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Dramatic advances in noninvasive imaging, cardiopulmonary bypass, surgical technique, and intensive care now allow most patients with congenital cardiovascular defects to undergo surgery during the neonatal period or in later infancy. With these advances, mortality has declined, but many patients are at risk for neurodevelopmental impairment. 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. Much of what is known about the relationship between early intervention for complex cardiovascular disease and neurodevelopmental outcome has been gleaned from this study. However, it is now apparent that injury to the brain may occur during fetal life, at birth, preoperatively, intraoperatively, and postoperatively. The interplay between brain development and the circulation is complex and occurs at many levels. This chapter reviews mechanisms influencing neurologic outcome, including (1) shared genetic and developmental pathways, (2) physiologic effects of congenital cardiovascular lesions on brain blood flow, and (3) the timing, appearance, and mechanism of acquired brain injuries. We summarize how these pathogenic mechanisms result in a neurodevelopmental “signature” of congenital cardiovascular disease. Finally, we will speculate on how these mechanisms suggest strategies of neuroprotection, repair, and recovery that may improve outcome.


Shared Genetic Pathways in Brain and Heart Development

Certain aspects of heart and brain development occur simultaneously in the human fetus (summarized in Chapter 1 for heart and below 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 those in the Ras-MAPK pathway, members of the transforming growth factor β family, fibroblast growth factor family members, notch and notch ligands, and vascular endothelial growth factor. Disruption of shared fundamental genetic pathways that result in cardiac defects will affect brain development as well.

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

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