Purinergic Signalling

, Volume 14, Issue 2, pp 191–199 | Cite as

Uric acid levels are associated with endothelial dysfunction and severity of coronary atherosclerosis during a first episode of acute coronary syndrome

  • Mélanie Gaubert
  • Marion Marlinge
  • Marine Alessandrini
  • Marc Laine
  • Laurent Bonello
  • Julien Fromonot
  • Jennifer Cautela
  • Franck Thuny
  • Jeremie Barraud
  • Giovanna Mottola
  • Pascal Rossi
  • Emmanuel Fenouillet
  • Jean Ruf
  • Régis Guieu
  • Franck Paganelli
Original Article


The role of serum uric acid in coronary artery disease has been extensively investigated. It was suggested that serum uric acid level (SUA) is an independent predictor of endothelial dysfunction and related to coronary artery lesions. However, the relationship between SUA and severity of coronary atherosclerosis evaluated via endothelial dysfunction using peripheral arterial tone (PAT) and the reactive hyperhemia index (RHI) has not been investigated during a first episode of acute coronary syndrome (ACS). The aim of our study was to address this point. We prospectively enrolled 80 patients with a first episode of ACS in a single-center observational study. All patients underwent coronary angiography, evaluation of endothelial function via the RHI, and SUA measurement. The severity of the coronary artery lesion was assessed angiographically, and patients were classified in three groups based on the extent of disease and Gensini and SYNTAX scores. Endothelial function was considered abnormal if RHI < 1.67. We identified a linear correlation between SUA and RHI (R2 = 0.66 P < 0.001). In multivariable analyses, SUA remained associated with RHI, even after adjustment for traditional cardiovascular risk factors and renal function. SUA was associated with severity of coronary artery disease. SUA is associated with severity of coronary atherosclerosis in patients with asymptomatic hyperuricemia. This inexpensive, readily measured biological parameter may be useful to monitor ACS patients.


Coronary artery disease First episode of acute coronary syndrome Serum uric acid Endothelial dysfunction 



Sophie Rushton-Smith, PhD (MedLink Healthcare Communications Ltd.), provided editorial assistance on the final version and was compensated by the authors.

Compliance with ethical standards

Conflicts of interest

Mélanie Gaubert declares that she has no conflict of interest.

Marion Marlinge declares that she has no conflict of interest.

Marine Alessandrini declares that she has no conflict of interest.

Marc Laine declares that he has no conflict of interest.

Laurent Bonello declares that he has no conflict of interest.

Julien Fromonot declares that he has no conflict of interest.

Jennifer Cautela declares that she has no conflict of interest.

Franck Thuny declares that he has no conflict of interest.

Jeremie Barraud declares that he has no conflict of interest.

Giovanna Mottola declares that he has no conflict of interest.

Pascal Rossi declares that he has no conflict of interest.

Emmanuel Fenouillet declares that he has no conflict of interest.

Jean Ruf declares that he has no conflict of interest.

Régis Guieu declares that he has no conflict of interest.

Ethical approval

The study was approved by the hospital’s institutional review board and was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.

Supplementary material

11302_2018_9604_MOESM1_ESM.docx (52 kb)
ESM 1 (DOCX 52 kb)


