Abstract 608: Integrated Omics and Network Analysis Identify Drivers of Calcific Bicuspid Aortic Valve Disease

Objectives: Calcific aortic valve disease (CAVD) shares risk factors with atherosclerosis but has no pharmacotherapy. Bicuspid aortic valve (BAV) is the most common congenital cardiac defect (2% of humans), and individuals with BAVs acquire CAVD at a rate >15-25x of those with tricuspid aortic valves (TAVs). The causes and mechanisms of accelerated BAV-CAVD remain unclear. This study demonstrates the integrated transcriptome and proteome of BAV-CAVD. Methods: Quantification of gated chest CTs assessed aortic valve calcification. We performed transcriptomics using Illumina sequencing and global unlabeled proteomics by LC-MS/MS in a total of 55 human aortic valves (24 stenotic TAVs and 25 stenotic BAVs from valve replacement surgeries segmented into fibrotic and calcific portions, and 6 non-diseased aortic valves from heart transplants). Results: Calcific burden did not differ between BAVs and TAVs (Agatston score: p = 0.88), but BAV mineralization was significantly accelerated as BAVs underwent surgery 11.5±1.74 years earlier than TAVs (p < 0.01). Transcriptomics sequenced 11,223 genes and proteomics identified 1,798 proteins. Of these, 174 genes (fibrotic = 121, calcified = 53) and 98 proteins (fibrotic = 24, calcified = 74) were differentially expressed between BAV- and TAV-CAVD. Pathway analysis of proteins enriched in BAVs vs. TAVs found significant enhancement of iron metabolism and proteoglycan function in BAV-CAVD, while complement activation and collagen biosynthesis distinguished TAVs. When overrepresented proteins were mapped to the protein-protein interactome, network analysis identified disease stage- and valve type-specific subnetworks. While numerous protein-protein interactions existed between the fibrosis and calcification subnetworks of TAVs, a disconnection between these two pathological processes was identified in BAV subnetworks. Conclusions: Integrated multi-omics of CAVD stratified by disease stage and valve type identify unique contributors to BAV pathogenesis and shed light on molecular drivers of disease. Network analysis finds that while fibrocalcific responses are linked in TAVs, fibrosis and calcification may develop independently in BAVs, with vital implications for targeting of therapeutics.