Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

Abstract

Congenital heart disease (CHD) is the most common type of birth defect and is both a significant pediatric and adult health problem, in light of a growing population of survivors. The etiology of CHD has been considered to be multifactorial with genetic and environmental factors playing important roles. The combination of advances in cardiac developmental biology, which have resulted in the elucidation of molecular pathways regulating normal cardiac morphogenesis, and genome sequencing technology have allowed the discovery of numerous genetic contributors of CHD ranging from chromosomal abnormalities to single gene variants. On the other hand, mechanistic details of the contribution of environmental factors to CHD remain unknown. Maternal diabetes mellitus (matDM) is a well-established and increasingly prevalent environmental risk factor for CHD, but the underlying etiologic mechanisms by which pre-gestational matDM increases the vulnerability of embryos to cardiac malformations remains largely elusive. Here, we will briefly discuss the multifactorial etiology of CHD with a focus on the epidemiologic link between matDM and CHD. We will describe the animal models used to study the underlying mechanisms between matDM and CHD and review the numerous cellular and molecular pathways affected by maternal hyperglycemia in the developing heart. Lastly, we discuss how this increased understanding may open the door for the development of novel prevention strategies to reduce the incidence of CHD in this high-risk population.

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

“…Serum from diabetic animals with normalized glucose levels were found to be teratogenic in in vitro models . Also, numerous studies have shown that treatment with antioxidants alone are able to significantly reduce malformation rates in in vivo models, despite not having effects on hyperglycemic status . While the present study did not show a direct causal relationship between reducing oxidative stress and beneficial effects of exercise, prior studies strongly indicate that oxidative stress is a key teratogenic component leading to diabetic embryopathy …”

“…However, whether maternal exercise may lead to up‐regulation of endogenous antioxidants and/or, reduced ROS production due to improved mitochondrial efficiency in our model remains to be studied. Notably, eNOS‐derived NO promotes Notch signalling, cell proliferation, EMT and differentiation during heart development, and has been implicated to play a role in ROS handling . In the present study, although there was no difference in the total eNOS protein levels between all four groups, levels of phosphorylated eNOS varied, being the lowest in OMD and highest in the two groups with maternal exercise.…”

“…Studies have shown that oxidative stress is a major driver of CHD pathogenesis . In our study, E14.5 embryonic hearts from the offspring of diabetic mice had significantly higher levels of superoxide and lipid peroxidation, an indicator of oxidative damage .…”

Pregestational diabetes in pregnancy: Complications, management, surveillance, and mechanisms of disease—A review

“…The mechanisms by which prenatal exposure to maternal diabetes significantly impacts fetal growth and development is complex and multifactorial. It includes epigenetic modifications, changes in the expression of genes involved in critical developmental pathways, and increased oxidative stress (reviewed in Basu and Marquez-Valdez 14,15 ). In this regard, animal models of diabetes in pregnancy have been particularly useful and necessary.…”

Environmental Risk Factors for Congenital Heart Disease

“…When broken down into specific subtypes, it is clear that some of these carry a particularly increased risk, for example, the risk of PTA is increased 14-fold (Hoang et al 2017). The mechanism by which maternal diabetes increases CHD risk is far from clear (Basu and Garg 2018). This is because it is a complex metabolic disease.…”