  1. 1.
    Soltani Z, Rasheed K, Kapusta DR, Reisin E (2009) Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep 15:175–181CrossRefGoogle Scholar
  2. 2.
    Kanbay M, Segal M, Afsar B, Kang D-H, Rodriguez-Iturbe B, Johnson RJ (2013) The role of uric acid in the pathogenesis of human cardiovascular disease. Heart Br Card Soc 99:759–766Google Scholar
  3. 3.
    Katsiki N, Karagiannis A, Athyros VG, Mikhailidis DP (2013) Hyperuricaemia: more than just a cause of gout? J Cardiovasc Med Hagerstown Md 14:397–402CrossRefGoogle Scholar
  4. 4.
    Mercuro G, Vitale C, Cerquetani E, Zoncu S, Deidda M, Fini M, Rosano GMC (2004) Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. Am J Cardiol 94:932–935CrossRefPubMedGoogle Scholar
  5. 5.
    Erdogan D, Gullu H, Caliskan M, Yildirim E, Bilgi M, Ulus T, Sezgin N, Muderrisoglu H (2005) Relationship of serum uric acid to measures of endothelial function and atherosclerosis in healthy adults. Int J Clin Pract 59:1276–1282CrossRefPubMedGoogle Scholar
  6. 6.
    Fromonot J, Dignat-Georges F, Rossi P, Mottola G, Kipson N, Ruf J, Bonello L, Guieu R, Paganelli F (2016) Ticagrelor improves peripheral arterial function in acute coronary syndrome patients. Relationship With Adenosine Plasma Level J Am Coll Cardiol 67:1967–1968PubMedGoogle Scholar
  7. 7.
    Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A (2010) Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 31:1142–1148CrossRefPubMedGoogle Scholar
  8. 8.
    Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606CrossRefPubMedGoogle Scholar
  9. 9.
    Sianos G, Morel M-A, Kappetein AP, Morice M-C, Colombo A, Dawkins K, van den Brand M, Van Dyck N, Russell ME, Mohr FW, Serruys PW (2005) The SYNTAX score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol 1:219–227Google Scholar
  10. 10.
    Alderman MH, Cohen H, Madhavan S, Kivlighn S (1999) Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 34:144–150CrossRefPubMedGoogle Scholar
  11. 11.
    Burnstock G (2016) Purinergic signalling and endothelium. Curr Vasc Pharmacol 14(2):130–145 ReviewCrossRefPubMedGoogle Scholar
  12. 12.
    Zoccali C, Maio R, Mallamaci F, Sesti G, Perticone F (2006) Uric acid and endothelial dysfunction in essential hypertension. J Am Soc Nephrol 17:1466–1471CrossRefPubMedGoogle Scholar
  13. 13.
    Kato M, Hisatome I, Tomikura Y, Kotani K, Kinugawa T, Ogino K, Ishida K, Igawa O, Shigemasa C, Somers VK (2005) Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol 96:1576–1578CrossRefPubMedGoogle Scholar
  14. 14.
    Canepa M, Viazzi F, Strait JB, Ameri P, Pontremoli R, Brunelli C, Studenski S, Ferrucci L, Lakatta EG, AlGhatrif M (2017) Longitudinal association between serum uric acid and arterial stiffness: results from the Baltimore longitudinal study of aging. Hypertension 69:228–235CrossRefPubMedGoogle Scholar
  15. 15.
    Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJS, Anker SD, Hambrecht R (2002) Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation 105:2619–2624CrossRefPubMedGoogle Scholar
  16. 16.
    Farquharson CAJ, Butler R, Hill A, Belch JJF, Struthers AD (2002) Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 106:221–226CrossRefPubMedGoogle Scholar
  17. 17.
    Li P, Zhang L, Zhang M, Zhou C, Lin N (2016) Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: a mechanism for uric acid-induced endothelial dysfunction. Int J Mol Med 37:989–997CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ (2005) Hyperuricemia induces endothelial dysfunction. Kidney Int 67:1739–1742CrossRefPubMedGoogle Scholar
  19. 19.
    Sánchez-Lozada LG, Tapia E, López-Molina R, Nepomuceno T, Soto V, Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M (2007) Effects of acute and chronic L-arginine treatment in experimental hyperuricemia. Am J Physiol Renal Physiol 292:F1238–F1244CrossRefPubMedGoogle Scholar
  20. 20.
    Papežíková I, Pekarová M, Kolářová H, Klinke A, Lau D, Baldus S, Lojek A, Kubala L (2013) Uric acid modulates vascular endothelial function through the down regulation of nitric oxide production. Free Radic Res 47:82–88CrossRefPubMedGoogle Scholar
  21. 21.
    Woo JS, Jang WS, Kim HS, Lee JH, Choi EY, Kim JB, Kim W-S, Kim KS, Kim W (2014) Comparison of peripheral arterial tonometry and flow-mediated vasodilation for assessment of the severity and complexity of coronary artery disease. Coron Artery Dis 25:421–426CrossRefPubMedGoogle Scholar
  22. 22.
    Borgi L, McMullan C, Wohlhueter A, Curhan GC, Fisher ND, Forman JP (2017) Effect of uric acid-lowering agents on endothelial function: a randomized, double-blind, placebo-controlled trial. Hypertension 69:243–248CrossRefPubMedGoogle Scholar
  23. 23.
