Skip to main content Accessibility help

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

  • Constantine D. Mavroudis (a1), Daniel Seung Kim (a2) (a3) (a4), Nancy Burnham (a1), Alexandra H. Morss (a1), Jerry H. Kim (a5), Amber A. Burt (a2), David R. Crosslin (a4), Donna M. McDonald-McGinn (a6), Elaine H. Zackai (a6), Meryl S. Cohen (a7), Susan C. Nicolson (a8), Thomas L. Spray (a1), Ian B. Stanaway (a4) (a9), Deborah A. Nickerson (a4), Mark W. Russell (a10), Hakon Hakonarson (a11), Gail P. Jarvik (a2) and J. William Gaynor (a1)...



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.


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.


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).


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.


Corresponding author

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:


Hide All
1. Feinstein, JA, Benson, DW, Dubin, AM, et al. Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol 2012; 59: 142.
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: 117122.
3. Mital, S, Chung, WK, Colan, SD, et al. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation 2011; 123: 23532362.
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: 104110; discussion 110-1.
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: 64116415.
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: 15091516.
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: 105111.
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: 899907.
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: 17361745.
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: 241250.
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.
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: 347357.
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: 18051813.
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: 904909.
15. Gaynor, JW, Mahle, WT, Cohen, MI, et al. Risk factors for mortality after the Norwood procedure. Eur J Cardiothorac Surg 2002; 22: 8289.
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: 885894.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Cardiology in the Young
  • ISSN: 1047-9511
  • EISSN: 1467-1107
  • URL: /core/journals/cardiology-in-the-young
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed