Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein

  • Svetlana Krasnokutsky
  • Aaron Garza Romero
  • Daisy Bang
  • Virginia C. Pike
  • Binita Shah
  • Talia F. Igel
  • Irina Dektiarev
  • Yu Guo
  • Judy Zhong
  • Stuart D. Katz
  • Michael H. Pillinger
Original Article
  • 18 Downloads

Abstract

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n = 34) and non-gout healthy controls (n = 64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20 ± 0.53 vs 3.56 ± 0.31, p = 0.021) and NMD (16.69 ± 1.54 vs 24.51 ± 0.90, p = 0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta = − 1.36 (SE 0.58), p = 0.02; adjusted beta = − 1.16 (SE 0.78), p = 0.14 and NMD unadjusted beta = − 7.68 (SE 1.78), p < 0.0001; adjusted beta = − 5.33 (SE 2.46), p = 0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R = − 0.5, p = 0.003), and between FMD and hsCRP (R = − 0.42, p = 0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.

Keywords

Arterial function Endothelium Flow-mediated dilation Gout Hyperuricemia Inflammation 

Notes

Acknowledgements

The authors thank Drs. Jonathan Samuels, Cesar Fors, Stephen Bernstein, Adey Berhanu, and Sabina Sandigursky for referring their patients for the study, and Dr. Bruce Cronstein for helpful input.

Compliance with ethical standards

Approval and consent statement

The studies described in this manuscript were approved by the Institutional Review Boards of New York University School of Medicine and the New York Harbor Health Care System, United States Department of Veterans Affairs. All participating subjects gave their informed consent in writing prior to participation in the study.

Conflict of interest statement

None of the authors have any conflict of interest regarding this manuscript. For the purposes of full transparency, we acknowledge the following disclosures. S.K. has served as a consultant for Crealta, Horizon, and Ironwood. B.S. serves on the Philips Volcano Medical Education Steering Committee and has a research grant from Siemens Medical Solutions. M.H.P. serves and/or has served as a consultant for AstraZeneca, Crealta, Horizon, Ironwood, and SOBI, and has been an investigative site for a sponsored trial by Takeda.

