Congenital heart disease: An important cause of brain injury and dysmaturation

Transposition of the great arteries

TGA ( Fig. 16.2 ) results from ventriculoarterial discordance when the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. This leads to the systemic circulation, being supplied with deoxygenated venous blood returning from the body, and the pulmonary circulation, being supplied with oxygenated blood returning from the lungs, to be in parallel rather than in series as they are in a normal heart. This results in the affected infant being cyanosed. TGA can be associated with other cardiac abnormalities, such as ventricular septal defects, left ventricular outflow tract obstruction, or coarctation of the aorta. TGA can be difficult to diagnose antenatally with ultrasound, while affected infants can present with cyanosis and tachypnea. The severity of symptoms depends on the presence of other cardiac anomalies and the degree of mixing between the two parallel circulations.

The initial management of TGA is to stabilize the infant until the corrective surgery is performed. This includes maintaining the patency of the ductus arteriorus using prostaglandin E1 infusion to optimize circulatory mixing. Balloon atrial septostomy may also be performed to improve oxygenation and survival in neonates with d-TGA. In this intervention, a balloon is passed into the left atrium, inflated, and pulled vigorously across the atrial septum to create a larger atrial septal defect. The arterial switch operation is now the standard corrective procedure for TGA.

Hypoplastic left heart syndrome

HLHS ( Fig. 16.2 ) describes a spectrum of cardiac malformations characterized by underdevelopment of the left heart with normally related great arteries, leaving the right ventricle to perfuse both the pulmonary and systemic circulations. In HLHS, there is significant hypoplasia of the left ventricle which is associated with atresia, stenosis, or hypoplasia of the aortic and/or mitral valves, and hypoplasia of the ascending aorta and arch. The anatomic spectrum varies from almost complete absence of left ventricle combined with aortic and mitral atresia to milder hypoplasia of the left ventricle combined with aortic and mitral valve hypoplasia but without stenosis or atresia. Survival is dependent on a patent ductus arteriosus and nonrestrictive atrial septal defect to ensure adequate systemic perfusion and mixing of oxygenated and deoxygenated blood. Affected infants become symptomatic when the ductus arteriosus closes and pulmonary vascular resistance decreases as expected after birth, progressing to cardiogenic shock and respiratory failure. Infants with a restrictive or intact atrial septal defect present with severe cyanosis and respiratory distress at birth because of pulmonary blood flow. Fortunately, a prenatal diagnosis is made in approximately 50% to 75% of cases with routine obstetrical ultrasound, typically between 18 and 24 weeks gestation, and is associated with improved survival and decreased morbidity.

The initial management of infants with HLHS is focused on ensuring adequate systemic perfusion, which is achieved with intravenous prostaglandin E1 infusion to maintain patency of the ductus arteriosus. Balloon atrial septostomy may also be used in patients with a restrictive or intact atrial septum. The surgical palliation approach usually consists of a three-staged approach: (1) Norwood procedure (neonatal period), (2) bidirectional Glenn procedure (around 3–6 months of age), and (3) Fontan procedure (typically 2–5 years of age). In the Norwood procedure, a neoaorta is created by using the proximal pulmonary artery and homograft material, which is then connected to the native ascending aorta. A source of pulmonary blood flow is established either via a right ventricle to pulmonary artery conduit (Sano) or by connecting the innominate artery with the proximal right pulmonary artery via a Gore Tex tube (called modified Blalock-Taussig shunt). By 6 months of age, the arterial shunt can usually be substituted with a bidirectional cavo-pulmonary shunt (SVC to pulmonary artery anastomosis), which results in diminished volume loading for the ventricle. As the child grows further, the Fontan circulation can be completed. In this third stage, the inferior vena cava is connected to the pulmonary arteries, allowing the entire systemic venous return to pass through the lungs, driven by the suction force of the heart and finally achieving near normal arterial oxygen saturations.

