechanistic understanding of the Ca 2+ -handling disturbances and Ca 2+ -driven arrhythmogenic events in males vs females and establish their responses to Ca 2+ -targeted interventions. Methods and Results: We incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca 2+ -handling proteins and in ultrastructural properties and dimensions of atrial myocytes into our recently developed 3D atrial myocyte model that couples electrophysiology with spatially detailed Ca 2+ -handling processes. Simulations show increased incidence of Ca 2+ sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to developing pacing-induced spontaneous Ca 2+ releases (SCRs, Figure 1A,B ) and augmented beat-to-beat variability in action potential (AP)-elicited Ca 2+ transients compared with the male model ( Figure 1C ). Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations ( Figure 2 ). Specifically, increased ryanodine receptor phosphorylation in female AF myocytes emerged as the major SCR contributor, while reduced L-type Ca 2+ current was protective against SCRs for male AF myocytes. Furthermore, simulations of Ca 2+ -targeted interventions identified potential strategies to attenuate Ca 2+ -driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase), and revealed enhanced efficacy when applied in combination. Conclusions: Our sex-specific computational models of human atrial myocytes uncover the increased female propensity to Ca 2+ -driven arrhythmogenic events vs male in AF, and identify combined Ca 2+ -targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms.