Sex-specific lipidomic signatures in aortic valve disease reflect differential fibro-calcific progression

Fibro-calcific aortic valve disease (FCAVD) is the most common valvular heart disease manifesting in pathological remodeling of the aortic valve (AV) leaflets, ultimately leading to aortic stenosis. Although dyslipidemia is a driver of FCAVD pathogenesis, the precise lipidome-wide changes underlying AV fibrosis and calcification remain largely unknown. Here, we performed deep quantitative lipidomics to profile the metabolic trajectories in human tricuspid and bicuspid AVs, and found stage-dependent extrinsic and intrinsic lipid trends. Furthermore, lipids derived from infiltrating lipoproteins are further metabolized within the AV. Intrinsic lipid remodeling suggested tissue degeneration with a loss of phosphatidylserines. Surprisingly, male and female patients showed markedly different lipid signatures of FCAVD progression, with female patients accumulating significantly higher levels of sphingomyelins and ceramides. The high extent of sexual dimorphism in the valve lipidome strongly suggests that tailored approaches should be undertaken to enhance mechanistic insight and to facilitate pharmacological intervention for FCAVD.