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Hyperuricemia: a novel old disorder—relationship and potential mechanisms in heart failure

  • Claudio BorghiEmail author
  • Alberto Palazzuoli
  • Matteo Landolfo
  • Eugenio Cosentino
Article

Abstract

Uric acid, the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is an old emerging metabolic disorder, and interaction among uric acid and cardiovascular diseases has been clearly described. Several illness including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related with uric acid levels increase. In this review, we will discuss the pathophysiology of hyperuricemia and describe the biological plausibility for this metabolite to participate in the pathogenesis of cardiovascular disorders. In particular, we will focus on the implications of hyperuricemia in the onset and progression of heart failure, paying special attention to the pathophysiology and the possible clinical implications. We will conclude by discussing the effects of lowering plasma uric acid concentration on the prognosis of heart failure by reviewing most of available data on the different classes of drugs directly or indirectly involved in the hyperuricemia management.

Keywords

Uric acid Xanthine oxidase Cardiovascular diseases Heart failure 

Notes

References

  1. 1.
    Ndrepepa G (2018) Uric acid and cardiovascular disease. Clin Chim Acta 484:150–163.  https://doi.org/10.1016/j.cca.2018.05.046 CrossRefPubMedGoogle Scholar
  2. 2.
    Wu XW, Lee CC, Muzny DM, Caskey CT (1989) Urate oxidase: primary structure and evolutionary implications. Proc Natl Acad Sci 86:9412–9416.  https://doi.org/10.1073/pnas.86.23.9412 CrossRefPubMedGoogle Scholar
  3. 3.
    Williams B, Mancia G, Spiering W et al (2018) 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 39:3021–3104.  https://doi.org/10.1093/eurheartj/ehy339 CrossRefPubMedGoogle Scholar
  4. 4.
    Wu X, Muzny DM, Chi Lee C, Thomas Caskey C (1992) Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 34:78–84.  https://doi.org/10.1007/BF00163854 CrossRefPubMedGoogle Scholar
  5. 5.
    Culleton BF, Larson MG, Kannel WB, Levy D (1999) Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 131:7.  https://doi.org/10.7326/0003-4819-131-1-199907060-00003 CrossRefPubMedGoogle Scholar
  6. 6.
    Borghi C, Rosei EA, Bardin T et al (2015) Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens 33:1729–1741.  https://doi.org/10.1097/HJH.0000000000000701 CrossRefPubMedGoogle Scholar
  7. 7.
    Kim KM, Henderson GN, Frye RF et al (2009) Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography–mass spectrometry. J Chromatogr B 877:65–70.  https://doi.org/10.1016/j.jchromb.2008.11.029 CrossRefGoogle Scholar
  8. 8.
    Bobulescu IA, Moe OW (2012) Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis 19:358–371.  https://doi.org/10.1053/j.ackd.2012.07.009 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Richette P, Bardin T (2010) Gout. Lancet 375:318–328.  https://doi.org/10.1016/S0140-6736(09)60883-7 CrossRefPubMedGoogle Scholar
  10. 10.
    Borghi C, Desideri G (2016) Urate-lowering drugs and prevention of cardiovascular disease: the emerging role of xanthine oxidase inhibition. Hypertension 67:496–498.  https://doi.org/10.1161/HYPERTENSIONAHA.115.06531 CrossRefPubMedGoogle Scholar
  11. 11.
    Landmesser U, Spiekermann S, Dikalov S et al (2002) Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106:3073–3078.  https://doi.org/10.1161/01.CIR.0000041431.57222.AF CrossRefPubMedGoogle Scholar
  12. 12.
    Pacher P (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58:87–114.  https://doi.org/10.1124/pr.58.1.6 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Choi HK, Mount DB, Reginato AM (2005) Pathogenesis of gout. Ann Intern Med 143:499.  https://doi.org/10.7326/0003-4819-143-7-200510040-00009 CrossRefPubMedGoogle Scholar
  14. 14.
    Cooper D, Stokes KY, Tailor A, Granger DN (2002) Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. Cardiovasc Toxicol 2:165–180.  https://doi.org/10.1007/s12012-002-0002-7 CrossRefPubMedGoogle Scholar
  15. 15.
    Biscaglia S, Ceconi C, Malagù M et al (2016) Uric acid and coronary artery disease: an elusive link deserving further attention. Int J Cardiol 213:28–32.  https://doi.org/10.1016/j.ijcard.2015.08.086 CrossRefPubMedGoogle Scholar
