Abstract 15521: Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Congenital Myxomatous Valve Disease

Abstract

Introduction: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to cardiac dysfunction and heart failure. MVD in a mouse model of Marfan syndrome (MFS) includes valve leaflet thickening and increased immune cell infiltration. However, the underlying mechanisms by which immune cells are recruited in MFS valves remain undefined. Hypothesis: Inhibition of Wnt signaling prevents MVD progression in MFS valves. Methods: Mice with the Fibrillin 1 variant Fbn1 C1039G/+ recapitulate histopathological features of MFS and Wnt signaling activity was detected in TCF/Lef-lacZ reporter mice. Single-cell RNA sequencing was performed from mitral valves of WT and Fbn1 C1039G/+ mice at 1 month-of-age. Inhibition of Wnt signaling was achieved by conditional induction of Wnt inhibitor Dkk1 in valve interstitial cells of Fbn1 C1039G/+ ; Periostin-Cre; tetO-Dkk1; R26-rtTA mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for immune cells were performed. Results: Wnt signaling pathway gene expression is activated early in mitral valve disease progression, prior to immune cell infiltration in Fbn1 C1039G/+ mice. Single cell transcriptomics revealed similar mitral valve cell heterogeneity between WT and Fbn1 C1039G/+ mice at 1 month-of-age. Wnt ligands and responsive genes were predominantly increased in valve interstitial cells and valve endothelial cells of Fbn1 C1039G/+ mice. Inhibition of Wnt signaling by Dkk1 induction at 1 month-of-age prevented the initiation of MVD as indicated by reduced valve leaflet thickness with decreased CD45+ leukocytes and CCR2+ immune cells in Fbn1 C1039G/+ mice. However, later Wnt inhibition starting at 2 months when inflammation and myxomatous changes are occurring did not prevent the progression of MVD. Conclusions: Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation, but is not responsible for valve disease progression once it has been initiated. Thus, Wnt signaling inhibition prevents initiation of congenital MVD, which provides a promising therapeutic target for the early treatment of congenital MVD.