Advertisement

Uric acid and cardiovascular disease: A clinical review

Open ArchivePublished:December 30, 2020DOI:https://doi.org/10.1016/j.jjcc.2020.12.013

      Highlights

      • Elevated serum uric acid levels are associated with cardiovascular diseases.
      • Serum uric acid is also useful for predicting future cardiovascular outcomes.
      • Whether uric acid is a causal risk factor of cardiovascular disease remains unknown.
      • Some clinical benefits of urate-lowering therapy have been shown in small studies.
      • The efficacy of urate-lowering therapy is not yet established in large-scale trials.

      Abstract

      Uric acid, the end-product of purine metabolism in humans, is not only a cause of gout, but also may play roles in developing cardiovascular diseases such as hypertension, atrial fibrillation, chronic kidney disease, heart failure, coronary artery disease, and cardiovascular death. Several clinical investigations have reported serum uric acid as a predictive marker for cardiovascular outcomes. Although the causal relationship of hyperuricemia to cardiovascular diseases remains controversial, there has been a growing interest in uric acid because of the increased prevalence of hyperuricemia worldwide. This review article summarizes current evidence concerning the relation between hyperuricemia and cardiovascular diseases.

      Keywords

      Introduction

      Uric acid represents the end-product of purine metabolism in apes and humans, which is mainly regulated by xanthine oxidoreductase (XOR), converting hypoxanthine to xanthine and xanthine to uric acid (Fig. 1). Intake of alcohol, red meat, seafood, potato, and others can increase uric acid exogenously, although overall diet explains much less variance in serum uric acid levels when compared with inherited genetic variants [
      • Major T.J.
      • Topless R.K.
      • Dalbeth N.
      • Merriman T.R.
      Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts.
      ,
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • Willett W.
      • Curhan G.
      Purine-rich foods, dairy and protein intake, and the risk of gout in men.
      ]. Uric acid is also endogenously synthesized in the liver, intestines, muscle, and vascular endothelium [
      • El Ridi R.
      • Tallima H.
      Physiological functions and pathogenic potential of uric acid: a review.
      ]. In many mammals, uric acid is further degraded to allantoin by uricase and eventually to ammonia by urease [
      • Furuhashi M.
      New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.
      ], but the lack of uricase in humans results in uric acid levels at the theoretical limit of solubility in the serum (6.8 mg/dl) (Fig. 1) [
      • Dalbeth N.
      • Merriman T.R.
      • Stamp L.K.
      Gout.
      ]. Pathological hyperuricemia caused by a purine/fructose-rich diet, genetic or environmental factors, as well as overproduction from hepatic metabolism and cell turnover, and renal underexcretion or extra-renal underexcretion leads to crystal precipitation in the joints, soft tissue, kidneys, and other organs [
      • Dalbeth N.
      • Merriman T.R.
      • Stamp L.K.
      Gout.
      ]. It has been well known that uric acid plays significant roles in gout and kidney stones formation. Beyond crystalline arthropathy and urolithiasis, accumulating evidence points toward an indicative marker or a possible etiologic role of increased uric acid levels in the pathogenesis of cardiovascular risk factors and diseases such as hypertension, atrial fibrillation (AF), chronic kidney disease (CKD), heart failure (HF), coronary artery disease (CAD), and cardiovascular death [
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • Willett W.
      • Curhan G.
      Purine-rich foods, dairy and protein intake, and the risk of gout in men.
      ,
      • El Ridi R.
      • Tallima H.
      Physiological functions and pathogenic potential of uric acid: a review.
      ,
      • Furuhashi M.
      New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.
      ]. Although experimental studies have shown that hyperuricemia provokes endothelial dysfunction via increases in inflammation and oxidative stress [
      • Maruhashi T.
      • Hisatome I.
      • Kihara Y.
      • Higashi Y.
      Hyperuricemia and endothelial function: from molecular background to clinical perspectives.
      ], it has not been established whether serum uric acid is merely a maker for cardiovascular disease, or is a causal risk factor and a potential therapeutic target in clinical practice. In this review article, we provide a summary concerning the relation between uric acid and cardiovascular disease from a clinical perspective.
      Fig. 1
      Fig. 1Purine metabolism and putative mechanisms underlying cardiovascular disease. Many mammals have low serum uric acid because of the existence of uricase, while the lack of the enzyme results in uric acid levels at the theoretical limit of solubility in humans and apes. Oxygen species (O2) are generated by XOR during purine metabolism, leading to inflammatory reaction and endothelial dysfunction. It is hypothesized that intracellular uric acid also induces inflammation, oxidative stress, and subsequent endothelial dysfunction.
      XOR, xanthine oxidoreductase.

      Inflammation, oxidative stress, and endothelial dysfunction

      Although uric acid has been recognized as an antioxidant by experimental studies [
      • Davies K.J.
      • Sevanian A.
      • Muakkassah-Kelly S.F.
      • Hochstein P.
      Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid.
      ], it is also known that uric acid induces inflammation in vascular endothelial and smooth muscle cells, and intracellular oxidative stress [
      • Kang D.H.
      • Park S.K.
      • Lee I.K.
      • Johnson R.J.
      Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.
      ,
      • Sharaf El Din U.A.A.
      • Salem M.M.
      • Abdulazim D.O
      Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: a review.
      ], leading to endothelial dysfunction (Fig. 1). While extracellular uric acid acts as an antioxidant, intracellular uric acid represents a pro-oxidant agent [
      • Sharaf El Din U.A.A.
      • Salem M.M.
      • Abdulazim D.O
      Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: a review.
      ]. During purine metabolism, oxygen species are generated by activity of xanthine oxidase (XO), promoting inflammatory reaction and impairing endothelial function (Fig. 1) [
      • Maruhashi T.
      • Hisatome I.
      • Kihara Y.
      • Higashi Y.
      Hyperuricemia and endothelial function: from molecular background to clinical perspectives.
      ]. The endothelium functions as an endocrine organ secreting vasodilators (e.g. nitric oxide and prostaglandin I2) and vasoconstrictors (e.g. endothelin-1, thromboxane A2, and angiotensin II) to regulate vascular tone, thrombosis, inflammation, and oxidation [
      • Maruhashi T.
      • Hisatome I.
      • Kihara Y.
      • Higashi Y.
      Hyperuricemia and endothelial function: from molecular background to clinical perspectives.
      ]. Endothelial dysfunction refers to a condition in which homeostasis is disturbed by an imbalance between endothelium-derived vasodilating and vasoconstricting factors. Despite numerous confounding factors, previous in vivo studies have demonstrated that elevated uric acid level was significantly associated with endothelial dysfunction assessed by different endothelial function testing (e.g. flow-mediated dilation, reactive hyperemia index, and intracoronary acetylcholine testing) in various populations [
      • Mercuro G.
      • Vitale C.
      • Cerquetani E.
      • Zoncu S.
      • Deidda M.
      • Fini M.
      • et al.
      Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk.
      ,
      • Prasad M.
      • Matteson E.L.
      • Herrmann J.
      • Gulati R.
      • Rihal C.S.
      • Lerman L.O.
      • et al.
      Uric acid is associated with inflammation, coronary microvascular dysfunction, and adverse outcomes in postmenopausal women.
      ,
      • Saito Y.
      • Kitahara H.
      • Nakayama T.
      • Fujimoto Y.
      • Kobayashi Y.
      Relation of elevated serum uric acid level to endothelial dysfunction in patients with acute coronary syndrome.
      ,
      • Tanaka A.
      • Kawaguchi A.
      • Tomiyama H.
      • Ishizu T.
      • Matsumoto C.
      • Higashi Y.
      • et al.
      Cross-sectional and longitudinal associations between serum uric acid and endothelial function in subjects with treated hypertension.
      ]. Although it remains controversial whether uric acid per se is a causal factor inducing inflammation, oxidative stress, and endothelial dysfunction, these pathways are putative mechanisms for the relations between uric acid and cardiovascular diseases (Fig. 1).

