Abstract
A bicuspid aortic valve (BAV) is the most common cardiac malformation, found in 0.5% to 2% of the population. BAVs are present in approximately 50% of patients with severe aortic stenosis and are an independent risk factor for aortic aneurysms. Currently, there are no therapeutics to treat BAV, and the human mutations identified to date represent a relatively small number of BAV patients. However, the discovery of BAV in an increasing number of genetically modified mice is advancing our understanding of molecular pathways that contribute to BAV formation. In this study, we utilized the comparison of BAV phenotypic characteristics between murine models as a tool to advance our understanding of BAV formation. The collation of murine BAV data indicated that excess versican within the provisional extracellular matrix (P-ECM) is a common factor in BAV development. While the percentage of BAVs is low in many of the murine BAV models, the remaining mutant mice exhibit larger and more amorphous tricuspid AoVs, also with excess P-ECM compared to littermates. The identification of common molecular characteristics among murine BAV models may lead to BAV therapeutic targets and biomarkers of disease progression for this highly prevalent and heterogeneous cardiovascular malformation.
Highlights
A bicuspid aortic valve (BAV), as opposed to the normal tricuspid arrangement, is the most common cardiac malformation and is found in approximately 0.5% to 2% of the population [1,2]
We examined the current findings from all the murine models to date to identify the common molecular criteria that may intersect in BAV formation
The conversion of the provisional extracellular matrix (P-ECM) to mature ECM (M-ECM) in aortic valve (AoV) development involves the reduction of the Vcan–HA matrix and the generation of a complex stratified ECM that includes a collagen-rich fibrous matrix, proteoglycan-rich, spongiosa and elastic fibrosa that integrates with aortic root tissues for strength and support
Summary
A bicuspid aortic valve (BAV), as opposed to the normal tricuspid arrangement, is the most common cardiac malformation and is found in approximately 0.5% to 2% of the population [1,2]. BAVs are an independent risk factor for ascending aortic aneurysms, which can lead to rupture (dissection) and sudden death. This association may be a result of their common developmental origin and/or abnormal changes in hemodynamic forces due to a BAV [4]. BAVs has given insight into the cell and molecular interactions required for normal aortic valve (AoV) development. Since BAVs appear to have a complex origin and exhibit an unpredictable disease progression, the discovery of common characteristics among murine. BAV models may reveal novel therapeutic targets that are effective for a significant cohort of BAV patients
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