|Hyperuricemia and Cardiovascular Disease
|Alberto Palazzuoli1, Helen Hashemi2, Lauren C. Jameson3, Peter A. McCullough2, 4, 5
|1 Cardiology Unit, Department of Internal Medicine, University of Siena, Italy
2 Baylor University Medical Center, Dallas, TX
3 Southern Methodist University, Dallas, TX
4 Baylor Heart and Vascular Hospital, Dallas, TX
5 Baylor Heart and Vascular Institute, Dallas, TX
Uric acid (UA), the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is a common metabolic disorder, and interaction among UA and cardiovascular diseases has been clearly described. Several illnesses, including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related to increases in UA levels. In this article, we discuss the pathophysiology of hyperuricemia and describe the biologic plausibility of this metabolite's participation in the pathogenesis of cardiovascular illness. We conclude by discussing the implications of lowering plasma UA concentrations to reduce the risk of cardiovascular events, including myocardial infarction, stroke, heart failure, and cardiovascular death.
| 1. Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: primary structure and evolutionary implica-tions. Proc Natl Acad Sci U S A. 1989;86:9412-9416.
2. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7-13.
3. Wu XW, Muzny DM, Lee CC, Caskey CT. Two inde-pendent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78-84.
4. Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension. 2002;40:355-360.
5. Choi HK, Curhan G. Soft drinks, fructose consump-tion, and the risk of gout in men: prospective cohort study. BMJ. 2008;336:309-312.
6. Jin M, Yang F, Yang I, et al. Uric acid, hyperuricemia and vascular diseases. Front Biosci (Landmark Ed.) 2012;17:656-669.
7. Choi HK, Mount DB, Reginato AM, et al. Pathogen-esis of gout. Ann Intern Med. 2005;143:499-516.
8. Cooper D, Stokes KY, Tailor A, Granger DN. Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. Cardiovasc Toxicol. 2002;2:165-180.
9. Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19:358-371.
10. Richette P, Bardin T. Gout. Lancet. 2010;375:318- 328.
11. Dhanasekar C, Kalaiselvan S, Rasool M. Morin, a bioflavonoid suppresses monosodium urate crystal-induced inflammatory immune response in RAW 264.7 macrophages through the inhibition of inflam-matory mediators, intracellular ROS levels and NF-κB activation. PLoS ONE. 2015;10:e0145093.
12. Liu-Bryan R, Scott P, Sydlaske A, et al. Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expres-sion is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 2005;52:2936-2946.
13. Sabina EP, Nagar S, Rasool M. A role of piperine on monosodium urate crystal-induced inflammation-an experimental model of gouty arthritis. Inflammation. 2011;34:184-192.
14. Kodithuwakku ND, Pan M, Zhu YL, et al. Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis. J Ethnopharmacol. 2013;150:1071-1079.
15. Van der Heijden T, Kritikou E, Venema W, et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipopro-tein E–deficient mice. Arterioscler Thromb Vasc Biol. 2017;37:1457-1461.
16. Duwell P, Kono H, Rayner KJ, et al . NLRP3 inflamma-somes are required for atherogenesis and activated by cholesterol crystals that form early in disease. Nature. 2010;464:1357-1361.
17. Tosato G, Jones KD. Interleukin-1 induces interleu-kin-6 production in peripheral blood monocytes. Blood. 1990;75:1305-1310.
18. Gervois P, Kleemann R, Pilon A, et al. Global sup-pression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha acti-vator fenofibrate. J Biol Chem. 2004;279:16154-16160.
19. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843.
20. Janoudi A, Shamoun FE, Kalavakunta JK, Abela GS. Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque. Eur Heart J. 2016;37:1959-1967.
21. Mancia G, Bombelli M, Facchetti R, et al. Impact of different definitions of the metabolic syndrome on the prevalence of organ damage, cardiometabolic risk and cardiovascular events. J Hypertens. 2010;28:999-1006.
22. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640-1645.
23. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care. 2005;28:1769-1778.
24. Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Re-lationship between resistance to insulin-mediated glu-cose uptake urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991;266:3008-3011.
25. Kannellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction inflammation and vascular diseases. Semin Nephrol. 2005; 25: 39-42.
26. Zharikov S, Krotova K, Hu H, et al. Uric acid decreases NO production and increases arginase activity in cul-tured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295:C1183-C1190.
27. Cheung KJ, Tzameli I, Pissios P, et al. Xanthine oxido-reductase is a regulator of adipogenesis and PPARga-mma activity. Cell Metab. 2007;5:115-128.
28. Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of the proinflammatory endocrine im-balance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011;60:1258-1269.
29. Grayson PC, Kim SY, LaValley M, Choi HK. Hyper-uricemia and incident hypertension: a systemic review and meta-analysis. Arthritis Care Res. 2011;63:102-110.
30. Johnson RJ, Kang DH, Feig D, et al. Is there a pathoge-netic role for uric acid in hypertension and cardiovas-cular and renal disease? Hypertension. 2003;41:1183-1190.
31. Menè P, Punzo G. Uric acid: bystander or culprit in hypertension and progressive renal disease? J Hypertens. 2008;26:2085-2092.
32. Bellomo G, Venanzi S, Verdura C, et al. Associa-tion of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010;56:264-272.
33. Hsu C, Iribarren C, McCulloch CE, et al. Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med. 2009;169:342-350.
34. Sánchez-Lozada LG, Tapia E, Santamaría J, et al. Mild hyperuricemia induces vasoconstriction and main-tains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005;67:237-247.
35. Ruggiero C, Cherubini A, Ble A, et al. Uric acid and inflammatory markers. Eur Heart J. 2006;27:1174-1181.
36. Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increas-ing platelet-derived growth factor A-chain expression. J Biol Chem. 1991;266:8604-8608.
37. Kuo CF, See LC, Yu KH, et al. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology. 2013;52:127-134.
38. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7-13.
39. Moriarity JT, Folsom AR, Iribarren C, et al. Serum uric acid and risk of coronary heart disease: Atherosclero-sis Risk in Communities (ARIC) Study. Ann Epide-miol. 2000;10:136-143.
40. Krishnan E, Pandya BJ, Chung L, Dabbous O. Hy-peruricemia and the risk for subclinical coronary atherosclerosis--data from a prospective observational cohort study. Arthritis Res Ther. 2011;13:R66.
41. Bos MJ, Koudstaal PJ, Hofman A, et al. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke. 2006;37:1503-1507.
42. Chuang SY, Chen JH, Yeh WT, et al. Hyperurice-mia and increased risk of ischemic heart disease in a large Chinese cohort. Int J Cardiol. 2012;154:316-321.
43. Zhang JW, He LJ, Cao SJ, et al. Association of serum uric acid and coronary artery disease in premeno-pausal women. PLoSOne.2014;9:e106130.
44. Baumann S, Huseynov A, Koepp J, et al. Comparison of serum uric acid, bilirubin, and C-reactive protein as prognostic biomarkers of in-hospital MACE between women and men with ST-segment elevation myocar-dial infarction. Angiology. 2016;67:272-280.
45. Bagheri B, Zargari M, Meshkini F, et al. Uric acid and coronary artery disease, two sides of a single coin: a determinant of antioxidant system or a factor in metabolic syndrome. J Clin Diagn Res. 2016;10:OC27-OC31.
46. Lazzeri C, Valente S, Chiostri M, et al. Uric acid in the acute phase of ST elevation myocardial infarction submitted to primary PCI: its prognostic role and relation with inflammatory markers: a single center experience. Int J Cardiol. 2010;138:206-209.
47. Ndrepepa G, Braun S, Haase HU, et al. Prognostic value of uric acid in patients with acute coronary syn-dromes. Am J Cardiol. 2012;109:1260-1265.
48. Zuo T, Liu X, Jiang L, et al. Hyperuricemia and coronary heart disease mortality: a meta-analysis of prospective cohort studies. BMC Cardiovasc Disord. 2016;16:207.