      Uric acid and cardiovascular disease

      Uric acid level is potentially associated with cardiovascular disease and prognosis, but the impact in general populations is unclear. The large community-based Framingham Heart Study showed that uric acid level at baseline did not predict future cardiovascular events including coronary heart disease and death, after adjustment for confounding clinical factors [
      • Culleton B.F.
      • Larson M.G.
      • Kannel W.B.
      • Levy D.
      Serum uric acid and risk for cardiovascular disease and death: the Framingham heart study.
      ], while there are some studies indicating that serum uric acid levels were independently and significantly associated with a risk of cardiovascular mortality [
      • Niskanen L.K.
      • Laaksonen D.E.
      • Nyyssönen K.
      • Alfthan G.
      • Lakka H.M.
      • Lakka T.A.
      • et al.
      Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study.
      ,
      • Fang J.
      • Alderman M.H.
      Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National health and nutrition examination survey.
      ]. Given that uric acid level is often useful as an indicative marker for predicting subsequent clinical events in patients with established cardiovascular disease including hypertension, diabetes, chronic coronary syndrome, acute myocardial infarction (MI), and HF [
      • Verdecchia P.
      • Schillaci G.
      • Reboldi G.
      • Santeusanio F.
      • Porcellati C.
      • Brunetti P.
      Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study.
      ,
      • Lehto S.
      • Niskanen L.
      • Rönnemaa T.
      • Laakso M.
      Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.
      ,
      • Okuya Y.
      • Saito Y.
      • Takahashi T.
      • Kishi K.
      Impact of elevated serum uric acid level on target lesion revascularization after percutaneous coronary intervention for chronic total occlusion.
      ,
      • Kojima S.
      • Sakamoto T.
      • Ishihara M.
      • Kimura K.
      • Miyazaki S.
      • Yamagishi M.
      • et al.
      Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study).
      ,
      • Anker S.D.
      • Doehner W.
      • Rauchhaus M.
      • Sharma R.
      • Francis D.
      • Knosalla C.
      • et al.
      Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging.
      ], the prognostic impact may be more evident in high-risk patients than in general populations.

