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Genetic Insights into Bicuspid Aortic Valve Formation

DOI: 10.1155/2012/180297

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Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the population. It is generally diagnosed late in adulthood when deterioration of the abnormal leaflet becomes clinically evident. BAV patients have an increased risk of developing serious complications, including stenosis, regurgitation, endocarditis, dilation of the aorta, aortic dissection, and aneurysm. BAV is a heritable trait, but the genetic basis underlying this cardiac malformation remains poorly understood. In the last decade, thanks to studies in animal models as well as genetic and biochemical approaches, a large number of genes that play important roles in heart development have been identified. These discoveries provided valuable insight into cardiac morphogenesis and uncovered congenital-heart-disease-causing genes. This paper will summarize the current knowledge of valve morphogenesis as well as our current understanding of the genetic pathways involved in BAV formation. The impact of these advances on human health including diagnosis of BAV and prevention of cardiovascular complications in individuals with BAV or with a family history of BAV is also discussed. 1. Overview of Valve Development In human and other mammals, cardiac valves are essential for unidirectional blood flow which is crucial for proper functioning and survival of the organism. Defects in valve structure or function can profoundly alter cardiovascular homeostasis and are among the leading causes of human morbidity and mortality. Thus, understanding the molecular basis of normal and pathologic valve development is of utmost importance and clinical relevance. The valves of the four chambered heart can be classified in 2 groups: atrioventricular valves (mitral and tricuspid) separate the atria from the ventricles while semilunar valves (aortic and pulmonary) divide the ventricles from the great arteries. Normal aortic valve is tricuspid, meaning it possesses three leaflets (or cusps) but defective development involving fusion of two of these produces bicuspid aortic valve (BAV). At 1-2% prevalence in the human population, BAV is the most common form of congenital heart disease and a significant risk factor for premature cardiovascular complications and valve replacement in young adults. In the embryo, the heart is the first organ to develop starting with the specification and migration of the anterior lateral plate mesoderm cells to form the cardiac crescent [1]. This is closely followed (embryonic day (E) 8.5 in the mouse and 3 weeks gestation in human) by migration of the cardiac


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