Native aortic stenosis progression: a focus on sex differences

Aortic stenosis (AS) is a growing health problem in aging populations, with known sex-specific differences in its pathophysiology and progression. Men tend to develop more calcific AS, while women exhibit more valve fibrosis and concentric left-ventricular (LV) remodelling in response to chronic increased after load.1–3 Although sex-differences in AS haemodynamic and LV adaptation have been reported, most studies focus on severe AS and are limited by short follow-up, confounding factors, and broad inclusion criteria (i.e. preserved and depressed LV ejection fraction—LVEF).4,5 Moreover, AS progression is often narrowly and erroneously defined by increasing gradients/velocities, overlooking stroke volume trends that may mask the disease progression. In this study, we aimed to investigate sex differences in the natural history and long-term outcomes of patients with at least mild to moderate AS. The study was approved by our IRB, who waived the necessity of a written consent. The data that support the findings of this study are available from the corresponding author upon reasonable request and IRB approval. We retrospectively included patients ≥18 years with at least mild to moderate AS (aortic valve area, AVA ≤1.5 cm², maximum aortic velocity, Vmax ≥2.5 m/s, or mean gradient, MG ≥25 mmHg) who underwent baseline and ≥1 follow-up echocardiography ≥6 months apart at Institut universitaire de cardiologie et de pneumologie de Québec between 2014 and 2019. Exclusion criteria included LVEF < 50%, prior valve interventions, significant aortic/mitral regurgitation, congenital heart disease (other than valve morphology), hypertrophic cardiomyopathy, radiation-related AS and cardiac amyloidosis. Clinical data and echocardiographic parameters were retrospectively collected. Stroke volume index (SVi) and AVA were derived per standard guidelines. The primary endpoint was all-cause mortality; the secondary was the composite of aortic valve replacement (AVR) or death. AVR data were obtained from charts; death data were confirmed via provincial registries. Sex differences were analysed using inverse propensity weighting (IPW) and 1:1 matching (based on age, MG, AVA, body mass index, diabetes, and hypertension)—Figure 1. Annualized echocardiographic changes were computed considering the time between baseline and final echo. Survival analyses were carried out adopting Kaplan-Meier curves and Cox regression. Sex-differences in Native Aortic Stenosis Progression. Despite significant differences are present in AS progression and left ventricular remodeling between men and women, similar long-term outcome was found. AS, aortic stenosis; LV, left ventricle; Vmax, aortic maximum velocity. The study cohort was composed by 677 consecutive patients (38.1% women, mean age 70.8 ± 13.2 years), men had more diabetes (36.5% vs. 25.6%, P = 0.003) and coronary artery disease (54.9% vs. 31.8%, P < 0.0001), while women were more often symptomatic (57.4% vs. 45.8%, P = 0.003). Severe AS was present in 53 patients (8.1%, n = 36 men, n = 17 women), while paradoxical low-flow low-gradient in 102 patients (15%, n = 50 men, n = 52 women). Women had a smaller LV end diastolic diameter, lower LV mass index (P < 0.0001), and higher LVEF (66.7% vs. 65.5%, P = 0.037); AS severity parameters were similar between sexes at baseline. Median follow-up of the cohort was 4.9 (3.5–6.4) years. In the original cohort without applying IPW or 1:1 matching, men presented a higher annualized progression ratio in Vmax [mean difference 9.91 (95% CI: 3.96–15.2) cm/s/year, P = 0.002] and in MG [mean difference 1.7 (95% CI: 0.83–2.71) mmHg/year, P = 0.001] compared with women. After adjusting for covariates in the IPW cohort, men presented higher annualized progression ratio in Vmax [mean difference 9.56 (5.7–13.4) cm/s/year, P < 0.0001], in MG [mean difference 1.77 (1.10–2.43) mmHg/year, P < 0.0001] and in SVi annualized progression [mean difference 0.80 (0.18–1.43) mL/m2/year, P = 0.012]. Actually, SVi decreased significantly in women (P = 0.0002), but not in men (P = 0.21). On the contrary, in the IPW cohort men presented lower annualized LVMi and RWT progression ratio than women [mean difference −2.51 (−4.56 to −0.45) mg/m2/year, P = 0.017 and −0.007 (−0.01 to −0.003), P = 0.039 respectively]. No differences were found in AVAi annualized progression ratio (P ≥ 0.60) in the original and IPW cohort. Similar results were obtained in the matched 1:1 cohort for the annualized progression ratio in Vmax (P = 0.038), MG (P = 0.041) and SVi (P = 0.039). All-cause mortality occurred in 118 patients (17.4%; 72 men, 46 women), with no sex difference at 4 years (11% vs. 12%, P = 0.84). AVR was performed in 211 patients (31.2%; 138 men, 73 women), with similar cumulative death/AVR rates (39% vs. 38.5%, P = 0.44). Sex was not predictive of mortality or composite outcome in Cox or AVR in the competing risk models. Mortality under medical management was also similar (18.7% vs. 15.4%, P = 0.86). This study is subject to potential bias and residual confounding despite statistical adjustments due to its retrospective nature. Strict inclusion criteria were applied, but unmeasured variables may have influenced results. Prospective studies using biomarkers, myocardial deformation, and multi-modality imaging are needed to further explore sex-related differences. With this study we demonstrated that, in patients with at least mild to moderate AS and preserved LVEF, men exhibited faster progression in peak velocity and MGs. In contrast, women showed greater concentric remodelling and LV hypertrophy, along with a significant decline in stroke volume over time. This reduction in flow may blunt the increase in transvalvular velocities and gradients, potentially masking true AS progression. Despite these distinct remodelling and haemodynamic patterns, no sex-related differences in mortality were observed after adjustment. P.S. holds a research grant from University of Verona (Michele Pighi scholarship)—Italy. J.B. is supported by Fonds de Recherche du Québec—Santé. M.-A.C. holds the Canadian Research Chair on Women’s Cardiac Valvular Health from the Canadian Institutes of Health Research (CIHR, Ottawa, Canada).

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