      Hypertension

      Several clinical studies indicated a significant relation of serum uric acid to the risk of incident hypertension [
      • Masuo K.
      • Kawaguchi H.
      • Mikami H.
      • Ogihara T.
      • Tuck M.L.
      Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
      ,
      • Alper Jr, A.B.
      • Chen W.
      • Yau L.
      • Srinivasan S.R.
      • Berenson G.S.
      • Hamm L.L
      Childhood uric acid predicts adult blood pressure: the Bogalusa heart study.
      ]. In the longitudinal cohort study in Japan, 433 young (age ≤50 years), non-obese, and normotensive men with no medication at baseline were investigated. Systolic blood pressure (BP) was significantly increased from baseline to 5-year follow-up (123±8 vs. 130±7 mmHg, p<0.05), and the increase in BP was associated with baseline BP and serum uric acid levels [
      • Masuo K.
      • Kawaguchi H.
      • Mikami H.
      • Ogihara T.
      • Tuck M.L.
      Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
      ]. A meta-analysis of 25 observational studies with 97,824 participants showed the risk of incident hypertension increased by 13% for every 1 mg/dl increase in the uric acid level [
      • Wang J.
      • Qin T.
      • Chen J.
      • Li Y.
      • Wang L.
      • Huang H.
      • et al.
      Hyperuricemia and risk of incident hypertension: a systematic review and meta-analysis of observational studies.
      ]. Serum uric acid level is also associated with future cardiovascular events in hypertensive patients. In the PIUMA study, 1720 patients with essential hypertension were followed-up for a mean duration of 4 years and were divided into 4 groups according to the quartiles of serum uric acid (4.5, 5.2, and 6.2 mg/dl in men and 3.2, 3.9, and 4.6 mg/dl in women) [
      • Verdecchia P.
      • Schillaci G.
      • Reboldi G.
      • Santeusanio F.
      • Porcellati C.
      • Brunetti P.
      Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study.
      ]. In this study, fatal cardiovascular events were observed in 0.41, 0.33, 0.38, and 1.23 per 100 person-years in the 4 groups, suggesting that elevated uric acid level was a risk marker for subsequent cardiovascular outcomes in hypertensive patients [
      • Verdecchia P.
      • Schillaci G.
      • Reboldi G.
      • Santeusanio F.
      • Porcellati C.
      • Brunetti P.
      Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study.
      ].
      Interestingly, in a rat model, experimentally-induced hyperuricemia by the administration of oxonic acid, an inhibitor of uricase, increased systolic BP. In this experimental model, elevated systolic BP was significantly reduced by lowering uric acid with an XO inhibitor, febuxostat [
      • Sanchez-Lozada L.G.
      • Tapia E.
      • Soto V.
      • Avila-Casado C.
      • Franco M.
      • Zhao L.
      • et al.
      Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia.
      ]. Effect of uric acid-lowering therapy on BP was also observed in humans in randomized, double-blinded, placebo-controlled trials [
      • Soletsky B.
      • Feig D.I.
      Uric acid reduction rectifies prehypertension in obese adolescents.
      ,
      • Higgins P.
      • Walters M.R.
      • Murray H.M.
      • McArthur K.
      • McConnachie A.
      • Lees K.R.
      • et al.
      Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
      ]. In the single-center study, 60 prehypertensive, obese, adolescents were included and randomized to receive allopurinol, probenecid, or matching placebo. At 2 months, 24-hour systolic BP was decreased by 9.2 and 8.9 mm Hg from baseline in the allopurinol and probenecid groups, while it was increased by 1.9 mm Hg in the placebo group (p<0.001) (Table 1) [
      • Soletsky B.
      • Feig D.I.
      Uric acid reduction rectifies prehypertension in obese adolescents.
      ]. Another randomized control trial (RCT) also showed that allopurinol significantly reduced brachial and central BP in patients with recent ischemic stroke or transient ischemic attack [
      • Higgins P.
      • Walters M.R.
      • Murray H.M.
      • McArthur K.
      • McConnachie A.
      • Lees K.R.
      • et al.
      Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
      ]. It should be noted that these trials only included a specific population, and recent RCTs did not show such an effect by lowering serum uric acid level in various groups of patients (e.g. hyperuricemia, hypertension, diabetes, and CKD) [
      • Tanaka A.
      • Taguchi I.
      • Teragawa H.
      • Ishizaka N.
      • Kanzaki Y.
      • Tomiyama H.
      • et al.
      Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial.
      ,
      • Segal M.S.
      • Srinivas T.R.
      • Mohandas R.
      • Shuster J.J.
      • Wen X.
      • Whidden E.
      • et al.
      The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic.
      ,
      • Wada T.
      • Hosoya T.
      • Honda D.
      • Sakamoto R.
      • Narita K.
      • Sasaki T.
      • et al.
      Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study).
      ,
      • Kimura K.
      • Hosoya T.
      • Uchida S.
      • Inaba M.
      • Makino H.
      • Maruyama S.
      • et al.
      Febuxostat therapy for patients with Stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
      ,
      • Badve S.V.
      • Pascoe E.M.
      • Tiku A.
      • Boudville N.
      • Brown F.G.
      • Cass A.
      • et al.
      Effects of allopurinol on the progression of chronic kidney disease.
      ,
      • Doria A.
      • Galecki A.T.
      • Spino C.
      • Pop-Busui R.
      • Cherney D.Z.
      • Lingvay I.
      • et al.
      Serum urate lowering with allopurinol and kidney function in type 1 diabetes.
      ]. Therefore, uric acid may be a part of causal factor in the development of hypertension, but therapeutic intervention of lowering uric acid for BP control should be limited in clinical practice so far.
      Table 1Key randomized control trials investigating urate-lowering therapy.
      Population/Study (author)Sample sizeDesignTested strategiesComparatorResults
      Hypertension
      Soletsky et al.
      • Soletsky B.
      • Feig D.I.
      Uric acid reduction rectifies prehypertension in obese adolescents.
      60DB, crossoverAllopurinol and probenecidPlaceboIn prehypertensive obese adolescents, urate-lowering therapy reduced clinic SBP (−10.1 vs. −10.2 vs. 1.7 mmHg, p<0.001)
      Segal et al.
      • Segal M.S.
      • Srinivas T.R.
      • Mohandas R.
      • Shuster J.J.
      • Wen X.
      • Whidden E.
      • et al.
      The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic.
      110DBAllopurinol plus chlorthalidonePlacebo plus chlorthalidoneIn hypertensive African-Americans, allopurinol non-significantly reduced clinic SBP (−3.4 vs. 0.8 mmHg, p = 0.06)
      Ischemic stroke
      Higgins et al.
      • Higgins P.
      • Walters M.R.
      • Murray H.M.
      • McArthur K.
      • McConnachie A.
      • Lees K.R.
      • et al.
      Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
      80DBAllopurinolPlaceboAllopurinol lowered central and brachial SBP and reduced carotid IMT progression
      Type 1 DM
      PERL
      • Doria A.
      • Galecki A.T.
      • Spino C.
      • Pop-Busui R.
      • Cherney D.Z.
      • Lingvay I.
      • et al.
      Serum urate lowering with allopurinol and kidney function in type 1 diabetes.
      530DBAllopurinolPlaceboAllopurinol did not delay GFR decline (between-group difference 0.001, 95% CI −1.9 to 1.9 ml/min/1.73 m2)
      CKD
      UPWARD
      • Wada T.
      • Hosoya T.
      • Honda D.
      • Sakamoto R.
      • Narita K.
      • Sasaki T.
      • et al.
      Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study).
      65DBTopiroxostatPlaceboChanges in eGFR were superior in the topiroxostat group (−0.2 vs. −4.0 ml/min/1.73 m2, p = 0.03)
      FEATHER
      • Kimura K.
      • Hosoya T.
      • Uchida S.
      • Inaba M.
      • Makino H.
      • Maruyama S.
      • et al.
      Febuxostat therapy for patients with Stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
      441DBFebuxostatPlaceboIn CKD patients with hyperuricemia, febuxostat did not mitigate the decline in eGFR slope (0.23 vs. −0.47 ml/min/1.73 m2 per year, p = 0.1)
      CKD-FIX
      • Badve S.V.
      • Pascoe E.M.
      • Tiku A.
      • Boudville N.
      • Brown F.G.
      • Cass A.
      • et al.
      Effects of allopurinol on the progression of chronic kidney disease.
      363DBAllopurinolPlaceboThe change in eGFR was not significantly different between the 2 groups (−3.33 vs. −3.23 ml/min/1.73 m2, p = 0.85)
      Heart failure
      Farquharson et al.
      • Farquharson C.A.
      • Butler R.
      • Hill A.
      • Belch J.J.
      • Struthers A.D.
      Allopurinol improves endothelial dysfunction in chronic heart failure.
      11DB, crossoverAllopurinolPlaceboAllopurinol improved endothelial dysfunction assessed by forearm blood flow response to acetylcholine
      OPT-CHF
      • Hare J.M.
      • Mangal B.
      • Brown J.
      • Fisher Jr, C.
      • Freudenberger R.
      • Colucci W.S.
      • et al.
      Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.
      405DBOxypurinolPlaceboClinical improvements including events and HF status did not differ between the 2 groups (45% vs. 43%, p = 0.42)
      EXACT-HF
      • Givertz M.M.
      • Anstrom K.J.
      • Redfield M.M.
      • Deswal A.
      • Haddad H.
      • Butler J.
      • et al.
      Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) Study.
      253DBAllopurinolPlaceboIn hyperuricemic patients with HFrEF, allopurinol did not improve clinical status, exercise capacity, QOL, or LVEF
      CAD
      Noman et al.
      • Noman A.
      • Ang D.S.
      • Ogston S.
      • Lang C.C.
      • Struthers A.D.
      Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
      65DB, crossoverAllopurinolPlaceboAllopurinol increased time to ST depression (median difference 43 s, 95% CI 31–58 s) and exercise time (difference 58 s, 95% CI 45–77 s)
      Hyperuricemia/gout
      PRIZE
      • Tanaka A.
      • Taguchi I.
      • Teragawa H.
      • Ishizaka N.
      • Kanzaki Y.
      • Tomiyama H.
      • et al.
      Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial.
      483Open-labelFebuxostatLifestyle modificationMean% change of CCA-IMT in the febuxostat group was not significantly different (1.2% vs. 1.4%, p = 0.83)
      FREED
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • Hisatome I.
      • Waki M.
      • Uchiyama K.
      • et al.
      Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.
      1070Open-labelFebuxostatAllopurinol (100 mg) allowedFebuxostat was superior in the rate of composite cerebral, cardiovascular, and renal events (23.3% vs. 28.7%, p = 0.02)
      CARES
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • Borer J.S.
      • Gorelick P.B.
      • Whelton A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      6190DBFebuxostatAllopurinolNon-inferiority of febuxostat was met (p = 0.002), though all-cause and CV mortality was significantly higher in the febuxostat group
      FAST
      • Mackenzie I.S.
      • Ford I.
      • Nuki G.
      • Hallas J.
      • Hawkey C.J.
      • Webster J.
      • et al.
      Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.
      6128Open-labelFebuxostatAllopurinolNon-inferiority of febuxostat was met (p<0.001) with no significant increase of risk of death
      CAD, coronary artery disease; CCA, common carotid artery; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; DB, double-blind; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IMT, intima-media thickness; LVEF, left ventricular ejection fraction; QOL, quality of life; SBP, systolic blood pressure.

      Atrial fibrillation

      Several studies have found an association between elevated serum uric acid and an increased risk of AF, although whether uric acid plays a mechanistic role in the cause and maintenance of AF remains unclear. Oxidative stress, inflammation, renin-angiotensin-aldosterone system activation, and endothelial dysfunction, and subsequent atrial remodeling may explain the pathogenic link between uric acid and AF. A large-scale Japanese cross-sectional cohort of general population (n = 285,882) showed a significant relation of uric acid to AF in both sexes [
      • Kawasoe S.
      • Kubozono T.
      • Yoshifuku S.
      • Ojima S.
      • Oketani N.
      • Miyata M.
      • et al.
      Uric acid level and prevalence of atrial fibrillation in a Japanese general population of 285,882.
      ]. A meta-analysis including 6 cross-sectional studies and 3 cohort studies confirmed an increase in the risk of AF among those with high serum uric acid (defined as >7 mg/dl or the highest level cut-off or quartile reported in the study) compared to those with normal serum uric acid levels [relative risk 1.67, 95% confidence interval (CI) 1.23–2.27] [
      • Tamariz L.
      • Hernandez F.
      • Bush A.
      • Palacio A.
      • Hare J.M.
      Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis.
      ]. Data on therapeutic challenge for AF are scarce, but in a canine model, allopurinol suppressed AF promotion by preventing both electrical and structural remodeling [
      • Sakabe M.
      • Fujiki A.
      • Sakamoto T.
      • Nakatani Y.
      • Mizumaki K.
      • Inoue H.
      Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction.
      ].

