Sunday, May 25, 2025
5/25/2025
Bicuspid Aortic Valve Biomechanics and Calcification - PROJECT ABSTRACT Calcific aortic stenosis (CAS) is the most prevalent heart valve disorder affecting up to 50% of adolescents with congenital valve disease and over 25% of those over age 75, following life-long exposure to risk factors. Independent of age, outcomes are poor following the onset of aortic stenotic (AS) symptoms, unless outflow obstruction is relieved. CAS is progressive and manifests as cusp thickening with osteogenic-like remodeling, calcium deposition in regions of high mechanical demand and narrowing of the valve opening. Despite this, the mechanisms underlying these phenotypes and their contributions to the severity of AS pathogenesis are not well defined, but biomechanical stress was implicated. This is best illustrated in congenital bicuspid aortic valve (BAV) disease, causing structural narrowing of the aortic valve (AoV) opening and increased biomechanical stress over the cusp surface. In more than half of BAV patients, CAS develops at least 10-15 years earlier than tri-leaflet AoVs and up to 25 years sooner in those born with fusion between right and non-coronary cusps (R/NC). Current clinical management is limited to periodic surveillance of AoV dysfunction and only when the valve becomes stenotic during late stages, is intervention recommended. Historically, surgical AoV replacement has been the most effective treatment for CAS, and BAV patients account for almost 50% of these cases. However, due to surgical-related complications, especially in high-risk patients, less-invasive transcatheter AoV replacement (TAVR) approaches have been introduced that show significantly reduced mortality in low-risk patients, but similar poor post-procedure outcomes in high-risk groups, including BAV patients. Therefore, there is a critical need to develop more effective treatments of CAS, but what do we therapeutically target, and when? To address this deficit, we have initiated studies in humans and mouse models of R/NC and right/left (R/L) BAV to temporally examine CAS pathogenesis, based on structure, function, biomechanical and molecular phenotypes, and mechanistically understand how these pathological milestones interact to initiate and advance CAS. Based on our data thus far, we hypothesize that CAS progression is a multi-step process, initiated by structural valve abnormalities (i.e. BAV) that increase wall shear stress on the valve endothelial cells to a threshold sufficient to activate mechanosensitive pathways and promote osteogenic changes in valve interstitial cells. To do this, we will: 1) Determine subject- and structure-specific biomechanical stress along the cusps of young patients with congenital BAV disease types, prior to the onset of calcification, using fluid structure interaction (FSI) simulations; 2) Determine the pathophysiological milestones and outcomes predictors of calcific aortic stenosis in mouse models of R/L and R/NC BAV; and 3) Mechanistically delineate the mechanotransduction of abnormal biomechanical stress on osteogenic signaling pathways in CAS. Outcomes from these studies will provide insights for the development of predictive diagnostics and mechanistic-based therapeutic targets that can be administered early to prevent CAS onset, or halt progression.
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