SEX DIFFERENCES IN AORTIC STENOSIS PROGRESSION IN A MURINE MODEL

Sex differences in stenosed aortic valve have been recently demonstrated, however sex-specific progression of aortic stenosis (AS) remains unstudied. This study aims to examine the impact of sex and sex hormones on the progression of AS in a murine model of AS.

LDL-/- ApoB100/100 IGF-II+/- mice fed with high fat/sucrose/cholesterol diet were divided in 6 groups: intact males (IM), intact females (IF), castrated males (CM), ovariectomized females (OF), CM with testosterone supplementation (CMT) and OF with estrogen supplementation (OFE). Echocardiographic evaluation of AS and valve tissue histological analysis were performed at 12 and 36 weeks. Among male mice, IM had the fastest progression of peak aortic jet velocity (Vpeak) (24.2±5.7 cm/s; p < 0.001) compared to CM (6.2±1.4; p=0.42) who did not progress significantly, and CMT had a significant intermediate progression of Vpeak (15.1±3.5; p=0.002; p for interaction=0.02 - Figure). Accordingly, indexed aortic valve area (AVAi) decreased significantly in the IM and CMT groups, while the decrease in AVAi was smaller and did not reach statistical significance in the CM group (IM: -0.68±0.21cm2/m2; p < 0.001 vs. CMT: -0.40±0.20 cm2/m2; p < 0.001 vs. CM: -0.15±0.28 cm2/m2; p=0.07; p for interaction < 0.001). Among female mice, Vpeak progression was significant and similar in all groups (IF: 25.8±5.3; p < 0.001; OF: 12.8±2.6; p=0.03; OFE: 18.5±3.4; p=0.003; p=0.29 - Figure). Accordingly, AVAi decreased in the three female groups (IF: -0.60±0.22cm2/m2; p < 0.001, OFE: -0.66±0.19 cm2/m2; p < 0.001, OF: -0.43±0.22 cm2/m2; p < 0.001; p for interaction < 0.001). Aortic valve leaflets were thicker at 36 weeks compared to 12 weeks (median [IQR]: 0.143[0.120-0.188] vs.0.103[0.056-0.120] mm; p < 0.001). The largest decrease of leaflet fibrosis was seen in CMT (-13.76±4.53%), compared to CM (-8.67±4.53%) and IM (-5.18±7.22%) (p=0.02). Leaflet fibrosis increased among female groups (OF: 14.43±7.04; IF: 5.31±14.41; OFE: 9.21±17.04%; p=0.46). At 12 weeks, we found no evidence of leaflet calcification. At 36weeks, female mice had lower amounts of calcification than male mice (IF: 0.00[0.00-0.43], OF: 0.40[0.17-1.38], OFE: 0.45[0.07-1.85], IM: 6.01[1.87-40.7], CMT: 4.00[0.00-7.05], CM: 1.66[0.06-21.80] %; p=0.02).

In this murine model of AS, testosterone played an important role in hemodynamic AS progression in male mice unlike estrogen on hemodynamic AS progression in female mice. Despite valve thickness increasing in all groups, the composition of the valve leaflet was different between male and female mice, and testosterone presence was associated with higher calcification of the valve.