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Accumulating evidence demonstrates substantial sex-related differences in atrial fibrillation (AF), which is the most common arrhythmia, with female patients faring worse with the condition. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs. females and establish their responses to Ca2+-targeted interventions. By integrating known sex-differential components into our computational spatiotemporal atrial cardiomyocyte model, we found that female vs male atrial cardiomyocytes in AF exhibit greater propensity to developing arrhythmia-promoting spontaneous Ca2+ release events and elevated beat-to-beat variability in action potential-elicited Ca2+ transients. Computational analyses provided novel mechanistic insights into these sex differences. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential treatment strategies that attenuated Ca2+-driven arrhythmogenic events in female atria (e.g., tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), which reveal additive efficacy when applied in combination. Our study uncovers and validate sex-specific AF mechanisms and establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms.

Link to the manuscript

Highlights from the Grandi lab at BPS 2024:

• H Ni, N Khorasani, Y Wu, S Morotti, D Dobrev, E Grandi. Computational modeling identifies increased background Ca2+ influx as a potential promoter of arrhythmogenic Ca2+ instability in atrial fibrillation. Biophysical Journal 123 (3), 384a, 2024
• NT Herrera, H Ni, C Smith, D Dobrev, S Morotti, E Grandi. In silico investigation of sex-specific atrial electrophysiologic mechanisms and arrhythmia vulnerability. Biophysical Journal 123 (3), 192a, 2024
• N Khorasani, H Ni, D Dobrev, E Grandi. Revealing key mechanisms of atrial fibrillation-associated fibrosis through computational modeling of cardiac fibroblast. Biophysical Journal 123 (3), 278a 2024
• Y Wu, X Zhang, WE Louch, MA Colman, H Ni, E Grandi. Unveiling sex-specific mechanisms of atrial Ca2+ dysregulation and Ca2+-driven arrhythmia via multiscale modeling. Biophysical Journal 123 (3), 383a, 2024
• R Shetty, S Morotti, V Sobota, JD Bayer, H Ni, E Grandi. Translating electrocardiogram features across sexes. Biophysical Journal 123 (3), 458a. 2024