  16. 16.
    Gersch C, Palii SP, Kim KM et al (2008) Inactivation of nitric oxide by uric acid. Nucleosides Nucleotides Nucleic Acids 27:967–978.  https://doi.org/10.1080/15257770802257952 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zharikov S, Krotova K, Hu H et al (2008) Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Phys Cell Phys 295:C1183–C1190.  https://doi.org/10.1152/ajpcell.00075.2008 CrossRefGoogle Scholar
  18. 18.
    Dhanasekar C, Kalaiselvan S, Rasool M (2015) Morin, a bioflavonoid suppresses monosodium urate crystal-induced inflammatory immune response in RAW 264.7 macrophages through the inhibition of inflammatory mediators, intracellular ROS levels and NF-κB activation. PLOS ONE 10:e0145093.  https://doi.org/10.1371/journal.pone.0145093 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liu-Bryan R, Scott P, Sydlaske A et al (2005) Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52:2936–2946.  https://doi.org/10.1002/art.21238 CrossRefPubMedGoogle Scholar
  20. 20.
    Ridker PM, Everett BM, Thuren T, for CANTOS Trial Group et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131CrossRefGoogle Scholar
  21. 21.
    Dick SA, Epelman S (2016) Chronic heart failure and inflammation: what do we really know? Circ Res 119:159–176.  https://doi.org/10.1161/CIRCRESAHA.116.308030 CrossRefPubMedGoogle Scholar
  22. 22.
    Janoudi A, Shamoun FE, Kalavakunta JK, Abela GS (2016) Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque. Eur Heart J 37:1959–1967.  https://doi.org/10.1093/eurheartj/ehv653 CrossRefPubMedGoogle Scholar
  23. 23.
    Mancia G, Bombelli M, Facchetti R et al (2010) Impact of different definitions of the metabolic syndrome on the prevalence of organ damage, cardiometabolic risk and cardiovascular events. J Hypertens 28:999–1006.  https://doi.org/10.1097/HJH.0b013e328337a9e3 CrossRefPubMedGoogle Scholar
  24. 24.
    Alberti KGMM, Eckel RH, Grundy SM et al (2009) 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 120:1640–1645.  https://doi.org/10.1161/CIRCULATIONAHA.109.192644 CrossRefPubMedGoogle Scholar
  25. 25.
    Ford ES (2005) Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 28:1769–1778CrossRefGoogle Scholar
  26. 26.
    Han T, Lan L, Qu R et al (2017) Temporal relationship between hyperuricemia and insulin resistance and its impact on future risk of hypertension. Hypertension 70:703–711.  https://doi.org/10.1161/HYPERTENSIONAHA.117.09508 CrossRefPubMedGoogle Scholar
  27. 27.
    Grayson PC, Kim SY, LaValley M, Choi HK (2011) Hyperuricemia and incident hypertension: a systematic review and meta-analysis: risk of incident hypertension associated with hyperuricemia. Arthritis Care Res 63:102–110.  https://doi.org/10.1002/acr.20344 CrossRefGoogle Scholar
  28. 28.
    Johnson RJ, Kang D-H, Feig D et al (2003) Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41:1183–1190.  https://doi.org/10.1161/01.HYP.0000069700.62727.C5 CrossRefPubMedGoogle Scholar
  29. 29.
    Menè P, Punzo G (2008) Uric acid: bystander or culprit in hypertension and progressive renal disease? J Hypertens 26:2085–2092.  https://doi.org/10.1097/HJH.0b013e32830e4945 CrossRefPubMedGoogle Scholar
  30. 30.
    Bellomo G, Venanzi S, Verdura C et al (2010) Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis 56:264–272.  https://doi.org/10.1053/j.ajkd.2010.01.019 CrossRefPubMedGoogle Scholar
  31. 31.
    Hsu C, Iribarren C, McCulloch CE et al (2009) Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med 169:342.  https://doi.org/10.1001/archinternmed.2008.605 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kuo C-F, See L-C, Yu K-H et al (2013) Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology 52:127–134.  https://doi.org/10.1093/rheumatology/kes223 CrossRefPubMedGoogle Scholar
  33. 33.
    Moriarity JT, Folsom AR, Iribarren C et al (2000) Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 10:136–143CrossRefGoogle Scholar
  34. 34.
    Krishnan E, Pandya BJ, Chung L, Dabbous O (2011) Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study. Arthritis Res Ther 13:R66.  https://doi.org/10.1186/ar3322 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bos MJ, Koudstaal PJ, Hofman A et al (2006) Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke 37:1503–1507.  https://doi.org/10.1161/01.STR.0000221716.55088.d4 CrossRefPubMedGoogle Scholar
