Sex Differences in Aortic Stenosis: From the Pathophysiology to the Intervention, Current Challenges, and Future Perspectives.

Calcific aortic stenosis (AS) is a major cause of morbidity and mortality in high-income countries. AS presents sex-specific features impacting pathophysiology, outcomes, and management strategies. In women, AS often manifests with a high valvular fibrotic burden, small valvular annuli, concentric left ventricular (LV) remodeling/hypertrophy, and, frequently, supernormal LV ejection fraction coupled with diastolic dysfunction. Paradoxical low-flow low-gradient AS epitomizes these traits, posing significant challenges post-aortic valve replacement due to limited positive remodeling and significant risk of patient-prosthesis mismatch. Conversely, men present more commonly with LV dilatation and dysfunction, indicating the phenotype of classical low-flow low-gradient AS, i.e., with decreased LV ejection fraction. However, these distinctions have not been fully incorporated into guidelines for AS management. The only treatment for AS is aortic valve replacement; women are frequently referred late, leading to increased heart damage caused by AS. Therefore, it is important to reassess surgical planning and timing to minimize irreversible cardiac damage in women. The integrity and the consideration of sex differences in the management of AS is critical. Further research, including sufficient representation of women, is needed to investigate these differences and to develop individualized, sex-specific management strategies.