Article

Uric Acid and Cardiovascular Disease: An Update

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.

  • Views: 4375

  • Likes: 0

  • Downloads: 4

  • Citations: 84

Average (ratings)
No ratings
Your rating

Abstract

In recent years, serum uric acid (SUA) as a determinant of cardiovascular (CV) risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia SUA are at increased risk of cardiac, renal and vascular damage and CV events. There is now some evidence to suggest that urate-lowering treatment may reduce CV risk in this group and, thus, may represent a new strategy in risk reduction.

Keywords

Uric acid, CV disease, xanthine-oxidase inhibitors, AF, heart failure, target organ damage,

Disclosure:The authors have no conflicts of interest to declare

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2016:4:2

Correspondence Details:Maria Lorenza Muiesan, Clinical and Experimental Sciences Department, University of Brescia, 2° Medicina Generale Spedali Civili, 25121 Brescia, Italy. E: marialorenza.muiesan@unibs.it

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Uric acid (UA) represents the final product of purine metabolism, in humans mainly regulated by the xanthine-oxidoreductase enzyme, which converts hyoxantine to xanthine and xanthine to UA. Dietary factors may influence serum UA (SUA), increasing its levels (meat, seafood, fructose, alcohol and sodium) or decreasing them (coffee and ascorbic acid). In addition, high cellular turnover conditions, i.e. in neoplastic diseases, may increase UA concentration.

UA may have an opposite role to oxidative stress, according to its intracellular (anti-oxidant) and extracellular (pro-oxidant) localisation.1 The xanthine-oxidoreductase enzyme isoform xanthine-oxidase (XO) generates reactive oxygen species (ROS) as byproducts and may have a detrimental effect on vascular endothelium. The production of ROS induced by UA seems paradoxical since UA is considered to be one of the anti-oxidants that protects the cardiovascular (CV) system from stress. UA prevents the protein nitrosylation induced by peroxynitrite, the peroxidation of lipids and proteins and the inactivation of tetrahydrobiopterin, which results in scavenging free radicals and chelating transitional metal ions.2 UA administration in healthy volunteers and athletes reduced ROS production,3 confirming its intrinsic anti-oxidant activity.

Experimental and human studies have demonstrated the role of UA as a pro-oxidant, inducing endothelial dysfunction. This may be improved by the administration of XO inhibitors, while other urate-lowering drugs (ULDs) acting through an uricosuric action are ineffective.4 The increase in oxidative stress resulting from the increased activity of XO could also explain the link between elevated UA and hypertension, as observed in animal models. In rats, the administration of oxonic acid, an inhibitor of uricase, may induce hyperuricaemia and a proportional increase in blood pressure (BP).5

UA may also stimulate the renin–angiotensin system (RAS), further contributing to vascular smooth cell growth, and arterial function impairment and stiffening. The possible role of systemic inflammation – measured by markers such as C-reactive protein (CRP), tumour necrosis factor or chemokine associated with hyperuricaemia – has also been explored, showing a further contribution to CV damage.6

The role of SUA in the development of arterial hypertension (AH) was highlighted in 1879 and 10 years later Haig7 proposed a low-purine diet as a means to prevent hypertension and CV diseases (CVDs). In 1909, Huchard described the association between renal arteriosclerosis and chronic hyperuricaemia.8

Since 1960, a number of epidemiological studies have found an association between SUA levels and different CV risk factors or diseases, such as AH, ischaemic stroke and acute and chronic heart failure (HF). The correlation is clearly present at SUA levels of 5–5.5 mg/dl,9 a range that is lower than the <6 mg/dl suggested by the European League Against Rheumatism10 and the American College of Rheumatology.11

The lack of a clear causal mechanism explaining the association between hyperuricaemia and CV risk factors and disease has led to the relevance of SUA being ignored.12 The results of the Framingham study, comprising 6,763 subjects followed for about 20 years, did not confirm an increase in the risk of CV death and SUA in men, but did in women.13 However, the increased risk lost statistical significance after taking into account confounders. On the contrary, Abbott et al.14 described in the same population a significant increase in coronary artery disease (CAD) in men with chronic hyperuricaemia and crystal deposits.

A systematic review has confirmed that chronic hyperuricaemia with crystals deposit is strictly related to an increased risk of CV and allcause death.15

The exact role of SUA as a marker or cause of CVD has been extensively discussed.16 In most of the published studies, SUA concentrations are related to age, sex, degree of kidney function, BP levels and metabolic abnormalities.

