Researchers from the Cardiac Center and other divisions of The Children's Hospital of Philadelphia found that children carrying the epsilon2 version (APOE ?2) of the apolipoprotein E gene were significantly more likely to have worse neurodevelopmental outcomes at age one, compared to children who also underwent surgery but did not have APOE ?2. APOE ?2 occurs in approximately 8 percent of the population.
The APOE ?2 gene variant may decrease the ability of neurons to repair themselves following open heart surgery, with the result that children score lower in developmental evaluations of psychomotor skills. The study was published in the December 2003 issue of the Journal of Thoracic and Cardiovascular Surgery.
"As surgical and medical advances have dramatically increased survival of children with heart defects in recent years, we have turned our attention to the adverse neurodevelopmental outcomes in some survivors," said cardiothoracic surgeon J William Gaynor, MD, the leader of the study. "Even among children with the same heart defect receiving the same surgeries, there is considerable variation in developmental outcome. This was one of the first studies to investigate the role of gene variants in influencing neurologic injury in children with congenital heart disease."
The research team evaluated 244 children at age one who had undergone surgery to repair a congenital heart defect at less than six months of age. All the children were patients at the Cardiac Center at The Children's Hospital of Philadelphia.
Evaluators who were blinded to each child's genotype assessed the children using the Bayley Scales of Infant Development. Within those measurements, children with APOE ?2 had significantly lower scores in the Psychomotor Developmental Index (PDI), which assesses gross muscle function needed for crawling and walking. The PDI also assesses fine muscle skills such as those needed for grasping and imitating hand movements.
The association between APOE ?2 and lower neurodevelopmental scores was consistent, even after researchers controlled for variables such as gestational age, age at surgery, socioeconomic status, type of cardiac defect and surgical techniques.
Apolipoprotein genes, which help to regulate how the body transports cholesterol in the blood, also affect neurons in the brain in ways that are incompletely understood, but which play a role in repair of the brain after injury. The apolipoprotein E epsilon4 (APOE ?4) gene variant, which is more common than APOE ?2, has been studied in adults, for whom it confers a higher risk of suffering Alzheimer's disease and of worse recovery after brain injury or cardiac surgery. However, the researchers did not find that APOE e4 had an effect on neurodevelopment in children in the study.
In the analysis presented in the journal article, there were no significant differences between children with the APOE ?2 gene and children with other APOE gene variants in the Mental Development Index (MDI), in neuromuscular examinations or in head circumference. However, adds DrGaynor, further evaluation of a larger sample of eligible patients confirmed the lower scores on the PDI, and also found a significant effect of APOE ?2 in predicting worse outcomes in the MDI, which assesses memory, language and social skills. Importantly, the larger sample (329 patients, compared to 244 in the journal article) also showed a link between APOE ?2 and a smaller head circumference at one year of age, a finding consistent with poor brain growth. Dr Gaynor presented these results at the American Heart Association Scientific Sessions in November 2003.
"The adverse effect on neurodevelopment that we found at one year of age does not necessarily predict long-term outcome for these children," cautiona Dr Gaynor. "Children will need to be evaluated as they reach school age to determine whether the APOE ?2 gene is a risk factor for worse long-term outcome." Dr Gaynor's team recently received funding from the National Institutes of Health to pursue their outcome studies in the same children between ages four and five -- a point at which the researchers will further gauge the patients' developmental progress.
In addition to colleagues from The Children's Hospital of Philadelphia, Dr Gaynor's co-authors were from Duke University Medical Center and the University of Washington, Seattle.