The Mechanobiology of Notch1 Deficiency in Calcific Aortic Valve Disease
Calcific aortic valve disease (CAVD) is the predominant valvular disease in the developed world, affecting over five million individuals in the United States alone and manifests itself as a progressive disease resulting in the obstruction of left ventricular outflow, decreased cardiac output, and eventual heart failure. Presently, treatment for CAVD is limited to surgical aortic valve replacement, a high risk procedure especially for the population affected, and although significant advances have been made to reduce the associated risk with this procedure, a non-surgical treatment option is preferred. Unfortunately, current efforts to develop pharmacological treatments have been largely unsuccessful at preventing or slowing down the progression of CAVD; this lack of efficacy can be attributed to the incomplete understanding of the etiology of CAVD. Thus, focused attention must be placed on elucidating the underlying mechanisms of CAVD initiation and evolution in order to develop novel and effective pharmacological drugs. At the tissue level, normal supple leaflets are transformed into thickened, stiff, and calcified leaflets; these striking changes are attributed to the aberrant behavior of the resident cell population, the aortic valve interstitial cells (AVICs), which are believed to play significant roles in leaflet thickening and calcification. Investigating what factors contribute to AVIC differentiation into pathological phenotypes and further how they generate valvular calcification is essential to the understanding of CAVD etiology. It has been demonstrated that CAVD development is tightly regulated by biomolecular, mechanobiological, and genetic factors. Previous studies have focused on describing the effect of biomolecular cues on CN development; however, many mechanobiological and genetic factors that have significant in vivo relevance have not been thoroughly assessed. In an effort to gather insight towards CAVD processes in vivo, we believe that investigations into the role of mechanical strain and the effect of Notch1 mutation on AVIC biology and calcification would provide novel insights towards CAVD etiology that can contribute to the development of effect therapeutics.