Тhe link of T(–786)C аnd G894T polymorphisms of the endothelial NO-synthase gene with endothelial vasodilatory function and long-term clinical prognosis in patients with chronic heart failure and reduced left ventricular ejection fraction

Main Article Content

L. G. Voronkov
I. D. Mazur
N. G. Gorovenko

Abstract

The aim – сhronic heart failure (CHF) is associated with endothelial dysfunction. The pivotal role of nitric oxide in the maintenance of endothelial function (EF) is well-known. But it is unknown whether endothelial nitric oxide synthase (eNOS) gene polymorphismis associated with both EF and clinical outcomes in systolic CHF.
Materials and methods. 116 stable (NYHA II–III) ischemic CHF patients with left ventricular ejection fraction (LVEF)
≤ 45 % were examined. Flow-mediated vasodilation (FMVD) of a. brachialis was carried out by standard cuff test. Patients were followed-up for a median of twenty months to determine long-term outcomes. The frequency of T(–786)C genotypes was: TT – 40.5 % (n=47), TC – 43.1 % (n=50), CC – 16.4 % (n=19); the frequency of G894T genotypes was: GG 56.0 % (n=65), GT 33.6 % (n=39), ТТ 10.4 % (n=12).
Results and discussion. FMVD in patients with TT genotype of T(–786)C polymorphisms was 7.2 [4.7; 8.3] %, in patients with TC – 6.6 [4.4; 9.1] %, where as FMVD in patients with genotype CC was 4.7 [2.8; 6.0] %, p=0.034 for TT vs. CC; p=0.046 for TC vs. CC. FMVD in patients with GG genotype of G894T polymorphisms was 7.1 [4.3; 9.4] %, in patients with GT – 6.2 [5.1; 8.1] %, in patients with genotype TT was 4.2 [2.5; 5.3] %. The difference between FMVD was significant only TT vs. CC – p=0.030. The patients with CC genotype demonstrated a significantly higher heart failure hospitalization rate (log-rank 5.304, p=0.021) and higher cardiovascular (CV) mortality rate (log-rank 4.011, p=0.045) as compared with the TT homozygote group. LVEF, FMVD, and CC genotype were the predictors of CV mortality in univariate Cox regression analysis, and only LVEF and FMVD in multivariate Cox model. Long-term outcomes were similar in patients with GG, GT and TT genotypes of G894T polymorphisms.
Conclusion. In stable ischemic systolic CHF CC T(–786)C eNOS genotype is associated with worse FMVD response and worse long-term outcome versus TT T(–786)C eNOS genotype. TT G(984)T eNOS genotype is associated with worse FMVD response only, but not with long-term outcomes versus GG G(894)T eNOS genotype.

Article Details

Keywords:

heart failure, endothelial nitricoxide synthase, T(–786)C gene polymorphism, G(984)T gene polymorphism, long-term outcome

References

Barton M, Haudenschild CC. Endothelium and patheroge­­nesis: endothelial therapyrevisited. J Cardiovasc Pharmacol. 2001;38:23–5. https://doi.org/10.1097/00005344-200111002-00007.

Celermajer DS, Sorensen KE, Gooch VM. Non-invasive detection of endothelial dysfunction in children and adultsat risk of atherosclerosis. Lancet. 1992;340:1111–5. https://doi.org/10.1016/0140-6736(92)93147-f .

Çiftçi Ç, Melil S, Çebi Y, et al. Association of endothelial nitric oxide synthase promoter region (T-786C) gene polymorphism with acute coronary syndrome and coronary heart disease. Lipids Health Dis. 2008;7:5. https://doi.org/10.1186/1476-511x-7-5.

Dell’Omo G, Penno G, Pucci L, et al. Lack of association between endothelial nitric oxide synthase gene polymorphisms, microalbuminuria and endothelial dysfunction in hypertensive men. J Hypertens. 2007;25(7):1389–95. https://doi.org/10.1097/hjh.0b013e3281268548.

Dosenko V, Zagoriy V, Lutay Y, et al. Allelic polymorphism in the promoter (T–786→C), but not in exon 7 (G894→T) or the variable number tandem repeat in intron 4, of the endothelial nitric oxide synthase gene is positively associated with acute coronary syndrome in the Ukrainian population. Exp Clin Cardiol. 2006;11(1):11–3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2274837/

Doshi AA, Ziolo MT, Wang H, et al. A promoter polymorphism of the endothelial nitric oxide synthase gene is associated with reduced mRNA and protein expression in failing human myocardium. J Card Fail. 2010;16(4):314–9. https://doi.org/10.1016/j.cardfail.2009.12.013 .

Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992;69:1596–1601. https://doi.org/10.1016/0002-9149(92)90710-g.

Erbs S, Möbius-Winkler S, Linke A, et al. Both T-786C and G894T polymorphism of endothelial nitric oxide synthase affect in-vitro endothelium-dependent relaxation of internal mammary artery rings from patients with coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2006;13(5):826–31. https://doi.org/10.1097/01.hjr.0000230100.70900.37.

Fellmann F, van El CG, Charron Ph, et al. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27(12):1763–73. https://doi.org/10.1038/s41431-019-0445-y.

Fischer D, Rossa S, Landmesser U, et al. Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation or death. Eur Heart J. 2005;26(1):65–9. https://doi.org/10.1093/eurheartj/ehi001.

Giannitsi S, Bougiakli M, Bechlioulis A, et al. Endothelial dysfunction and heart failure: A review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovasc Dis. 2019;8:1–7. https://doi.org/10.1177/2048004019843047.