An independent relationship between UA and CV events has been frequently observed and a causal role of SUA has been proposed. The evidence that BP values may improve by treatment that lowers SUA seems to support a possible causal link between SUA and CVD.17,18

Hyperuricaemia and Target Organ Damage

The association between elevated SUA and CV risk factors, all contributing to the development of vascular, cardiac and renal target organ damage, has been extensively evaluated, with some controversial results.

Some studies have reported that elevated SUA is strongly associated with coronary19 and carotid 20,21 atherosclerosis, especially in women. The Atherosclerosis Risk in Communities (ARIC) study22 observed that the SUA level was significantly associated with B-mode ultrasound carotid intima-media thickness (considered an early measure of atherosclerosis). Subsequently, Mutluay et al. reported that hyperuricaemia is an independent predictor of early atherosclerosis in hypertensive subjects with normal renal function.23 Similar results were obtained by Cicero et al. in an Italian epidemiological study evaluating 248 men and 371 women adult individuals not consuming anti-hypertensive, anti-diabetic, lipid- or UA-lowering drugs.24 These results suggest that SUA may have an atherogenic role in the pathophysiology of CVDs; however, the precise mechanisms have not been fully elucidated. Experimental studies have shown that UA may stimulate vascular smooth muscle cell proliferation in vitro, with the production of pro-inflammatory and pro-oxidative and vasoconstrictive substances.25,26 Moreover humans’ atherosclerotic plaque may contain a considerable amount of UA,27 which may increase platelet adhesion and thrombus formation.28 On the other hand, some studies also show a role for XO, which is responsible for oxidative processes29 and endothelial dysfunction, thus independendtly affecting the occurrence of CVDs.

Hypertensive patients with left ventricular hypertrophy (LVH) have higher SUA levels, independent of other CV risk factors, and a more strict association between SUA and LV mass index was observed in women.30–34 When 24-hour BP values were taken into account, a Japanese study confirmed this association.33 In some of these studies the association was more evident in women than in men33 or vice versa.32

More recently, in uncomplicated patients without chronic kidney disease (CKD), and with a recent diagnosis of hypertension34 or at low CV risk,35 the correlation between SUA and LV mass did not reach statistical significance when all the potential confounders, including 24-hour BP, were taken into account.

Iwashima et al.36 also observed that hyperuricaemia and LVH were independent predictors of CV events (acute MI, angina, HF, stroke or transient ischaemic attack), but the combination of LVH and hyperuricaemia was associated with a further increase in the incidence of CV events.

Several mechanisms may explain the increase in LV mass in the presence of hyperuricaemia, including the systemic inflammatory response, RAS activity,37 endothelial dysfunction38 or the expression of endothelin-1 in cardiac fibroblasts, thus favouring cardiac interstitial fibrosis.39 In addition, some indirect effects of hyperuricaemia, such as increased BP, the parallel decrease of glomerular filtration rate (GFR), the impairment of platelet adhesion and aggregation and the increase in aortic stiffness, could further contribute to the development of LVH.Vlachopoulos et al.40 observed a close relationship between carotid– femoral pulse wave velocity and SUA in a large cohort of never-treated hypertensive patients, mainly in women; an increase in large artery stiffness and arterial wave reflections are important determinants of LV mass and function and coronary blood flow.

In the Framingham Offspring cohort (n=2,169, mean age 57 years, 55 % women) a decrease in systolic function parameters was observed in subjects with SUA >6.2 mg⁄dl compared with those with lower.41 These results, showing an early impairment of LV function in the presence of a modest increase in SUA could, in part, explain the association between elevated SUA and the increased risk of incident HF and poor outcomes in HF patients with elevated SUA, as recently confirmed in a meta-analysis42 and suggested by the Framingham Offspring study.43 A more severe impairment of diastolic function has been observed in hypertensive patients with hyperuricaemia.33

Few data are available on the effect of changes in SUA induced by diet modification or pharmacological treatment. In the Losartan Intervention For Endpoint reduction in Hypertension study (LIFE), patients with electrocardiographic signs of LVH were randomised to losartan or atenolol: a greater decrease in LVH was associated with a less marked increase in SUA level during therapy with losartan compared with atenolol.44

The effect of allopurinol and febuxostat were compared in a small number of patients with gout. A more favourable effect of febuxostat on both carotid–femoral pulse wave velocity and oxidative stress was found.45

Only one study has examined the effect of UA-lowering treatment on target organ damage in patients with CKD,46 which showed a decrease of LV mass (evaluated by nuclear magnetic resonance), and an improvement of flow-mediated vasodilation and of augmentation index after allopurinol treatment compared with placebo.

