부산대학교 도서관

Introduction: Unicuspid aortic valves account for ~5% of aortic valve replacements. Mechanisms by which congenitally malformed valves progress to overt valvular heart disease are poorly understood, and there are no known effective medical therapies. Epithelial growth factor receptor (EGFR) signaling modulates embryonic formation of aortic valves in mice and humans. We hypothesized that mice with a dominant negative Egfr mutation (Egfr) would have congenital aortic valve anomalies.Methods: Valve structure was examined using light microscopy, scanning EM, and immunohistochemistry in Control (Egfr) and Egfr mice. Valves were identified as unicuspid when they were thick and poorly demarcated from the aorta, had <1 commissure, and opened in a funnel shape. Valve and LV function were studied with echocardiography. RT-qPCR reported myocardial gene expression.Results: Anatomic anomalies resembling human unicuspid aortic valves occurred in 79% of Egfr (n=14) and in 0 Egfr valves (n=6) (p<0.05) (Figure). Histologic architecture was grossly distorted in Egfr aortic valves, but valve calcification was minimal or absent. Significant aortic regurgitation or stenosis was present in 38% of Egfr mice at 2.5 months of age and in 74% by 8 months of age (p<0.05). Left ventricular enlargement, hypertrophy, and reversion to fetal myocardial gene expression occurred in Egfr mice with aortic valve dysfunction, but not in Egfr mice with near-normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups.Conclusions: A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The model may be useful to elucidate mechanisms by which congenitally anomalous valves become critically dysfunctional with consequent overt valvular cardiomyopathy.