  36. 36.
    Chuang S-Y, Chen J-H, Yeh W-T et al (2012) Hyperuricemia and increased risk of ischemic heart disease in a large Chinese cohort. Int J Cardiol 154:316–321.  https://doi.org/10.1016/j.ijcard.2011.06.055 CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang J, He L, Cao S et al (2014) Association of serum uric acid and coronary artery disease in premenopausal women. PLoS One 9:e106130.  https://doi.org/10.1371/journal.pone.0106130 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lazzeri C, Valente S, Chiostri M et al (2010) Uric acid in the acute phase of ST elevation myocardial infarction submitted to primary PCI: its prognostic role and relation with inflammatory markers. Int J Cardiol 138:206–209.  https://doi.org/10.1016/j.ijcard.2008.06.024 CrossRefPubMedGoogle Scholar
  39. 39.
    Ndrepepa G, Braun S, Haase H-U et al (2012) Prognostic value of uric acid in patients with acute coronary syndromes. Am J Cardiol 109:1260–1265.  https://doi.org/10.1016/j.amjcard.2011.12.018 CrossRefPubMedGoogle Scholar
  40. 40.
    Cicero AFG, Kuwabara M, Johnson R et al (2018) LDL-oxidation, serum uric acid, kidney function and pulse-wave velocity: data from the Brisighella Heart Study cohort. Int J Cardiol 261:204–208.  https://doi.org/10.1016/j.ijcard.2018.03.077 CrossRefPubMedGoogle Scholar
  41. 41.
    Catar R, Müller G, Heidler J et al (2007) Low-density lipoproteins induce the renin-angiotensin system and their receptors in human endothelial cells. Horm Metab Res 39:801–805.  https://doi.org/10.1055/s-2007-991158 CrossRefPubMedGoogle Scholar
  42. 42.
    Saito Y, Nakayama T, Sugimoto K et al (2015) Relation of lipid content of coronary plaque to level of serum uric acid. Am J Cardiol 116:1346–1350.  https://doi.org/10.1016/j.amjcard.2015.07.059 CrossRefPubMedGoogle Scholar
  43. 43.
    Ando K, Takahashi H, Watanabe T et al (2016) Impact of serum uric acid levels on coronary plaque stability evaluated using integrated backscatter intravascular ultrasound in patients with coronary artery disease. J Atheroscler Thromb 23:932–939.  https://doi.org/10.5551/jat.33951 CrossRefPubMedGoogle Scholar
  44. 44.
    Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M et al (2011) Hyperuricemia predicts adverse outcomes in patients with heart failure. Int J Cardiol 151:143–147.  https://doi.org/10.1016/j.ijcard.2010.05.002 CrossRefPubMedGoogle Scholar
  45. 45.
    Anker SD, Doehner W, Rauchhaus M et al (2003) Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 107:1991–1997.  https://doi.org/10.1161/01.CIR.0000065637.10517.A0 CrossRefPubMedGoogle Scholar
  46. 46.
    Kaufman M, Guglin M (2013) Uric acid in heart failure: a biomarker or therapeutic target? Heart Fail Rev 18:177–186.  https://doi.org/10.1007/s10741-012-9322-2 CrossRefPubMedGoogle Scholar
  47. 47.
    Chrysohoou C, Pitsavos C, Barbetseas J et al (2008) 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: the Hellenic Heart Failure Study. Congest Heart Fail 14:229–233.  https://doi.org/10.1111/j.1751-7133.2008.00005.x CrossRefPubMedGoogle Scholar
  48. 48.
    Filippatos GS, Ahmed MI, Gladden JD et al (2011) Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J 32:712–720.  https://doi.org/10.1093/eurheartj/ehq473 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Shimizu T, Yoshihisa A, Kanno Y et al (2015) Relationship of hyperuricemia with mortality in heart failure patients with preserved ejection fraction. Am J Phys Heart Circ Phys 309:H1123–H1129.  https://doi.org/10.1152/ajpheart.00533.2015 CrossRefGoogle Scholar
  50. 50.
    Huang H, Huang B, Li Y et al (2014) Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 16:15–24.  https://doi.org/10.1093/eurjhf/hft132 CrossRefPubMedGoogle Scholar
  51. 51.
    Borghi C, Cosentino ER, Rinaldi ER, Cicero AFG (2014) Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Investig 44:573–577.  https://doi.org/10.1111/eci.12273 CrossRefGoogle Scholar
  52. 52.
    Amin A, Vakilian F, Maleki M (2011) Serum uric acid levels correlate with filling pressures in systolic heart failure: filling pressures in systolic heart failure. Congest Heart Fail 17:79–83.  https://doi.org/10.1111/j.1751-7133.2010.00205.x CrossRefGoogle Scholar
  53. 53.
