Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model

Abstract

BackgroundNewly developed white matter (WM) injury is common after cardiopulmonary bypass (CPB) in severe/complex congenital heart disease. Fractional anisotropy (FA) allows measurement of macroscopic organization of WM pathology but has rarely been applied after CPB. The aims of our animal study were to define CPB‐induced FA alterations and to determine correlations between these changes and cellular events after congenital heart disease surgery.Methods and ResultsNormal porcine WM development was first assessed between 3 and 7 weeks of age: 3‐week‐old piglets were randomly assigned to 1 of 3 CPB‐induced insults. FA was analyzed in 31 WM structures. WM oligodendrocytes, astrocytes, and microglia were assessed immunohistologically. Normal porcine WM development resembles human WM development in early infancy. We found region‐specific WM vulnerability to insults associated with CPB. FA changes after CPB were also insult dependent. Within various WM areas, WM within the frontal cortex was susceptible, suggesting that FA in the frontal cortex should be a biomarker for WM injury after CPB. FA increases occur parallel to cellular processes of WM maturation during normal development; however, they are altered following surgery. CPB‐induced oligodendrocyte dysmaturation, astrogliosis, and microglial expansion affect these changes. FA enabled capturing CPB‐induced cellular events 4 weeks postoperatively. Regions most resilient to CPB‐induced FA reduction were those that maintained mature oligodendrocytes.ConclusionsReducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. Studies using this model can provide important data needed to better interpret human imaging studies.

Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease

“…Recent animal models of CHD suggest that abnormal cerebral cortical development is secondary to cerebral white matter abnormalities, likely reflecting developmental vulnerability of the developing subplate 2 , 3 . In parallel, recent CHD neuroimaging studies have delineated important subcortical morphological reductions that are not only present in the fetal and preoperative neonatal period, but are also persistent across the lifespan and likely mediate poor neurocognitive outcomes 4 – 8 .…”

“…However, the relationship between subcortical morphology and white matter/subplate vulnerability has not been studied in detail in infants with CHD. Hypoxia associated with congenital heart disease reduces proliferation and neurogenesis in the subplate structures and developing white matter, thus reducing long-term growth of both cortical and likely also subcortical structures 2 , 3 .…”

“…(3) these white matter locations are known to demonstrate vulnerability in recent animal models of congenital heart disease (Fig. 1 ) 2 , 3 . For comparative purpose, a grey matter voxel was placed in the parietal –occipital midline region as previously described 12 , 16 – 18 , 20 , 21 .…”

“…Neonates with congenital heart disease (CHD) are known to be at risk for impaired neurodevelopmental outcomes, which is likely related to an interplay of cerebral dysmaturation and acquired brain injury, including white matter injury 1 . Recent animal model and correlative neuropathological studies suggest that cortical dysmaturation is linked to white matter abnormalities, including developmental vulnerability of the subplate in CHD 2 , 3 . Recent neuroimaging studies have documented subcortical morphological abnormalities in CHD patients across the lifespan 4 – 8 , but the relationship between subcortical morphological abnormalities and subplate/white matter vulnerability in CHD is unknown, despite this link being well-established in preterm infants 9 – 12 .…”

Impact of Mesenchymal Stromal Cell Delivery Through Cardiopulmonary Bypass on Postnatal Neurogenesis

“…Our previous studies have demonstrated that CPB and circulatory arrest-induced brain insults resulted in apoptosis and dysmaturation of oligodendrocyte lineage and microglia expansion. 20,21,36 In the damaged rodent white matter, MSCs promote endogenous proliferation and differentiation of oligodendrocyte progenitors. 17,37 Administration of MSCs also regulates microglia activation after hypoxic-ischemic brain injury.…”