Hostname: page-component-cd9895bd7-gxg78 Total loading time: 0 Render date: 2024-12-28T18:32:44.607Z Has data issue: false hasContentIssue false
  • English
  • Français

A vascular endothelial growth factor A genetic variant is associated with improved ventricular function and transplant-free survival after surgery for non-syndromic CHD

Published online by Cambridge University Press:  20 September 2017

Constantine D. Mavroudis ,
Daniel Seung Kim ,
Nancy Burnham ,
Alexandra H. Morss ,
Jerry H. Kim ,
Amber A. Burt ,
David R. Crosslin ,
Donna M. McDonald-McGinn ,
Elaine H. Zackai  and
Meryl S. Cohen
...Show all authors
Constantine D. Mavroudis
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Daniel Seung Kim
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Biostatistics, School of Public Health, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Nancy Burnham
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Alexandra H. Morss
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Jerry H. Kim
Affiliation:
Department of Anesthesia and Pain Medicine, The University of Washington School of Medicine, Seattle, Washington, United States of America
Amber A. Burt
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America
David R. Crosslin
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Donna M. McDonald-McGinn
Affiliation:
Department of Clinical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Elaine H. Zackai
Affiliation:
Department of Clinical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Meryl S. Cohen
Affiliation:
Department of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Susan C. Nicolson
Affiliation:
Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Thomas L. Spray
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Ian B. Stanaway
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Environmental and Occupational Health Services, The University of Washington School of Medicine, Seattle, Washington, United States of America
Deborah A. Nickerson
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Mark W. Russell
Affiliation:
Department of Cardiology, CS Mott Children’s Hospital, Ann Arbor, Michigan, United States of America
Hakon Hakonarson
Affiliation:
The Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Gail P. Jarvik
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America
J. William Gaynor*
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
*
Correspondence to: J. W. Gaynor, MD, Department of Cardiothoracic Surgery, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, United States of America. Tel: 215 590 2708; Fax: 215 590 2715; E-mail: Gaynor@email.chop.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.

Methods

This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike’s information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.

Results

Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).

Conclusions

These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype–phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.

Keywords

CHDcongenital heart surgeryechocardiographygenes/polymorphismsoutcomes
Type
Original Articles
Information
Cardiology in the Young , Volume 28 , Issue 1 , January 2018 , pp. 39 - 45
Check for updates
Copyright
© Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Feinstein, JA, Benson, DW, Dubin, AM, et al. Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol 2012; 59: 1–42.CrossRefGoogle ScholarPubMed
2. Kirshbom, PM, Mahle, WT, Joyner, RW, et al. The endothelin-1 G5665T polymorphism impacts transplant-free survival for single ventricle patients. J Thorac Cardiovasc Surg 2008; 136: 117–122.CrossRefGoogle ScholarPubMed
3. Mital, S, Chung, WK, Colan, SD, et al. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation 2011; 123: 2353–2362.CrossRefGoogle ScholarPubMed
4. Kim, DS, Kim, JH, Burt, AA, et al. Patient genotypes impact survival after surgery for isolated congenital heart disease. Ann Thorac Surg 2014; 98: 104–110; discussion 110-1.CrossRefGoogle ScholarPubMed
5. Vailati, FB, Crispim, D, Sortica, DA, Souza, BM, Brondani, LA, Canani, LH. The C allele of -634G/C polymorphism in the VEGFA gene is associated with increased VEGFA gene expression in human retinal tissue. Invest Ophthalmol Vis Sci 2012; 53: 6411–6415.CrossRefGoogle Scholar
6. Matsudaira, K, Maeda, K, Okumura, N, et al. Impact of low levels of vascular endothelial growth factor after myocardial infarction on 6-month clinical outcome. Circ J 2012; 76: 1509–1516.CrossRefGoogle ScholarPubMed
7. Guo, HD, Cui, GH, Yang, JJ, et al. Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction. Biochem Biophys Res Commun 2012; 424: 105–111.CrossRefGoogle ScholarPubMed
8. Zangi, L, Lui, KO, Von Gise, A, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 2013; 31: 899–907.CrossRefGoogle ScholarPubMed
9. Gaynor, JW, Gerdes, M, Zackai, EH, et al. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg 2003; 126: 1736–1745.CrossRefGoogle ScholarPubMed
10. Gaynor, JW, Nord, AS, Wernovsky, G, et al. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery. Pediatrics 2009; 124: 241–250.CrossRefGoogle ScholarPubMed
11. Kim, DS, Stanaway, IB, Rajagopalan, R, et al. Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy. PLoS ONE 2012; 7: e45936.CrossRefGoogle ScholarPubMed
12. Clancy, RR, McGaurn, SA, Wernovsky, G, et al. Preoperative risk-of-death prediction model in heart surgery with deep hypothermic circulatory arrest in the neonate. J Thorac Cardiovasc Surg 2000; 119: 347–357.CrossRefGoogle ScholarPubMed
13. Patel, A, Hickey, E, Mavroudis, C, et al. Impact of noncardiac congenital and genetic abnormalities on outcomes in hypoplastic left heart syndrome. Ann Thorac Surg 2010; 89: 1805–1813.CrossRefGoogle ScholarPubMed
14. Price, AL, Patterson, NJ, Plenge, RM, Weinblatt, ME, Shadick, NA, Reich, D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.CrossRefGoogle ScholarPubMed
15. Gaynor, JW, Mahle, WT, Cohen, MI, et al. Risk factors for mortality after the Norwood procedure. Eur J Cardiothorac Surg 2002; 22: 82–89.CrossRefGoogle ScholarPubMed
16. Weis, S, Shintani, S, Weber, A, et al. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest 2004; 113: 885–894.CrossRefGoogle ScholarPubMed