      Chronic kidney disease

      It has been widely accepted that elevated serum uric acid at least predicts the development of CKD [
      • Johnson R.J.
      • Nakagawa T.
      • Jalal D.
      • Sanchez-Lozada L.G.
      • Kang D.H.
      • Ritz E.
      Uric acid and chronic kidney disease: which is chasing which?.
      ], although again, the causality remains controversial. The possible causative role of serum uric acid on CKD was observed in large-scale cohort studies [
      • Jing J.
      • Kielstein J.T.
      • Schultheiss U.T.
      • Sitter T.
      • Titze S.I.
      • Schaeffner E.S.
      • et al.
      Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German chronic kidney disease (GCKD) study.
      ]. Even in normotensive healthy individuals with normal renal function, a prospective observational cohort (n = 900) found the association between elevated serum uric acid and the likelihood of longitudinal kidney damage was confirmed after adjusting for clinical factors [
      • Bellomo G.
      • Venanzi S.
      • Verdura C.
      • Saronio P.
      • Esposito A.
      • Timio M.
      Association of uric acid with change in kidney function in healthy normotensive individuals.
      ]. In addition, as shown in meta-analyses, higher serum uric acid level is a prognostic marker of cardiovascular mortality in patients with CKD [
      • Luo Q.
      • Xia X.
      • Li B.
      • Lin Z.
      • Yu X.
      • Huang F.
      Serum uric acid and cardiovascular mortality in chronic kidney disease: a meta-analysis.
      ]. Elevated serum uric acid may be related to renal involvement such as glomerulosclerosis and interstitial fibrosis by a deposition of urate crystal, leading to impaired uric acid excretion and tubular secretion, and a reduced renal blood flow [
      • Messerli F.H.
      • Frohlich E.D.
      • Dreslinski G.R.
      • Suarez D.H.
      • Aristimuno G.G.
      Serum uric acid in essential hypertension: an indicator of renal vascular involvement.
      ]. Although hypertension can cause CKD and vice versa, diuretics are often used for treating both hypertension and CKD, and other confounding disorders including insulin resistance, metabolic syndrome, and diabetes exist, the relation between serum uric acid level and renal function decline was so linear and robust that several RCTs have been conducted as described below.

      Heart failure

      Hyperuricemia is frequently found in patients with HF. A Japanese multicenter, observational study (n = 1869) demonstrated that more than half of patients had hyperuricemia with the mean serum uric acid level of 7.3 ± 2.4 mg/dl at discharge in a population of hospitalized HF [
      • Hamaguchi S.
      • Furumoto T.
      • Tsuchihashi-Makaya M.
      • Goto K.
      • Goto D.
      • Yokota T.
      • et al.
      Hyperuricemia predicts adverse outcomes in patients with heart failure.
      ]. In the Framingham Offspring study (n = 4912), the incidence of HF was six-fold higher among individuals with serum uric acid levels in the higher quartile (>6.3 mg/dl) than those in the lowest quartile (<3.4 mg/dl) [adjusted hazard ratio (HR) 2.1, 95% CI 1.04–4.22] [
      • Krishnan E.
      Hyperuricemia and incident heart failure.
      ]. A meta-analysis reported that for every 1 mg/dl elevation in serum uric acid level, the likelihood of HF development increased by 19% (HR 1.19, 95% CI 1.17–1.21), and the risk of mortality in patients with HF increased by 4% (HR 1.04, 95% CI 1.02–1.06) [
      • Huang H.
      • Huang B.
      • Li Y.
      • Huang Y.
      • Li J.
      • Yao H.
      • et al.
      Uric acid and risk of heart failure: a systematic review and meta-analysis.
      ], suggesting serum uric acid level as a prognostic marker in patients with HF. Hyperuricemia has a deleterious effect on exercise capacity, oxygen consumption, diastolic dysfunction, and cachexia [
      • Lee S.J.
      • Oh B.K.
      • Sung K.C.
      Uric acid and cardiometabolic diseases.
      ]. Although the mechanisms in which uric acid influences HF development is incompletely understood, XO upregulation, renin-angiotensin-aldosterone system activation, and use of diuretics may be associated.
      An experimental study showed that febuxostat may reduce the development of left ventricular hypertrophy and the amount of cardiac collagen content, thus improving systolic function in mice [
      • Xu X.
      • Hu X.
      • Lu Z.
      • Zhang P.
      • Zhao L.
      • Wessale J.L.
      • et al.
      Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice.
      ]. Two small double-blind, placebo-control RCTs clearly demonstrated that allopurinol improved endothelial function in patients with chronic HF [
      • Doehner W.
      • Schoene N.
      • Rauchhaus M.
      • Leyva-Leon F.
      • Pavitt D.V.
      • Reaveley D.A.
      • et al.
      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.
      ,
      • Farquharson C.A.
      • Butler R.
      • Hill A.
      • Belch J.J.
      • Struthers A.D.
      Allopurinol improves endothelial dysfunction in chronic heart failure.
      ]. Another small RCT reinforced the beneficial effect of allopurinol but not probenecid with dose-response relationship in improving endothelial function in HF patients [
      • George J.
      • Carr E.
      • Davies J.
      • Belch J.J.
      • Struthers A.
      High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
      ]. However, in a subsequent large RCT (n = 405), oxypurinol, a XO inhibitor, did not improve clinical composite scores and outcomes in patients with symptomatic HF [
      • Hare J.M.
      • Mangal B.
      • Brown J.
      • Fisher Jr, C.
      • Freudenberger R.
      • Colucci W.S.
      • et al.
      Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.
      ]. Furthermore, the EXACT-HF trial ultimately showed the negative results, in which 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dl were randomized to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind manner [
      • Givertz M.M.
      • Anstrom K.J.
      • Redfield M.M.
      • Deswal A.
      • Haddad H.
      • Butler J.
      • et al.
      Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) Study.
      ]. Although uric acid levels were significantly reduced with allopurinol, no significant differences were observed between the 2 groups in clinical status, HF scores, and 6-minute walk distances [
      • Givertz M.M.
      • Anstrom K.J.
      • Redfield M.M.
      • Deswal A.
      • Haddad H.
      • Butler J.
      • et al.
      Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) Study.
      ]. In summary, XO inhibition has some effects on surrogates, but it is not translated into a clinical benefit in patients with HF.

