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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

Title: Functional Microdomains in the Heart’s Pacemaker: A New Dimension of Cardiac Remodeling

Major goals This project aims to determine the cellular, molecular and electrophysiological mechanisms of mechanical regulation of the sinoatrial node, the primary natural pacemaker of the heart. Our work will define how specialized cardiac cell membrane mechanosensitive domains and associated signaling molecules contribute to both physiological regulation of the sinoatrial node and its remodeling and dysfunction during chronically elevated mechanical overload in hypertension.

Title: Multiomic and Functional Analysis of PVC-Driven Idiopathic VF Predicts New Druggable Targets

In this project, We aim to unravel the mechanistic bases of idiopathic ventricular fibrillation by combining multiomic data, functional phenotyping, and computational modeling, and to use this knowledge to inform new antiarrhythmic strategies.