Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation

Abstract

In the past 2 decades, it has become evident that individuals born with congenital heart disease (CHD) are at risk of developing life-long neurological deficits. Multifactorial risk factors contributing to neurodevelopmental abnormalities associated with CHD have been identified; however, the underlying causes remain largely unknown, and efforts to address this issue have only recently begun. There has been a dramatic shift in focus from newly acquired brain injuries associated with corrective and palliative heart surgery to antenatal and preoperative factors governing altered brain maturation in CHD. In this review, we describe key time windows of development during which the immature brain is vulnerable to injury. Special emphasis is placed on the dynamic nature of cellular events and how CHD may adversely impact the cellular units and networks necessary for proper cognitive and motor function. In addition, we describe current gaps in knowledge and offer perspectives about what can be done to improve our understanding of neurological deficits in CHD. Ultimately, a multidisciplinary approach will be essential to prevent or improve adverse neurodevelopmental outcomes in individuals surviving CHD.

Keywords: brain; models, animal; neuroimaging; risk factors.

Figure 1

Severity of congenital heart disease positively correlates with increased incidence of neurological impairments. Reprinted from Wernovsky. Copyright © 2006 Cambridge University Press.

Figure 2

(A) Cortical gyrification increases throughout fetal and perinatal brain development. w, weeks. Legend demarks the four lobes of the cortex. (B) Gyrification indices and cortical surface areas of fetuses with HLHS compared with normal fetuses. Adapted from Dubois and Dehaene-Lambertz (A) and Clouchoux et al. (B), with permission from Elsevier.

Figure 3

Risk factors (A) associated with neurodevelopmental outcomes in CHD during progressive epochs of brain development (B). Adapted from Morton et al., with permission from Elsevier.

Figure 4

(A) 3D reconstruction of the corpus callosum of a neonatal piglet defined by tractography with DTI. Immunostains illuminating the oligodendroctye (OL) lineage 3 days (B–E) and 4 weeks (F,J) following severe CPB. 3 days following severe-CPB, OPCs (Mash1⁺ (B), PDGFRα⁺ (C)) and mature OLs (CC1⁺ (E)) display resilience to the surgical insult, whereas pre-OLs (O4⁺) are susceptible to programmed cell death (Casp3⁺ (D)) in the corpus callosum (CC) – a WM tract connecting the left and right hemisphere of the brain. Severe-CPB results in fewer mature OLs (F,J) and less myelin basic protein (MBP) (G,K) in the CC, 1 month following surgery. Severe-CPB also results in an increase in the number of microglia (Iba1⁺) in the CC (H,L), 3 days after surgery. (G,M) Astrocytic response in a mouse brain slice model of CPB. Three hours after oxygen-glucose deprivation (OGD) at 15°C WM astrocytes (GFAP-GFP⁺) in the CC display a distinct change in morphology (M compared to I). Scale bars, 50 μm (B–M). Adapted from Morton et al., with permission from Elsevier.