Sex differences in aortic valve inflammation and remodeling in chronic severe aortic regurgitation

Aortic regurgitation (AR) is more prevalent in males, although cellular and molecular mechanisms underlying the sex differences in prevalence and pathophysiology are unknown. This study evaluates the impact of sex on aortic valve (AV) inflammation and remodeling and the cellular differences in valvular interstitial cells (VICs) and valvular endothelial cells (VECs) in patients with AR. A total of 144 patients (27.5% female) with severe chronic AR were included. AVs were analyzed by imaging, histological, and molecular biology techniques (ELISA, RT-PCR). VICs and VECs isolated from patients with AR were characterized and further treated with transforming growth factor (TGF)-β. Anatomically, male had smaller index aortic dimensions and greater AV thickness. Proteome profiler analyzes in AVs (n = 40/sex) evidenced higher expression of inflammatory markers in male and that was further validated (interleukins, chemokines). Histological composition showed higher expression of inflammatory mediators and collagen thick fibers in AVs from male. Male VICs and VECs secreted higher levels of inflammatory markers than female cells. Interestingly, male VICs produced higher amounts of collagen type I and lower fibronectin and aggrecan, whereas male VECs secreted lower decorin. TGF-β exclusively enhanced inflammation in male VICs and decorin and aggrecan in female VICs. Compared with male, AVs from female were thinner, less inflamed, and fibrotic. VICs seem to be the key cell type responsible for the sex-differences. Valvular inflammation associated with an active remodeling process could be a key pathophysiological process involved in AR.NEW & NOTEWORTHY The pathogenesis of chronic aortic regurgitation (AR) is different in male and female. Female patients with AR showed less aortic valve inflammation and collagen accumulation as compared with male. Valvular cells from female patients secreted less inflammatory molecules and collagen and higher levels of proteoglycans. Valvular interstitial cells from females were more sensitive to transforming growth factor (TGF)-β-induced proteoglycans secretion. Our study opens a new perspective oriented toward sex-specific molecular pathways and therapeutic targets in chronic severe AR.