Introduction to the Compendium on Calcific Aortic Valve Disease

Etiology of Valvular Heart Disease in the 21st Century

“…Bicuspid aortic valve appears to be familial and at least three gene loci have been defined (fig. 2) [16,17,18,19]. …”

Light to Moderate Alcohol Consumption Is Associated With Lower Risk of Aortic Valve Sclerosis

“…3 Indeed, a moderate proportion of individuals, ranging from 2% to 5% in population-based samples, have a more evolved disease, resulting in stenosis of the aortic valve with a consequent obstruction of the left ventricular outflow 3,6,7 and subsequent cardiovascular symptoms and even death if a replacement of the aortic valve is not performed. 2 The pathophysiologic mechanisms and risk factors leading to the initial sclerosis and subsequent calcification of the aortic valve are incompletely understood, but show some similarities with the atherosclerotic disease process. [8][9][10] Traditional risk factors, [3][4][5]11,12 as well as inflammatory markers, seem to play a role, as supported by the presence of inflammatory cells in compromised valves and high levels of circulating C-reactive protein in individuals with AVS.…”

Osteopontin–CD44v6 Interaction Mediates Calcium Deposition via Phospho-Akt in Valve Interstitial Cells From Patients With Noncalcified Aortic Valve Sclerosis

“…1,2,4,5,8 AVSc is present in 25% to 30% of patients over 65 years of age, and it is characterized by thickening of the leaflets with none or marginal effects on the mechanical proprieties of the valve making its presentation asymptomatic. 1,2,4,5,10,11 In addition, aortic sclerosis is challenging to define due to the variable and qualitative nature of its description by echocardiographic evaluation. 1,2,4,5,8 Moreover, tissues from asymptomatic patients with aortic sclerosis are generally unavailable to investigators because these valves are not surgically replaced until moderate to severe stenosis occurs.…”

“…12 At the onset of early symptoms of calcific aortic stenosis, the survival curve declines rapidly from the expected event-free curve, with a dramatic deviation in case of severe symptomatic stenosis. 4,11,13 Despite its high prevalence, little is known about the initiating pathogenetic mechanisms determining the activation of valve interstitial cells (VICs) toward osteogenic-like phenotype and calcification.…”

“…Our extensive work on the pathogenesis of the early stage of CAVD has demonstrated that noncalcified leaflets from patients with AVSc can be induced to express markers of osteogenic transdifferentiation (osteopontin, osteonectin, runt-related transcription factor 2, α-smooth muscle actin, and alkaline phosphatase). 6,7,14,15 Notably, we can promote biomineralization of noncalcified tissues through the combinatory effect of bone morphogenetic protein 4 (BMP4) and mechanical stimulation (15% stretch at 1 Hz) 11 or through oxidative stress. 14 VIC activation is a hallmark of pathological remodeling of the aortic valve leaflet even in the absence of clinical symptoms.…”