Background-Calcific aortic valve stenosis (AS) is a major societal and economic burden that is rising after the current shift toward an older population. Understanding the pathobiology of AS is crucial to implementing better preventive and therapeutic options. Research conducted during the past decade clearly points to active molecular and cellular processes involved in disease pathogenesis. However, no genomic approaches were used to identify genes and pathways that are differentially regulated in aortic valves of patients with and without AS. Methods and Results-A large-scale quantitative measurements of gene expression was performed on 5 normal and 5 AS valves using Affymetrix GeneChips. A total of 409 and 306 genes were significantly up-and downregulated in AS valves, respectively. The 2 most highly upregulated genes were matrix metalloproteinase 12 and chitinase 3-like 1. The upregulation of these 2 biologically relevant genes in AS was validated by real-time polymerase chain reaction in 38 aortic valves (12 normal and 26 AS). To provide a global biological validation of the whole-genome gene expression analysis, the microarray experiment was repeated in a second set of aortic valves with (nϭ5) or without (nϭ5) AS. There was an overrepresentation of small P values among genes claimed significant in the first microarray experiment. A total of 223 genes were replicated (PϽ0.05 and fold change Ͼ1.2), including matrix metalloproteinase 12 and chitinase 3-like 1. Conclusions-This study reveals many unrecognized genes potentially implicated in the pathogenesis of AS. These new genes were overlaid on known pathological pathways leading to AS to refine our molecular understanding of this disease. (Circ Cardiovasc Genet. 2009;2:489-498.)Key Words: aortic valve Ⅲ microarray Ⅲ real-time PCR Ⅲ pathways analyses Ⅲ candidate genes C alcific aortic valve disease is a growing health problem with important clinical consequences. 1 The condition is initiated with focal subendothelial lesions on the aortic side of the leaflet, similar to atherosclerosis plaques, which eventually progress to aortic stenosis (AS). Histopathologically, AS is characterized by massive calcification and fibrous thickening of the valve cusps leading to left ventricular outflow tract obstruction. 2,3 Patients with AS have an 80% risk of valve replacement, progression to heart failure, or death in the next 5 years after diagnosis. 4 A rapid increase in the incidence of hospitalization because of AS was noticed during the past decades. 1 In the same timeframe, there was also a marked increase in the number of aortic valve replacement procedures. The cost associated with these surgical procedures is very high. 5 In addition, as the prevalence of the disease increases markedly with age, 6 the population at risk rises in proportion to the improvement in life expectancy. Accordingly, AS is now a major societal and economic burden that is likely to be substantiated in a near future. It is thus an urgent priority to understand the pathobiological processes l...

Aortic stenosis (AS) is the most common valvular heart disease, and it is suspected that atherosclerotic mechanisms are involved in the development of this disorder. Therefore, the retention of lipids within the aortic valve may play a role in the pathobiology of AS. In this study, a gene expression microarray experiment was conducted on human aortic valves with and without AS. The expression levels of transcripts encoding proteoglycans and enzymes involved in lipid retention were compared between the two groups. The microarray results were subsequently replicated in a cohort of 87 AS valves and 36 control valves. In addition, the interaction between proteoglycan and lipid-modifying enzyme was documented in isolated valve interstitial cells (VICs). The microarray results indicated that only biglycan (BGN) and phospholipid transfer protein (PLTP) were overexpressed in the AS valves. These results were then confirmed by quantitative PCR. The immunohistochemical analysis revealed a colocalization of BGN, PLTP, and Toll-like receptor-2 (TLR 2) in AS valves. In vitro, we showed that BGN induces the production of PLTP in VICs via the stimulation of TLR 2. Thus , increased accumulation of BGN in AS valves contributes to the production of PLTP via TLR 2. These results suggest that intricate links between valve matrix proteins , inflammation , and lipid retention are involved in the pathobiology

The localisation of SPARC to mature blood vessels and its predominant expression in AS valves with a lower calcification grade suggest that the spatial and temporal distribution of this matricellular protein is tightly controlled to participate in the neovascularisation of AS valves.