Genetic basis of aortic valvular disease

Aortic valve disease is relatively common and encompasses both congenital and acquired forms. Bicuspid aortic valve (BAV) is the most common type of cardiac malformation and predisposes to the development of calcific aortic valve disease (CAVD). Since the description of the link between NOTCH1, BAV and CAVD approximately a decade ago, there have been significant advances in the genetic and molecular understanding of these diseases.

Recent work has defined the congenital cardiac phenotypes linked to mutations in NOTCH1, and in addition, novel etiologic genes for BAV have been discovered using new genetic technologies in humans. Furthermore, several mouse models of BAV have been described defining the role of endothelial Notch1 in aortic valve morphogenesis, whereas others have implicated new genes. These murine models along with other cell-based studies have led to molecular insights in the pathogenesis of CAVD.

These findings provide important insights into the molecular and genetic basis of aortic valve malformations, including BAV, specifically highlighting the etiologic role of endothelial cells. In addition, numerous investigations in to the mechanisms of CAVD demonstrate the importance of developmental origins and signaling pathways as well as communication between valve endothelial cells and the underlying interstitial cells in valve disease onset and progression.