      Coronary artery disease

      In the Rotterdam study, 4385 adults aged 55 years and older showed that high serum uric acid levels were associated with risk of MI and stroke after the adjustment for other vascular risk factors [
      • Bos M.J.
      • Koudstaal P.J.
      • Hofman A.
      • Witteman J.C.
      • Breteler M.M.
      Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study.
      ]. A meta-analysis of prospective cohort studies indicated that for every 1 mg/dl increase in the serum uric acid level, the risk of CAD and all-cause mortality increased by 20% and 9%, respectively [
      • Zuo T.
      • Liu X.
      • Jiang L.
      • Mao S.
      • Yin X.
      • Guo L.
      Hyperuricemia and coronary heart disease mortality: a meta-analysis of prospective cohort studies.
      ]. As a marker for predicting clinical events, uric acid is also useful in patients with CAD. In a multicenter, retrospective, observational study in Japan (n = 1124), acute MI patients with elevated serum uric acid level (>6.7 mg/dl) had higher mortality than their counterparts [
      • Kojima S.
      • Sakamoto T.
      • Ishihara M.
      • Kimura K.
      • Miyazaki S.
      • Yamagishi M.
      • et al.
      Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study).
      ]. Similarly, in patients with chronic coronary syndrome, serum uric acid level ≥6.5 mg/dl was associated with an increased risk of target lesion revascularization after contemporary drug-eluting stent implantation under intravascular ultrasound guidance [
      • Okuya Y.
      • Saito Y.
      • Takahashi T.
      • Kishi K.
      Impact of elevated serum uric acid level on target lesion revascularization after percutaneous coronary intervention for chronic total occlusion.
      ,
      • Saito Y.
      • Kobayashi Y.
      • Fujii K.
      • Sonoda S.
      • Tsujita K.
      • Hibi K.
      • et al.
      Clinical expert consensus document on standards for measurements and assessment of intravascular ultrasound from the Japanese association of cardiovascular intervention and therapeutics.
      ,
      • Saito Y.
      • Kobayashi Y.
      Contemporary coronary drug-eluting and coated stents: a mini-review.
      ]. Coronary atherosclerosis may be enhanced by the mechanisms mentioned before including inflammation, oxidative stress, and endothelial dysfunction [
      • Maruhashi T.
      • Hisatome I.
      • Kihara Y.
      • Higashi Y.
      Hyperuricemia and endothelial function: from molecular background to clinical perspectives.
      ]. We and other groups previously reported that elevated serum uric acid level was correlated with greater coronary lipid plaques assessed by integrated backscatter-intravascular ultrasound in vivo [
      • Saito Y.
      • Nakayama T.
      • Sugimoto K.
      • Fujimoto Y.
      • Kobayashi Y.
      Relation of lipid content of coronary plaque to level of serum uric acid.
      ,
      • Ando K.
      • Takahashi H.
      • Watanabe T.
      • Daidoji H.
      • Otaki Y.
      • Nishiyama S.
      • et al.
      Impact of serum uric acid levels on coronary plaque stability evaluated using integrated backscatter intravascular ultrasound in patients with coronary artery disease.
      ], indicating that uric acid is a possible surrogate of having vulnerable plaque in patients with acute coronary syndrome. Beyond the level of serum uric acid, we also recently showed a significant relation of XOR to coronary lipid plaques evaluated by near-infrared spectroscopy in patients with chronic coronary syndrome [
      • Mori N.
      • Saito Y.
      • Saito K.
      • Matsuoka T.
      • Tateishi K.
      • Kadohira T.
      • et al.
      Relation of plasma xanthine oxidoreductase activity to coronary lipid core plaques assessed by near-infrared spectroscopy intravascular ultrasound in patients with stable coronary artery disease.
      ]. Of note, however, no relations between XOR activity and systemic inflammation or endothelial function was found, suggesting that there might be other mechanisms in the development of coronary atherosclerosis with uric acid and XOR beyond endothelial dysfunction and inflammatory reaction [
      • Saito Y.
      • Mori N.
      • Murase T.
      • Nakamura T.
      • Akari S.
      • Saito K.
      • et al.
      Greater coronary lipid core plaque assessed by near-infrared spectroscopy intravascular ultrasound in patients with elevated xanthine oxidoreductase: a mechanistic insight.
      ]. In addition to epicardial obstructive CAD, serum uric acid is reportedly associated with inflammation and endothelial function in patients with non-obstructive CAD (e.g. vasospastic angina and coronary microvascular dysfunction) [
      • Prasad M.
      • Matteson E.L.
      • Herrmann J.
      • Gulati R.
      • Rihal C.S.
      • Lerman L.O.
      • et al.
      Uric acid is associated with inflammation, coronary microvascular dysfunction, and adverse outcomes in postmenopausal women.
      ,
      • Saito Y.
      • Kitahara H.
      • Nishi T.
      • Fujimoto Y.
      • Kobayashi Y.
      Systemic endothelial dysfunction in patients with vasospastic and microvascular angina: serum uric acid as a marker of reactive hyperemia index.
      ]. In this context, Watanabe et al. [
      • Watanabe K.
      • Shishido T.
      • Otaki Y.
      • Watanabe T.
      • Sugai T.
      • Toshima T.
      • et al.
      Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm.
      ] showed that XOR activity significantly deteriorated coronary vasospasm assessed by intracoronary acetylcholine provocation test [
      • Suzuki S.
      • Kaikita K.
      • Yamamoto E.
      • Jinnouchi H.
      • Tsujita K.
      Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease.
      ]. From a multifactorial perspective, uric acid and XOR may play a role in the development of CAD. Therapeutic significance in this population remains largely unknown.

      Mendelian randomization and genetic studies

      As mentioned above, associations of uric acid concentration with cardiovascular and renal diseases have been reported in numerous observational studies, although the causal role of uric acid in this context have been widely questioned [
      • Li X.
      • Meng X.
      • Timofeeva M.
      • Tzoulaki I.
      • Tsilidis K.K.
      • Ioannidis J.P.
      • et al.
      Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.
      ]. These associations may be either confounded by other risk factors or may be representative of reverse causality [
      • Feig D.I.
      • Kang D.H.
      • Johnson R.J.
      Uric acid and cardiovascular risk.
      ]. To overcome the limitation of observational study, several Mendelian randomization studies have been conducted. This method employs the random allocation of genetic variants, protecting genotype-to-phenotype associations from the usual sources of confounding factors and from reverse causation. If genetic variants are associated with both biomarkers (e.g. uric acid) and risk of outcome in an instrumental variable regression, this suggests the biomarker has a causal role for the outcome. Using Mendelian randomization, Kleber et al. indicated that the high serum uric acid level was causally related to cardiovascular death (HR corresponding to each 1-mg/dl increase in serum uric acid 1.77, 95% CI 1.12–2.81) [
      • Kleber M.E.
      • Delgado G.
      • Grammer T.B.
      • Silbernagel G.
      • Huang J.
      • Kramer B.K.
      • et al.
      Uric acid and cardiovascular events: a Mendelian randomization study.
      ]. However, there are many other Mendelian randomization studies showing conflicting results [
      • Li X.
      • Meng X.
      • Timofeeva M.
      • Tzoulaki I.
      • Tsilidis K.K.
      • Ioannidis J.P.
      • et al.
      Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.
      ], probably because even Mendelian randomization is potentially confounded by pleiotropy (the situation where variation in a gene associates with multiple phenotypes such as blood pressure and lipid profiles). Another study in which newly developed Egger Mendelian randomization was employed to estimate a causal effect accounting for unmeasured pleiotropy implicated a modest, if any, causal effect of serum uric acid level in the development of CAD [
      • White J.
      • Sofat R.
      • Hemani G.
      • Shah T.
      • Engmann J.
      • Dale C.
      • et al.
      Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
      ]. More recently, a phenome-wide Mendelian randomization study with sensitivity analyses indicated a robust association of serum uric acid with cardiovascular diseases such as hypertension, CKD, HF, and CAD, although the association was probably due to the pleiotropic effects of genetic variants on uric acid and metabolic traits [
      • Li X.
      • Meng X.
      • He Y.
      • Spiliopoulou A.
      • Timofeeva M.
      • Wei W.Q.
      • et al.
      Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: a phenome-wide Mendelian randomization study.
      ]. An umbrella review including a few hundred observational and Mendelian randomization studies reinforced findings that convincing evidence of causal role of uric acid only exists for gout and nephrolithiasis rather than cardiovascular diseases [
      • Li X.
      • Meng X.
      • Timofeeva M.
      • Tzoulaki I.
      • Tsilidis K.K.
      • Ioannidis J.P.
      • et al.
      Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.
      ]. Mendelian randomization is helpful in this context but does not draw a conclusion, and serum uric acid levels are attributed to many environmental factors such as nutrient intake, volume status, acid base balance, renal function, and the use of drugs, beyond genetic factors. Serum uric acid level is at least useful for risk stratification, and urate-lowering therapy may improve clinical outcomes irrespective of the causality.

