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.