Influence of eNOS Gene Polymorphisms (894G/T; - 786C/T) on Postoperative Hemodynamics After Cardiac Surgery

Abstract

Background: Differences in vascular reactivity have been associated with variable NO release due to 894G/T and - 786C/T polymorphisms of the eNOS gene. Carriers of the 894T and - 786C alleles are known to have enhanced vascular responsiveness to vasoconstrictor stimulation due to decreased NO generation. Thus, we hypothesized that eNOS gene polymorphism could influence perioperative hemodynamics and catecholamine support in patients undergoing cardiac surgery with CPB. Methods: In 105 patients undergoing elective CABG with CPB, systemic hemodynamics, cardiac index (CI), systemic and pulmonary vascular resistance indices (SVRI, PVRI) and catecholamine support were measured at baseline and 1 h, 4 h, 10 h and 24 h after CPB. Genotyping for the 894G/T and - 786C/T eNOS gene polymorphisms was performed by polymerase chain reaction amplification. Patients were divided according to their genotype (894G/T: GG = group 1, GT and TT = group 2; - 786C/T: TT = group 3, CT and CC = group 4). Results: Genotype distribution for 894G/T polymorphism was 41 % (GG), 52.4 % (GT), 6.6 % (TT) and for - 786C/T polymorphism 37.1 % (TT), 41.9 % (CT) and 21 % (CC). Pre- and intraoperative characteristics and systemic hemodynamics did not differ between groups. CI, SVRI and PVRI remained unaffected by genotype distribution. Statistical analysis of postoperative data revealed no difference between groups, especially for pharmacologic inotropic or vasopressor support. Also, coexistence of the 894T and - 786C alleles had no impact on perioperative variables compared to homozygous 894G and - 786T allele carriers. Conclusions: In contrast to current suggestions, the 894G/T and - 786C/T genetic polymorphisms of the eNOS gene do not influence early perioperative hemodynamics after cardiac surgery with CPB.

Key words

Genetics - nitric oxide - hemodynamics - cardiopulmonary bypass

References

• 1 Ruel M, Khan T A, Voisine P, Bianchi C, Sellke F W. Vasomotor dysfunction after cardiac surgery.  Eur J Cardiothorac Surg. 2004;  26 1002-1014
• 2 Nakayama M, Yasue H, Yoshimura M. et al . T‐786 → C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.  Circulation. 1999;  99 2864-2870
• 3 Hingorani A D, Liang C F, 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
• 4 Wang X L, Sim A S, Wang M X, Murrell G A, Trudinger B, Wang J. Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity.  FEBS Lett. 2000;  471 45-50
• 5 Tesauro M, Thompson W C, Rogliani P, Qi L, Chaudhary P P, 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 USA. 2000;  97 2832-2835
• 6 Miyamoto Y, Saito Y, Kajiyama N. et al . Endothelial nitric oxide synthase gene is positively associated with essential hypertension.  Hypertension. 1998;  32 3-8
• 7 Yoshimura M, Yasue H, Nakayama M. et al . 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
• 8 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
• 9 Philip I, Plantefeve G, Vuillaumier-Barrot S. et al . G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine.  Circulation. 1999;  99 3096-3098
• 10 Cattaruzza M, Guzik T J, Slodowski W. et al . Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease.  Circ Res. 2004;  95 841-847
• 11 Nakayama M, Yasue H, Yoshimura M. et al . T (- 786) → C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis.  Am J Cardiol. 2000;  86 628-634
• 12 Guzik T J, Black E, West N E. et al . Relationship between the G894T polymorphism (Glu298Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis.  Am J Med Genet. 2001;  100 130-137
• 13 Granath B, Taylor R R, van Bockxmeer F M, Mamotte C D. Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population.  J Cardiovasc Risk. 2001;  8 235-241
• 14 Kajiyama N, Saito Y, Miyamoto Y. et al . Lack of association between T‐786 → C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene and essential hypertension.  Hypertens Res. 2000;  23 561-565
• 15 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
• 16 Cai H, Wilcken D E, Wang X L. 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
• 17 Jeerooburkhan N, Jones L C, Bujac S. et al . Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease.  Hypertension. 2001;  38 1054-1061
• 18 Fricker R, Hesse C, Weiss J. et al . Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation.  Br J Clin Pharmacol. 2004;  58 169-177
• 19 Li R, Lyn D, Lapu-Bula R. et al . Relation of endothelial nitric oxide synthase gene to plasma nitric oxide level, endothelial function, and blood pressure in African Americans.  Am J Hypertens. 2004;  17 560-567
• 20 Fatini C, Sofi F, Sticchi E. et al . Influence of endothelial nitric oxide synthase gene polymorphisms (G894T, 4a4 b, T-786C) and hyperhomocysteinemia on the predisposition to acute coronary syndromes.  Am Heart J. 2004;  147 516-521