Robert M. Weiss, Yi Chu, Robert M. Brooks, Donald D. Lund, Justine Cheng, Kathy A. Zimmerman, Melissa K. Kafa, Phanicharan Sistla, Hardik Doshi, Jian Q. Shao, Ramzi N. El Accaoui, Catherine M. Otto, Donald D. Heistad

The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss-of-function mutation in epithelial growth factor receptor, which are Egfr Vel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy. Aortic valves from Egfr Vel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional Egfr Vel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of Egfr Vel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in Egfr Vel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of Egfr Vel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in Egfr Vel/+ mice with aortic valve dysfunction, but not in Egfr Vel/+ mice with near-normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups. 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 new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.