SUA level has also emerged as a risk factor for the development and progression of CKD. Afferent arteriolar thickening and ischaemic renal changes, associated with an increase in systemic BP and renal glomerular pressure, have been described in rats with hyperuricaemia induced by oxonic acid or a high-fructose diet; all these changes may be prevented by lowering SUA with XO inhibitors.47–49 Furthermore, epidemiological studies have reported that asymptomatic hyperuricaemia is strongly associated with both CKD and endstage kidney disease;50–52 however, hyperuricaemia may represent a consequence of reduced renal excretion in patients with CKD and therefore be a marker of kidney function. A recent review and metaanalysis has shown that SUA-lowering therapy with allopurinol may slow the progression of CKD. Further adequately powered randomised trials are required to evaluate the benefits and risks of SUA-lowering therapy in CKD.53

Hyperuricaemia and Cardiovascular Disease

In the past 50 years, the results of several studies have assessed and promoted the role of UA as an independent risk factor for CV and renal diseases. In this regard, strong evidence comes from the first National Health and Nutrition Examination Survey (NHANES I), performed in the US between 1971 and 1975 in a general population sample of 20,729 individuals aged 25–74 years. In the National Health Epidemiologic Follow-up Study (NHEFS), all participants in the NHANES I were prospectively followed, and the all-cause, CV and CAD deaths were assessed; in a subgroup of 6,912 subjects data were analysed according to SUA level.54 The results showed a significant positive association between increasing levels of SUA and CV (including CAD) mortality, independent of other traditional risk factors, in both men and women, confirming previous data obtained after a shorter follow-up of the NHANES I population.55 In the previous study55 elevated SUA level was an independent predictor of all-cause and ischaemic heart disease mortality for women only and 1 mg/dl increase of SUA was associated with a 48 % increase in the risk of CAD.55

In a prospective study conducted in Rotterdam, 4,385 men and women >55 years of age without history of stroke or coronary heart disease, an association between baseline SUA levels and risk of both MI and stroke was confirmed.56 In a further analysis, a U-shape relationship between SUA and both all-cause and CV mortality was shown, indicating that both low and high SUA levels were prognostically deleterious.57

A further demonstration of the association between SUA and CV risk is given by the results of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, in which individuals aged 25–74 years were examined and followed-up for up to 16 years.58 For 2,045 subjects a baseline SUA was available: a mean value of 4.9±1.3 mg/dl was observed with significantly higher values in men with respect to women. During follow-up, 342 subjects died, (32 % from CV causes). Mean SUA (5.54 mg/dl) observed in patients who died was higher when compared with those who survived (4.82 mg/dl); a significant difference in mean SUA level was observed between patients who died of CV causes (5.74 mg/dl) or (4.89 mg/dl).59 A significant increase of the risk of CV death for every 1 mg/dl increase of SUA was observed, while the same was not true for all-cause death after adjustment for confounders.

The effect of elevated SUA levels on the incidence of CADs seems to be stronger in women than in men, as shown by an epidemiological study conducted in the US, which originally enrolled 3,102 subjects between 1960 and 1962, with a follow-up of 7 to 9 years. In 2,530 subjects attending the second examination, SUA was measured and urate concentrations were about 1 mg/dl higher in men than in women in the younger decades of age, while in women a consistent increase in SUA was observed after physiological menopause;60 race did not protect significant differences.

Other studies have analysed the association between SUA and CV risk in hypertensive and/or patients with diabetes.

In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, which examined 1,720 untreated hypertensive patients enrolled between 1986 and 1996,61 the highest SUA levels (>6.2 mg/ dl in men; >4.6 mg/dl in women) were significant predictors of allcause deaths and of CV events, again independently of traditional confounders, including LVH. Also in this study, a J-shaped curve relationship between SUA levels and CV events was observed, with the lowest risk occurring at UA concentrations of 4.5–5.2 mg/dl in men and 3.2–3.9 mg/dl in women.

Almost 8,000 patients with mild to moderate hypertension living in New York, USA were studied by Alderman et al. from 1973 to 1996, showing that baseline SUA levels were associated with the subsequent occurrence of CV events; more precisely, the in-treatment SUA levels were predictive of a worse CV prognosis,independently of creatinine, diuretic treatment, race and all traditional CV risk factors.62

The LIFE study presented data from 9,193 hypertensive patients with electrocardiographic LVH, and showed a greater efficacy of a losartanbased therapeutic regimen compared with atenolol in the regression of LVH and in the prevention of fatal and non-fatal CV events (acute MI, stroke and CV deaths). At study end, UA levels were lower in patients treated with losartan than with atenolol, with a relative risk reduction of 29 % for CV events. This difference reached statistical significance in women, but not in men, after adjustment for all traditional risk factors and confounders,44 supporting again the evidence that hyperuricaemia may confer a less favourable CV prognosis in women rather than in men.

In the observational study Blood Pressure control rate and CV Risk profilE (BP-CARE), in which 7,800 treated hypertensive patients from Central and Eastern Europe were included,63 the CV risk profile was positively and significantly related to SUA levels and to the presence of urate deposits (gout).

When examining the population with diabetes, similar results have been obtained. In 1993, Rathmann et al. reported a positive correlation between SUA and CAD in women with type 1 or 2 diabetes.64 In a prospective study including 1,017 men and women (aged 45–64 at baseline) patients with type 2 diabetes were followed up for 7 years;65 31 patients died from stroke and 114 patients had a fatal or non-fatal stroke. High SUA levels were associated with the risk of fatal and nonfatal stroke (hazard ratio [HR] 1.93; CI 95 % [1.30–2.86]; P<0.001) and stroke incidence increased significantly by SUA quartiles.

In patients with diabetes, the correlation between SUA and CV function has been attributed to the same mechanisms that lead to renal dysfunction, including activation of the renin-angiotensinaldosterone system (RAAS) and ROS pathways, nitric oxide (NO) synthase inhibition, autonomic dysfunction and increase in BP.49,66,67

A large meta-analysis published in 2013, evaluating only prospective studies on CV or all-cause mortality related to SUA confirmed that baseline SUA is an independent predictor of future CV mortality. Elevated SUA appears to significantly increase the risk of all-cause mortality in men, but not women. No conclusive data on whether low SUA predicts mortality were shown.68

Most of the differences and limitations of currently available published studies are the limited number of individuals included and the inclusion criteria. Urate deposits are difficult to evaluate and therefore we do not know whether individuals included in the studies have urate deposits or not.

Despite epidemiological data showing lower mean SUA in women, some studies report that an increase in SUA has a detrimental effect on CV health in women30,55 and one meta-analysis has shown a significant relationship between an increase in SUA and coronary events in women but not in men.69 The mechanisms that underlie the unfavourable influence of SUA on major CV events in women remain uncertain and whether different cut-off vales according to sex are needed should be assessed in future studies.

Hyperuricaemia and Atrial Fibrillation

Oxidative stress may influence the development of AF, in addition to neurohormonal and inflammatory activation. Both inflammation and neurohormones may activate XO and increase SUA. In experimental studies, oxidative stress has been shown to induce atrial electric remodelling, thus favouring the re-entry mechanism70 as well as NO decrease, shortening of action potential plateau duration, increase of the repolarisation velocity and AF.71,72 The relationship between the increase in oxidative stress markers and AF has been observed in patients with valvular diseases or after coronary bypass surgery; after radiofrequency ablation AF recurrence was higher in patients with the higher levels of oxidative stress markers.73 In addition, it is reasonable that other risk factors (RAAS hyperactivity), vascular abnormalities (endothelial dysfunction) or LVH associated with UA increase may further promote the development of AF

A case-control study examining Greek patients with AF was among the first to suggest an association between SUA and AF.74 In the ARIC study, which included 15,382 subjects aged 45–64 years, the incidence of AF paralleled the increase in SUA concentration, and the relationship remained significant after taking into account all the possible confounders, including diuretic treatment and P-wave duration (index of left atrial enlargement). In this study the increase of 1 standard deviation of SUA was associated with a 16 % increase in AF risk, mainly among African Americans and women.75 The rate of hyperuricaemia observed in African Americans could be ascribed to genetic differences, since African Americans have a higher prevalence of the gene SLC2A9, favouring SUA reabsorption in the proximal renal tubule.75 The data have been further confirmed in patients with paroxysmal or permanent AF.76

A recent meta-analysis77 that evaluated six cross-sectional studies (n=7,930) and three cohort studies (n=138,306 subjects without AF) confirmed an increase in the relative risk of AF among those with high SUA (relative risk = 1.67 (95 % CI [1.23–2.27]) compared with those with normal SUA.

