Sex-specific arrhythmogenic mechanisms of atrial fibrillation

University Of California At Davis, Davis CA

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Abstract

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, significantly contributing to ischemic strokes, increased morbidity, and mortality. Despite its prevalence, AF pharmacotherapy remains limited by poor efficacy and severe side effects, particularly in female patients, who experience greater mortality and more severe AF-related symptoms than male patients. The mechanistic basis for these sex differences in atrial electrophysiology (EP) and arrhythmia susceptibility is poorly understood due to the underrepresentation of female subjects in clinical and preclinical cardiovascular research. This project aims to address this critical knowledge gap by developing the first biophysically detailed, sex-specific computational models of human atrial myocytes and tissues. These models will incorporate sex-specific ion channel profiles, calcium handling properties, and structural differences in atrial tissue, informed by multi-level experiments in human atrial myocytes and trabeculae from male and female patients in normal sinus rhythm and with chronic AF. The acute and chronic effects of sex hormones will be determined though optical mapping experiments in rabbit atria. The combined experimental and modeling design will test the central hypothesis that AF-induced remodeling of ion channels, calcium handling proteins, and tissue architecture is delayed in females due to estrogen's protective effects, but once remodeling occurs, the consequences are more severe in females, contributing to higher arrhythmia vulnerability. Aim 1 will focus on revealing sex-specific mechanisms of atrial EP and calcium handling that underlie arrhythmia vulnerability. Computational models of male and female atrial cells and tissues will be developed and validated against experimental data from male and female patient samples with and without AF. Aim 2 will investigate the contribution of sex hormones, particularly estrogen and testosterone, to sex-based differences in atrial EP and arrhythmia risk. Using a combination of experimental and computational approaches, we will simulate hormone fluctuations during different physiological states and test how these variations impact arrhythmia susceptibility. Aim 3 seeks to identify new sex-specific anti-AF strategies by using the computational models to simulate and optimize drug therapies. We will test the hypothesis that targeting sex-specific AF mechanisms in combination, such as ion channel blockade and calcium release modulation, can reduce arrhythmia risk more effectively than current monotherapy one-size-fits-all treatments. This work will provide novel mechanistic insights into sex differences in AF, highlighting the importance of considering sex as a biological variable in cardiovascular research. Ultimately, these findings are expected to guide the development of personalized, sex-specific AF therapies, improving treatment outcomes and reducing AF-related health disparities between male and female patients.