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Predicting Sex-Specific Antiarrhythmic Strategies for Atrial Fibrillation through a Regression-Guided Computational

Nathaniel T Herrera1, Haibo Ni1, Charlotte E R Smith1

  • 1Department of Pharmacology, University of California Davis, Davis, California, United States.

Biorxiv : the Preprint Server for Biology
|February 23, 2026
PubMed
Summary

Sex-specific drug combinations are needed to effectively treat atrial fibrillation (AF). This study developed a computational pipeline revealing distinct therapeutic targets for males and females, improving treatment strategies.

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Area of Science:

  • Computational biology and pharmacology
  • Cardiovascular research
  • Sex-based medicine

Background:

  • Atrial fibrillation (AF) is a common arrhythmia with sex-specific differences in mechanisms and treatment response.
  • Current AF treatments are largely sex-neutral, leading to limited efficacy and increased adverse effects in women.
  • Understanding sex-specific electrophysiological and calcium handling properties is crucial for effective AF therapy.

Purpose of the Study:

  • To develop a computational drug-screening pipeline for identifying sex-specific antiarrhythmic therapies for AF.
  • To evaluate multi-target drug combinations based on sex-specific human atrial cardiomyocyte models.
  • To restore normal sinus rhythm (nSR) by addressing sex-specific electrophysiological and Ca2+ handling properties.

Main Methods:

  • Developed a computational pipeline integrating multivariable regression and mechanistic modeling.
  • Utilized sex-specific human atrial cardiomyocyte models constrained by experimental data.
  • Systematically tested multi-target combinations of ion channel inhibitors and Ca2+ handling modulators.

Main Results:

  • Identified distinct optimal drug combinations for males and females with AF.
  • In males, Na+ and K+ channel inhibition improved electrical stability and reduced arrhythmia vulnerability.
  • In females, Ca2+ handling modulation was additionally required to suppress triggered activity and delayed afterdepolarizations (DADs).

Conclusions:

  • Established a multiscale computational pipeline for sex-informed, multi-target antiarrhythmic drug discovery.
  • Sex-specific drug strategies effectively reduce triggered activity and reentry in atrial tissue.
  • Findings support the translation of sex-specific therapies for AF to clinical practice.