Sex Differences In Aortic Stenosis: Mechanistic Insights And Clinical Implications
Rafael Sádaba1, Lara Matilla2, Vanessa Arrieta1, Amaia García-De La Peña1, Amaya Fernández-Celis2, Adela Navarro1, Alicia Gainza2, Virginia Álvarez-Asiain1, Eva Jover2, Natalia López-Andrés2.
1Complejo Hospitalario de Navarra, Pamplona, Spain, 2NavarraBiomed, Pamplona, Spain.
OBJECTIVE:Aortic stenosis (AS) is a progressive, degenerative disease associated with fibrosis and calcification of the aortic valves (AVs). Molecular, cellular and interstitial events activate multifactorial and complex cues with a significant contribution by valve interstitial cells (VICs). We aim to analyse sex-specific differences in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients.
METHODS:184 patients with severe AS undergoing surgical valve replacement were recruited. 148 AVs (44.6% women) were used for ex vivo analyses and 36 AVs (33.3% women) for in vitro experiments.
RESULTS:AVs from men presented increased levels of the inflammatory molecules interleukin (IL)-1β, IL-6, Rantes and CD45. Oxidative stress (eNOS, myeloperoxidase, malondialdehyde and nitrotyrosine) was upregulated in male AVs. Concerning fibrosis, increased levels of collagen type I, fibronectin, active Lox-1 and syndecan-1 were found in AVs from men compared with women. Extracellular matrix (ECM) remodelling was characterized by reduced metalloproteinase-1 and 9 expression and increased tissue inhibitor of metalloproteinase-2 expression in male AVs. Importantly, osteogenic markers (bone morphogenetic protein-9, Rank-L, osteopontin, periostin, osteocalcin and Sox-9) and apoptosis (Bax, Caspase 3, p53 and PARP1) were greatly enhanced in AVs from men as compared to women. Isolated male VICs presented higher myofibroblast-like phenotype than female VICs. In line with our ex vivo results, male VICs exhibited increased inflammatory, oxidative stress, fibrotic, apoptosis and osteogenic differentiation markers.
CONCLUSIONS:Our results suggest that the mechanisms driving the pathogenesis of AS could be different in men and women. Male AVs and isolated VICs presented more inflammation, oxidative stress, fibrosis, ECM remodelling and calcification as compared to those from women. A better understanding of the pathophysiological pathways in AVs and VICs will allow the development of sex-specific options for the treatment of AS.
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