{"doi":"10.1101/2024.03.04.583217","title":"Enhanced Ca <sup>2+</sup> -Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling","abstract":"Abstract Background and Aims Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca 2+ dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca 2+ -driven instabilities compared to male cardiomyocytes. In this study, we aim to gain 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 cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca 2+ -handling processes. Our simulations of quiescent cardiomyocytes 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 develop pacing-induced spontaneous Ca 2+ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca 2+ transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca 2+ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative 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 Ca²⁺-ATPase), and revealed enhanced efficacy when applied in combination. Conclusions Our sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca 2+ -driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to 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. Translational perspective 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. By integrating known sex-differential components into our computational atrial cardiomyocyte model we found that female atrial cardiomyocytes in AF exhibit greater propensity to develop Ca 2+ -driven arrhythmia than male cardiomyocytes. Model analyses provided novel mechanistic insights and suggested strategies such as t-tubule restoration, correction of Ca 2+ -handling disturbances, and the combination of both, as promising approaches to treat AF in female patients. Our study uncovers and validate sex-specific AF mechanisms and inform the development of targeted anti-AF strategies. Graphical abstract: Sex-specific 3D spatiotemporal models of human atrial cardiomyocyte Ca 2+ signaling reveal a greater propensity to develop Ca 2+ -driven arrhythmic events in female vs male atrial cardiomyocytes in AF. Model analysis links sex-specific AF remodeling to arrhythmogenic mechanisms. AF, atrial fibrillation; SCR, spontaneous Ca 2+ release; CaT, cytosolic Ca 2+ transient; RyR2-P, phosphorylated ryanodine receptor type 2 (RyR2); CSQ, calsequestrin; LTCC, L-type Ca 2+ channel; PLB, phospholamban; SERCA, sarcoendoplasmic reticulum Ca 2+ ATP","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488076,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1240557,"name":"Yixuan Wu","orcid":"0000-0002-3521-6894","position":1,"is_corresponding":false},{"id":892997,"name":"Charlotte Smith","orcid":"0000-0002-1165-1752","position":2,"is_corresponding":false},{"id":380698,"name":"William E. Louch","orcid":"0000-0002-0511-6112","position":3,"is_corresponding":false},{"id":322548,"name":"Stefano Morotti","orcid":"0000-0001-8679-665X","position":4,"is_corresponding":false},{"id":58218,"name":"Dobromir Dobrev","orcid":"0000-0002-4612-117X","position":5,"is_corresponding":false},{"id":471958,"name":"Eleonora Grandi","orcid":"0000-0002-4401-8857","position":6,"is_corresponding":false},{"id":471954,"name":"Haibo Ni","orcid":"0000-0003-0083-4286","position":7,"is_corresponding":false},{"id":561900,"name":"Xianwei Zhang","orcid":"0000-0003-4665-9145","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:08:15.008850Z","pmid":"38496584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}