      Uric acid lowering treatment on renal and cardiovascular disease

      Urate-lowering treatment can be divided into two main categories, reducing uric acid production with XO inhibitors (e.g. allopurinol, febuxostat, and topiroxostat) and increasing uric acid excretion by using uricosurics (e.g. probenecid, benzbromarone, and dotinurad). Key RCTs of urate-lowering therapy are shown in Table 1.
      Based on the rationale that reduced kidney function decreases urate excretion in urine and increases uric acid crystals in renal tubules, interstitial nephritis complicating kidney stones, and crystalline deposits in the renal medulla, many clinical trials have been conducted in CKD populations. A meta-analysis of 19 RCTs with only 992 participants showed a small but statistically significant improvement in estimated glomerular filtration rate (mean difference 3.2 ml/min/1.73 m2, p = 0.04) in patients with stages 3–5 CKD who were taking allopurinol for 4–24 months [
      • Kanji T.
      • Gandhi M.
      • Clase C.M.
      • Yang R.
      Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis.
      ]. However, recently reported double-blind, placebo-control RCTs such as the FEATHER (n = 441), CKD-FIX (n = 363), and PEAL (n = 530) found no evidence of clinical benefits of serum uric acid reduction with allopurinol or febuxostat on kidney outcomes among patients with CKD [
      • Kimura K.
      • Hosoya T.
      • Uchida S.
      • Inaba M.
      • Makino H.
      • Maruyama S.
      • et al.
      Febuxostat therapy for patients with Stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
      ,
      • Badve S.V.
      • Pascoe E.M.
      • Tiku A.
      • Boudville N.
      • Brown F.G.
      • Cass A.
      • et al.
      Effects of allopurinol on the progression of chronic kidney disease.
      ,
      • Doria A.
      • Galecki A.T.
      • Spino C.
      • Pop-Busui R.
      • Cherney D.Z.
      • Lingvay I.
      • et al.
      Serum urate lowering with allopurinol and kidney function in type 1 diabetes.
      ]. Thus, a renoprotective effect of urate-lowering therapy is unclear.
      While a small, double-blind, placebo-controlled RCT (n = 80) showed a significant reduction in carotid intima-media thickness by allopurinol in patients with recent ischemic stroke [
      • Higgins P.
      • Walters M.R.
      • Murray H.M.
      • McArthur K.
      • McConnachie A.
      • Lees K.R.
      • et al.
      Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
      ], the PRIZE study, a recent, multicenter, open-label, blinded-endpoint RCT (n = 483) did not indicate a delay of carotid atherosclerosis progression assessed by an independent core laboratory with 24 months of febuxostat treatment in patients with asymptomatic hyperuricemia [
      • Tanaka A.
      • Taguchi I.
      • Teragawa H.
      • Ishizaka N.
      • Kanzaki Y.
      • Tomiyama H.
      • et al.
      Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial.
      ].
      Allopurinol is the conventional uric acid-lowering treatment and febuxostat is a recently well-studied drug. In this context, the CARES study questioned the cardiovascular safety of febuxostat [
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • Borer J.S.
      • Gorelick P.B.
      • Whelton A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      ]. In this double-blind, non-inferiority RCT, 6190 patients with gout were randomized to receive either febuxostat or placebo and followed for a median of 32 months. The primary endpoint occurred in 10.8% and 10.4% in the febuxostat and allopurinol groups, meeting the non-inferiority of febuxostat (p = 0.002), although all-cause (7.8% vs. 6.4%, p = 0.04) and cardiovascular mortality (4.3% vs. 3.2%, p = 0.03) were significantly higher in the febuxostat group than in the allopurinol group [
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • Borer J.S.
      • Gorelick P.B.
      • Whelton A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      ]. According to the results, the US Food and Drug Administration has added a boxed warning for an increased risk of death with febuxostat. However, in the CARES study, a large number of patients discontinued the trial treatment and did not complete clinical follow-up. The recently published FAST study (n = 6128), an open-label, blinded-endpoint, non-inferiority RCT found no signals of increased death with febuxostat than allopurinol during the median follow-up period of 48 months [
      • Mackenzie I.S.
      • Ford I.
      • Nuki G.
      • Hallas J.
      • Hawkey C.J.
      • Webster J.
      • et al.
      Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.
      ]. The non-inferiority of febuxostat was met, and all-cause mortality was even lower in the febuxostat group than in the allopurinol group (3.5% vs. 5.7%, HR 0.75, 95% CI 0.59–0.95). Furthermore, the FREED study alluded to a possible benefit of febuxostat compered to allopurinol [
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • Hisatome I.
      • Waki M.
      • Uchiyama K.
      • et al.
      Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.
      ]. In this open-label, blinded-endpoint RCT done in Japan, a total of 1070 patients with hyperuricemia and cardiovascular risks were randomly assigned to febuxostat (target dose of 40 mg/day) and non-febuxostat (no antihyperuricemic agent or 100 mg of allopurinol was allowed) groups [
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • Hisatome I.
      • Waki M.
      • Uchiyama K.
      • et al.
      Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.
      ]. Cerebral, cardiovascular, and renal events and all deaths occurred in 23.3% and 28.7% in the febuxostat and non-febuxostat groups during the median follow-up period of 35 months (p = 0.02), mainly driven by a difference in worsening proteinuria. The FEATHER, FREED, and PRIZE studies found no signals of increased mortality with febuxostat in Japanese patients as well as the FAST study, reinforcing the safety of the drug. Other than allopurinol and febuxostat, the therapeutic impact of antihyperuricemic drugs on clinical outcomes is mostly unknown.
      In summary, although XO inhibition by allopurinol and febuxostat may provide a benefit on surrogate endpoints such as BP, endothelial function, proteinuria, and carotid intima-media thickness in a specific population as shown in small clinical trials, the efficacy of uric acid-lowering treatment on clinical outcomes has not been established (Table 1).

      Conclusions

      Elevated serum uric acid level is associated with cardiovascular diseases such as hypertension, CKD, HF, and CAD, and is useful for risk stratification. Despite numerous investigations including Mendelian randomization studies, the causality is still controversial. The beneficial effect of uric acid-lowering treatment has been suggested on surrogate endpoints, although the improvement in clinical outcomes remains unknown. Future studies focusing on patients with elevated uric acid levels and high cardiovascular risks are warranted.

      Funding

      None.

      Declaration of Competing Interest

      Yuichi Saito, Atsushi Tanaka, and Yoshio Kobayashi declare no conflicts of interest to disclose. Koichi Node reports research grants from Asahi Kasei, Astellas, Boehringer Ingelheim Japan, Mitsubishi Tanabe Pharma, Teijin Pharma, and Terumo, scholarship grants from Astellas, Bayer Yakuhin, Bristol-Myers Squibb, Daiichi Sankyo Healthcare, Takeda Pharmaceutical, Teijin Pharma, and honoraria from Astellas, AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Daiichi Sankyo Healthcare, Eli Lilly Japan, Kowa, Mitsubishi Tanabe Pharma, MSD, Novo Nordisk Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Teijin Pharma.

      References

        • Major T.J.
        • Topless R.K.
        • Dalbeth N.
        • Merriman T.R.
        Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts.
        BMJ. 2018; 363: k3951
        • Choi H.K.
        • Atkinson K.
        • Karlson E.W.
        • Willett W.
        • Curhan G.
        Purine-rich foods, dairy and protein intake, and the risk of gout in men.
        N Engl J Med. 2004; 350: 1093-1103
        • El Ridi R.
        • Tallima H.
        Physiological functions and pathogenic potential of uric acid: a review.
        J Adv Res. 2017; 8: 487-493
        • Furuhashi M.
        New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.
        Am J Physiol Endocrinol Metab. 2020; 319: E827-E834
        • Dalbeth N.
        • Merriman T.R.
        • Stamp L.K.
        Gout.
        Lancet. 2016; 388: 2039-2052
        • Maruhashi T.
        • Hisatome I.
        • Kihara Y.
        • Higashi Y.
        Hyperuricemia and endothelial function: from molecular background to clinical perspectives.
        Atherosclerosis. 2018; 278: 226-231
        • Davies K.J.
        • Sevanian A.
        • Muakkassah-Kelly S.F.
        • Hochstein P.
        Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid.
        Biochem J. 1986; 235: 747-754
        • Kang D.H.
        • Park S.K.
        • Lee I.K.
        • Johnson R.J.
        Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.
        J Am Soc Nephrol. 2005; 16: 3553-3562
        • Sharaf El Din U.A.A.
        • Salem M.M.
        • Abdulazim D.O
        Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: a review.
        J Adv Res. 2017; 8: 537-548
        • Mercuro G.
        • Vitale C.
        • Cerquetani E.
        • Zoncu S.
        • Deidda M.
        • Fini M.
        • et al.
        Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk.
        Am J Cardiol. 2004; 94: 932-935
        • Prasad M.
        • Matteson E.L.
        • Herrmann J.
        • Gulati R.
        • Rihal C.S.
        • Lerman L.O.
        • et al.
        Uric acid is associated with inflammation, coronary microvascular dysfunction, and adverse outcomes in postmenopausal women.
        Hypertension. 2017; 69: 236-242
        • Saito Y.
        • Kitahara H.
        • Nakayama T.
        • Fujimoto Y.
        • Kobayashi Y.
        Relation of elevated serum uric acid level to endothelial dysfunction in patients with acute coronary syndrome.
        J Atheroscler Thromb. 2019; 26: 362-367
        • Tanaka A.
        • Kawaguchi A.
        • Tomiyama H.
        • Ishizu T.
        • Matsumoto C.
        • Higashi Y.
        • et al.
        Cross-sectional and longitudinal associations between serum uric acid and endothelial function in subjects with treated hypertension.
        Int J Cardiol. 2018; 272: 308-313
        • Culleton B.F.
        • Larson M.G.
        • Kannel W.B.
        • Levy D.
        Serum uric acid and risk for cardiovascular disease and death: the Framingham heart study.
        Ann Intern Med. 1999; 131: 7-13
        • Niskanen L.K.
        • Laaksonen D.E.
        • Nyyssönen K.
        • Alfthan G.
        • Lakka H.M.
        • Lakka T.A.
        • et al.
        Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study.
        Arch Intern Med. 2004; 164: 1546-1551
        • Fang J.
        • Alderman M.H.
        Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National health and nutrition examination survey.
        JAMA. 2000; 283: 2404-2410
        • Verdecchia P.
        • Schillaci G.
        • Reboldi G.
        • Santeusanio F.
        • Porcellati C.
        • Brunetti P.
        Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study.
        Hypertension. 2000; 36: 1072-1078
        • Lehto S.
        • Niskanen L.
        • Rönnemaa T.
        • Laakso M.
        Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.
        Stroke. 1998; 29: 635-639
        • Okuya Y.
        • Saito Y.
        • Takahashi T.
        • Kishi K.
        Impact of elevated serum uric acid level on target lesion revascularization after percutaneous coronary intervention for chronic total occlusion.
        Am J Cardiol. 2019; 124: 1827-1832
        • Kojima S.
        • Sakamoto T.
        • Ishihara M.
        • Kimura K.
        • Miyazaki S.
        • Yamagishi M.
        • et al.
        Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study).
        Am J Cardiol. 2005; 96: 489-495
        • Anker S.D.
        • Doehner W.
        • Rauchhaus M.
        • Sharma R.
        • Francis D.
        • Knosalla C.
        • et al.
        Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging.
        Circulation. 2003; 107: 1991-1997
        • Masuo K.
        • Kawaguchi H.
        • Mikami H.
        • Ogihara T.
        • Tuck M.L.
        Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
        Hypertension. 2003; 42: 474-480
        • Alper Jr, A.B.
        • Chen W.
        • Yau L.
        • Srinivasan S.R.
        • Berenson G.S.
        • Hamm L.L
        Childhood uric acid predicts adult blood pressure: the Bogalusa heart study.
        Hypertension. 2005; 45: 34-38
        • Wang J.
        • Qin T.
        • Chen J.
        • Li Y.
        • Wang L.
        • Huang H.
        • et al.
        Hyperuricemia and risk of incident hypertension: a systematic review and meta-analysis of observational studies.
        PLoS One. 2014; 9e114259
        • Sanchez-Lozada L.G.
        • Tapia E.
        • Soto V.
        • Avila-Casado C.
        • Franco M.
        • Zhao L.
        • et al.
        Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia.
        Nephrol Dial Transplant. 2008; 23: 1179-1185
        • Soletsky B.
        • Feig D.I.
        Uric acid reduction rectifies prehypertension in obese adolescents.
        Hypertension. 2012; 60: 1148-1156
        • Higgins P.
        • Walters M.R.
        • Murray H.M.
        • McArthur K.
        • McConnachie A.
        • Lees K.R.
        • et al.
        Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
        Heart. 2014; 100: 1085-1092
        • Tanaka A.
        • Taguchi I.
        • Teragawa H.
        • Ishizaka N.
        • Kanzaki Y.
        • Tomiyama H.
        • et al.
        Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial.
        PLoS Med. 2020; 17e1003095
        • Segal M.S.
        • Srinivas T.R.
        • Mohandas R.
        • Shuster J.J.
        • Wen X.
        • Whidden E.
        • et al.
        The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic.
        J Am Soc Hypertens. 2015; 9 (610-9 e1)
        • Wada T.
        • Hosoya T.
        • Honda D.
        • Sakamoto R.
        • Narita K.
        • Sasaki T.
        • et al.
        Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study).
        Clin Exp Nephrol. 2018; 22: 860-870
        • Kimura K.
        • Hosoya T.
        • Uchida S.
        • Inaba M.
        • Makino H.
        • Maruyama S.
        • et al.
        Febuxostat therapy for patients with Stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
        Am J Kidney Dis. 2018; 72: 798-810
        • Badve S.V.
        • Pascoe E.M.
        • Tiku A.
        • Boudville N.
        • Brown F.G.
        • Cass A.
        • et al.
        Effects of allopurinol on the progression of chronic kidney disease.
        N Engl J Med. 2020; 382: 2504-2513
        • Doria A.
        • Galecki A.T.
        • Spino C.
        • Pop-Busui R.
        • Cherney D.Z.
        • Lingvay I.
        • et al.
        Serum urate lowering with allopurinol and kidney function in type 1 diabetes.
        N Engl J Med. 2020; 382: 2493-2503
        • Kawasoe S.
        • Kubozono T.
        • Yoshifuku S.
        • Ojima S.
        • Oketani N.
        • Miyata M.
        • et al.
        Uric acid level and prevalence of atrial fibrillation in a Japanese general population of 285,882.
        Circ J. 2016; 80: 2453-2459
        • Tamariz L.
        • Hernandez F.
        • Bush A.
        • Palacio A.
        • Hare J.M.
        Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis.
        Heart Rhythm. 2014; 11: 1102-1108
        • Sakabe M.
        • Fujiki A.
        • Sakamoto T.
        • Nakatani Y.
        • Mizumaki K.
        • Inoue H.
        Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction.
        J Cardiovasc Electrophysiol. 2012; 23: 1130-1135
        • Johnson R.J.
        • Nakagawa T.
        • Jalal D.
        • Sanchez-Lozada L.G.
        • Kang D.H.
        • Ritz E.
        Uric acid and chronic kidney disease: which is chasing which?.
        Nephrol Dial Transplant. 2013; 28: 2221-2228
        • Jing J.
