Side- and Disease-Dependent Changes in Human Aortic Valve Cell Population and Transcriptomic Heterogeneity Determined...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genomics

Background:

• Calcific aortic valve disease (CAVD) is common in the elderly, lacking effective drug therapies.
• CAVD preferentially affects the fibrosa side of aortic valves, with unknown reasons.
• Hypothesis: Side-dependent transcriptomic and cellular differences predispose the fibrosa to CAVD.

Purpose of the Study:

• Investigate side-dependent transcriptomic and cellular phenotypes in human aortic valves.
• Identify mechanisms underlying CAVD development in the fibrosa layer.
• Discover potential therapeutic targets for CAVD.

Main Methods:

• Single-cell RNA sequencing of endothelial-enriched samples from fibrosa and ventricularis sides.
• Analysis of human aortic valve leaflets from five donors across disease spectrum.
• Utilized a novel method for side-specific sample collection.

Main Results:

• Identified 27 cell clusters, including valvular endothelial cells (VECs), valvular interstitial cells (VICs), and immune cells.
• Discovered side-dependent VEC subtypes with distinct gene expression.
• Observed increased inflammatory VICs, macrophages, and T-cells with CAVD progression.
• Found upregulation of AP-1 transcription factors and EGR1 in fibrosa of diseased leaflets.
• Identified CAVD-associated VEC clusters linked to inflammation, EMT, apoptosis, and fibrosis.

Conclusions:

• Valvular endothelial cells (VECs) exhibit significant heterogeneity dependent on tissue side and CAVD status.
• Unique VEC clusters and pathways in the fibrosa of diseased valves suggest novel pathogenic mechanisms.
• Differentially regulated genes and pathways in fibrosa VECs represent potential therapeutic targets for CAVD.