Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Calcified aortic valve stenosis (CAVS) is one of the most common heart valvular diseases whose prevalence is likely to increase in the future. Aortic valve calcification (AVC) is a common finding in patients with aortic stenosis (AS) and has been shown to be a predictor of more rapid progression of AS and increased risk of adverse cardiac events. Histopathologic studies have now demonstrated that the development and progression of calcified AS is based on an active process, sharing a number of similarities with atherosclerosis. Inflammation, lipid fat infiltration, dystrophic calcification, ossification (bone formation), platelet deposition (clotting) and endothelial dysfunction have been observed in both diseases. Previously, our laboratory has demonstrated that the Wnt/ B-catenin signaling pathway, regulating GSK3B activity and B-catenin status played a key role in the expression of an entire gene program of pro-atherogenic (pro-hardening of the arteries) factors. There is growing evidence to support that cardiovascular risk factors can induce the valve myofibroblast cell to differentiate to an osteoblast-like phenotype. Examination of human calcified aortic valve tissue has shown that several pathologic pathways are involved. Due to the similarities between atherosclerosis and AVC, we suggest that the mineralization process in aortic valves is a consequence of abnormal activation of the canonical Wnt pathway, and that agents which regulate this pathway might be able to prevent AVC. In this work will test the hypotheses that insulin resistance and diabetes mediate activation of Wnt signaling and promote inflammation and an osteogenic phenotype in the aorta and aortic valve in an insulin resistance mouse model.