Measures of High-Density Lipoprotein Function and Composition in Men and Women with Severe Aortic Valve Stenosis

Introduction and Hypothesis: Aortic valve calcification (AVC), is the intrinsic mechanism of valvular obstruction in severe aortic stenosis (AS), sharing similarities with atherosclerosis. There are differences in AVC by sex, with women having a lower burden of calcification than men, but the mechanism for this is unclear. Improved HDL functionality has been associated with protection against coronary artery calcification, but its relationship to AVC is less studied.Methods: We evaluated measures of high-density lipoprotein (HDL) functionality in 46 patients with severe AS, n= 30 men, n=16 women. ATP-Binding Cassette A1 (ABCA1) mediated cholesterol efflux capacity (CEC) was measured from human cultured Tamm-Horsfall protein 1 (THP-1) macrophages to apoB-depleted patient plasma samples. Lipid profile, lecithin-cholesterol acyltransferase activity (LCAT), fast protein liquid chromatography (FPLC), HDL size, and small pre-β1 and α-HDL particles, were measured in apolipoprotein B-depleted patient plasma. Proteomic analysis was used to explore sex-based differences in the HDL proteome.Results: Women with severe AS had higher ABCA1-mediated CEC, as compared to men (n=46, p=0.04). We found differences in FPLC profiles between sexes in severe AS along with a reduction in preβ and α-particles in men vs women by spectral counts, (preβ-HDL, 15661.74±789.00 vs 20298.29±1076.15, p=0.002), and (α-HDL, 50447.00± 546.52 vs 63006.35±756.81, p=0.03). Conversion of free cholesterol into cholesteryl esters by LCAT was decreased in men vs. women (12.00±8.07 %/h vs 16.44±9.11 %/h, p=0.03). We identified 108 HDL-associated proteins in a representative man and woman, of which, 15 were found only in the female sampleConclusions: Sex-specific differences in measures of HDL functionality were found in patients with severe AS. Future studies should consider whether sex-based differences in HDL functionality might account for the decreased burden of calcification in women vs. men with severe AS.