Abstract 10265: Sex Hormones Impact the Progression of Aortic Stenosis - A Murine Model

Abstract

Listen

Translate article

Introduction: Lesions observed in aortic valve stenosis (AS) have been shown to be sex-specific, with women presenting with extensive fibrotic remodeling while men develop more calcium deposits. This study aimed to evaluate the influence of sex and sex-hormones on the pathophysiology of AS. Methods: Two hundred and ten (210) LDLr -/- ApoB 100/100 IGF-II +/- mice were separated into 6 groups: 1) intact males (IM), 2) intact females (IF), 3) castrated males at 8 weeks (CM), 4) ovariectomized females at 8 weeks (OF), 5) CM with testosterone supplementation (CMT), and 6) OF with 17β-estradiol supplementation (OFE). Mice were fed a high fat / high sucrose / high cholesterol diet for 6 months. Hemodynamic progression of AS was measured by transthoracic echocardiography (at 12 and 36 weeks) and aortic valves were collected for histological and digital droplet PCR analysis. Results: Hemodynamic progression of AS was comparable in IF and IM (24.2±5.7 vs. 25.8±5.3 cm/s; p=0.68), but IF presented with less severe hemodynamic AS. Between the 3 groups of male mice, AS progression and calcification of the explanted aortic valves at 36 weeks were more important in IM (increase in peak velocity: 24.2±5.7 cm/s; p<0.001) compared to CM (6.2±1.4; p=0.42), and CMT (15.1±3.5; p=0.002). In the 3 groups of female mice, there was no statistical differences in AS progression or valve remodeling. Digital PCR analysis revealed an important upregulation of the osteogenic gene RunX2 in IM (p<0.0001) and downregulation of the pro-calcifying gene ALPL in IF (p<0.05). Conclusions: Male sex and testosterone play a role in the upregulation of pro-calcific genes and calcification of the aortic valve, thus in the hemodynamic progression of AS. Female mice appeared to be protected against calcification, characterized by downregulation of pro-osteogenic genes, but presented similar AS hemodynamic progression. Impact of sex-hormone in females requires further studies.