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Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and acute pulmonary hypertension post cardiopulmonary bypass in children with congenital cardiac diseases

Published online by Cambridge University Press:  10 December 2010

Tsvetomir Loukanov ,
Katharina Hoss ,
Pentcho Tonchev ,
Homa Klimpel ,
Raul Arnold ,
Christian Sebening ,
Matthias Karck  and
Matthias Gorenflo
Tsvetomir Loukanov*
Affiliation:
Department of Cardiac Surgery, Surgical Clinic, University of Heidelberg, Germany
Katharina Hoss
Affiliation:
Department of Paediatric Cardiology, University of Heidelberg, Germany
Pentcho Tonchev
Affiliation:
Department of General Surgery, University of Pleven, Bulgaria
Homa Klimpel
Affiliation:
Department of Paediatric Cardiology, University of Heidelberg, Germany
Raul Arnold
Affiliation:
Department of Paediatric Cardiology, University of Heidelberg, Germany
Christian Sebening
Affiliation:
Department of Cardiac Surgery, Surgical Clinic, University of Heidelberg, Germany
Matthias Karck
Affiliation:
Department of Cardiac Surgery, Surgical Clinic, University of Heidelberg, Germany
Matthias Gorenflo
Affiliation:
Department of Paediatric Cardiology, University of Heidelberg, Germany
*
Correspondence to: Dr T. Loukanov, Department of Cardiac Surgery, Surgical Clinic, University of Heidelberg, D-69120 Heidelberg, INF 110, Germany. Tel: 004962215636274; Fax: 00496221565919; E-mail: tsloukanov@abv.bg
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Abstract

Background

Intra-cardiac repair of congenital cardiac diseases in children with left–right shunt is often associated with acute elevation of pulmonary artery pressure following cardiopulmonary bypass. We studied the correlation between the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and pulmonary hypertension in children with congenital cardiac diseases.

Methods and results

A total of 80 children with congenital cardiac diseases at a median age of 3.8 years, ranged 0.1–36.2 years, and 136 controls were enrolled. Most patients presented with significant left-to-right shunt – pulmonary-to-systemic blood flow of 2.8, with a range from 0.6 to 7.5. In all, 40 out of 80 children showed pulmonary hypertension with mean pressure of 42, ranged 26–82, millimetres of mercury. Thirty-one out of 40 children underwent intra-cardiac repair and 15 out of 31 operated patients were found to have an acute elevation of pulmonary artery pressure after cardiopulmonary bypass. The Glu298Asp polymorphism was identified using polymerase chain reaction and restriction fragment length polymorphism. Both in patients and in controls, the genotype distribution corresponded to the Hardy–Weinberg equilibrium. The gene frequency for Glu298Glu, Glu298Asp and Asp298Asp was not different in the control group compared to the patients (Armitage trend test: p = 0.37). The endothelial nitric oxide synthase polymorphism was related to acute post-operative elevation of pulmonary artery pressure (genotypic frequency 53.3 versus 25%; Armitage trend test: p = 0.038). In addition, the allelic frequency of the Glu298Asp was related to post-operative pulmonary hypertension (Fischer’s exact test: p = 0.048). The positive predictive value was 71.43%.

Conclusion

Patients with left-to-right shunt are more likely to develop acute elevation of pulmonary artery pressure after cardiopulmonary bypass when presenting with the Glu298Asp polymorphism of the gene endothelial nitric oxide synthase. This could be used as a genetic marker for the predisposition for the development of pulmonary hypertension after intra-cardiac repair.

