Enhanced Ca2+-Driven Arrhythmogenic Events in Female Patients With Atrial Fibrillation
Bibliographic record
Abstract
Background Substantial sex-based differences have been reported in atrial fibrillation (AF), but the underlying mechanisms are poorly understood. Objectives This study sought to gain a mechanistic understanding of Ca -handling disturbances and Ca -driven arrhythmogenic events in male vs female atrial cardiomyocytes and establish their responses to Ca -targeted interventions. Methods We integrated reported sex differences and AF-associated changes (ie, expression and phosphorylation of Ca -handling proteins, cardiomyocyte ultrastructural characteristics, and dimensions) into our human atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca -handling processes. Sex-specific responses of atrial cardiomyocytes to arrhythmia-provoking protocols and Ca -targeted interventions were evaluated. Results Simulated quiescent cardiomyocytes showed increased incidence of Ca 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 releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca transients compared with the male model. Sensitivity analysis uncovered distinct arrhythmogenic contributions of each component involved in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation emerged as the major SCR contributor in female AF cardiomyocytes, whereas reduced L-type Ca current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulated Ca -targeted interventions identified potential strategies (eg, t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca ⁺-ATPase) to attenuate Ca -driven arrhythmogenic events in women, and revealed enhanced efficacy when applied in combination. Conclusions Sex-specific modeling uncovers increased Ca -driven arrhythmogenic events in female vs male atria in AF, and suggests combined Ca -targeted interventions are promising therapeutic approaches in women.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".