Grant: Operating Grant

Calcific aortic valve stenosis (AS) is the most common heart valve disease and the third cause of cardiovascular death. AS is a progressive disorder in which a chronic mineralization of the aortic valve leads with the years to an obstruction and a narrowing of the aortic valve orifice. In the late stage of the disease process when AS is severe, the life expectancy is shortened drastically and the only hope for a cure is an open-heart surgery, which consists in the replacement of the diseased valve. It is important to underline that, for a vast majority of patients, AS can be diagnosed early in its evolution and could thus be treated with a pharmaceutical agent. However, so far, no medical treatment has shown efficacy in preventing the progression of AS once diagnosed. This is largely due to the absence of specific molecular target to AS, which could, in turn, be used to develop novel pharmaceutical agents. To this effect, we have recently discovered such an important target, which is playing a key role in the calcification of aortic valve and the clinical progression rate of AS. Ectonucleotide pyrophosphatase/phosphodiesterase-1, or in short ENPP-1, is one of 700 genes or so found differentially regulated in AS, but which plays a fundamental role in the disease process. In fact, we have found that ENPP-1, by its ability to hydrolyze nucleotide to phosphate, promotes the calcification of the aortic valve. In the next several years, the goal of our studies will be to further understand the role of ENPP-1 in the development of AS and to characterize the potential implication of this gene in diabetes and hypertension, two important risk factors for the development of AS. These experiments will, for the first time, give several important insights into the pathophysiology of AS and will certainly help to translate those findings into the clinical practice.