Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein
- 118 Downloads
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.
KeywordsArterial function Endothelium Flow-mediated dilation Gout Hyperuricemia Inflammation
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.
This work was supported by a New York State Empire Clinical Research Investigator Program (ECRIP) award, to S.D.K. and S.K. S.K. was also supported in part by an Investigator Award from the Rheumatology Research Foundation. B.S. was supported in part by the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (I01BX007080). M.H.P. and S.D.K. received support from a CTSA award (1UL1TR001445) to New York University from the National Center for the Advancement of Translational Science, National Institutes of Health.
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.
- 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
- 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
- 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
- 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
- 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
- 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.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
- 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
- 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