Role of Vascular Endothelial Growth Factor as a Potential Biomarker in Congenital Heart Defects: A Systematic Review
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Abstract
Background: Several studies have investigated the role of vascular endothelial growth factor (VEGF) variants, serum levels, and correlations with other extrinsic factors in congenital heart defects (CHDs); however, the findings need confirmation. The present systematic review evaluates the association between CHDs and genetic polymorphisms and serum expressions.
Methods: Relevant literature was searched through electronic databases using keywords and MeSH terms. VEGF activity was comparatively assessed between cyanotic and acyanotic CHDs, and the association between different polymorphisms and heart defects was evaluated.
Results: We ultimately evaluated 12 studies regarding the association between VEGF serum patterns and found that serum VEGF levels were upregulated or downregulated in correlation with hypoxia and hemoglobin levels and were significantly associated with cyanotic CHDs compared with acyanotic CHDs. Our results also showed a significant role for different single-nucleotide polymorphisms, including rs699947, rs2010963, and rs3025039.
Conclusion: The findings of the current study suggested a significant association between CHDs and VEGF genetic polymorphisms or varied serum levels. Nevertheless, more comprehensive studies may provide conclusive results and valuable insights into the pathogenesis of CHDs and relevant treatment strategies.
1. Ashiq S, Ashiq K, Sabar MF. The role of NKX2-5 gene polymorphisms in congenital heart disease (CHD): a systematic review and meta-analysis. Egypt Heart J 2021;73:72.
2. Zhang S, Wang L, Yang T, Chen L, Zhao L, Wang T, Chen L, Ye Z, Zheng Z, Qin J. Parental alcohol consumption and the risk of congenital heart diseases in offspring: An updated systematic review and meta-analysis. Eur J Prev Cardiol 2020;27:410-421.
3. Liu Y, Chen S, Zühlke L, Black GC, Choy MK, Li N, Keavney BD. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol 2019;48:455-463.
4. Hoang TT, Goldmuntz E, Roberts AE, Chung WK, Kline JK, Deanfield JE, Giardini A, Aleman A, Gelb BD, Mac Neal M, Porter GA Jr, Kim R, Brueckner M, Lifton RP, Edman S, Woyciechowski S, Mitchell LE, Agopian AJ. The Congenital Heart Disease Genetic Network Study: Cohort description. PLoS One 2018;13:e0191319.
5. Tariq M, Zahid I, Hashmi S, Amanullah M, Shahabuddin S. The Glenn procedure: Clinical outcomes in patients with congenital heart disease in pakistan. Ann Card Anaesth 2021;24:30-35.
6. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241-2247.
7. Geddes GC, Earing MG. Genetic evaluation of patients with congenital heart disease. Curr Opin Pediatr 2018;30:707-713.
8. Darbar D. Unraveling the genomic basis of congenital heart disease. J Clin Invest 2021;131:e145377.
9. Pate N, Jawed S, Nigar N, Junaid F, Wadood AA, Abdullah F. Frequency and pattern of congenital heart defects in a tertiary care cardiac hospital of Karachi. Pak J Med Sci 2016;32:79-84.
10. Mahle WT, Newburger JW, Matherne GP, Smith FC, Hoke TR, Koppel R, Gidding SS, Beekman RH 3rd, Grosse SD; American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Interdisciplinary Council on Quality of Care and Outcomes Research; American Academy of Pediatrics Section on Cardiology and Cardiac Surgery, and Committee on Fetus and Newborn. Role of pulse oximetry in examining newborns for congenital heart disease: a scientific statement from the American Heart Association and American Academy of Pediatrics. Circulation 2009;120:447-458.
11. Izhar FM, Abqari S, Shahab T, Ali SM. Clinical score to detect congenital heart defects: Concept of second screening. Ann Pediatr Cardiol 2020;13:281-288.
12. Muntean I, Togănel R, Benedek T. Genetics of Congenital Heart Disease: Past and Present. Biochem Genet 2017;55:105-123.
13. Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, Kahle KT, Brueckner M, Jin SC. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes (Basel) 2021;12:1020.
14. Braile M, Marcella S, Cristinziano L, Galdiero MR, Modestino L, Ferrara AL, Varricchi G, Marone G, Loffredo S. VEGF-A in Cardiomyocytes and Heart Diseases. Int J Mol Sci 2020;21:5294.
