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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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