49. White J, Sofat R, Hemani G, et al. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2016;4:327-336.
50. Biscaglia S, Ceconi C, Malagù M, et al. Uric acid and coronary artery disease: an elusive link deserving fur-ther attention. Int J Cardiol. 2016;213:28-32.
51. Kim KM, Henderson GN, Frye RF, et al. Simultane-ous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography-mass spectrometry. J Chro-matogr B Analyt Technol Biomed Life Sci. 2009;877: 65-70.
52. Gersch C, Palii SP, Kim KM, et al. Inactivation of nitric oxide by uric acid. Nucleosides Nucleotides Nucleic Acids. 2008;27:967-978.
53. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemody-namic staging. Circulation. 2003;107:1991-1997.
54. Hamaguchi S, Furumoto T, Tsuchihash-Makaya M, et al; JCARE-CARD Investigators. Hyperuricemia predicts adverse outcomes in patients with heart failure. Int J Cardiol. 2011;151:143-147.
55. Kaufman M, Guglin M. Uric acid in heart failure: a biomarker or therapeutic target? Heart Fail Rev. 2013;18:177-186.
56. Filippatos GS, Ahmed MI, Gladden JD, et al.. Hy-peruricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J. 2011;32:712-720.
57. Huang H, Huang B, Li Y, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail. 2014;16:15-24.
58. Amin A, Vakilian F, Maleki M. Serum uric acid levels correlate with filling pressures in systolic heart failure. Congest Heart Fail. 2011;17:80-84.
59. Chrysohoou C, Pitsavos C, Barbetseas J, et al. Serum uric acid levels correlate with left atrial function and systolic right ventricular function in patients with newly diagnosed heart failure: the Hellenic Heart Failure study. Congest Heart Fail. 2008;14:229-233.
60. Cicoira M, Zanolla L, Rossi A, et al. Elevated serum uric acid levels are associated with diastolic dysfunc-tion in patients with dilated cardiomyopathy. Am Heart J. 2002;143:1107-1111.
61. Palazzuoli A, Ruocco G, Pellegrini M, et al. Prognostic significance of hyperuricemia in patients with acute heart failure. Am J Cardiol. 2016;117:1616-1621.
62. Vaduganathan M, Greene SJ, Ambrosy AP, et al; EVEREST trial investigators. 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;114:1713-1721.
63. Pascual-Figal DA, Hurtado-Martínez JA, Redondo B, et al. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail. 2007;9:518-524.
64. Qu LH, Jiang H, Chen JH. Effect of uric acid-lowering therapy on blood pressure: systematic review and meta-analysis. Ann Med. 2017;49:142-156.
65. Larsen KS, Potteg?rd A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med. 2016;129:299-306.
66. Reimer KA, Jennings RB. Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs. Circulation. 1985;71:1069-1075.
67. Castelli P, Condemi AM, Brambillasca C, et al. Im-provement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol. 1995;25:119-125.
68. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled cross-over trial. Lancet. 2010;375:2161-2167.
69. Mackenzie IS, Ford I, Walker A, et al. Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open. 2016;6:e013774.
70. MacDonald TM, Ford I, Nuki G, et al; Mem-bers of the FAST Study Group. Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovas-cular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open. 2014;4:e005354.
71. Kim SC, Schneeweiss S, Choudhry N, et al. Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study Am J Med. 2015; 128:653.e7-653.e16.
72. Gavin AD, Struthers AD. Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure. Heart. 2005;91:749-753.
73. Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ. 2005;330:625.
74. Cingolani HE, Plastino JA, Escudero EM, et al. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata study. J Card Fail. 2006; 12:491-498.
75. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail. 2010;3:73-81.
76. Cappola TP, Kass DA, Nelson GS, et al. Allopu-rinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation. 2001;104:2407-2411.
77. Engberding N, Spiekermann S, Schaefer A, et al. Al-lopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction. Circulation. 2004;110:2175-2179.
78. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in pa-tients with hyperuricemia and gout. N Engl J Med. 2005;353:2450-2461.
