Journal of Pediatric Cardiology and Cardiac Surgery

Congenital heart disease (CHD) is the most common type of birth defect. Malformations involving the cardiac outflow tract and semilunar valves account for greater than 50% of CHD cases and are largely due to bicuspid aortic valve (BAV), which has a population prevalence of approximately 1%. Mutations in NOTCH1 were linked to BAV and aortic valve calcification in humans, consistent with the expression of Notch1 in the developing and adult aortic valves. With the use of cellular and murine model systems, we have begun to elucidate the molecular mechanisms by which deficiency in Notch1 signaling results in BAV and aortic valve calcification. In vitro, loss of Notch signaling has been shown to contribute to aortic valve calcification via multiple pathways, including Runx2, Sox9, and Bmp2, and appear to be responsive to endothelial nitric oxide signaling during the calcific process. We previously reported a highly penetrant model of dysplastic aortic valves with aortopathy in Notch1 haploinsufficient adult mice backcrossed into a Nos3-null background. Analysis of Notch1^+/−;Nos3^−/− compound mutant embryos has demonstrated a spectrum of congenital anomalies involving both the left and right ventricular outflow tract; these phenotypes are the result of loss of Notch1 in endothelial and endothelial-derived cells. These congenital cardiac phenotypes are strikingly similar to the recently published NOTCH1 mutations in families with malformations in both left and right ventricular outflow tracts. Thoracic aortic aneurysms are also associated with BAV in humans; echocardiographic analysis of Notch1^+/−;Nos3^−/− adult mice revealed an early evidence of ascending aortic aortopathy. In summary, discovery of NOTCH1 mutations as a cause of aortic valve disease in humans has been supported by the development of cellular and mouse models, which are now beginning to shed light on the underlying mechanisms of BAV and its associated diseases of calcification and aortopathy.