Keywords

Cardiac surgerypost-operative complicationsprognostic factors
Type
Original Articles
Information
Cardiology in the Young , Volume 21 , Issue 2 , April 2011 , pp. 161 - 169
Copyright
Copyright © Cambridge University Press 2010

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References

1. Lindberg, L, Olsson, AK, Jogi, P, et al. How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 2002; 123: 1155–1163.CrossRefGoogle ScholarPubMed
2. Bando, K, Turrentine, MW, Sharp, TG, et al. Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg 1996; 112: 1600–1607; discussion 1607–1609.CrossRefGoogle Scholar
3. Miller, OI, Tang, SF, Keech, A, et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet 2000; 356: 1464–1469.CrossRefGoogle ScholarPubMed
4. Palmer, RMJ, Rees, DD, Ashton, DS, Moncada, S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Comm 1988; 153: 1251–1256.CrossRefGoogle ScholarPubMed
5. Droma, Y, Hanaoka, M, Ota, M, et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 2002; 106: 826–830.CrossRefGoogle ScholarPubMed
6. Ahsan, A, Mohd, G, Norboo, T, Baig, MA, Qadar Pasha, MA. Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema. Chest 2006; 130: 1511–1519.CrossRefGoogle ScholarPubMed
7. Lacolley, P, Gautier, S, Poirier, O, Pannier, B, Cambien, F, Benetos, A. Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects. J Hypertens 1998; 16: 31–35.CrossRefGoogle ScholarPubMed
8. Yoshimura, M, Yasue, H, Nakayama, M, Shimasaki, Y, Sumida, H, Sugiyama, S. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese. Hum Genet 1998; 103: 65–69.CrossRefGoogle ScholarPubMed
9. Shimasaki, Y, Yasue, H, Yoshimura, M, Nakayama, M, Kugiyama, K, Ogawa, H. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 1998; 31: 1506–1510.CrossRefGoogle ScholarPubMed
10. Hingorani, AD, Liang, CF, Fatibene, J, et al. A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999; 100: 1515–1520.CrossRefGoogle Scholar
11. Marsden, PA, Heng, HH, Scherer, SW, et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem 1993; 268: 17478–17488.CrossRefGoogle ScholarPubMed
12. Tanus-Santos, JE, Desai, M, Flockhart, DA, et al. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Phrmacogenetics 2001; 11: 719–725.CrossRefGoogle ScholarPubMed
13. Galiè, N, Torbicki, A, Barst, R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004; 25: 2243–2278.Google ScholarPubMed
14. Wilkinson, JL. Haemodynamic calculations in the catheter laboratory. Heart 2001; 85: 113–120.CrossRefGoogle ScholarPubMed
15. Shoji, M, Tsutaya, S, Saito, R, Takamatu, H, Yasujima, M. Positive association of endothelial nitric oxide synthase gene polymorphism with hypertension in northern Japan. Life Sci 2000; 66: 2557–2562.CrossRefGoogle ScholarPubMed
16. Miyamoto, Y, Saito, Y, Kajiyama, N, et al. Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 1998; 32: 3–8.CrossRefGoogle ScholarPubMed
17. Sasieni, PD. From genotypes to genes: doubling the sample size. Biometrics 1997; 53: 1253–1261.CrossRefGoogle ScholarPubMed
18. Storm, TM, Wienker, TF. DeFinetti Program. http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl. 2005Google Scholar
19. Sackett, DL, Richardson, WS, Rosenberg, W, Haynes, RB. Evidence -Based Medicine. How to Practice Teach EBM. Churchill Livingstone, New York, 1997.Google Scholar
20. Godfrey, V, Chan, SL, Cassidy, A, et al. The functional consequence of the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in young healthy volunteers. Cardiovasc Drug Rev 2007; 25: 280–288.CrossRefGoogle ScholarPubMed
21. Tesauro, M, Thompson, WC, Rogliani, P, Qi, L, Chaudhary, PP, Moss, J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci U S A 2000; 97: 2832–2835.CrossRefGoogle ScholarPubMed
22. Fairchild, TA, Fulton, D, Fontana, JT, Gratton, JP, McCabe, TJ, Sessa, WC. Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase. J Biol Chem 2001; 276: 26674–26679.CrossRefGoogle ScholarPubMed