79. Kojima S, Matsui K, Ogawa H, et al. Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovas-cular, and renal events in patients with hyperuricemia. J Cardiol. 2017;69:169-175.
80. Li Y, Shi Z, Chen L, et al. Discovery of a potent, selec-tive renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J Med Chem. 2017;60:4173-4184.
81. Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycos-uria. Biopharm Drug Dispos. 2014; 35:391-404.
82. Davies MJ, Trujillo A, Vijapurkar U, et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17:426-429.
83. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and car-diovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
84. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovas-cular outcomes, and mortality in type 2 diabetes, N Engl J Med. 2015;373:2117-2128.
85. Tamariz L, Agarwal S, Soliman EZ, et al. Association of serum uric acid with incident atrial fibrillation (from the Atherosclerosis Risk in Communities [ARIC] study). Am J Cardiol. 2011;108:1272-1276.
86. Liang WY, Liu VW, Liu ML, et al. Serum uric acid level and left ventricular hypertrophy in elderly patients with nonvalvular atrial fibrillation. Nutr Metab Car-diovasc Dis. 2016; 26:575-580.
87. Nyrnes A, Toft I, Nj?lstad I, et al. Uric acid is as-sociated with future atrial fibrillation: an 11-year follow-up of 6308 men and women—the Tromso Study. Europace. 2014;16:320-326.
88. Tamariz L, Hare JM. Xanthine oxidase inhibitors in heart failure: where do we go from here? Circulation. 2015;131:1741-1744.
89. Kuwabara M, Niwa K, Nishihara S, et al. Hyperurice-mia is an independent competing risk factor for atrial fibrillation. Int J Cardiol. 2017;15;231:137-142.
90. Mantovani A, Rigolon R, Pichiri I, et al. Hyperuri-cemia is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. J Endocrinol Invest. 2016;39:159-167.
91. Valbusa F, Bertolini L, Bonapace S, et al. Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. Am J Cardiol. 2013;112:499-504.
92. Tamariz L, Hernandez F, Bush A, et al. Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm. 2014;11:1102-1108.
93. Chao TF, Hung CL, Chen SJ, et al. The association between hyperuricemia, left atrial size and new-onset atrial fibrillation. Int J Cardiol. 2013;168:4027-4032.
94. Maharani N, Ting YK, Cheng J, et al. Molecular mechanisms underlying urate-induced enhancement of Kv1.5 channel expression in HL-1 atrial myocytes. Circ J. 2015;79:2659-2668.
95. Yang CS, Shin DM, Jo EK. The role of NLR-related protein 3 inflammasome in host defense and inflam-matory diseases. Int Neurourol J. 2012;16:2-12.
96. Dick SA, Epelman S. Chronic heart failure and inflam-mation. Circ Res. 2016;119:159-176.
97. Karantalis V, Schulman IH, Hare JM. Nitroso-redox imbalance affects cardiac structure and function. J Am Coll Cardiol. 2013;61:933-935.
98. Feig DI, Soletsky B, Johnson RJ. Effect of allopu-rinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300:924-932.
99. Lytvyn Y, Har R, Locke A, et al. Renal and vascular effects of uric acid lowering in normouricemic pa-tients with uncomplicated type 1 diabetes. Diabetes. 2017;66:1939-1949.
100. Tani S, Nagao K, Hirayama A. Effect of febuxostat, a xanthine oxidase inhibitor, on cardiovascular risk in hyperuricemic patients with hypertension: a pro-spective, open-label, pilot study. Clin Drug Invest. 2015;35:823-831.
101. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Ef-fect of allopurinol in chronic kidney disease progres-sion and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388-1393.
102. Goicoechea M, Garcia de Vinuesa S, Verdalles U, et al. Allopurinol and progression of CKD and cardiovas-cular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis. 2015;65:543-549.
103. Meng H, Liu G, Zhai J, et al. Prednisone in uric acid lowering in symptomatic heart failure patients with hyperuricemia – the PUSH-PATH3 Study. J Rheumatol. 2015;42:866-869.
|No Suggested Reading articles found!