Padang R, Bagnall RD, Tsoutsman T, Bannon PG, Semsarian C
Physiol. Genomics 2014 Dec;:physiolgenomics.00115.2014
Intrinsic valvular degeneration and dysfunction is the most common complication of bicuspid aortic valve (BAV) disease. Phenotypically, it ranges from calcific aortic stenosis to redundant or prolapsing regurgitant leaflets. The underlying molecular mechanism underpinning phenotype heterogeneity of valvular degeneration in BAV is poorly understood. We used RNA-sequencing to identify genes and pathways responsible for valvular degeneration in BAV, compared to tricuspid aortic valve (TAV). Comparative transcriptome analysis on total RNA of aortic valve tissues of patients with diseased BAV (n=5) and calcified TAV (n=3). A total of 59 and 177 genes were significantly up- and downregulated, respectively, in BAV compared to TAV. Hierarchical clustering indicated heterogeneity within the BAV group, separating those with heavy calcification (BAVc) from those with redundant leaflets and/or minimal calcification (BAVr). Interestingly, the gene expression profile of the BAVc group closely resembled the TAV, with shared up- and downregulation of inflammatory and NOTCH1 signaling pathways, respectively. Downregulation of matrix protease ADAMTS9 and protein aggrecan were observed in BAVr compared to TAV. Dysregulation of fetal gene programs were also present, with notable downregulation of SEMA6B and SEMA3F in BAVr and BAVc compared to TAV, respectively. Upregulation of TBX20 was observed exclusively in BAVr compared to BAVc. In conclusion, diverging molecular mechanisms underpin phenotype heterogeneity of valvular degeneration in BAV and data from the present study suggest that there may be shared mechanisms leading to calcification in BAV and TAV. Recognition of these pathways is fundamental to improve our understanding of the molecular basis of human BAV disease.