Enhanced Ca <sup>2+</sup> -Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling
Bibliographic record
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+ ATPase; SR, sarcoplasmic reticulum.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".