Brain dysmaturation begins in utero in CHD

Abnormalities in brain maturation and growth are common brain changes seen in CHD and are key contributors to adverse neurodevelopmental outcomes. Neonates with severe CHD have preoperative abnormalities in brain microstructural and metabolic maturation when compared to healthy controls. ^, Smaller head circumferences, decreased total and regional brain volumes, reduced cortical folding, ^, and alterations in structural and functional brain network connectivity ^{, ,} are also present at birth, even before neonates with CHD undergo surgery ( Table 16.2 ). Some studies have observed a link between brain dysmaturation in the neonatal period and adverse neurodevelopmental outcomes later in childhood in CHD, although additional studies are required to further elucidate this relationship. These alterations in brain maturation persist through childhood and adolescence and are also associated in long-term neurodevelopmental outcomes in CHD. ^, Recent studies have observed smaller brain volumes and altered white matter microstructure in adults with CHD, which are associated with cognitive function. ^, Table 16.3 summarizes a selected list of studies that have observed associations between brain abnormalities and neurodevelopment and cognition in CHD.

Brain dysmaturation in CHD begins during fetal brain development ( Table 16.4 ). A fetal neuroimaging study of fetuses with CHD observed smaller total brain volumes and lower NAA:choline ratios (reflective of metabolic maturation) compared to controls. In this study, the differences in metabolic maturation and brain volumes between CHD and control fetuses widened over the third trimester during a period when brain growth and maturation is expected to accelerate, suggesting that the impairments in brain maturation observed in fetuses with CHD progress throughout gestation. Fetuses with CHD also have smaller regional brain volumes, slower head growth, ^, and delayed cortical development. ^, Interestingly, fetuses with CHD had less pronounced reductions in regional brain volumes when compared to fetuses with a family history of CHD rather than when compared to control fetuses with no family history of CHD, suggesting that genetic or shared environmental factors may contribute to brain dysmaturation in fetuses with CHD.

Findings of animal studies suggest that hypoxia-ischemia plays a key role in fetal neuronal and white matter dysmaturation in CHD, possibly mediated by the hypoxia-inducible-factor signaling pathway and impaired angiogenesis. This is of particular importance given alterations in cerebral blood flow and oxygenation that are observed in fetuses with CHD. In particular, the immature white matter in the developing brain is especially vulnerable to hypoxia-ischemia. The primary myelinating cells in the brain are oligodendrocytes which undergo expected maturation from neural stem cells to oligodendrocyte precursor cells to immature pre-oligodendrocytes and finally into mature myelinating oligodendrocytes. Hypoxia-ischemia causes pre-oligodendrocyte cell injury following which the injured pre-oligodendrocyte cells degenerate. ^, New pre-oligodendrocytes regenerate from the population of oligodendrocyte progenitor cells that are resistant to hypoxia-ischemia. However, these new pre-oligodendrocytes experience maturational arrest and do not differentiate into mature myelinating oligodendrocytes, resulting in impaired myelination and white matter microstructural abnormalities.

Imaging studies of human fetuses with CHD in vivo have found an association between brain dysmaturation and altered fetal cerebral oxygenation and blood flow. Fetuses with CHD have decreased umbilical blood flow and streaming of oxygenated blood from the placenta to the ascending aorta, which is associated with lower oxygen saturations in the ascending aorta. These hemodynamic changes correlate with less cerebral oxygen delivery and smaller brain volumes in fetuses with CHD. A recent study using a novel fetal imaging technique to quantify fetal cerebral oxygenation (measuring T2* decay) observed a similar association between reduced cerebral oxygenation in fetuses with CHD compared to control, which was associated with reduced brain volumes. Reduced regional brain volumes in important structures containing maturing neurons and glial cells (subplate, intermediate zone, ventricular zone) in fetuses with CHD is also associated with less cerebral substrate delivery. These studies support the hypothesis that altered fetal hemodynamics and cerebral oxygenation play a critical role in brain dysmaturation in fetuses with CHD. Thus, current studies are investigating the use of maternal hyperoxygenation as a potential neuroprotective strategy in CHD.