Bicuspid aortic valve (BAV) is the most common congenital cardiovascular defect and characterized by formation of two, rather than three cusps. Approximately 50% of young adults with BAV prematurely develop calcification and significant stenosis, which is typically more severe in right/non-coronary (R/NC) fusion. Mechanisms underlying this process are unknown. However, based on BAV-induced narrowing of the valve orifice and obstruction of blood flow, it has been speculated that abnormal biomechanical stimuli play a major role. Despite this, validation studies correlating these stimuli to molecular changes that promote calcification in BAV are lacking. Our objective is to define biomechanical stimuli in young patients and mice with R/NC BAV prior to calcification onset, and further use the murine model to correlate biomechanical indices with transcriptomic changes indicative of mechanosensitive regulators of calcification.Fluid-structure interaction (FSI) models and quantified biomechanical indices (wall shear stress (WSS), von Mises stress) are being generated from echocardiography and MRI from young adults and NfatC1 cre(+) ;Exoc5 fl/+ mice with R/NC BAV, and age-matched tricuspid aortic valve controls. In parallel, tissue sections collected from diseased mice are being subject to spatial transcriptomics (10x Visium) to determine the localization of differentially expressed genes relative to abnormal biomechanical stimuli. FSI results from a 23 y/o BAV patient indicate that cusp fusion leads to higher WSS on the fibrosa surface compared to the control, and high von Mises stress at the fusion site, both of which are regions prone to calcification in humans. To date, we have identified aortic valve stenosis in 25% NfatC1 cre(+) ;Exoc5 fl/+ mice, and spatial transcriptomics in these mice is currently underway. To our knowledge these are the first FSI models to characterize biomechanical stimuli for a young adult with R/NC BAV prior to calcification. Our FSI studies in mice will validate the use of a mouse model to study human disease by comparison of biomechanical indices. Furthermore, parallel transcriptomic studies in BAV mice will allow us to correlate biomechanical stimuli with transcriptomic changes underlying premature calcification.