15. Colliva A, Braga L, Giacca M, Zacchigna S. Endothelial cell-cardiomyocyte crosstalk in heart development and disease. J Physiol 2020;598:2923-2939.
16. Vannay A, Vásárhelyi B, Környei M, Treszl A, Kozma G, Györffy B, Tulassay T, Sulyok E. Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects. Am Heart J 2006;151:878-881.
17. Xie J, Yi L, Xu ZF, Mo XM, Hu YL, Wang DJ, Ren HZ, Han B, Wang Y, Yang C, Zhao YL, Shi DQ, Jiang YZ, Shen L, Qiao D, Chen SL, Yu BJ. VEGF C-634G polymorphism is associated with protection from isolated ventricular septal defect: case-control and TDT studies. Eur J Hum Genet 2007;15:1246-1251.
18. Smedts HP, Isaacs A, de Costa D, Uitterlinden AG, van Duijn CM, Gittenberger-de Groot AC, Helbing WA, Steegers EA, Steegers-Theunissen RP. VEGF polymorphisms are associated with endocardial cushion defects: a family-based case-control study. Pediatr Res 2010;67:23-28.
19. Baghdady Y, Hussein Y, Shehata M. Vascular endothelial growth factor in children with cyanotic and acyanotic and congenital heart disease. Arch Med Sci 2010;6:221-225.
20. El-Melegy NT, Mohamed NA. Angiogenic biomarkers in children with congenital heart disease: possible implications. Ital J Pediatr 2010;36:32.
21. Liu ZL, Wu ZS, Hu JG, Yang YF, Chen Y, Gao H, Hu YR. [Correlation of serum levels of VEGF and SDF-1 with the number and function of circulating EPCs in children with cyanotic congenital heart disease]. Zhongguo Dang Dai Er Ke Za Zhi 2009;11:267-272.
22. Hu J, Sun P, Ruan X, Chao A, Lin Y, Li XY. Mechanism of myocardial microvessel formation in cyanotic congenital heart disease. Circ J 2005;69:1089-1093.
23. Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Vascular endothelial growth factor in children with congenital heart disease. Ann Thorac Surg 2003;75:1523-1526.
24. Himeno W, Akagi T, Furui J, Maeno Y, Ishii M, Kosai K, Murohara T, Kato H. Increased angiogenic growth factor in cyanotic congenital heart disease. Pediatr Cardiol 2003;24:127-132.
25. Starnes SL, Duncan BW, Kneebone JM, Rosenthal GL, Jones TK, Grifka RG, Cecchin F, Owens DJ, Fearneyhough C, Lupinetti FM. Vascular endothelial growth factor and basic fibroblast growth factor in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 2000;119:534-539.
26. Zhang YH, Xiang RL, Hu XT, Wen HK, Zhu MP, Ren Y, Wu RZ, Chen Q. [Changes of serum leptin and vascular endothelial growth factor in children with congenital heart disease]. Zhongguo Dang Dai Er Ke Za Zhi 2009;11:802-804.
27. Suda K, Matsumura M, Miyanish S, Uehara K, Sugita T, Matsumoto M. Increased vascular endothelial growth factor in patients with cyanotic congenital heart diseases may not be normalized after a Fontan type operation. Ann Thorac Surg 2004;78:942-946.
28. Nassef YE, Hamed MA, Aly HF. Inflammatory cytokines, apoptotic, tissue injury and remodeling biomarkers in children with congenital heart disease. Indian J Clin Biochem 2014;29:145-149.
29. Steurer MA, Norton ME, Baer RJ, Shaw GM, Keating S, Moon-Grady AJ, Chambers CD, Jelliffe-Pawlowski LL. The association of maternal lymphatic markers and critical congenital heart defects in the fetus-A population based case-control study. Am J Med Genet A 2017;173:1231-1236.
30. Sochet AA, Wilson EA, Das JR, Berger JT, Ray PE. Plasma and Urinary FGF-2 and VEGF-A Levels Identify Children at Risk for Severe Bleeding after Pediatric Cardiopulmonary Bypass: A Pilot Study. Med Res Arch 2020;8:2134.
31. Li X, Liu CL, Li XX, Li QC, Ma LM, Liu GL. VEGF Gene Polymorphisms are Associated with Risk of Tetralogy of Fallot. Med Sci Monit 2015;21:3474-3482.
