Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

J William Gaynor¹, Daniel Seung Kim², Cammon B Arrington³, Andrew M Atz⁴, David C Bellinger⁵, Amber A Burt⁶, Nancy S Ghanayem⁷, Jeffery P Jacobs⁸, Teresa M Lee⁹, Alan B Lewis¹⁰, William T Mahle¹¹, Bradley S Marino¹², Stephen G Miller¹³, Jane W Newburger¹⁴, Christian Pizarro¹⁵, Chitra Ravishankar¹⁶, Avni B Santani¹⁷, Nicole S Wilder¹⁸, Gail P Jarvik², Seema Mital¹⁹, Mark W Russell²⁰

Affiliations

¹ Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa. Electronic address: gaynor@email.chop.edu.
² Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, Wash.
³ Primary Children's Medical Center, Salt Lake City, Utah.
⁴ Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC.
⁵ Department of Neurology, Boston Children's Hospital, Boston, Mass, and Department of Neurology, Harvard Medical School, Boston, Mass.
⁶ Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Wash.
⁷ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis.
⁸ Johns Hopkins Children's Heart Institute, All Children's Hospital and Florida Hospital for Children, St Petersburg, Fla.
⁹ Department of Pediatrics, Columbia University Medical Center, New York, NY.
¹⁰ Children's Hospital Los Angeles, Los Angeles, Calif.
¹¹ Children's Healthcare of Atlanta, Atlanta, Ga.
¹² Ann and Robert F. Lurie Children's Hospital of Chicago, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
¹³ Division of Pediatric Oncology, Duke University Medical Center, Durham, NC.
¹⁴ Department of Cardiology, Boston Children's Hospital, Boston, Mass.
¹⁵ Nemours Cardiac Center, Alfred I. Dupont Hospital for Children, Wilmington, Del.
¹⁶ Division of Pediatric Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pa.
¹⁷ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pa.
¹⁸ Department of Anesthesia, University of Michigan Medical School, Ann Arbor, Mich.
¹⁹ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²⁰ Department of Pediatrics and Communicable Diseases (Division of Pediatric Cardiology), University of Michigan Medical School, Ann Arbor, Mich.

PMID: 25282659
PMCID: PMC4376113
DOI: 10.1016/j.jtcvs.2014.07.052

Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

J William Gaynor et al. J Thorac Cardiovasc Surg. 2014 Dec.

. 2014 Dec;148(6):2560-6.

doi: 10.1016/j.jtcvs.2014.07.052. Epub 2014 Aug 1.

Authors

Affiliations

¹ Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pa. Electronic address: gaynor@email.chop.edu.
² Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington School of Medicine, Seattle, Wash.
³ Primary Children's Medical Center, Salt Lake City, Utah.
⁴ Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC.
⁵ Department of Neurology, Boston Children's Hospital, Boston, Mass, and Department of Neurology, Harvard Medical School, Boston, Mass.
⁶ Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Wash.
⁷ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis.
⁸ Johns Hopkins Children's Heart Institute, All Children's Hospital and Florida Hospital for Children, St Petersburg, Fla.
⁹ Department of Pediatrics, Columbia University Medical Center, New York, NY.
¹⁰ Children's Hospital Los Angeles, Los Angeles, Calif.
¹¹ Children's Healthcare of Atlanta, Atlanta, Ga.
¹² Ann and Robert F. Lurie Children's Hospital of Chicago, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
¹³ Division of Pediatric Oncology, Duke University Medical Center, Durham, NC.
¹⁴ Department of Cardiology, Boston Children's Hospital, Boston, Mass.
¹⁵ Nemours Cardiac Center, Alfred I. Dupont Hospital for Children, Wilmington, Del.
¹⁶ Division of Pediatric Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pa.
¹⁷ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pa.
¹⁸ Department of Anesthesia, University of Michigan Medical School, Ann Arbor, Mich.
¹⁹ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²⁰ Department of Pediatrics and Communicable Diseases (Division of Pediatric Cardiology), University of Michigan Medical School, Ann Arbor, Mich.

PMID: 25282659
PMCID: PMC4376113
DOI: 10.1016/j.jtcvs.2014.07.052

Abstract

Objective: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association.

Methods: The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores.

Results: Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058).

Conclusions: These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

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Figures

**FIGURE 1**
The study cohort. *ISV*, Infant Single Ventricle trial; *SVR*, Single Ventricle Reconstruction trial; *APOE*, apolipoprotein E.

See this image and copyright information in PMC

Comment in

Discussion.
[No authors listed] [No authors listed] J Thorac Cardiovasc Surg. 2014 Dec;148(6):2566-8. doi: 10.1016/j.jtcvs.2014.07.055. Epub 2014 Oct 1. J Thorac Cardiovasc Surg. 2014. PMID: 25282658 No abstract available.
Validation accepted, but look at what else was revealed.
Austin EH 3rd. Austin EH 3rd. J Thorac Cardiovasc Surg. 2014 Dec;148(6):2568-9. doi: 10.1016/j.jtcvs.2014.10.008. Epub 2014 Oct 7. J Thorac Cardiovasc Surg. 2014. PMID: 25433876 No abstract available.

References

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Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

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Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants

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