Aortic Valve Remodelling Is Attenuated In Women With Severe Aortic Regurgitation.
Rafael Sádaba1, Adela Navarro1, Jaime Ibarrola2, Carolina Tiraplegui1, Amaia García-De La Peña1, Vanessa Arrieta1, Virginia Alvarez-Asiain1, Amaya Fernandez-Celis2, Alicia Gainza1, Felix Gomez-Blasco1, Javier De Diego1, Natalia López-Andrés2.
1Complejo Hospitalario de Navarra, Pamplona, Spain, 2NavarraBiomed, Pamplona, Spain.
OBJECTIVE:Aortic regurgitation (AR) is more prevalent in men than in women, and it is characterized by abnormalities in the extracellular matrix (ECM) of the valve leaflets. This study aims to analyse the pathophysiology of aortic valve (AV) remodelling according to sex in patients with AR, as well as the cellular differences in the response to damage of valvular interstitial cells (VICs).
METHODS: Blood samples and AVs from 97 patients (24 women) with severe AR undergoing AV replacement were analysed. ECM remodelling was assessed by RT-PCR, western blot and ELISA in AVs. VICs isolated from 4 women and 2 men matched for age, hypertension, diabetes mellitus and cardiac function were treated with transforming growth factor (TGF)-β. ECM proteins, VICs activation markers and osteogenic molecules were measured.
RESULTS: AVs from women exhibited diminished collagen Type III, fibronectin, proteoglycans and glycosaminoglycans. The decrease in ECM components was accompanied by a decrease in metalloproteinase (MMP)-1 expression and activity in AVs from women. Women AVs presented diminished levels of calcification markers (Runx2). In serum, MMP-1 levels were decreased in women as compared to men. In vitro, in VICs isolated from women, TGF-β slightly enhanced collagen type I without modifying collagen type III, VICs activation markers and fibronectin expressions. TGF-β decreased proteoglycans and calcification markers in female VICs. In contrast, TGF-β treatment increased collagen type I and III, VICs activation marker α-smooth muscle actin, fibronectin, proteoglycans, MMP-1 activity and calcification markers (osteopontin, BMP-2) in VICs isolated from AR men.
CONCLUSIONS: In this cohort of patients with severe AR, women showed less AV ECM remodelling compared with men. Moreover, VICs isolated from AR women were resistant to TGF-β effects, suggesting that female VICs may be intrinsically protected. These results propose that the pathophysiology of AR could vary according to sex.
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