        • Kielstein J.T.
        • Schultheiss U.T.
        • Sitter T.
        • Titze S.I.
        • Schaeffner E.S.
        • et al.
        Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German chronic kidney disease (GCKD) study.
        Nephrol Dial Transplant. 2015; 30: 613-621
        • Bellomo G.
        • Venanzi S.
        • Verdura C.
        • Saronio P.
        • Esposito A.
        • Timio M.
        Association of uric acid with change in kidney function in healthy normotensive individuals.
        Am J Kidney Dis. 2010; 56: 264-272
        • Luo Q.
        • Xia X.
        • Li B.
        • Lin Z.
        • Yu X.
        • Huang F.
        Serum uric acid and cardiovascular mortality in chronic kidney disease: a meta-analysis.
        BMC Nephrol. 2019; 20: 18
        • Messerli F.H.
        • Frohlich E.D.
        • Dreslinski G.R.
        • Suarez D.H.
        • Aristimuno G.G.
        Serum uric acid in essential hypertension: an indicator of renal vascular involvement.
        Ann Intern Med. 1980; 93: 817-821
        • Hamaguchi S.
        • Furumoto T.
        • Tsuchihashi-Makaya M.
        • Goto K.
        • Goto D.
        • Yokota T.
        • et al.
        Hyperuricemia predicts adverse outcomes in patients with heart failure.
        Int J Cardiol. 2011; 151: 143-147
        • Krishnan E.
        Hyperuricemia and incident heart failure.
        Circ Heart Fail. 2009; 2: 556-562
        • Huang H.
        • Huang B.
        • Li Y.
        • Huang Y.
        • Li J.
        • Yao H.
        • et al.
        Uric acid and risk of heart failure: a systematic review and meta-analysis.
        Eur J Heart Fail. 2014; 16: 15-24
        • Lee S.J.
        • Oh B.K.
        • Sung K.C.
        Uric acid and cardiometabolic diseases.
        Clin Hypertens. 2020; 26: 13
        • Xu X.
        • Hu X.
        • Lu Z.
        • Zhang P.
        • Zhao L.
        • Wessale J.L.
        • et al.
        Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice.
        J Card Fail. 2008; 14: 746-753
        • Doehner W.
        • Schoene N.
        • Rauchhaus M.
        • Leyva-Leon F.
        • Pavitt D.V.
        • Reaveley D.A.
        • et al.
        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. 2002; 105: 2619-2624
        • Farquharson C.A.
        • Butler R.
        • Hill A.
        • Belch J.J.
        • Struthers A.D.
        Allopurinol improves endothelial dysfunction in chronic heart failure.
        Circulation. 2002; 106: 221-226
        • George J.
        • Carr E.
        • Davies J.
        • Belch J.J.
        • Struthers A.
        High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
        Circulation. 2006; 114: 2508-2516
        • Hare J.M.
        • Mangal B.
        • Brown J.
        • Fisher Jr, C.
        • Freudenberger R.
        • Colucci W.S.
        • et al.
        Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.
        J Am Coll Cardiol. 2008; 51: 2301-2309
        • Givertz M.M.
        • Anstrom K.J.
        • Redfield M.M.
        • Deswal A.
        • Haddad H.
        • Butler J.
        • et al.
        Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) Study.
        Circulation. 2015; 131: 1763-1771
        • Bos M.J.
        • Koudstaal P.J.
        • Hofman A.
        • Witteman J.C.
        • Breteler M.M.
        Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study.
        Stroke. 2006; 37: 1503-1507
        • Zuo T.
        • Liu X.
        • Jiang L.
        • Mao S.
        • Yin X.
        • Guo L.
        Hyperuricemia and coronary heart disease mortality: a meta-analysis of prospective cohort studies.
        BMC Cardiovasc Disord. 2016; 16: 207
        • Saito Y.
        • Kobayashi Y.
        • Fujii K.
        • Sonoda S.
        • Tsujita K.
        • Hibi K.
        • et al.
        Clinical expert consensus document on standards for measurements and assessment of intravascular ultrasound from the Japanese association of cardiovascular intervention and therapeutics.
        Cardiovasc Interv Ther. 2020; 35: 1-12
        • Saito Y.
        • Kobayashi Y.
        Contemporary coronary drug-eluting and coated stents: a mini-review.
        Cardiovasc Interv Ther. 2020; https://doi.org/10.1007/s12928-020-00731-w
        • Saito Y.
        • Nakayama T.
        • Sugimoto K.
        • Fujimoto Y.
        • Kobayashi Y.
        Relation of lipid content of coronary plaque to level of serum uric acid.
        Am J Cardiol. 2015; 116: 1346-1350
        • Ando K.
        • Takahashi H.
        • Watanabe T.
        • Daidoji H.
        • Otaki Y.
        • Nishiyama S.
        • et al.
        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. 2016; 23: 932-939
        • Mori N.
        • Saito Y.
        • Saito K.
        • Matsuoka T.
        • Tateishi K.
        • Kadohira T.
        • et al.
        Relation of plasma xanthine oxidoreductase activity to coronary lipid core plaques assessed by near-infrared spectroscopy intravascular ultrasound in patients with stable coronary artery disease.
        Am J Cardiol. 2020; 125: 1006-1012
        • Saito Y.
        • Mori N.
        • Murase T.
        • Nakamura T.
        • Akari S.
        • Saito K.
        • et al.
        Greater coronary lipid core plaque assessed by near-infrared spectroscopy intravascular ultrasound in patients with elevated xanthine oxidoreductase: a mechanistic insight.
        Heart Vessels. 2020; https://doi.org/10.1007/s00380-020-01730-w
        • Saito Y.
        • Kitahara H.
        • Nishi T.
        • Fujimoto Y.
        • Kobayashi Y.
        Systemic endothelial dysfunction in patients with vasospastic and microvascular angina: serum uric acid as a marker of reactive hyperemia index.
        Coron Artery Dis. 2020; 31: 565-566
        • Watanabe K.
        • Shishido T.
        • Otaki Y.
        • Watanabe T.
        • Sugai T.
        • Toshima T.
        • et al.
        Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm.
        Heart Vessels. 2019; 34: 1-8
        • Suzuki S.
        • Kaikita K.
        • Yamamoto E.
        • Jinnouchi H.
        • Tsujita K.
        Role of acetylcholine spasm provocation test as a pathophysiological assessment in nonobstructive coronary artery disease.
        Cardiovasc Interv Ther. 2020; https://doi.org/10.1007/s12928-020-00720-z
        • Li X.
        • Meng X.
        • Timofeeva M.
        • Tzoulaki I.
        • Tsilidis K.K.
        • Ioannidis J.P.
        • et al.
        Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.
        BMJ. 2017; 357: j2376
        • Feig D.I.
        • Kang D.H.
        • Johnson R.J.
        Uric acid and cardiovascular risk.
        N Engl J Med. 2008; 359: 1811-1821
        • Kleber M.E.
        • Delgado G.
        • Grammer T.B.
        • Silbernagel G.
        • Huang J.
        • Kramer B.K.
        • et al.
        Uric acid and cardiovascular events: a Mendelian randomization study.
        J Am Soc Nephrol. 2015; 26: 2831-2838
        • White J.
        • Sofat R.
        • Hemani G.
        • Shah T.
        • Engmann J.
        • Dale C.
        • et al.
        Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
        Lancet Diabetes Endocrinol. 2016; 4: 327-336
        • Li X.
        • Meng X.
        • He Y.
        • Spiliopoulou A.
        • Timofeeva M.
        • Wei W.Q.
        • et al.
        Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: a phenome-wide Mendelian randomization study.
        PLoS Med. 2019; 16e1002937
        • Kanji T.
        • Gandhi M.
        • Clase C.M.
        • Yang R.
        Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis.
        BMC Nephrol. 2015; 16: 58
        • White W.B.
        • Saag K.G.
        • Becker M.A.
        • Borer J.S.
        • Gorelick P.B.
        • Whelton A.
        • et al.
        Cardiovascular safety of febuxostat or allopurinol in patients with gout.
        N Engl J Med. 2018; 378: 1200-1210
        • Mackenzie I.S.
        • Ford I.
        • Nuki G.
        • Hallas J.
        • Hawkey C.J.
        • Webster J.
        • et al.
        Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.
        Lancet. 2020; 396: 1745-1757
        • Kojima S.
        • Matsui K.
        • Hiramitsu S.
        • Hisatome I.
        • Waki M.
        • Uchiyama K.
        • et al.
        Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.
        Eur Heart J. 2019; 40: 1778-1786
        • Noman A.
        • Ang D.S.
        • Ogston S.
        • Lang C.C.
        • Struthers A.D.
        Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
        Lancet. 2010; 375: 2161-2167