Fetal surgical interventions and the development of the heart in congenital diaphragmatic hernia

Abstract

Selective left ventricular hypoplasia is a recognized feature of congenital diaphragmatic hernia (CDH). It is speculated that the herniated viscera act as a space occupying lesion that inhibit normal cardiac development. The purpose of this study was to determine the effect of two separate fetal surgical interventions on subsequent cardiac development in CDH. CDH lambs were created at 80 days gestation and underwent either tracheal ligation (CDH + TL) or diaphragmatic repair (CDH + repair) at 110 days gestation. At term (141 days gestation) the hearts were harvested and fixed in 4% paraformaldehyde solution. Anatomic dissections were performed and component heart weights determined. Fresh specimens were analyzed for DNA and protein content. All weights are expressed in grams/kilogram body weight and all data as mean +/- SEM. All measurements are compared to control and CDH tissues. There were seven CDH lambs, five control lambs, five CDH + TL lambs, and five CDH + repair lambs. There were no differences in body weight (kg) between CDH, CDH + TL, CDH + repair, and control littermates. CDH lambs have significantly decreased total heart (4.88 +/- .25* vs 6.75 +/- .49, P < 0.05), left ventricular (1.65 +/- .11* vs 2.15 +/- .19, P < 0.05), septal (1.29 +/- .11* vs 1.99 +/- .21, P < 0.05), and combined atrial (0.68 +/- .06* vs 1.14 +/- .15, P < 0.05) weights (g/kg lamb) without differences in RV weights (1.26 +/- .07 vs 1.57 +/- .17, P = NS) when compared to littermate controls. No differences were found in total heart (4.82 +/- 0.38 vs 4.88 +/- 0.25), left ventricular (1.48 +/- 0.13 vs 1.65 +/- 0.11), septal (1.26 +/- 0.17 vs 1.29 +/- 0.11), combined atrial weights (0.56 +/- 0.07 vs 0.68 +/- 0.06), and right ventricular (1.52 +/- 0.12 vs 1.26 +/- 0.07) between CDH + TL and CDH lambs. There were no differences in total heart (6.60 +/- 0.29 vs 6.75 +/- 0.49), left ventricular (2.10 +/- 0.15 vs 2.15 +/- 0.19), septal (1.97 +/- 0.18 vs 1.99 +/- 0.21), combined atrial (1.10 +/- 0.10 vs 1.14 +/- 0.15), or right ventricular (1.52 +/- 0.12 vs 1.57 +/- 0.17) weights between CDH + repair and control lambs. LV and RV wall thicknesses (cm), as well as total protein and DNA content, and DNA/total protein ratios were identical in all groups. CDH lambs have a significant reduction in total heart weights mainly caused by hypoplasia of the left ventricle (left ventricular "smallness") and the interventricular septum. Removal of the herniated viscera and repair of the diaphragmatic defect correct this abnormality, but tracheal ligation does not. We speculate that although tracheal ligation reverses pulmonary hypoplasia, the enlarging lungs act as space occupying lesions that adversely affect cardiac development. Further investigations are necessary to determine the functional significance of these findings.