Golser R, Gorren AC, Mayer B, et al. Functional characterization of Glu298Asp mutant human endothelial nitric oxide synthase purified from a yeast expression system. Nitric Oxide. 2003;8:7–14. https://pubmed.ncbi.nlm.nih.gov/12586536/

Imamura A, Takahashi R, Murakami R, et al. The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels. Eur J Endocrinol. 2008;158(2):189–95. https://doi.org/10.1530/eje-07-0632.

Ingelsson E, Syvänen AC, Lind L. Endothelium-dependent vasodilation in conduit and resistance vessels in relation to the endothelial nitric oxide synthase gene. J Hum Hypertens. 2008;22(8):569–78. https://doi.org/10.1038/jhh.2008.37.

Kampoli AM, Tentolouris C, Papageorgiou N, et al. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol. 2012;10(1):4–18. https://doi.org/10.2174/157016112798829760.

Katz SD, Hryniewicz K, Hriljac I, et al. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005;111(3):310–4. https://doi.org/10.1161/01.cir.0000153349.77489.cf.

Khalil M, Soltanpour MS, Kamali K. Assessment of the role of plasma nitric oxide levels, T-786C genetic polymorphism, and gene expression levels of endothelial nitric oxide synthase in the development of coronary artery disease. J Res Med Sci. 2017;22:34. https://doi.org/10.4103/1735-1995.202144.

Kim KM, Murray MD, Tu W, et al. Pharmacogenetics and health care out comes in patients with chronic heart failure. Eur J Clin Pharmacol. 2012;68(11):1483-91. https://doi.org/10.4103/1735-1995.202144,

Lombardi WL, Gilbert EM. Carvedilol in the failing heart. Clin Cardiol. 2001;24(12):757–66. https://doi.org/10.1002/clc.4960241202.

Lopez FA, Casado S. Heart failure, redox alterations, and endothelial dysfunction. Hypertension. 2001;38:1400–5. https://doi.org/10.1161/hy1201.099612.

Martinelli NC, Santos KG, Biolo A, et al. Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis. Nitric Oxide. 2012;26(3):141–7. https://doi.org/10.1016/j.niox.2012.01.003.

McNamara DM, Holubkov R, Postava L, et al. Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure. Circulation. 2003;107(12):1598–602. https://doi.org/10.1161/01.cir.0000060540.93836.aa.

Metzger IF, Ishizawa MH, Rios-Santos F, et al. Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J. 2011;11(6):393–9. https://doi.org/10.1038/tpj.2010.52.

Mudau M, Genis A, Lochner A, et al. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr. 2012;23:222–231. https://doi.org/10.5830/cvja-2011-068.

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;99:2864–70. https://doi.org/10.1161/01.cir.99.22.2864.

Paradossi U, Ciofini E, Clerico A, et al. Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298→Asp and T-786→C polymorphisms. Stroke. 2004;35(6):1305→9. https://doi.org/10.1161/01.str.0000126482.86708.37.

Park KH, Park WJ. Endothelial dysfunction: clinical implications in cardiovascular disease and therapeutic approaches. J Korean Med Sci. 2015;30(9):1213–25. https://doi.org/10.3346/jkms.2015.30.9.1213 .

Petroff MG, Kim SH, Pepe S, et al. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol. 2001;3:867–73. https://doi.org/10.1038/ncb1001-867.

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128.

Rossi G, Taddei S, Virdis A, Cavallin M, et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol. 2003;41(6):938–45. https://doi.org/10.1016/s0735-1097(02)03011-5.

Senthil D, Raveendran M, Shen Y, et al. Genotype-depen­­dent expression of Endothelial nitric oxide syntase (eNOS) and its regulatory proteins in cultured endothelial cell. DNA Cell Biol. 2005;24:218–24. https://doi.org/10.1089/dna.2005.24.218.

Shampa Nasreen, Toru Nabika, Hiroshi Shibata. T–786C Polymorphism in endothelial NO synthase gene affects cerebral circulation in smokers: possible gene-environmental interaction. Arterioscler Thromb Vasc Biol. 2002;22:605–10. https://doi.org/10.1161/01.atv.0000013286.60021.fe.

Terzi S, Emre A, Yesilcimen K, et al. The endothelial nitric oxide synthase (NOS3–786T>C) genetic polymorphism in chronic heart failure: effects of mutant -786C allele on long-term mortality. Acta Cardiol Sin. 2017;33(4):420–8. https://doi.org/10.1161/01.atv.0000013286.60021.fe.

Tesauro М, Thompson WC, Rogliani P. 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;97:832–2835. https://doi.org/10.1073/pnas.97.6.2832.

Vecoli C, Andreassi MG, Liga R, et al. T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy. BMC Med Genet. 2012;13:92. https://doi.org/10.1186/1471-2350-13-92.

Veverka A, Salinas JL. Nebivolol in the treatment of chronic heart failure. Vasc Health Risk Manag. 2007;3(5):647–54. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291309/

Wenquan Niu, Yue Qi An. Updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension. PLoS One. 2011;6(9):e24266. https://doi.org/10.1371/journal.pone.0024266.

Yoshihiro Miyamoto, Yoshihiko Saito, Noboru Kajiyama, et al. Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension. 1998;32:3–8. https://doi.org/10.1161/01.hyp.32.1.3.

Zakrzewski-Jakubiak M, de Denus S, Dubé MP, et al. Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Caucasian patients with heart failure. Br J Clin Pharmacol. 2008;65(5):742–51. https://doi.org/10.1111/j.1365-2125.2007.03091.x.

Zigra A, Rallidis LS, Anastasiou G, et al. eNOS gene variants and the risk of premature myocardial infarction. Dis Markers. 2013;34(6):431-6. https://doi.org/10.1155/2013/235056

Most read articles by the same author(s)

<< < 1 2