    Cicoira M, Zanolla L, Rossi A et al (2002) Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J 143:1107–1111CrossRefGoogle Scholar
  54. 54.
    Palazzuoli A, Ruocco G, Pellegrini M et al (2016) Prognostic significance of hyperuricemia in patients with acute heart failure. Am J Cardiol 117:1616–1621.  https://doi.org/10.1016/j.amjcard.2016.02.039 CrossRefPubMedGoogle Scholar
  55. 55.
    Vaduganathan M, Greene SJ, Ambrosy AP et al (2014) 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 114:1713–1721.  https://doi.org/10.1016/j.amjcard.2014.09.008 CrossRefPubMedGoogle Scholar
  56. 56.
    Pascual-Figal DA, Hurtado-Martínez JA, Redondo B et al (2007) Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail 9:518–524.  https://doi.org/10.1016/j.ejheart.2006.09.001 CrossRefPubMedGoogle Scholar
  57. 57.
    Otaki Y, Watanabe T, Kinoshita D et al (2017) Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int J Cardiol 228:151–157.  https://doi.org/10.1016/j.ijcard.2016.11.077 CrossRefPubMedGoogle Scholar
  58. 58.
    Ben Salem C, Slim R, Fathallah N, Hmouda H (2017) Drug-induced hyperuricaemia and gout. Rheumatology (Oxford) 56(5):679–688.  https://doi.org/10.1093/rheumatology/kew293) CrossRefGoogle Scholar
  59. 59.
    Larsen KS, Pottegård A, Lindegaard HM, Hallas J (2016) Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med 129:299–306.e2.  https://doi.org/10.1016/j.amjmed.2015.11.003 CrossRefPubMedGoogle Scholar
  60. 60.
    MacDonald TM, Ford I, Nuki G et al (2014) Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open 4:e005354.  https://doi.org/10.1136/bmjopen-2014-005354 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Mackenzie IS, Ford I, Walker A et al (2016) 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 6:e013774.  https://doi.org/10.1136/bmjopen-2016-013774 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kim SC, Schneeweiss S, Choudhry N et al (2015) Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study. Am J Med 128:653.e7–653.e16.  https://doi.org/10.1016/j.amjmed.2015.01.013 CrossRefGoogle Scholar
  63. 63.
    Gavin AD (2005) Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure. Heart 91:749–753.  https://doi.org/10.1136/hrt.2004.040477 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Doust JA, Pietrzak E, Dobson A, Glasziou P (2005) How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 330:625.  https://doi.org/10.1136/bmj.330.7492.625 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Cingolani HE, Plastino JA, Escudero EM et al (2006) The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. J Card Fail 12:491–498.  https://doi.org/10.1016/j.cardfail.2006.05.005 CrossRefPubMedGoogle Scholar
  66. 66.
    Ogino K, Kato M, Furuse Y et al (2010) Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 3:73–81.  https://doi.org/10.1161/CIRCHEARTFAILURE.109.868604 CrossRefPubMedGoogle Scholar
  67. 67.
    Cappola TP, Kass DA, Nelson GS et al (2001) Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 104:2407–2411CrossRefGoogle Scholar
  68. 68.
    Becker MA, Schumacher HR, Wortmann RL et al (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353:2450–2461.  https://doi.org/10.1056/NEJMoa050373 CrossRefPubMedGoogle Scholar
  69. 69.
    Engberding N, Spiekermann S, Schaefer A et al (2004) Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug? Circulation 110:2175–2179.  https://doi.org/10.1161/01.CIR.0000144303.24894.1C CrossRefPubMedGoogle Scholar
  70. 70.
    Xiao J, Deng S-B, She Q et al (2016) Allopurinol ameliorates cardiac function in non-hyperuricaemic patients with chronic heart failure. Eur Rev Med Pharmacol Sci 20:756–761PubMedGoogle Scholar
  71. 71.
    Hare JM, Mangal B, Brown J et al (2008) Impact of oxypurinol in patients with symptomatic heart failure. J Am Coll Cardiol 51:2301–2309.  https://doi.org/10.1016/j.jacc.2008.01.068 CrossRefPubMedGoogle Scholar
  72. 72.
    Givertz MM, Anstrom KJ, Redfield MM et al (2015) Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation 131:1763–1771.  https://doi.org/10.1161/CIRCULATIONAHA.114.014536 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kojima S, Matsui K, Ogawa H et al (2017) Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia. J Cardiol 69:169–175.  https://doi.org/10.1016/j.jjcc.2016.02.015 CrossRefPubMedGoogle Scholar