32. Wang E, Wang Z, Liu S, Gu H, Gong D, Hua K, Nie Y, Wang J, Wang H, Gong J, Zhang Y, Zhang H, Liu R, Hu S, Zhang H. Polymorphisms of VEGF, TGFβ1, TGFβR2 and conotruncal heart defects in a Chinese population. Mol Biol Rep 2014;41:1763-1770.
33. Yan L, Ge Q, Xi C, Zhang X, Guo Y. Genetic variations of VEGF gene were associated with tetralogy of fallot risk in a Chinese Han population. Genet Test Mol Biomarkers 2015;19:264-271.
34. Calderón JF, Puga AR, Guzmán ML, Astete CP, Arriaza M, Aracena M, Aravena T, Sanz P, Repetto GM. VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study. Biol Res 2009;42:461-468.
35. Sallmon H, Aydin T, Hort S, Kubinski A, Bode C, Klippstein T, Endesfelder S, Bührer C, Koehne P. Vascular endothelial growth factor polymorphism rs2010963 status does not affect patent ductus arteriosus incidence or cyclooxygenase inhibitor treatment success in preterm infants. Cardiol Young 2019;29:893-897.
36. Ding G, Wang Y, Tang W, Gu H, Liu C, Chen Y, Chen S, Qiu W. Polymorphisms of VEGF and congenital heart disease in a Chinese population. Int J Clin Exp Med. 2016;9:7281-7288.
38. Alidoosti M, Shanaki M, Mahdavi A, Mohammadtaghvaei N. Association between Vascular Endothelial Growth Factor Plasma Levels and rs699947 Polymorphism and Coronary Collateral Vessel Formation. J Teh Univ Heart Ctr 2019;14(3):121-127.
39. Hamada H, Ebata R, Higashi K, Tateno S, Niwa K, Honda T, Yasukawa K, Terai M. Serum vascular endothelial growth factor in cyanotic congenital heart disease functionally contributes to endothelial cell kinetics in vitro. Int J Cardiol 2007;120:66-71.
40. Yin HL, Luo CW, Dai ZK, Shaw KP, Chai CY, Wu CC. Hypoxia-inducible factor-1α, vascular endothelial growth factor, inducible nitric oxide synthase, and endothelin-1 expression correlates with angiogenesis in congenital heart disease. Kaohsiung J Med Sci 2016;32:348-355.
41. Wang W, Xu A, Xu H. The roles of vascular endothelial growth factor gene polymorphisms in congenital heart diseases: a meta-analysis. Growth Factors 2018;36:232-238.
42. Balistreri CR, Ammoscato CL, Scola L, Fragapane T, Giarratana RM, Lio D, Piccione M. Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes. Genes (Basel) 2020;11:1428.
2. Zhang S, Wang L, Yang T, Chen L, Zhao L, Wang T, Chen L, Ye Z, Zheng Z, Qin J. Parental alcohol consumption and the risk of congenital heart diseases in offspring: An updated systematic review and meta-analysis. Eur J Prev Cardiol 2020;27:410-421.
3. Liu Y, Chen S, Zühlke L, Black GC, Choy MK, Li N, Keavney BD. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol 2019;48:455-463.
4. Hoang TT, Goldmuntz E, Roberts AE, Chung WK, Kline JK, Deanfield JE, Giardini A, Aleman A, Gelb BD, Mac Neal M, Porter GA Jr, Kim R, Brueckner M, Lifton RP, Edman S, Woyciechowski S, Mitchell LE, Agopian AJ. The Congenital Heart Disease Genetic Network Study: Cohort description. PLoS One 2018;13:e0191319.
5. Tariq M, Zahid I, Hashmi S, Amanullah M, Shahabuddin S. The Glenn procedure: Clinical outcomes in patients with congenital heart disease in pakistan. Ann Card Anaesth 2021;24:30-35.
6. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241-2247.
7. Geddes GC, Earing MG. Genetic evaluation of patients with congenital heart disease. Curr Opin Pediatr 2018;30:707-713.
8. Darbar D. Unraveling the genomic basis of congenital heart disease. J Clin Invest 2021;131:e145377.
9. Pate N, Jawed S, Nigar N, Junaid F, Wadood AA, Abdullah F. Frequency and pattern of congenital heart defects in a tertiary care cardiac hospital of Karachi. Pak J Med Sci 2016;32:79-84.
