Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation

Abstract

Objective: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants. Methods: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34 C full flow for 60 minutes) and severe-CPB groups (25 C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development.Results: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons. Interpretation: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD.

Mesenchymal Stromal Cell Delivery Via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Model

“…Our structural imaging analyses demonstrated differences in the volume of frontal cortices among the 3 groups ( Supplemental Figure 12B ), consistent with MSC-induced inhibition of neuronal apoptosis. Similar to our previous studies, 6 the gyrification index was lower after CPB compared to controls ( Figures 5A and 5B ). Notably, CPB-induced alterations of gyrification were improved in the brain with BM-MSC treatment ( Figures 5A and 5B ).…”

“… 4 Our previous studies found prolonged microglia expansion and cortical dysmaturation after cardiopulmonary bypass (CPB). 5 , 6 Newly acquired brain damage is commonly recognized after surgery with current technologies. 7 , 8 Thus, further refinement of pediatric cardiac surgery will likely assist in the improvement of neurodevelopmental outcomes in CHD.…”