Both prospective clinical trials and retrospective clinical studies of development of children following surgery for congenital heart disease have documented worse outcomes for motor skills than cognitive abilities. This finding is consistent with several recent studies using magnetic resonance imaging (MRI) in newborns and infants after cardiac surgery which have documented evidence of white matter injury (WMI). A presumed selective vulnerability of the newborn to WMI has led some to suggest that corrective surgery should be avoided in the newborn period despite its many advantages. Suspected causative factors of WMI in the newborn include a unique susceptibility to the deleterious effects of cardiopulmonary bypass (CPB) including an exaggerated systemic inflammatory response as well as a risk of ischemia/reperfusion. Bypass strategies that include rapid cooling, extreme hemodilution and severe alkalinity as well as some techniques of circulatory arrest have been documented to critically limit oxygen delivery. Considerable attention has been directed towards understanding white matter development because ultra-low birthweight premature infants are also susceptible to deficits in motor development and also demonstrate evidence of WMI by MRI. Immunohistochemistry methods and specifically developed transgenic mice allow identification of the cell lineage leading to mature oligodendrocytes which are responsible for the laying down of myelin. The proposed study will test the following hypotheses: i) There is an age-dependent susceptibility of white matter to the inflammatory effects of CPB, ii) There is an age- dependent susceptibility of white matter to ischemia/reperfusion during CPB, iii) Age- dependent susceptibility is a consequence of selective vulnerability of specific oligodendrocyte precursor cells which will be defined, iv) Specific bypass strategies and anti-inflammatory adjunctive treatment can reduce the risk of WMI associated with CPB. The models that will be used will be a piglet model of CPB with survival to 3 and 24 days. End points will include behavioral studies, MRI assessment of white matter and detailed histological assessment including identification of oligodendrocyte cell lineage using piglet appropriate antibodies that we have recently identified. The second model is a mouse brain slice model using a custom built perfusion chamber that allows manipulation of conditions including cytokine levels, temperature, pH, oxygen and glucose levels, thereby recreating the stresses of CPB. This model will allow investigation of transgenic mice specifically developed for the study of white matter. The goal of this project is improve protection of developing white matter during pediatric cardiac surgery and to reduce the incidence of deficits in motor skills in children undergoing surgery for congenital heart disease.

Public Health Relevance

Congenital heart disease is the number one birth defect. Although most children today survive surgery, developmental studies have shown a high incidence of problems particularly with motor skills. This study will investigate how inflammation caused by the heart-lung machine selectively damages cerebral white matter which plays a key role in the development of motor skills.

National Institute of Health (NIH)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Evans, Frank
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Children's Research Institute
United States
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Lu, Zhaohui; Korotcova, Ludmila; Murata, Akira et al. (2014) Aprotinin, but not ýý-aminocaproic acid and tranexamic acid, exerts neuroprotection against excitotoxic injury in an in vitro neuronal cell culture model. J Thorac Cardiovasc Surg 147:1939-45
Agematsu, Kota; Korotcova, Ludmila; Scafidi, Joseph et al. (2014) Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res 75:618-25
Murata, Akira; Agematsu, Kota; Korotcova, Ludmila et al. (2013) Rodent brain slice model for the study of white matter injury. J Thorac Cardiovasc Surg 146:1526-1533.e1
Ishibashi, Nobuyuki; Scafidi, Joseph; Murata, Akira et al. (2012) White matter protection in congenital heart surgery. Circulation 125:859-71