    Gertler MM, Garn SM, Levine SA (1951) Serum uric acid in relation to age and physique in health and in coronary heart disease. Ann Intern Med 34:1421–1431CrossRefPubMedGoogle Scholar
  24. 24.
    Beard JT (1983) Serum uric acid and coronary heart disease. Am Heart J 106:397–400CrossRefPubMedGoogle Scholar
  25. 25.
    Fromonot J, Deharo P, Bruzzese L, Cuisset T, Quilici J, Bonatti S, Fenouillet E, Mottola G, Ruf J, Guieu R (2016) Adenosine plasma level correlates with homocysteine and uric acid concentrations in patients with coronary artery disease. Can J Physiol Pharmacol 94:272–277CrossRefPubMedGoogle Scholar
  26. 26.
    Gariboldi V, Vairo D, Guieu R, Marlingue M, Ravis E, Lagier D, Mari A, Thery E, Collart F, Gaudry M, Bonello L, Paganelli F, Condo J, Kipson N, Fenouillet E, Ruf J, Mottola G (2017) Expressions of adenosine A(2A) receptors in coronary arteries and peripheral blood mononuclear cells are correlated in coronary artery disease patients. Int J Cardiol 230:427–431CrossRefPubMedGoogle Scholar
  27. 27.
    Nihei S, Tasaki H, Yamashita K, Ozumi K, Morishita T, Tsutsui M, Okazaki M, Nakashima Y, Adachi T (2004) Hyperhomocysteinemia is associated with human coronary atherosclerosis through the reduction of the ratio of endothelium-bound to basal extracellular superoxide dismutase. Circ J 68:822–828CrossRefPubMedGoogle Scholar
  28. 28.
    Guieu R, Kipson N, Ruf J, Fournier N, Laine M, Foucher MC, Fromonot J, Mottola G, Bruzzese L, Boussuges A, Fenouillet E, Bonello L, Paganelli F (2015) Low basal expression of A2A adenosine receptors and increase in adenosine plasmaconcentration are associated with positive exercise stress testing. Int J Cardiol 180:15–17CrossRefPubMedGoogle Scholar
  29. 29.
    Ruf J, Paganelli F, Bonello L, Kipson N, Mottola G, Fromonot J, Condo J, Boussuges A, Bruzzese L, Kerbaul F, Jammes Y, Gariboldi V, Franceschi F, Fenouillet E, Guieu R (2016) Spare adenosine a(2a) receptors are associated with positive exercise stress test in coronary artery disease. Mol Med 22:530–536CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Sinan Deveci O, Kabakci G, Okutucu S, Tulumen E, Aksoy H, Baris Kaya E, Evranos B, Aytemir K, Tokgozoglu L, Oto A (2010) The association between serum uric acid level and coronary artery disease. Int J Clin Pract 64:900–907CrossRefPubMedGoogle Scholar
  31. 31.
    Gur M, Yilmaz R, Demirbag R, Aksoy N (2008) Relation of serum uric acid levels with the presence and severity of angiographic coronary artery disease. Angiology 59:166–171CrossRefPubMedGoogle Scholar
  32. 32.
    Duran M, Kalay N, Akpek M, Orscelik O, Elcik D, Ocak A, Inanc MT, Kasapkara HA, Oguzhan A, Eryol NK, Ergin A, Kaya MG (2012) High levels of serum uric acid predict severity of coronary artery disease in patients with acute coronary syndrome. Angiology 63:448–452CrossRefPubMedGoogle Scholar
  33. 33.
    Barbieri L, Verdoia M, Schaffer A, Marino P, Suryapranata H, De Luca G (2015) Atherosclerosis study group (NAS). Impact of sex on uric acid levels and its relationship with the extent of coronary artery disease: a single-centre study. Atherosclerosis 241:241–248CrossRefPubMedGoogle Scholar
  34. 34.
    Zhang J, He L, Cao S, Yang Q, Yang S, Zhou Y (2014) Association of serum uric acid and coronary artery disease in premenopausal women. PLoS One 9:e106130CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yu J, Han J, Mao J, Guo L, Gao W (2014) Association between serum uric acid level and the severity of coronary artery disease in patients with obstructive coronary artery disease. Chin Med J 127:1039–1045PubMedGoogle Scholar
  36. 36.
    Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA (2010) Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res 62:170–180Google Scholar
  37. 37.
    Wheeler JG, Juzwishin KDM, Eiriksdottir G, Gudnason V, Danesh J (2005) Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med 2:e76CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Mélanie Gaubert
    • 1
  • Marion Marlinge
    • 2
    • 3
  • Marine Alessandrini
    • 4
  • Marc Laine
    • 1
  • Laurent Bonello
    • 1
  • Julien Fromonot
    • 2
    • 3
  • Jennifer Cautela
    • 1
  • Franck Thuny
    • 1
  • Jeremie Barraud
    • 1
  • Giovanna Mottola
    • 2
    • 3
  • Pascal Rossi
    • 3
  • Emmanuel Fenouillet
    • 3
    • 5
  • Jean Ruf
    • 3
  • Régis Guieu
    • 2
    • 3
    • 6
  • Franck Paganelli
    • 1
  1. 1.Department of CardiologyHopital NordMarseilleFrance
  2. 2.Laboratory of BiochemistryHopital TimoneMarseilleFrance
  3. 3.UMR MD2Aix-Marseille UniversityMarseilleFrance
  4. 4.EA 3279 Public Health, Chronic Disease and Quality of Life-Research UnitAix-Marseille UniversityMarseilleFrance
  5. 5.Institut des Sciences Biologiques, CNRSParisFrance
  6. 6.Faculté de Médecine NordMarseilleFrance

Personalised recommendations