References

  1. 1.
    Zhu Y, Pandya BJ, Choi HK (2011) Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 63(10):3136–3141CrossRefPubMedGoogle Scholar
  2. 2.
    Zhu Y, Pandya BJ, Choi HK (2012) Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med 125(7):679–687 e671CrossRefPubMedGoogle Scholar
  3. 3.
    Keenan RT, O'Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, Krasnokutsky S, Oh C, Pillinger MH (2011) Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 124(2):155–163CrossRefPubMedGoogle Scholar
  4. 4.
    Choi HK, Curhan G (2007) Independent impact of gout on mortality and risk for coronary heart disease. Circulation 116(8):894–900CrossRefPubMedGoogle Scholar
  5. 5.
    Ndrepepa G, Braun S, King L, Hadamitzky M, Haase HU, Birkmeier KA, Schomig A, Kastrati A (2012) Association of uric acid with mortality in patients with stable coronary artery disease. Metabolism 61(12):1780–1786CrossRefPubMedGoogle Scholar
  6. 6.
    Krishnan E, Baker JF, Furst DE, Schumacher HR (2006) Gout and the risk of acute myocardial infarction. Arthritis Rheum 54(8):2688–2696CrossRefPubMedGoogle Scholar
  7. 7.
    Monica FZ, Bian K, Murad F (2016) The endothelium-dependent nitric oxide-cGMP pathway. Adv Pharmacol 77:1–27CrossRefPubMedGoogle Scholar
  8. 8.
    Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340(8828):1111–1115CrossRefPubMedGoogle Scholar
  9. 9.
    Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Thomas O, Deanfield JE (1995) Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 74(3):247–253CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM (2009) Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation 120(6):502–509CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Choi YJ, Yoon Y, Lee KY, Hien TT, Kang KW, Kim KC, Lee J, Lee MY, Lee SM, Kang DH, Lee BH (2014) Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. FASEB J 28(7):3197–3204CrossRefPubMedGoogle Scholar
  12. 12.
    Kang DH, Han L, Ouyang X, Kahn AM, Kanellis J, Li P, Feng L, Nakagawa T, Watanabe S, Hosoyamada M, Endou H, Lipkowitz M, Abramson R, Mu W, Johnson RJ (2005) Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol 25(5):425–433CrossRefPubMedGoogle Scholar
  13. 13.
    Kanbay M, Yilmaz MI, Sonmez A, Turgut F, Saglam M, Cakir E, Yenicesu M, Covic A, Jalal D, Johnson RJ (2011) Serum uric acid level and endothelial dysfunction in patients with nondiabetic chronic kidney disease. Am J Nephrol 33(4):298–304CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yelken B, Caliskan Y, Gorgulu N, Altun I, Yilmaz A, Yazici H, Oflaz H, Yildiz A (2012) Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol 77(4):275–282CrossRefPubMedGoogle Scholar
  15. 15.
    Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, 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(22):2619–2624CrossRefPubMedGoogle Scholar
  16. 16.
    Muir SW, Harrow C, Dawson J, Lees KR, Weir CJ, Sattar N, Walters MR (2008) Allopurinol use yields potentially beneficial effects on inflammatory indices in those with recent ischemic stroke: a randomized, double-blind, placebo-controlled trial. Stroke 39(12):3303–3307CrossRefPubMedGoogle Scholar
  17. 17.
    Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, Duranay M, Covic A, Johnson RJ (2011) A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin J Am Soc Nephrol 6(8):1887–1894CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Melendez-Ramirez G, Perez-Mendez O, Lopez-Osorio C, Kuri-Alfaro J, Espinola-Zavaleta N (2012) Effect of the treatment with allopurinol on the endothelial function in patients with hyperuricemia. Endocr Res 37(1):1–6CrossRefPubMedGoogle Scholar
  19. 19.
    Perez-Ruiz F, Becker MA (2015) Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease. Curr Med Res Opin 31(Suppl 2):9–14CrossRefPubMedGoogle Scholar
  20. 20.
    Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695CrossRefPubMedGoogle Scholar
  21. 21.
    Abd TT, Eapen DJ, Bajpai A, Goyal A, Dollar A, Sperling L (2011) The role of C-reactive protein as a risk predictor of coronary atherosclerosis: implications from the JUPITER trial. Curr Atheroscler Rep 13(2):154–161CrossRefPubMedGoogle Scholar
  22. 22.
    Schieir O, Tosevski C, Glazier RH, Hogg-Johnson S, Badley EM (2017) Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis. Ann Rheum Dis 76:1396–1404CrossRefPubMedGoogle Scholar
  23. 23.
    Avina-Zubieta JA, To F, Vostretsova K, De Vera M, Sayre EC, Esdaile JM: Risk of myocardial infarction and stroke in newly diagnosed systemic lupus erythematosus: a general population-based study. Arthritis Care Res (Hoboken) 2017Google Scholar
  24. 24.
    Yeh ET, Anderson HV, Pasceri V, Willerson JT (2001) C-reactive protein: linking inflammation to cardiovascular complications. Circulation 104(9):974–975CrossRefPubMedGoogle Scholar
  25. 25.
    Yeh ET (2004) CRP as a mediator of disease. Circulation 109(21 Suppl 1):II11–II14PubMedGoogle Scholar
  26. 26.
    Singh SK, Suresh MV, Voleti B, Agrawal A (2008) The connection between C-reactive protein and atherosclerosis. Ann Med 40(2):110–120CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, Brown M, Choi H, Edwards NL, Janssens HJ et al (2015) 2015 gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol 67(10):2557–2568CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R, American College of Rheumatology (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 64(10):1431–1446CrossRefGoogle Scholar
  29. 29.
