Can a computational model explain the role of sex hormones in atrial fibrillation?

Q: What does this research mean for the field?

Computational modeling indicates that estrogen protects against atrial fibrosis through coordinated ROS and JNK signaling converging on Smad3, suggesting that combined ROS/JNK inhibition could mimic estrogen's antifibrotic effects in atrial fibrillation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Judith Weng Zhu; Pim J. A. Oomen

doi:10.1152/ajpheart.00611.2026

July 28, 2026AJP Heart and Circulatory PhysiologyOpen Access

Can a computational model explain the role of sex hormones in atrial fibrillation?

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Key Points

To investigate the mechanistic pathways by which sex hormones modulate fibrotic signaling in cardiac fibroblasts and influence susceptibility to atrial fibrillation across age and biological sex.
Constructed a logic-based computational model of atrial-enriched fibroblast signaling integrating estrogen and testosterone pathways.
Calibrated and validated network predictions against published experimental datasets in cardiac and atrial fibroblasts.
Simulated aging- and sex-dependent physiological variations by altering hormone levels across young and aged male and female models.
The expanded model replicated antifibrotic effects of estrogen and testosterone with 81% accuracy in cardiac fibroblasts and 100% accuracy in atrial fibroblasts.
Testosterone reduced fibrosis primarily through Smad3 signaling, whereas estrogen acted through Smad3, AT1R, ROS, and JNK.
Simulated individual knockdown of ROS or JNK produced minimal change, but combined disruption of ROS and JNK suppressed all fibrotic markers and blunted fibrosis across males and aged females.

Structured PICO

P

Population

Computational model of an atrial-enriched fibroblast signaling network simulating young and aged female and male subjects

I

Intervention

Simulation of estrogen (E2) and testosterone (TS) effects, and ROS/JNK knockdown

O

Outcome

Fibrotic signaling and myofibroblast differentiation

Limitations

Network lacks the incorporation of other sex hormones such as progesterone
Model does not include aromatase-dependent conversion of testosterone to estrogen
Isolates the effects of sex hormones alone, excluding chromosomal and epigenetic regulation
Relies on uniform reaction Hill parameters derived from qualitative data, lacking reaction-specific kinetics

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Implication

This editorial highlights a computational model demonstrating that estrogen protects against atrial fibrosis via coordinated ROS/JNK feedback, identifying these pathways as potential therapeutic targets for atrial fibrillation.

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Cite This Study

Zhu et al. (2026) studied this question.

synapsesocial.com/papers/6a6b032f60e2b924d3ea257b https://doi.org/10.1152/ajpheart.00611.2026

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Can a computational model explain the role of sex hormones in atrial fibrillation?

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Can a computational model explain the role of sex hormones in atrial fibrillation?

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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