Notch Signaling in Congenital and Acquired Aortic Valve Disease

Calcific aortic valve disease represents the predominant pathology of tricuspid (trileaflet) and bicuspid aortic valves in developed countries (Ladich et al., 2011). Accounting for approxi‐ mately half of anatomically isolated aortic stenosis and 25 percent of patients with aortic regurgitation (Roberts, 1970), calcific bicuspid aortic valves requiring surgical intervention present at least two decades earlier than the tricuspid counterpart (Ward, 2000). Mechanisms important in cardiac and organ development — notably, the Notch pathway — have emerged as central players recapitulated and reused during the pathogenesis of calcific aortic valve disease, and support also a common etiology for bicuspid aortic valve and aortic valve calcification (Garg et al., 2005) (Table 1). Active engagement of inflammatory, remodeling, neovascularization and osteogenic (Aikawa et al., 2007a; Aikawa et al., 2007b; Miller et al., 2010; Rajamannan et al., 2003) pathways has conceptually replaced ‘degeneration’ in calcific aortic valve disease pathogenesis and progression (Dweck et al., 2012). Moreover, these pathways invoke similar mechanisms during cardiac morphogenesis. Dysregulated Notch activity has also been reported in vascular inflammation, macrophage activation (Fung et al., 2007), cardiometabolic disorder, and vascular and aortic valve calcification (Fukuda et al., 2012). Preclinical studies suggest that specific blockade of Notch ligand–receptor signaling potently suppresses vascular calcification and calcific aortic valve disease (Fukuda et al., 2012). In this chapter, we review the mechanisms of Notch signaling, aortic valve dysmor‐ phology pertinent to accelerated valve calcification, and discuss the pathways involving Notch that lead to aortic valve calcification and disease.