Congenital cardiac anomalies and white matter injury

Abstract

Cardiac abnormalities are the most common birth defects. Derangement of circulatory flow affects many vital organs; without proper supply of oxygenated blood, the brain is particularly vulnerable. Although surgical interventions have greatly reduced mortality rates, patients often suffer an array of neurological deficits throughout life. Neuroimaging provides a macroscopic assessment of brain injury and has shown that white matter (WM) is at risk. Oligodendrocytes and myelinated axons have been identified as major targets of WM injury, but still little is known about how congenital heart anomalies affect the brain at the cellular level. Further integration of animal model studies and clinical research will define novel therapeutic targets and new standards of care to prevent developmental delay associated with cardiac abnormalities.

Keywords: glial cells; heart; myelin; neuroimaging; oligodendrocyte.

Figure 1

Fetal cerebral circulation, white matter (WM) damage, and risk factors associated with neurological outcomes in congenital heart disease (CHD). (A,B) Cartoon illustrating fetal cerebral blood flow. In normal fetuses (A), oxygenated blood (red arrows) from the placenta is preferentially pumped to the left heart, exits through the carotid arteries, and flows to the brain. In fetuses with hyoplastic left heart syndrome (HLHS) (B), oxygenated and deoxygenated (blue arrows) blood mix (purple arrows) and is misdirected to the aorta, bypassing the carotid arteries. Retrograde flow of mixed blood exits through the carotid arteries at a low flow rate to the brain. In HLHS, developing fetal brains receive less and hypoxic blood, resulting in delayed WM maturation. (C,D) Risk factors associated with neurological deficits in CHD patients throughout life.

Figure 2

Immature oligodendrocytes (OLs) are highly vulnerable to cardiac surgery-induced brain injury which delays/impairs white matter (WM) development [21]. (A) Gross anatomy of perinatal pig brain. (B, C, F, G) Immunostains labeling apoptotic (Caspase3⁺) cells in the OL lineage within the corpus callosum (CC) 3 days following severe cardiopulmonary bypass (CPB) surgery. OL precursor (PDGFRα⁺) and progenitor cells (Mash1⁺, PDGFRα⁺), as well as mature OLs (CC1⁺), survive the surgical insult; however, immature (O4⁺) oligodendrocytes undergo cell death (O4⁺/Caspase3⁺) following CPB surgery (F). Fewer, mature OLs are present in the CC 4 weeks following surgery (H) compared to control piglets (D). Additionally, less myelin (MBP) is seen the corpus callosum following injury (I) when compared to control animals (E).