Effects of congenital heart disease on brain development

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Abstract

Brain and heart development occurs simultaneously in the fetus with congenital heart disease. Early morphogenetic programs in each organ share common genetic pathways. Brain development occurs across a more protracted time-course with striking brain growth and activity-dependent formation and refinement of connections in the third trimester. This development is associated with increased metabolic activity and the brain is dependent upon the heart for oxygen and nutrient delivery. Congenital heart disease leads to derangements of fetal blood flow that result in impaired brain growth and development that can be measured with advanced magnetic resonance imaging. Delayed development results in a unique vulnerability to cerebral white matter injury in newborns with congenital heart disease. Delayed brain development and acquired white matter injury may underlay mild but pervasive neurodevelopmental impairment commonly observed in children following neonatal congenital heart surgery.

Introduction

Despite established mechanisms that preserve brain oxygen and nutrient delivery, newborns with certain forms of congenital heart disease are born with smaller head circumferences possibly indicating impaired brain growth [1]. Somatic and brain growth patterns vary by type of congenital heart disease. Newborns with hypoplastic left heart syndrome (HLHS) are smaller in all dimensions, but head volume is disproportionately decreased. In a recent study, ascending aortic diameter predicted the degree of microcephaly in newborns with HLHS [2]. Hypoplasia or atresia of the ascending aorta limits antegrade cerebral blood flow and thus brain blood flow must arise from the ductus arteriosus in a retrograde fashion across the aortic isthmus. In comparison, infants with isolated aortic coarctation have a greater head circumference relative to birth weight, as flow to the head and neck vessels is unobstructed while blood flow in the descending aorta may be compromised. The relationship between amount of antegrade flow in the ascending aorta and brain growth fails to describe why newborns with d-transposition of the great arteries (d-TGA) have smaller head circumferences with a normal birth weight. d-TGA growth patterns suggest that blood flow alone does not completely describe the connection between heart and brain development.

Brain and heart development intersect at many levels. Early brain and heart organogenesis occur simultaneously in the human fetus and invoke similar developmental programs including stem and progenitor cell proliferation, cell fate commitment, migration, left/right and dorsal/ventral patterning [3], [4], [5]. At later stages, after completion of gross morphological development in both organs, brain development continues with a dramatic increase in brain size (Fig. 1) due to elaboration of neuronal microstructure (e.g. dendrites, axons and synapses) and the onset of myelination. The formation and refinement of connections in the brain requires neuronal activity, leading to an increase in brain metabolism with dependence upon heart function for oxygen and substrate delivery.

Section snippets

Shared genetic pathways in early brain and heart development

Similar morphogenetic events in brain and heart development engage many of the same genes including: sonic hedgehog (progenitor proliferation), notch, jagged, Nkx2.5 (cell fate commitment), fibroblast growth factor-8, nodal, lefty1 (left/right asymmetry), transforming growth factor beta, and retinoic acid (ventral patterning). It has long been recognized that many forms of syndromic congenital heart disease (e.g. Down's, DiGeorge, Noonan, and Williams–Beuren) include neurodevelopmental

Activity-dependent brain development

Gross morphologic events of brain development are completed by the end of the second trimester. The third trimester involves a period of dramatic brain growth and refinement of connections that is dependent upon endogenous, spontaneous neuronal activity arising at multiple levels [14]. In the visual system, this endogenous activity takes the form of spontaneous waves of neuronal activation that sweep across and tile the retina and are transmitted to thalamus and cortex. Patterned activity

White matter maturation

At a cellular level, this brain growth involves the elaboration of dendritic arbors and formation of neuronal connections. Myelination of neuronal axons also begins during this period, with a characteristic caudal to cranial pattern [18]. By the end of the third trimester, myelination extends to the posterior limb of the internal capsule and involves the motor fibers of the pyramidal tract. In neocortex, myelination begins in the optic radiations and occipital white matter soon after birth [19]

The effects of congenital heart disease on fetal brain oxygen delivery and growth

Fetal blood flow is unique in a number of respects that have distinct impact on cerebral blood flow. In the fetus, gas exchange occurs in the placenta with oxygenated blood returning through the umbilical vein and ductus venosus to the portal vein, inferior vena cava and right atrium and deoxygenated blood returning to the placenta via the umbilical artery (Fig. 2A). Prior to birth, blood flow to the lungs is very low due to elevated pulmonary vascular resistance and relatively low lung

Fetal ultrasound assessment of cerebral physiology

Blood flow to the fetal brain is estimated to be almost one quarter of the combined ventricular output in the third trimester [24]. Preferential blood flow to the brain is preserved through autoregulatory mechanisms during pathological states, such as placental insufficiency. This ‘brain sparing’ phenomenon results in relative preservation of head growth, despite somatic growth restriction [25], [26], [27]. Clinically, this fetal autoregulatory response can be assessed using Doppler ultrasound

Fetal brain MRI

The idea that delayed postnatal brain development results from disordered fetal cerebral blood flow suggests two predictions; 1) Delayed brain development should begin during fetal life; 2) Different forms of CHD should manifest different degrees of delayed development. Studies using fetal brain ultrasound have suggested that decline in head growth begins after mid-gestation in fetuses with HLHS [39]. Definitive evidence for delayed fetal brain development has recently been published for a

Transitional circulation

The transition from fetal (placental) circulation to neonatal circulation is complex and requires maintenance of CBF during a period of a precipitous decline in pulmonary vascular resistance [41] along with an increase in systemic vascular resistance [42]. In neonates without congenital heart defects, these changes are facilitated by the closure of the ductus arteriosus, with consequent isolation of the pulmonary blood flow from systemic blood flow. In neonates with complex CHD, closure of the

Magnetic resonance imaging identifies delayed brain development before surgery in CHD

Disordered fetal circulation places the brain at risk for disrupted growth and development during the third trimester. High resolution and advanced magnetic resonance imaging (MRI) techniques allow quantitative measurement of brain development. MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI) assess brain metabolism and microstructure respectively. Proton MRSI can be used to measure N-acetylaspartate (NAA) [52]. NAA is found predominantly in neurons (cell body and axon), so

Summary

Increasing data suggest that brain maturation and development is impaired in neonates with complex congenital heart defects. The delays in development arise from failures in brain oxygen and nutrient delivery unique to each form of congenital heart disease, with examples of deficient content (d-TGA) [24] or abnormalities in blood flow (HLHS) [33], [35]. Delayed fetal brain maturation and development in utero appears to begin in the 3rd trimester of gestation and is consistent with postnatal

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