Mechanisms of Congenital Heart Valve Disease Project Summary Congenital heart valve abnormalities due to morphological or extracellular matrix (ECM) defects can progress over time to myxomatous valve disease (MVD), necessitating surgical valve replacement. MVD affects up to 2% of the US population and more than 10% of individuals over 75 have mitral valve regurgitation. Currently, there is no medical therapy, and, if left untreated, MVD can lead to impaired left ventricular function, heart failure, and ultimately death. The current standard of care is valve repair or replacement, which is highly invasive, not always successful, of limited durability, and contraindicated by age and many common comorbidities. Congenital valve abnormalities, including those associated with Marfan Syndrome (MF) can develop into progressive MVD characterized by collagen fiber fragmentation and replacement by mucopolysaccharides and proteoglycans, leading to leaflet thickening and insufficiency. However, the mechanisms that promote progressive valve leaflet degeneration are not known, and there are currently no therapies available to prevent or reverse MVD progression. Our recent studies in mouse models of MVD, including the Fbn1C1039G model of Marfan syndrome, implicate Wnt signaling and myeloid cell infiltration in progressive MVD. Pigs with gene-edited mutations in Fbn1 also demonstrate characteristics of MFS, including thickening of mitral valve leaflets. We hypothesize that congenital ECM abnormalities lead to increased Wnt signaling in valve interstitial cells (VIC)s, resulting in increased cytokine expression and macrophage infiltration, that contribute to pathologic collagen remodeling and valve dysfunction characteristic of MVD progression. The Aims are: 1) Identify VIC sublineages, macrophage populations, and gene expression changes of MVD in mouse, pig and human MFS valves. 2) Determine if Wnt signaling in Fbn1C1039G valves is required for ECM dysregulation and progression of myxomatous disease. 3) Determine if infiltrating macrophages contribute to the pathogenic progression of ECM remodeling and myxomatous valve disease in MFS. The long-term goals of these studies are definition of regulatory pathways in MVD progression, including MVD resulting from congenital valve defects, and identification of new nonsurgical therapeutic approaches for MVD.