Table 1:

Examplar Studies Employing Omics to Define CAVD Pathogenesis

Tissue/Model	Species/Sample size	Data	Methods/Analytical tools	Major findings	Ref.
Stenotic aortic valves/spatiotemporal segmentation	Human 9/3	Yesa	LC-MS/MS, RNA-seq Qlucore Omics Explore, DESeq2, Proteome Discoverer, ConsensusPathDB	First spatially/temporally resolved multi-omics study of human CAVD tissue; identification of molecular regulatory networks in CAVD, demonstration of side-specific VIC calcification potential	26
Stenotic aortic valves/spatiotemporal segmentation	Human 9	Yesb	MS/MS (targeted PRM) Proteome Discoverer, Qlucore Omics Explorer, ConsensusPathDB	ApoC-III is increased in fibrotic and calcific tissues; induces calcification via mitochondrial dysfunction/inflammation	13
Stenotic aortic valves/bulk tissue (RNA); buffy coat (DNA)	Human 233 (TWAS) 5,115/354,072 cases/controls (GWAS)	Yesc	GWAS/TWAS (eQTL) PLINK, SNPTest	Implicates IL6, ALP and NAV1 as new genetic loci in CAVD pathogenesis	27
Stenotic aortic valves/bulk tissue; EDTA-plasma	Human 96/106	Yesd	MS (non-targeted metabolomics and targeted lipidomics) MetaboAnalyst, Cytoscape	Initial metabolomic map of human CAVD; LsyoPA is associated with CAVD severity and accelerated disease progression	28
Cultured VICs	Pig 7,037 cells	Yese	Single-cell RNA-seq Cell Ranger, DESeq2, Seurat	NO rescues aortic valve calcification by a S-nitrosylation of USP9X to activate NOTCH signaling	29
Calcific/non-diseased aortic valves	Human 6/6	Yesf	Bulk and single-cell RNA-seq CellRanger, STAR, Monocle	Identification of 14 cell subtypes; endothelial-to-mesenchymal transition contributes to CAVD pathogenesis	30

^ahttps://cics.bwh.harvard.edu/multiomics_databases

^bProteomeXchange Consortium; dataset identifier PXD021858

^cAvailable from the corresponding authors on reasonable request

^dEuropean Molecular Biology Laboratory–European Bioinformatic Institute MetaboLights database; identifier MTBLS1267

^eGEO; accession number GSE161123

^fBioProject database of NCBI; PRJNA562645 (single-cell sequencing raw data), PRJNA552159 (bulk sequencing raw data)