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Dramatic advances in echocardiography, cardiopulmonary bypass, surgical technique, and intensive care now allow most patients with congenital heart defects to undergo surgery during the neonatal period or infancy. With these advances mortality declined, but caretakers, patients, and families observe a significant burden of neurodevelopmental impairment in survivors. A natural assumption was that adverse neurologic outcome was directly related to brain injury sustained during neonatal surgical intervention, leading to a seminal study in the late 1980s. The Boston Circulatory Arrest Trial compared two methods of vital organ support in infants undergoing open-heart surgery to repair d-transposition of the great arteries. Consequently, much of what is known about the relationship between complex heart disease and neurodevelopmental outcome has been gleaned from this study. Importantly, it is apparent that injury to the brain may occur during fetal life, at birth, preoperatively, intraoperatively, and postoperatively. In fact, the interplay between the brain and the circulation is complex, occurring at many levels. This chapter will review mechanisms influencing neurologic outcome including: (1) shared genetic and developmental pathways; (2) physiologic effects of congenital heart lesions on brain blood flow; and (3) timing, appearance, and mechanism of acquired brain injuries. We will summarize how these pathogenic mechanisms result in a neurodevelopmental “signature” of congenital heart disease. Finally, we will speculate on how these mechanisms suggest strategies of neuroprotection, repair, and recovery that may improve outcome.

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Shared Genetic Pathways in Brain and Heart Development

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Certain aspects of heart and brain development occur simultaneously in the human fetus (summarized in Chapter 1 for heart and following text for brain). Many vertebrate organs undergo related developmental events (eg, cell fate determination, cell migration, dorsal/ventral patterning, left/right asymmetry, area specification, etc). Thus, it is not surprising that similar genes share important and similar developmental roles in both organs (Table 14-1). This includes genes such as members of the transforming growth factor-β family including bone morphogenic proteins, fibroblast growth factor family members, notch and notch-ligands, sonic hedgehog, vascular endothelial growth factor, and neuregulins. Disruption of shared fundamental genetic pathways that result in cardiac defects will affect brain development as well.

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Table 14-1. Genes with Identified Role(s) in Both Heart and Brain Development 

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