Uric Acid, Oxidative Stress and Inflammation in Chronic Heart Failure with Reduced Ejection Fraction

Open access


Background. Oxidative stress (OS) and inflammation are major mechanisms involved in the progression of chronic heart failure (CHF). Serum uric acid (sUA) is related to CHF severity and could represent a marker of xanthine-oxidase activation. The relationship between sUA, oxidative stress (OS) and inflammation markers was assessed in patients with moderate-severe CHF and reduced left ventricular (LV) ejection fraction (EF).

Methods. In 57 patients with stable CHF, functional NYHA class III, with EF<40%, the LV function was assessed by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels and echocardiographically through the EF and E/e’ ratio, a marker of LV filling pressures. The relationship between LV function, sUA, malondialdehyde (MDA), myeloperoxidase (MPO), paraoxonase 1 (PON-1) as OS markers and high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) as markers of systemic inflammation was evaluated.

Results. The mean sUA level was 7.9 ± 2.2 mg/dl, and 61% of the CHF patients had hyperuricemia. CHF patients with elevated LV filling pressures (E/e’ ≥ 13) had higher sUA (8.6 ± 2.3 vs. 7.3 ± 1.4, p=0.08) and NT-proBNP levels (643±430 vs. 2531±709, p=0.003) and lower EF (29.8 ± 3.9 % vs. 36.3 ± 4.4 %, p=0.001). There was a significant correlation between sUA and IL-6 (r = 0.56, p<0.001), MDA (r= 0.49, p= 0.001), MPO (r=0.34, p=0.001) and PON-1 levels (r= −0.39, p= 0.003).

Conclusion. In CHF, hyperuricemia is associated with disease severity. High sUA levels in CHF with normal renal function may reflect increased xanthine-oxidase activity linked with chronic inflammatory response.

1. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107(15):1991–7. DOI: 10.1161/01. CIR.0000065637.10517.A0

2. Kittleson MM, St John ME, Bead V, Champion HC, Kasper EK, Russell SD, et al. Increased levels of uric acid predict haemodynamic compromise in patients with heart failure independently of B-type natriuretic peptide levels. Heart 2007;93(3):365–7. DOI: 10.1136/hrt.2006.090845

3. Cengel A, Turkoglu S, Turfan M, Boyaci B, et al. Serum uric acid levels as a predictor of in-hospital death in patients hospitalized for decompensated heart failure. Acta Cardiologica 2005;60(5):489–92. DOI: 10.2143/AC.60.5.2004969

4. Sakai H, Tsutamoto T, Tsutsui T, Tanaka T, Ishikawa C, Horie M, et al. Serum level of uric acid, partly secreted from the failing heart, is a prognostic marker in patients with congestive heart failure. Circ J. 2006;70(8):1006–11. DOI: 10.1253/circj.70.1006

5. Tamariz L, Harzand A, Palacio A, Verma S, Jones J, Hare J, et al. Uric acid as a predictor of all-cause mortality in heart failure: a meta-analysis. Congest Heart Fail. 2011;17(1):25–30. DOI: 10.1111/j.1751-7133.2011.00200.x

6. Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. J Card Fail. 2012;18(9):694-701. DOI: 10.1016/j.cardfail.2012.06.528

7. Ashraf M, Samra ZQ. Subcellular distribution of xanthineoxidase during cardiac ischemia and reperfusion: an immunocytochemical study. J Submicrosc Cytol Pathol 1993; 25(2):193–201.

8. Terada LS, Guidot DM, Leff JA, Willingham IR, Hanley ME, Piermattei D, et al. Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci USA. 1992;89(8):3362–6. DOI: 10.1073/pnas.89.8.3362

9. Lazzarino G, Raatikainen P, Nuutinen M, Nissinen J, Tavazzi B, Di Pierro D, et al. Myocardial release of malondialdehyde and purine compounds during coronary bypass surgery. Circulation. 1994;90(1):291–7. DOI: 10.1161/01.CIR.90.1.291

10. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, et al. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 1998;19(12):1814–22. DOI: 10.1053/euhj.1998.1188

11. Anker SD, Leyva F, Poole-Wilson PA, Kox WJ, Stevenson JC, Coats AJ. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart. 1997;78(1):39–43. DOI: 10.1136/hrt.78.1.39

12. Doehner W, Rauchhaus M, Florea VG, Sharma R, Bolger AP, Davos CH, et al. Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance. Am Heart J. 2001;141(5):792–9. DOI: 10.1067/mhj.2001.114367

13. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur J Heart Fail 2008;10(10):933–989. DOI: 10.1016/j.ejheart.2008.08.005

14. Buchmann R, Hasilik A, Van Dyke TE, Lange DE. Amplified Crevicular Leukocyte Activity in Aggressive Periodontal Disease. J Dent Res. 2002. 81(10):716-721. DOI: 10.1177/154405910208101012

