Kazutoshi Shimoo

Tetralogy of Fallot, pulmonary valve stenosis, ventricular septal defect, and hypertrophic cardiomyopathy in WKY/NCrj rats.

ABSTRACT: We examined anatomically the hearts of 198 WKY/NCrj rats of 20 litters. There were 51 rats with moderate to severe thickening of the pulmonary valve and 19 rats with a ventricular septal defect; the two lesions occurred together in 16 rats, in 15 of which there were overriding of the aorta, stenosis of the pulmonary outflow tract, and hypertrophy of the right ventricle, fulfilling the criteria for tetralogy of Fallot in man. The papillary muscle of the conus was absent in 65 rats. The heart was abnormally heavy in 18. We analyzed the relationship between cardiac hypertrophy and valvular lesions and septal defects in these rats plus 27 selected WKY rats with abnormally heavy hearts. Of the 151 rats with neither severe valvular lesions nor septal defects, six rats had abnormally heavy hearts and 67 rats had disproportionate ventricular septal thickening. This situation in the rats is similar to hypertrophic cardiomyopathy. The occurrence of these abnormalities, isolated or in association, in rats of an established inbred strain strongly suggests that they are etiologically or genetically linked, and that the rats should be a useful animal model for these diseases in man.

Tetralogy of Fallot, Cardiac Hypertrophy, Pulmonary Hypertension, and Anomalies of Great Vessels in Fetuses and Neonates of WKY/NCrj Rats

ABSTRACT: We examined anatomically the hearts, lungs, and great vessels of 269 WKY/NCrj rats at three fetal and three neonatal stages. Severe pulmonary valve thickening was present in 16 and ventricular septal defects with overriding of the aorta in 15 of the 90 near-term fetuses and in 10 and nine, respectively, of the 79 neonates at 2-4 d of age. These abnormalities occurred together (tetralogy of Fallot) in seven of the near-term fetuses and in five of the neonates. A narrow pulmonary outflow tract was present in 55% of the fetuses and in 56% of the neonates. The wall of the pulmonary arterial branch was abnormally thick in 19% of the fetuses and in 26% of the neonates, most of which did not have septal defects. In about 80% of the fetuses, the middle latitudinal muscle bundle of the ventricular septum was not continuous with the left ventricular free wall, but rather with the right; after birth, it was discontinuous with both free walls. The heart was abnormally heavy in 49% of the 79 neonates. In about half of the heavy hearts, there were no septal defects or pulmonary valvular and arterial lesions. There were double aortic arches in four and right aortic arches in six of the total WKY fetuses and neonates; the ductus arteriosus was abnormally small in 47% and the aorta was large in 51% of the near-term fetuses. This constellation of congenital heart disease is genetic in origin, but altered by hemodynamics late in fetal life.

Hereditary transmission of tetralogy of Fallot, cardiac hypertrophy, and anomalies of great vessels in WKY/NCrj rats.

ABSTRACT: We examined 78 fetuses on d 21 of gestation (G21) and 83 neonates on d 2 after birth (A2), which were first generation offspring of WKY rats mated with normal Wistar rats (Fl). In addition, we examined six groups of fetuses on d 19 of gestation (G19): 65 Wistar rats, 111 WKY rats, 85 F1, 100 F1 × F1, 92 F1 × Wistar, and 97 F1 × WKY progeny. In the F1 at G19, G21, and A2, there were abnormalities of the pulmonary valve, pulmonary outflow tract, architecture of muscle bundle, and pulmonary arterial branch, as well as hypoplastic ductus arteriosus and postnatal cardiac hypertrophy, similarly in males and females but at a lower incidence and to a lesser extent than in the WKY rats. Severe pulmonary valve dysplasia and ventricular septal defect with overriding of the aorta (tetralogy of Fallot), usually associated with a markedly small ductus, were not present or were very rare in the F1 and the F1 × Wistar but were present in the F1 × WKY and in the F1 × F1 less prevalently than in the WKY. The size of the ductus showed a continuous distribution in all of the six groups; there was a large skewing toward lower values in the WKY, the F1 × WKY, and the F1 × F1. These results suggest that cardiovascular anomalies of WKY rats are transmitted as autosomal recessive or incomplete autosomal dominant traits with an incomplete penetrance and variable expressivity or as polygenic traits. Chromosomal analysis of 31 WKY fetuses revealed no abberations specifically related to the development of cardiovascular malformations.