The Pathophysiology of Sex Differences in Stroke Risk and Prevention in Atrial Fibrillation: A Comprehensive Review

Atrial fibrillation (AF) is the most common chronic arrhythmia and is a leading cause of stroke, with well-documented differences in pathophysiology, clinical manifestations, and prognosis according to the sex of the patient. This review provides an overview of known or hypothesized sex differences in physiology and stroke risk for patients with AF. Women are reported to have more extensive fibrosis of the left atrium, different functional properties of the atria, and higher sensitivity to prothrombotic stimuli, especially after menopause. Variations in stroke risk with AF are linked to age, hypertension, diabetes, and chronic kidney disease; overall, women have worse outcomes. The widely clinically implemented CHA2DS2-VASc score no longer considers sex as a variable, and its propriety for women is still debated. However, women are usually under prescribed anticoagulation despite having a higher long-term risk of stroke compared to men, suggesting a lack of equity of treatment for certain patient groups. New AI-based risk stratification models and precision medicine approaches are potentially useful in reducing these gaps. Future work should also aim to improve sex-based predictive models, considering different gender categories, and understanding the part played by hormonal alterations, atrial structural alterations, and thromboembolic risk in the treatment of AF.