15. Cabana VG, Reardon CA, Feng N, Neath S, Lukens J, Getz GS. Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response. J Lipid Res. 2003; 44(4):780-792. DOI: 10.1194/jlr. M200432-JLR200

16. Krishnan E. Interaction of inflammation, hyperuricemia, and the prevalence of hypertension among adults free of metabolic syndrome: NHANES 2009-2010. J Am Heart Assoc. 2014;3(2):e000157. DOI: 10.1161/JAHA.113.000157

17. Sinan Deveci O, Kabakci G, Okutucu S, Tulumen E, Aksoy H, Baris Kaya E, et al. The association between serum uric acid level and coronary artery disease. Int J Clin Pract. 2010; 64(7):900-7. DOI: 10.1111/j.1742-1241.2009.02263.x

18. Duran M, Kalay N, Akpek M, Orscelik O, Elcik D, Ocak A, et al. High levels of serum uric acid predict severity of coronary artery disease in patients with acute coronary syndrome. Angiology. 2012;63(6):448-52. DOI: 10.1177/0003319711426868

19. Gotsman I, Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des. 2005;11(32):4145-51. DOI: 10.2174/138161205774913255

20. Huang H, Huang B, Li Y, Huang Y, Li J, Yao H, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail. 2014;16(1):15-24. DOI: 10.1093/eurjhf/hft132

21. Filippatos GS, Ahmed MI, Gladden JD, Mujib M, Aban IB, Love TE, et al. Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J. 2011;32(6):712-20. DOI: 10.1093/eurheartj/ehq473

22. Amin A, Vakilian F, Maleki M. Serum uric acid levels correlate with filling pressures in systolic heart failure. Congest Heart Fail. 2011;17(2):80-4. DOI: 10.1111/j.1751-7133.2010.00205.x

23. Zhang YH, Lü R, Zhao XY, Kang LM, Yang YJ, Zhang J. Association of serum uric acid, plasma NT-proBNP, Hs-C reactive protein and invasive hemodynamic parameters in patients with heart failure. Zhonghua Xin Xue Guan Bing Za Zhi. 2009;37(2):126-9.

24. Wojciechowska C, Romuk E, Tomasik A, Skrzep-Poloczek B, Nowalany-Kozielska E, Birkner E, Jache W. Oxidative stress markers and c-reactive protein are related to severity of heart failure in patients with dilated cardiomyopathy. Mediators Inflamm. 2014;2014:147040. DOI: 10.1155/2014/147040

25. Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Brighetti G, et al. Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J. 2002; 143(6):1107-11. DOI: 10.1067/mhj.2002.122122

26. Vaduganathan M, Greene SJ, Ambrosy AP, Mentz RJ, Subacius HP, Chioncel O, et al. Relation of serum uric acid levels and outcomes among patients hospitalized for worsening heart failure with reduced ejection fraction (from the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan trial). Am J Cardiol. 2014;114(11):1713-21. DOI: 10.1016/j.amjcard.2014.09.008

27. Pinelli M, Bindi M, Filardo FP, Moroni F, Castiglioni M. Serum uric acid levels correlate with left ventricular ejection fraction and systolic pulmonary artery pressure in patients with heart failure. [Article in Italian] Recenti Prog Med. 2007;98(12):619-23.

28. Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest. 2014;44(6):573-8. DOI: 10.1111/eci.12273

29. Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, Colucci WS, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol. 2008; 51(24):2301-9. DOI: 10.1016/j.jacc.2008.01.068

30. Huang H, Huang B, Li Y, Huang Y, Li J, Yao H, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail. 2014;16(1):15-24. DOI: 10.1093/eurjhf/hft132

31. Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A, Omran AS, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol. 1998;31(6):1352–6. DOI: 10.1016/S0735-1097(98)00101-6

32. Díaz-Vélez CR, García-Casti-eiras S, Mendoza-Ramos E, Hernández-López E. Increased malondialdehyde in peripheral blood of patients with congestive heart failure. Am Heart J. 1996;131(1):146-52. DOI: 10.1016/S0002-8703(96)90063-0

33. Reina-Couto M, Carvalho J, Valente MJ, Vale L, Afonso J, Carvalho F, et al. Impaired resolution of inflammation in human chronic heart failure. Eur J Clin Invest. 2014; 44(6):527-38. DOI: 10.1111/eci.12265

34. Wilson Tang WH, Wu Y, Mann S, Pepoy M, Shrestha K, Borowski AG, et al. Diminished Anti-Oxidant Activity of High-Density Lipoprotein-Associated Proteins in Systolic Heart Failure. Circ Heart Fail. 2011;4(1):59–64. DOI: 10.1161/CIRCHEARTFAILURE.110.958348

35. Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation. 2002;106(24):3073–8. DOI: 10.1161/01.CIR.0000041431.57222.AF

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195

Cited By


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 178 178 17
PDF Downloads 105 105 19