23. Golser, R, Gorren, AC, Mayer, B, Schmidt, K. Functional characterization of Glu298Asp mutant human endothelial nitric oxide synthase purified from a yeast expression system. Nitric Oxide 2003; 8: 7–14.CrossRefGoogle ScholarPubMed
24. McDonald, DM, Alp, NJ, Channon, KM. Functional comparison of the endothelial nitric oxide synthase Glu298Asp polymorphic variants in human endothelial cells. Pharmacogenetics 2004; 14: 831–839.CrossRefGoogle ScholarPubMed
25. Hibi, K, Ishigami, T, Tamura, K, et al. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 1998; 32: 521–526.CrossRefGoogle ScholarPubMed
26. Shimasaki, Y, Yasue, H, Yoshimura, M, et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 1998; 31: 1506–1510.CrossRefGoogle ScholarPubMed
27. Cai, H, Wang, X, Colagiuri, S, Wilcken, DE. A common Glu298-->Asp (894G-->T) mutation at exon 7 of the endothelial nitric oxide synthase gene and vascular complications in type 2 diabetes. Diabetes Care 1998; 21: 2195–2196.CrossRefGoogle ScholarPubMed
28. Cai, H, Wilcken, DE, Wang, XL. The Glu-298-->Asp (894G-->T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. J Mol Med 1999; 77: 511–514.CrossRefGoogle ScholarPubMed
29. Liyou, N, Simons, L, Friedlander, Y, et al. Coronary artery disease is not associated with the E298-->D variant of the constitutive, endothelial nitric oxide synthase gene. Clin Genet 1998; 54: 528–529.CrossRefGoogle Scholar
30. Poirier, O, Mao, C, Mallet, C, et al. Polymorphisms of the endothelial nitric oxide synthase gene – no consistent association with myocardial infarction in the ECTIM study. Eur J Clin Invest 1999; 29: 284–290.CrossRefGoogle ScholarPubMed
31. Yoshimura, M, Yasue, H, Nakayama, M, et al. Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786-->C and missense Glu298Asp variants. J Investig Med 2000; 48: 367–374.Google ScholarPubMed
32. Lacolley, P, Gautier, S, Poirier, O, et al. Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects. J Hypertens 1998; 16: 31–35.CrossRefGoogle ScholarPubMed
33. Benjafield, AV, Morris, BJ. Association analyses of endothelial nitric oxide synthase gene polymorphisms in essential hypertension. Am J Hypertens 2000; 13: 994–998.CrossRefGoogle ScholarPubMed
34. Kato, N, Sugiyama, T, Morita, H, et al. Lack of evidence for association between the endothelial nitric oxide synthase gene and hypertension. Hypertension 1999; 33: 933–936.CrossRefGoogle ScholarPubMed
35. Lee, YC, Huang, CH, Wang, CJ, et al. The associations among eNOS G894T gene polymorphism, erectile dysfunction and related risk factors. BJU Int 2007; 100: 1116–1120.CrossRefGoogle ScholarPubMed
36. Rosas-Vargas, H, Coral-Vazquez, RM, Tapia, R, et al. Glu298Asp endothelial nitric oxide synthase polymorphism is a risk factor for erectile dysfunction in the Mexican Mestizo population. J Androl 2004; 25: 728–732.CrossRefGoogle ScholarPubMed
37. Eisenhardt, A, Sperling, H, Hauck, E, et al. ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction. Urology 2003; 62: 152–157.CrossRefGoogle ScholarPubMed
38. Li, M, Stenmark, KR, Shandas, R, Tan, W. Effects of pathological flow on pulmonary artery endothelial production of vasoactive mediators and growth factors. J Vasc Res 2009; 46: 561–571.CrossRefGoogle ScholarPubMed
39. Sud, N, Sharma, S, Wiseman, DA, et al. Nitric oxide and superoxide generation from endothelial NOS: modulation by HSP90. Am J Physiol Lung Cell Mol Physiol 2007; 293: L1444–L1453.CrossRefGoogle ScholarPubMed
40. Sharma, S, Kumar, S, Sud, N, et al. Alterations in lung arginine metabolism in lambs with pulmonary hypertension associated with increased pulmonary blood flow. Vascul Pharmacol 2009; 51: 359–364.CrossRefGoogle ScholarPubMed
41. Lopes, AA, Rabinovitch, M, Chang, A, et al. Statements on the Management of Pulmonary Hypertension Associated with Congenital Heart Disease. Cardiology in the Young 2009; 19 E-suppl.1: 1–53.CrossRefGoogle Scholar