Congenital Heart Disease (Atrioventricular Septal Defect) in the Mouse with Trisomy 16

Abstract

Failure of fusion between the superior and inferior cushions has usually been assumed to be the main morphogenetic event in producing hearts with deficient atrioventricular septation (atrioventricular septal, or endocardial cushion defects). Morphological studies on human autopsy specimens, however, showed that another consistent finding is the marked disproportion between the dimensions of the inlet and outlet of the left ventricle, which, until now, has no known developmental basis. We have studied the early formation of the hearts with atrioventricular septal defects, using a mouse model with trisomy 16. Animals were studied between the 10th and 19th days of gestation by stereomicroscopic examination, scanning electronmlcroscopy and the in-vitro incorporation of thymidine. The first detectable morphological abnormality of the heart in the trisomic mouse was observed on the 11th day, being a persistence of an infolding at the inferior atrioventricular junction. This infolding was present in both trisomic and eusomic animals on the 10th day. This morphology could be explained by a differential growth of the myocardium at the inferior atrioventricular junction, which was found to be a distinct zone with low incorporation of thymidine. On the 11th day, the inferior atrioventricular cushion was bigger in the trisomic hearts. The abnormalities of the cushions observed on the 12th day or later were deemed to be consequences of these primary defects. Sectioning of the heart from the left lateral aspect convincingly showed morphological changes of the superior and inferior cushion or bridging leaflets in this animal model. Abnormal endocardial cushions and abnormality in the proliferation index of the myocardium at the inferior atrioventricular junction play more significant roles in the formation of the hearts with deficient atrioventricular septation, than the abnormalities found in the atrioventricular cushions.