10. Mahle WT, Newburger JW, Matherne GP, Smith FC, Hoke TR, Koppel R, Gidding SS, Beekman RH 3rd, Grosse SD; American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Interdisciplinary Council on Quality of Care and Outcomes Research; American Academy of Pediatrics Section on Cardiology and Cardiac Surgery, and Committee on Fetus and Newborn. Role of pulse oximetry in examining newborns for congenital heart disease: a scientific statement from the American Heart Association and American Academy of Pediatrics. Circulation 2009;120:447-458.
11. Izhar FM, Abqari S, Shahab T, Ali SM. Clinical score to detect congenital heart defects: Concept of second screening. Ann Pediatr Cardiol 2020;13:281-288.
12. Muntean I, Togănel R, Benedek T. Genetics of Congenital Heart Disease: Past and Present. Biochem Genet 2017;55:105-123.
13. Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, Kahle KT, Brueckner M, Jin SC. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes (Basel) 2021;12:1020.
14. Braile M, Marcella S, Cristinziano L, Galdiero MR, Modestino L, Ferrara AL, Varricchi G, Marone G, Loffredo S. VEGF-A in Cardiomyocytes and Heart Diseases. Int J Mol Sci 2020;21:5294.
15. Colliva A, Braga L, Giacca M, Zacchigna S. Endothelial cell-cardiomyocyte crosstalk in heart development and disease. J Physiol 2020;598:2923-2939.
16. Vannay A, Vásárhelyi B, Környei M, Treszl A, Kozma G, Györffy B, Tulassay T, Sulyok E. Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects. Am Heart J 2006;151:878-881.
17. Xie J, Yi L, Xu ZF, Mo XM, Hu YL, Wang DJ, Ren HZ, Han B, Wang Y, Yang C, Zhao YL, Shi DQ, Jiang YZ, Shen L, Qiao D, Chen SL, Yu BJ. VEGF C-634G polymorphism is associated with protection from isolated ventricular septal defect: case-control and TDT studies. Eur J Hum Genet 2007;15:1246-1251.
18. Smedts HP, Isaacs A, de Costa D, Uitterlinden AG, van Duijn CM, Gittenberger-de Groot AC, Helbing WA, Steegers EA, Steegers-Theunissen RP. VEGF polymorphisms are associated with endocardial cushion defects: a family-based case-control study. Pediatr Res 2010;67:23-28.
19. Baghdady Y, Hussein Y, Shehata M. Vascular endothelial growth factor in children with cyanotic and acyanotic and congenital heart disease. Arch Med Sci 2010;6:221-225.
20. El-Melegy NT, Mohamed NA. Angiogenic biomarkers in children with congenital heart disease: possible implications. Ital J Pediatr 2010;36:32.
21. Liu ZL, Wu ZS, Hu JG, Yang YF, Chen Y, Gao H, Hu YR. [Correlation of serum levels of VEGF and SDF-1 with the number and function of circulating EPCs in children with cyanotic congenital heart disease]. Zhongguo Dang Dai Er Ke Za Zhi 2009;11:267-272.
22. Hu J, Sun P, Ruan X, Chao A, Lin Y, Li XY. Mechanism of myocardial microvessel formation in cyanotic congenital heart disease. Circ J 2005;69:1089-1093.
23. Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Vascular endothelial growth factor in children with congenital heart disease. Ann Thorac Surg 2003;75:1523-1526.
24. Himeno W, Akagi T, Furui J, Maeno Y, Ishii M, Kosai K, Murohara T, Kato H. Increased angiogenic growth factor in cyanotic congenital heart disease. Pediatr Cardiol 2003;24:127-132.
25. Starnes SL, Duncan BW, Kneebone JM, Rosenthal GL, Jones TK, Grifka RG, Cecchin F, Owens DJ, Fearneyhough C, Lupinetti FM. Vascular endothelial growth factor and basic fibroblast growth factor in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 2000;119:534-539.
26. Zhang YH, Xiang RL, Hu XT, Wen HK, Zhu MP, Ren Y, Wu RZ, Chen Q. [Changes of serum leptin and vascular endothelial growth factor in children with congenital heart disease]. Zhongguo Dang Dai Er Ke Za Zhi 2009;11:802-804.
27. Suda K, Matsumura M, Miyanish S, Uehara K, Sugita T, Matsumoto M. Increased vascular endothelial growth factor in patients with cyanotic congenital heart diseases may not be normalized after a Fontan type operation. Ann Thorac Surg 2004;78:942-946.
