Heart changes in 17‐day‐old fetuses of diabetic ICR (Institute of Cancer Research) mothers: Improvement with maternal immune stimulation

Abstract

Maternal diabetes mellitus is associated with increased fetal teratogenesis, including cardiovascular defects. Non-specific maternal immune stimulation with Freund's complete adjuvant (FCA) or interferon gamma (IFNgamma) has been associated with protection against birth malformations. Using a diabetic mouse model, late-gestation fetal heart and great vessel morphology were analyzed. Four groups of mice were used: non-diabetic females as a control group, hyperglycemic females induced by streptozotocin as a diabetic group, and diabetic females injected either with FCA or IFNgamma. At day 17 of gestation, females were euthanized and one fetus was arbitrarily selected per litter for fixation and sectioning. Treatment-induced changes in cardiac development were assessed from digital images of serial sections taken at standardized levels in the thorax. One-way parametric and non-parametric ANOVA and ordinal logistic regression were performed to compare the difference among groups (P<0.05). Maternal hyperglycemia altered morphology of the late-gestation fetal mouse heart by causing ventricular chamber dilation, sectional myocardial reduction, and an increase in transversal aortic area. FCA protected the fetal heart from cavitary dilation in diabetic mothers. FCA and IFNgamma protected the fetal heart against reduction of myocardial area, and ascending thoracic aorta dilation. Consequences of late gestation heart chamber dilation and myocardial reduction are not yet known. Maternal immune stimulation partially protected against these developmental defects by mechanisms that remain unclear.

Pregestational Diabetes and Congenital Heart Defects

“…Claudio Gutierrez et al 23 27 found an association between the hyperglycemic environment during pregnancy and the expansion of the ventricular compartment, decreased area of the ventricular myocardium, and dilation of the ascending aorta in the late stages of pregnancy. Other studies point to a correlation between PGD and hypertrophic fetal cardiomyopathy, 17 24 28 29 possibly due to the hyperinsulinemia that the fetus acquires in the context of maternal hyperglycaemia.…”

“…Hyperglycemia is the main teratogenic factor in diabetic pregnancies, and its presence prior to conception and in the 1 st trimester is associated with an increased risk of disturbed embryonic cardiac development. 7 17 20 21 22 23 24 25 Fetal hyperinsulinemia, inherent in pregnancies of diabetic mothers, is also thought to underlie diabetic embryopathy. 26 …”

“…Several mechanisms have been implicated in this association between PGD and CHDs. 7 Hyperglycemia plays a role as a promoter of oxidative stress by increasing reactive oxygen and nitrogen species, 7 22 23 27 which will promote the occurrence of genetic changes and abnormalities of the usual pattern of apoptosis in cardiac cells, 23 27 particularly in the neural crest, 17 which is a key part in cardiac development. 7 On the other hand, in an hyperglycemic environment, the alteration of multiple signaling pathways with repercussions in cardiac development is observed: (1) exacerbation of the expression of transforming growth factor beta 1 (TGF-β1), originating an excessive accumulation of extracellular matrix proteins in cardiac tissues; 27 (2) decreased levels of nitric oxide, which is essential for the proper functioning of cardiac endothelial cells and whose reduction leads to inhibition of other signaling pathways dependent on its effect; 22 and (3) excessive stimulation of nucleotide biosynthesis via pentose phosphate, which is responsible for glucose metabolization, preventing proper maturation of cardiac cells.…”