Maternal Pre-Existing Diabetes: A Non-Inherited Risk Factor for Congenital Cardiopathies

Abstract

Congenital heart defects (CHDs) are the most common form of birth defects in humans. They occur in 9 out of 1000 live births and are defined as structural abnormalities of the heart. Understanding CHDs is difficult due to the heterogeneity of the disease and its multifactorial etiology. Advances in genomic sequencing have made it possible to identify the genetic factors involved in CHDs. However, genetic origins have only been found in a minority of CHD cases, suggesting the contribution of non-inherited (environmental) risk factors to the etiology of CHDs. Maternal pregestational diabetes is associated with a three- to five-fold increased risk of congenital cardiopathies, but the underlying molecular mechanisms are incompletely understood. According to current hypotheses, hyperglycemia is the main teratogenic agent in diabetic pregnancies. It is thought to induce cell damage, directly through genetic and epigenetic dysregulations and/or indirectly through production of reactive oxygen species (ROS). The purpose of this review is to summarize key findings on the molecular mechanisms altered in cardiac development during exposure to hyperglycemic conditions in utero. It also presents the various in vivo and in vitro techniques used to experimentally model pregestational diabetes. Finally, new approaches are suggested to broaden our understanding of the subject and develop new prevention strategies.

Keywords: cardiogenesis; congenital heart defects; genetics and epigenetics; pregestational diabetes.

Figure 1

Schematic representation of the normal four-chambered mammalian heart and the structural abnormalities of the most common forms of congenital heart defects (CHDs). Black arrows indicate the direction of blood flow. TGA: Transposition of the Great Arteries; DORV: Double-Outlet Right Ventricle; PTA: Persistent Truncus Arteriosus; TOF: Tetralogy of Fallot; VSD: Ventricular Septal Defect; ASD: Atrial Septal Defect; HLHS: Hypoplastic Left Heart Syndrome; BAV: Bicuspid Aortic Valve; and CoA: Coarctation of the Aorta; RA: Right Atrium; RV: Right Ventricle; LA: Left Atrium; LV: Left Ventricle; PA: Pulmonary Artery; Ao: Aorta.

Figure 2

Representative scheme of the main stages of cardiac development. First, on gestation day 15 (equivalent to gestation day 7.5 in mice), the two cardiac lineages derived from the embryonic mesoderm, the First Heart Field (FHF) progenitor cells (red) and the Second Heart Field (SHF) progenitor cells (green), form the cardiac crescent. Around day 20 (equivalent to day 8.5 in mice), the 2 heart fields merge to form the elongated heart tube, which loops rightward on day 26 (equivalent to day 9.5 in mice). The looped heart contains the FHF, which begins to differentiate into left ventricle cardiomyocytes (red), anterior SHF (aSHF, light green), posterior SHF (pSHF, dark green), and migrating cardiac neural crest cells (yellow dots). Cardiogenesis proceeds through a series of proliferation, differentiation, and maturation, culminating in a four-chambered adult heart (D). Ap: Arterial pole; Vp: Venous pole; V: Ventricle; A: Atrium; RA: Right Atrium; RV: Right Ventricle; LA: Left Atrium; LV: Left Ventricle; PA: Pulmonary Artery; Ao: Aorta.

Figure 3

Role of glucose metabolism in cell physiology, genetics, and epigenetics. (Upper panel) In the cell, glucose and fatty acid are metabolized into pyruvate and fatty acyl CoA, respectively, which are converted to acetyl-CoA in the mitochondria. In a process known as oxidative phosphorylation (OXPHOS), acetyl-CoA enters the Krebs cycle, generating an energy substrate for the cell (ATP), cofactors, and Reactive Oxygen Species (ROS). The molecules generated, such as NADH and α-KG, serve as cofactors for epigenetic remodeling enzymes. Hyperglycemia leads to excessive ROS production. If the cells defense mechanisms (antioxidant activity) fail to restore homeostasis, oxidative stress results. ROS can induce cellular damage by regulating cell proliferation, differentiation, apoptosis, and inflammation. (Lower panel) During early cardiogenesis, glucose is the main source of energy. The transition from embryonic stage to fetal stage (the maturing of the heart) is accompanied by a switch in the energy substrate to fatty acid.

Figure 4

Gene–environment interaction (G&E) as a two-hit risk factor for congenital heart defects associated with pregestational diabetes. This scheme illustrates the interaction between genetic predisposition to CHDs and maternal hyperglycemia in embryonic heart development. The molecular and structural abnormalities of the developing heart resulting from this G&E interaction are shown. In vivo and in vitro models are proposed to examine genomic (transcriptomic and epigenomic) changes in response to maternal hyperglycemia, using single-cell approaches. The contribution of the paternal genetics and nutrition to abnormal heart development is also suggested.