Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation,and apoptosis in TGF-beta(2)-knockout mice

Background-Transforming growth factor-beta (2) (TGF-beta (2)) is a member o f a family of growth factors with the potential to modify multiple processe s. Mice deficient in the TGF beta (2) gene die around birth and show a vari ety of defects of different organs, including the heart. Methods and Results-We studied the hearts of TGF-beta (2)-null mouse embryo s from 11.5 to 18.5 days of gestation to analyze the types of defects and d etermine which processes of cardiac morphogenesis are affected by the absen ce of TGF-beta (2). Analysis of serial sections revealed malformations of t he outflow tract (typically a double-outlet right ventricle) in 87.5%. Ther e was 1 case of common arterial trunk. Abnormal thickening of the semilunar valves was seen in 4.2%. Associated malformations of the atrioventricular (AV) canal were found in 62.5% and were composed of perimembranous inlet ve ntricular septal defects (37.5%), AV valve thickening (33.3%), overriding t ricuspid valve (25.0%), and complete AV septal defects (4.2%). Anomalies of the aorta and its branches were seen in 33.3%, Immunohistochemical stainin g showed failure of myocardialization of the mesenchyme of the atrial septu m and the ventricular outflow tract as well as deficient valve differentiat ion. Morphometry documented this to be associated with absence of the norma l decrease of total endocardial cushion volume in the older stages. Apoptos is in TGF-beta (2)-knockout mice was increased, although regional distribut ion was normal. Concusions-TGF-beta (2)-knockout mice exhibited characteristic cardiovascul ar anomalies comparable to malformations seen in the human population.