28. Nassef YE, Hamed MA, Aly HF. Inflammatory cytokines, apoptotic, tissue injury and remodeling biomarkers in children with congenital heart disease. Indian J Clin Biochem 2014;29:145-149.
29. Steurer MA, Norton ME, Baer RJ, Shaw GM, Keating S, Moon-Grady AJ, Chambers CD, Jelliffe-Pawlowski LL. The association of maternal lymphatic markers and critical congenital heart defects in the fetus-A population based case-control study. Am J Med Genet A 2017;173:1231-1236.
30. Sochet AA, Wilson EA, Das JR, Berger JT, Ray PE. Plasma and Urinary FGF-2 and VEGF-A Levels Identify Children at Risk for Severe Bleeding after Pediatric Cardiopulmonary Bypass: A Pilot Study. Med Res Arch 2020;8:2134.
31. Li X, Liu CL, Li XX, Li QC, Ma LM, Liu GL. VEGF Gene Polymorphisms are Associated with Risk of Tetralogy of Fallot. Med Sci Monit 2015;21:3474-3482.
32. Wang E, Wang Z, Liu S, Gu H, Gong D, Hua K, Nie Y, Wang J, Wang H, Gong J, Zhang Y, Zhang H, Liu R, Hu S, Zhang H. Polymorphisms of VEGF, TGFβ1, TGFβR2 and conotruncal heart defects in a Chinese population. Mol Biol Rep 2014;41:1763-1770.
33. Yan L, Ge Q, Xi C, Zhang X, Guo Y. Genetic variations of VEGF gene were associated with tetralogy of fallot risk in a Chinese Han population. Genet Test Mol Biomarkers 2015;19:264-271.
34. Calderón JF, Puga AR, Guzmán ML, Astete CP, Arriaza M, Aracena M, Aravena T, Sanz P, Repetto GM. VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study. Biol Res 2009;42:461-468.
35. Sallmon H, Aydin T, Hort S, Kubinski A, Bode C, Klippstein T, Endesfelder S, Bührer C, Koehne P. Vascular endothelial growth factor polymorphism rs2010963 status does not affect patent ductus arteriosus incidence or cyclooxygenase inhibitor treatment success in preterm infants. Cardiol Young 2019;29:893-897.
36. Ding G, Wang Y, Tang W, Gu H, Liu C, Chen Y, Chen S, Qiu W. Polymorphisms of VEGF and congenital heart disease in a Chinese population. Int J Clin Exp Med. 2016;9:7281-7288.
38. Alidoosti M, Shanaki M, Mahdavi A, Mohammadtaghvaei N. Association between Vascular Endothelial Growth Factor Plasma Levels and rs699947 Polymorphism and Coronary Collateral Vessel Formation. J Teh Univ Heart Ctr 2019;14(3):121-127.
39. Hamada H, Ebata R, Higashi K, Tateno S, Niwa K, Honda T, Yasukawa K, Terai M. Serum vascular endothelial growth factor in cyanotic congenital heart disease functionally contributes to endothelial cell kinetics in vitro. Int J Cardiol 2007;120:66-71.
40. Yin HL, Luo CW, Dai ZK, Shaw KP, Chai CY, Wu CC. Hypoxia-inducible factor-1α, vascular endothelial growth factor, inducible nitric oxide synthase, and endothelin-1 expression correlates with angiogenesis in congenital heart disease. Kaohsiung J Med Sci 2016;32:348-355.
41. Wang W, Xu A, Xu H. The roles of vascular endothelial growth factor gene polymorphisms in congenital heart diseases: a meta-analysis. Growth Factors 2018;36:232-238.
42. Balistreri CR, Ammoscato CL, Scola L, Fragapane T, Giarratana RM, Lio D, Piccione M. Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes. Genes (Basel) 2020;11:1428.
| Files | ||
| Issue | Vol 18 No 4 (2023): J Teh Univ Heart Ctr | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jthc.v18i4.14822 | |
| Keywords | ||
| Heart defects; congenital Polymorphism; genetic Vascular endothelial growth factors | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Ashiq S, Hyder SN, Ashiq K, Sabar MF. Role of Vascular Endothelial Growth Factor as a Potential Biomarker in Congenital Heart Defects: A Systematic Review. J Tehran Heart Cent. 2023;18(4):237-243.
