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

Patricia Prabutzki, Michele Wölk, Julia Böttner, Zhixu Ni, Sarah Werner, Holger Thiele, Jürgen Schiller, Petra Büttner, Florian Schlotter () and Maria Fedorova ()
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Patricia Prabutzki: Institute for Medical Physics and Biophysics, Leipzig University
Michele Wölk: University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden
Julia Böttner: Heart Center Leipzig at Leipzig University
Zhixu Ni: University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden
Sarah Werner: Heart Center Leipzig at Leipzig University
Holger Thiele: Heart Center Leipzig at Leipzig University
Jürgen Schiller: Institute for Medical Physics and Biophysics, Leipzig University
Petra Büttner: Heart Center Leipzig at Leipzig University
Florian Schlotter: Heart Center Leipzig at Leipzig University
Maria Fedorova: University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60411-2

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