title: White matter protection in congenital heart surgery.
abstract: BACKGROUND
  Neurodevelopmental delays in motor skills and white matter (WM) injury have been documented in congenital heart disease and after pediatric cardiac surgery. The lack of a suitable animal model has hampered our understanding of the cellular mechanisms underlying WM injury in these patients. Our aim is to identify an optimal surgical strategy for WM protection to reduce neurological injury in congenital heart disease patients.
  
  
  RESULTS
  We developed a porcine cardiopulmonary bypass model that displays area-dependent WM maturation. In this model, WM injury was identified after cardiopulmonary bypass-induced ischemia-reperfusion injury. The degree of injury was inversely correlated with the maturation stage, which indicates maturation-dependent vulnerability of WM. Within different oligodendrocyte developmental stages, we show selective vulnerability of O4+ preoligodendrocytes, whereas oligodendrocyte progenitor cells were resistant to insults. This indicates that immature WM is vulnerable to cardiopulmonary bypass-induced injury but has an intrinsic potential for recovery mediated by endogenous oligodendrocyte progenitor cells. Oligodendrocyte progenitor cell number decreased with age, which suggests that earlier repair allows successful WM development. Oligodendrocyte progenitor cell proliferation was observed within a few days after cardiopulmonary bypass-induced ischemia-reperfusion injury; however, by 4 weeks, arrested oligodendrocyte maturation and delayed myelination were detected. Logistic model confirmed that maintenance of higher oxygenation and reduction of inflammation were effective in minimizing the risk of injury at immature stages of WM development.
  
  
  CONCLUSIONS
  Primary repair in neonates and young infants potentially provides successful WM development in congenital heart disease patients. Cardiac surgery during this susceptible period should avoid ischemia-reperfusion injury and minimize inflammation to prevent long-term WM-related neurological impairment.
authors.affiliation: Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010-2970, USA.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishibashi
authors.forename: Joseph
authors.initials: J
authors.lastname: Scafidi
authors.forename: Akira
authors.initials: A
authors.lastname: Murata
authors.forename: Ludmila
authors.initials: L
authors.lastname: Korotcova
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jonas
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001921:Brain / Q000473:pathology*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D053148:Caspase 3 / Q000032:analysis; D049109:Cell Proliferation; D005260:Female; D006330:Heart Defects, Congenital / Q000601:surgery*; D009186:Myelin Sheath / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009836:Oligodendroglia / Q000502:physiology; D013552:Swine
chemical_list: D053148:Caspase 3