Abstract
Aortic valve stenosis (AVS) exhibits significant sexual dimorphism, influencing its pathophysiology, clinical presentation, and outcomes. Despite growing recognition of sex as a biological variable in cardiovascular diseases, the molecular mechanisms underlying AVS remain inadequately explored through a sex-specific lens. This paper investigates the role of sexual dimorphism in AVS by analyzing a large cohort of congenital heart disease (CHD) cases in Saudi Arabia, utilizing a comprehensive dataset of over 3 million variables. Our findings confirm a strong male predominance in AVS cases, with a male-to-female ratio of 3:1 (p=0.003), suggesting intrinsic biological differences in disease development. This paper highlights key genetic, epigenetic, and hormonal factors contributing to these disparities, including X-chromosome inactivation escape genes, Y-chromosome-linked risk factors, and sex-specific variations in valvular interstitial cell behavior. Furthermore, transcriptomic analyses reveal distinct male and female responses to fibrotic and calcific remodeling, potentially guiding future sex-based precision therapies. These insights emphasize the need to incorporate sex-specific considerations into AVS diagnosis, treatment, and therapeutic development, promoting a shift toward personalized medicine in congenital and acquired cardiovascular diseases.