Diffusion Tensor Imaging Identifies White Matter Dysmaturation in a Hypoxic Porcine Model of Congenital Heart Disease

BACKGROUND Mortality and morbidity in the severe/complex congenital heart disease population have been significantly reduced due to advances in neonatal cardiac surgery and hospital care. However, even with these successes, congenital heart disease patients are at risk for developing long-term neurological deficits. Non-invasive peri-operative neuroimaging has suggested white matter underdevelopment and/or injury as a possible etiology. Despite these findings, the developmental mechanisms underpinning white matter deficits in congenital heart disease remain largely unexplored due to the technical challenges of in utero brain imaging and ethical concerns regarding the use of invasive technologies. To address these shortcomings, a porcine hypoxia model has been developed to recapitulate the white matter pathologies associated with pre-operative cerebral hypoxia in congenital heart disease. In this preliminary porcine study, diffusion tensor imaging (DTI) was used to assess the extent of white matter macroscopic and microstructural dysmaturation due to hypoxia. METHODS Female Yorkshire piglets were housed in a hypoxic environment (10.5% FiO2) between days 3 and 14 after birth in order to model brain development under hypoxic conditions during the late third gestational trimester and early infancy (normoxic control n=2, experimental n=3). At 14 days of age, DTI images were obtained from postmortem brains using a segmented diffusion echo planar MRI sequence. Volume, fractional anisotropy, and axial diffusivity were computed for the corpus callosum and the internal capsule. RESULTS Following hypoxia, corpus callosum and internal capsule volumes were 14% and 22% smaller, respectively, despite a moderate total brain volume difference of 4%. In addition, hypoxic corpus callosum fractional anisotropy values were on average 13% lower than normoxic controls, whereas fractional anisotropy values for the internal capsule were only 2% lower. Hypoxic corpus callosum and internal capsule axial diffusivity values were 9% and 12% lower, respectively, compared with normoxic controls. Low fractional anisotropy in white matter regions has been correlated with reduced structural integrity and hypomyelination in a variety of neurological diseases. Additionally, decreases in axial diffusivity have been associated with axonal injury. CONCLUSION The findings of this experiment show that cerebral hypoxia results in reduced white matter maturation during critical periods of brain development. Furthermore, the results strengthen the evidence supporting pre-operative hypoxia as an etiology for the long-term neurologic sequelae of congenital heart disease