  74. 74.
    Kimura K, Hosoya T, Uchida S et al (2018) Febuxostat therapy for patients with stage 3 ckd and asymptomatic hyperuricemia: a randomized trial. Am J Kidney Dis 72:798–810.  https://doi.org/10.1053/j.ajkd.2018.06.028 CrossRefPubMedGoogle Scholar
  75. 75.
    Zhang M, Solomon DH, Desai RJ et al (2018) Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol: population-based cohort study. Circulation 138:1116–1126.  https://doi.org/10.1161/CIRCULATIONAHA.118.033992 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    White WB, Saag KG, Becker MA et al (2018) Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 378:1200–1210.  https://doi.org/10.1056/NEJMoa1710895 CrossRefPubMedGoogle Scholar
  77. 77.
    Kuwabara M (2019) Letter by Kuwabara regarding article, “Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol: Population-Based Cohort Study.”. Circulation 139:1348–1349.  https://doi.org/10.1161/CIRCULATIONAHA.118.037976 CrossRefPubMedGoogle Scholar
  78. 78.
    Yokota T, Fukushima A, Kinugawa S et al (2018) Randomized trial of effect of urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia (LEAF-CHF): study design. Int Heart J 59:976–982.  https://doi.org/10.1536/ihj.17-560 CrossRefPubMedGoogle Scholar
  79. 79.
    Li Y, Shi Z, Chen L et al (2017) Discovery of a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J Med Chem 60:4173–4184.  https://doi.org/10.1021/acs.jmedchem.6b01818 CrossRefPubMedGoogle Scholar
  80. 80.
    Chino Y, Samukawa Y, Sakai S et al (2014) SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria: uricosuric effect Of SGLT2 inhibitor. Biopharm Drug Dispos 35:391–404.  https://doi.org/10.1002/bdd.1909 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Davies MJ, Trujillo A, Vijapurkar U et al (2015) Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab 17:426–429.  https://doi.org/10.1111/dom.12439 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644–657.  https://doi.org/10.1056/NEJMoa1611925 CrossRefPubMedGoogle Scholar
  83. 83.
    Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128.  https://doi.org/10.1056/NEJMoa1504720 CrossRefPubMedGoogle Scholar
  84. 84.
    Inzucchi SE, Zinman B, Fitchett D et al (2018) How does empagliflozin reduce cardiovascular mortality? insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 41:356–363.  https://doi.org/10.2337/dc17-1096 CrossRefPubMedGoogle Scholar
  85. 85.
    McMurray JJV, Packer M, Desai AS et al (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004.  https://doi.org/10.1056/NEJMoa1409077 CrossRefPubMedGoogle Scholar
  86. 86.
    Mogensen UM, Køber L, Jhund PS et al (2018) Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF: sacubitril/valsartan, uric acid, and heart failure. Eur J Heart Fail 20:514–522.  https://doi.org/10.1002/ejhf.1056 CrossRefPubMedGoogle Scholar
  87. 87.
    Feig D, Soletsky B, Johnson R (2008) Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension. JAMA 300 (8):924.CrossRefGoogle Scholar
  88. 88.
    Lytvyn Y, Har R, Locke A et al (2017) Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes. Diabetes 66 (7):1939-1949.CrossRefGoogle Scholar
  89. 89.
    Tani S, Nagao K, Hirayama A (2015) Effect of Febuxostat, a Xanthine Oxidase Inhibitor, on Cardiovascular Risk in Hyperuricemic Patients with Hypertension: A Prospective, Open-label, Pilot Study. Clin Drug Investig 35 (12):823-831.CrossRefGoogle Scholar
  90. 90.
    Goicoechea M, Garcia de Vinuesa S, Verdalles U et al (2015) Allopurinol and Progression of CKD and Cardiovascular Events: Long-term Follow-up of a Randomized Clinical Trial. Am J Kidney Dis 65 (4):543-549.CrossRefGoogle Scholar
  91. 91.
    Meng H, Liu G, Zhai J et al (2015) Prednisone in Uric Acid Lowering in Symptomatic Heart Failure Patients with Hyperuricemia — The PUSH-PATH3 Study. The Journal of Rheumatology 42 (5):866-869.CrossRefGoogle Scholar
  92. 92.
    Noman A, Ang D, Ogston S et al (2010) Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. The Lancet 375 (9732):2161-2167.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
  2. 2.Department of Internal MedicineOspedale Policlinico S.Orsola-MalpighiBolognaItaly
  3. 3.Cardiology Unit, Department of Internal MedicineUniversity of SienaSienaItaly

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