    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381CrossRefPubMedGoogle Scholar
  30. 30.
    Zheng H, Cable R, Spencer B, Votto N, Katz SD (2005) Iron stores and vascular function in voluntary blood donors. Arterioscler Thromb Vasc Biol 25(8):1577–1583CrossRefPubMedGoogle Scholar
  31. 31.
    Zheng H, Patel M, Cable R, Young L, Katz SD (2007) Insulin sensitivity, vascular function, and iron stores in voluntary blood donors. Diabetes Care 30(10):2685–2689CrossRefPubMedGoogle Scholar
  32. 32.
    Jelani QU, Norcliffe-Kaufmann L, Kaufmann H, Katz SD (2015) Vascular endothelial function and blood pressure regulation in afferent autonomic failure. Am J Hypertens 28(2):166–172CrossRefPubMedGoogle Scholar
  33. 33.
    Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R, International Brachial Artery Reactivity Task Force (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39(2):257–265CrossRefPubMedGoogle Scholar
  34. 34.
    Campia U, Choucair WK, Bryant MB, Waclawiw MA, Cardillo C, Panza JA (2002) Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans. J Am Coll Cardiol 40(4):754–760CrossRefPubMedGoogle Scholar
  35. 35.
    Esen AM, Barutcu I, Acar M, Degirmenci B, Kaya D, Turkmen M, Melek M, Onrat E, Esen OB, Kirma C (2004) Effect of smoking on endothelial function and wall thickness of brachial artery. Circ J 68(12):1123–1126CrossRefPubMedGoogle Scholar
  36. 36.
    Campion EW, Glynn RJ, DeLabry LO (1987) Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 82(3):421–426CrossRefPubMedGoogle Scholar
  37. 37.
    Waring WS, McKnight JA, Webb DJ, Maxwell SR (2006) Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes 55(11):3127–3132CrossRefPubMedGoogle Scholar
  38. 38.
    Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A (2012) Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol 59(3):235–242CrossRefPubMedGoogle Scholar
  39. 39.
    Kelkar A, Kuo A, Frishman WH (2011) Allopurinol as a cardiovascular drug. Cardiol Rev 19(6):265–271CrossRefPubMedGoogle Scholar
  40. 40.
    Gagliardi AC, Miname MH, Santos RD (2009) Uric acid: a marker of increased cardiovascular risk. Atherosclerosis 202(1):11–17CrossRefPubMedGoogle Scholar
  41. 41.
    Mercuro G, Vitale C, Cerquetani E, Zoncu S, Deidda M, Fini M, Rosano GM (2004) Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. Am J Cardiol 94(7):932–935CrossRefPubMedGoogle Scholar
  42. 42.
    Komori H, Yamada K, Tamai I (2018) Hyperuricemia enhances intracellular urate accumulation via down-regulation of cell-surface BCRP/ABCG2 expression in vascular endothelial cells. Biochim Biophys Acta 1860:973–980CrossRefPubMedGoogle Scholar
  43. 43.
    Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalal D, Feig DI, Johnson RJ (2010) Uric acid and hypertension: cause or effect? Curr Rheumatol Rep 12(2):108–117CrossRefPubMedGoogle Scholar
  44. 44.
    Kang DH, Park SK, Lee IK, Johnson RJ (2005) Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 16(12):3553–3562CrossRefPubMedGoogle Scholar
  45. 45.
    Rongen GAvI, I.; Kok, M.; Vonkeman, H.; Janssen, M.; Jansen, T.L.: Vasodilator function worsens after cessation of tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis only if a flare occurs. Clin Rheumatol 2018, Epub ahead of printGoogle Scholar
  46. 46.
    Igel TF, Krasnokutsky S, Pillinger MH (2017) Recent advances in understanding and managing gout. F1000Res 6:247CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Di Minno MN, Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R, Tremoli E (2015) Clinical assessment of endothelial function in patients with rheumatoid arthritis: a meta-analysis of literature studies. Eur J Intern Med 26(10):835–842CrossRefPubMedGoogle Scholar
  48. 48.
    Mikolajczyk TP, Osmenda G, Batko B, Wilk G, Krezelok M, Skiba D, Sliwa T, Pryjma JR, Guzik TJ (2016) Heterogeneity of peripheral blood monocytes, endothelial dysfunction and subclinical atherosclerosis in patients with systemic lupus erythematosus. Lupus 25(1):18–27CrossRefPubMedGoogle Scholar
  49. 49.
    Brook RD, Yalavarthi S, Myles JD, Khalatbari S, Hench R, Lustig S, Marder W, Neidert A, Kaplan MJ (2011) Determinants of vascular function in patients with chronic gout. J Clin Hypertens (Greenwich) 13(3):178–188CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Svetlana Krasnokutsky
    • 1
    • 2
    • 3
  • Aaron Garza Romero
    • 1
    • 2
    • 3
  • Daisy Bang
    • 1
    • 2
    • 3
  • Virginia C. Pike
    • 1
    • 2
    • 3
  • Binita Shah
    • 3
    • 4
    • 5
  • Talia F. Igel
    • 1
    • 2
    • 3
  • Irina Dektiarev
    • 3
    • 4
    • 5
  • Yu Guo
    • 3
    • 5
    • 6
  • Judy Zhong
    • 3
    • 5
    • 6
  • Stuart D. Katz
    • 3
    • 5
  • Michael H. Pillinger
    • 1
    • 2
    • 3
    • 7
  1. 1.Section of RheumatologyVA New York Harbor Health Care SystemNew YorkUSA
  2. 2.Division of Rheumatology (Crystal Diseases Study Group)New York University School of MedicineNew YorkUSA
  3. 3.TRIAD (Translational Research in Inflammation and Atherosclerotic Disease)New York University School of MedicineNew YorkUSA
  4. 4.Section of CardiologyVA New York Harbor Health Care SystemNew YorkUSA
  5. 5.Division of Cardiology, Department of MedicineNew York University School of MedicineNew YorkUSA
  6. 6.Division of Biostatistics, Department of Population HealthNew York University School of MedicineNew YorkUSA
  7. 7.Division of RheumatologyNYU Hospital for Joint DiseasesNew YorkUSA

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