Impact of sex on the management and outcome of aortic stenosis patients.

OBJECTIVE: The aim of this study was to assess the impact of sex on the management and outcome of patients according to aortic stenosis (AS) severity. INTRODUCTION: Sex differences in the management and outcome of AS are poorly understood. METHODS: Doppler echocardiography data of patients with at least mild-to-moderate AS [aortic valve area (AVA) ≤1.5 cm2 and peak jet velocity (VPeak) ≥2.5 m/s or mean gradient (MG) ≥25 mmHg] were prospectively collected between 2005 and 2015 and retrospectively analysed. Patients with reduced left ventricular ejection fraction (<50%), or mitral or aortic regurgitation >mild were excluded. RESULTS: Among 3632 patients, 42% were women. The mean indexed AVA (0.48 ± 0.17 cm2/m2), VPeak (3.74 ± 0.88 m/s), and MG (35.1 ± 18.2 mmHg) did not differ between sexes (all P ≥ 0.18). Women were older (72.9 ± 13.0 vs. 70.1 ± 11.8 years) and had more hypertension (75% vs. 70%; P = 0.0005) and less coronary artery disease (38% vs. 55%, P < 0.0001) compared to men. After inverse-propensity weighting (IPW), female sex was associated with higher mortality (IPW-HR: 1.91 [1.14-3.22]; P = 0.01) and less referral to valve intervention (competitive model IPW-HR: 0.88 [0.82-0.96]; P = 0.007) in the whole cohort. This excess mortality in women was blunted in concordant non-severe AS initially treated conservatively (IPW-HR = 1.03 [0.63-1.68]; P = 0.88) or in concordant severe AS initially treated by valve intervention (IPW-HR = 1.25 [0.71-2.21]; P = 0.43). Interestingly, the excess mortality in women was observed in discordant low-gradient AS patients (IPW-HR = 2.17 [1.19-3.95]; P = 0.01) where women were less referred to valve intervention (IPW-Sub-HR: 0.83 [0.73-0.95]; P = 0.009). CONCLUSION: In this large series of patients, despite similar baseline hemodynamic AS severity, women were less referred to AVR and had higher mortality. This seemed mostly to occur in the patient subset with discordant markers of AS severity (i.e. low-gradient AS) where women were less referred to AVR.

Impact of sex and sex hormones on pathophysiology and progression of aortic stenosis in a murine model.

The lesions observed in AS have been shown to be sex specific, with women presenting extensive fibrotic remodeling while men developing more calcification deposit. We thus aimed to evaluate the influence of sex and sex hormones on the pathophysiology of aortic valve stenosis (AS) in our mouse model of AS. LDLr-/- ApoB100/100 IGF-II+/- mice (n = 210) were separated in six different groups: (1) intact male (IM), (2) intact female (IF), (3) castrated male (CM), (4) ovariectomized females (OF), (5) CM with testosterone supplementation (CMT), and (6) OF with 17ß-estradiol supplementation (OFE). Mice were fed a high-fat/high-sucrose/high-cholesterol diet for 6 months. Hemodynamic progression of AS was followed by transthoracic echocardiography (at 12 and 36 weeks) and analyzed in all mice alive at 36 weeks. Aortic valves were collected for histological and digital droplet PCR* analysis. Increases in peak velocity were 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 AS. Between the three groups of male mice, AS progression was 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 three groups of female mice, there were no statistical differences in AS progression. 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). Male sex and testosterone play an important role in upregulation of pro-calcifying genes and hemodynamic progression of AS. However, female mice appeared to be protected against calcification, characterized by downregulation of pro-osteogenic genes, but presented a similar AS hemodynamic progression.

Sex and Race Differences in the Pathophysiology, Diagnosis, Treatment, and Outcomes of Valvular Heart Diseases.

Valvular heart diseases have long been considered to be similar in men and women and across races/ethnicities. Recently, studies have demonstrated major differences between sexes. Unfortunately, studies on valvular heart diseases, as on other cardiovascular diseases, are mostly performed in Caucasian men or in cohorts with a vast majority of Caucasian men. Therefore, our knowledge on valvular diseases in women and non-Caucasians remains limited. Nevertheless, aortic stenosis has been shown to be almost as prevalent in women as in men, and less prevalent in African Americans. Men appear to have a more calcified aortic valve lesion, and women tend to have a more fibrosed one. Primary mitral regurgitation is more frequent in women who have more rheumatic and Barlow etiologies, whereas men have more fibroelastic deficiency and posterior leaflet prolapse/flail. Left ventricular remodelling due to valvular heart diseases is sex related in terms of geometry and probably also in composition of the tissue. Outcomes seem to be worse in women after surgical interventions and better than or equivalent to men after transcatheter ones. Regarding other valvular heart diseases, very few studies are available: Aortic regurgitation is more frequent in men, isolated tricuspid regurgitation more frequent in women. Rheumatic valve diseases are more frequent in women and are mostly represented by mitral and aortic stenoses. Many other sex/gender- and race/ethnic-specific studies are still needed in epidemiology, pathophysiology, presentation, management, and outcomes. This review aims to report the available data on sex differences and race specificities in valvular heart diseases, with a primary focus on aortic stenosis and mitral regurgitation.

Sex-differences in echocardiographic assessment of aortic valve in young adult LDLr-/-/ApoB100/100/IGF-II+/- mice.

BACKGROUND: LDLr-/-/ApoB100/100/IGF-II+/- mice are used as a calcific aortic valve disease (CAVD) model. However, normal aortic valve hemodynamics i.e. remotely from CAVD onset and the sex-related differences are poorly known. METHODS AND RESULTS: Four groups of mice, intact males (IM, n = 49) and females (IF, n = 50), castrated males (CxM, n = 79) and ovariectomized females (OxF: 73), underwent a Doppler-echocardiography at 12 weeks of age. Gonadectomy was performed at 8 weeks. Aortic valve assessment using effective orifice area (EOA, using the continuity equation) and peak aortic transvalvular velocity (VPeak) was feasible in 89% of the mice with good to excellent reliability (intraclass correlation coefficients ranging from 0.90 to 0.98, p < 0.001). Mean VPeak was 104 ± 17 cm/s and mean EOA was 1.18*10-2 ± 0.22*10-2 cm2. EOA indexed to body surface area was 1.5 ± 0.3 cm2/m2. The 95th percentile of Vpeak was 132 cm/s and the 5th percentile of indexed EOA was 1.0 cm2/m2. Interestingly, IM had the highest VPeak (114 ± 14 cm/s) vs each of the other groups (CxM: 106 ± 19 cm/s, OxF: 97 ± 13 cm/s and IF: 96 ± 12 cm/s, ANOVA and corrected p < 0.001). This was mostly explained by a higher stroke volume (ANOVA and corrected p < 0.001) in IM compared to other groups. There were no major sex-differences in ventricular systolic function parameters. CONCLUSION: In LDLr-/-/ApoB100/100/IGF-II CAVD mice model, an aortic EOA <0.8*10-2 cm2 (or indexed EOA <1.0cm2/m2), and a peak aortic valve velocity > 132 cm/s may be proposed as thresholds to define CAVD. Intact male mice appear to have higher velocities.