Mid-Atlantic Consortium Newsletter Summer 2013

Early Surgery to Repair CHD May Reduce Developmental Delays

clockResearchers at Children’s National Medical Center in Washington are gaining insight into how to best protect the brains of infants undergoing surgery for congenital heart defects (CHD).

CHD is a major public health concern, affecting 1 in every 100 infants, according to experts. Many develop neurological impairments, including fine and gross motor deficits, following corrective heart surgery that requires time on a cardiopulmonary bypass machine early in life.

The CNMC team, directed by Richard Jonas, M.D., chief of cardiac surgery at the hospital, is studying how bypass affects areas of the brain, using baby pigs as study subjects because of circulatory system similarities between them and people. The investigators monitored development of the animals’ white matter, which forms the connections between brain structures, at one, three and seven weeks of age. Then they divided the pigs into three groups: two groups underwent different types of bypass; the third had no bypass. They then examined the piglets’ brains three days and four weeks following surgery.

The scientists found that white matter in the animals develops in three distinct stages, and the amount of injury linked to bypass depends on the maturity of oligodendrocytes, cells that support a messaging network through which signals pass between areas of the nervous system. Immature oligodendrocyte cells called preoligodendrocytes were vulnerable to bypass damage, but younger oligodendrocyte progenitor cells (OPCs) – cells that had not yet become oligodendrocytes — were resistant to damage and helped repair injury to white matter.

The team also observed that bypass surgery that resulted in a low-oxygen state and inflammation caused the most cell damage. Four weeks following this type of bypass, white matter cells were no longer growing and maturing, a finding consistent with neurological deficits seen in congenital heart disease patients. A report on this work was published last year in the journal Circulation.

White matter development in humans begins at around five months of gestation, and continues throughout the first two decades of life. The process involves the maturation of cells called oligodendrocytes through different stages; if there is a disruption, such as oxygen deprivation or inflammation, the cells and the brain networks they form can’t develop normally, resulting in neurological deficits.

Though some question whether CHD repairs should be performed in infants, this study suggests that early repairs have the potential to promote recovery of neurodevelopmental delays seen in newborns with CHD, Jonas says.

“We’ve come to appreciate that children with congenital heart disease, even by the time they are born, may already have some white matter injury,” Jonas says. “Our study indicates that the optimal time window for CHD surgical repair is during the period in which the white matter contains the largest number of OPCs, which are highly resistant to damage from bypass and available to promote repair.”

The piglet study also demonstrates that cardiac surgery in newborns and young infants should focus on preventing injury during the restoration of natural blood flow, and that efforts should be made to maintain high levels of oxygen and reduce inflammation, Jonas says.

Future studies using magnetic resonance imaging of infants’ brains will be necessary to better identify the corresponding developmental time windows between humans and the piglet model, Jonas says.

“Our goal is to optimize developmental outcomes for children with CHD,” he says.

Other participating investigators are Noboyuki Ishibashi, M.D., Akira Murata, M.D., and Ludmila Korotcova, M.D., of CNMC’s cardiac surgery research lab; and Joseph Scafidi, D.O., and Vittorio Gallo, Ph.D., of the medical center’s Children’s Research Institute.

 

For more information about CNMC’s research in white matter development and diseases, see http://www.childrensnational.org/research/ourresearch/disorders/cgmr/whitematter.aspx

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