Hyperuricaemia and Heart Failure

In the Cardiovascular Health Study, the incidence of HF was 21 % in participants with chronic hyperuricaemia and 18 % in those without; the results showed that an increase of 1 mg/dl in SUA conferred a 12 % increase in risk of new HF.78 In the Framingham Offspring study the incidence of HF was sixfold higher among individuals with SUA levels in the higher quartile (>6.3 mg/dl) than those with levels in the lowest quartile (<3.4 mg/dl).79–81

Chronic hyperuricaemia is a frequent finding in patients with HF, with a prevalence >50 % in hospitalised patients with chronic HF.82 The severity of hyperuricaemia is related to New York Heart Association (NYHA) functional class, to higher maximal oxygen consumption and to the degree of diastolic dysfunction impairment. The highest UA concentrations may be observed in patients with advanced chronic HF or cardiac cachessia.

In the Derivation study, SUA was the strongest prognostic variable in patients with severe chronic HF (NYHA class III or IV):78,79 in patients with chronic hyperuricaemia (SUA >9.5 mg/dl) the relative risk of death was 7.4.

In patients with acute and chronic HF, SUA concentration represents a prognostic marker of all-cause mortality independent of traditional prognostic determinants, as shown by Tamaris et al.81

A more recent meta-analysis addressing the association between SUA and incidents HF and/or the prognosis of HF patients, was performed by Huang et al.42 Five studies reporting on incident HF and 28 studies reporting on HF outcomes were included. The results showed that hyperuricaemia was associated with an increased risk of incident HF (HR 1.65; 95 % CI [1.41–1.94]). In addition, for every 1 mg/dl increase in SUA the risk of all-cause mortality and the composite endpoint in HF increased by 4 % and 28 %, respectively. Subgroup analyses supported the positive association between SUA and HF.

A retrospective case-control-led analysis of patients with symptomatic HF showed that hyperuricaemia was significantly associated with increased events (HF hospital readmission or all-cause mortality).42 In this study the use of allopurinol was associated with a reduction in events (adjusted relative risk 0.69; 95 % CI [0.60–0.79]).82 In the Greek Atorvastatin and Coronary-Heart-Disease Evaluation (GREACE) study, 1,600 patients with CAD were followed for 3 years, and a reduction in SUA concentrations, possibly induced by the use of atorvastatin, was associated with a lower incidence of CV events, including coronary events.83

SUA plays a role in HF incidence and development that is not still completely understood. The impairment in GFR, even to a mild degree, causes a decrease in renal UA excretion.84–86 The increase in lactate concentration, and the hyperactivity of the sympathetic nervous system and the RAASs, may further contribute to SUA increases by increasing UA reabsorption. Finally, in patients with HF, the use of diuretics may induce a further reduction in UA excretion.87

According to another pathogenetic hypothesis, SUA functionally up-regulates XO, which is a key enzyme in purine metabolism. XO-derived ROS may account for a range of detrimental processes in the pathophysiology of HF, such as cardiac hypertrophy, myocardial fibrosis, LV remodelling and contractility impairment. In addition, UA per se may represent a ‘proinflammatory’ substance, frequently associated with other inflammatory markers such as CRP, interleukin-6 and neutrophil leukocytes. In fact, in a large group of older patients, affected by mild-to-moderate hypertensive and/or ischaemic HF, SUA was inversely related with ejection fraction (EF); the predicted role of SUA was apparently independent of filtration rate and use of diuretics.88

In the Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients With New York Heart Association Class III–IV Congestive HF (OPT-CHF), which enrolled 405 patients with systolic HF (EF >40 %), randomised to treatment with allopurinol or placebo, on top of standard therapy, the use of the XO inhibitor was associated with an increase in EF and to a clinical improvement among patients with elevated SUA.89 Thus, XO inhibition may be associated with an improvement in haemodynamics and clinical outcomes in hyperuricaemic patients.89,90 Conversley, this was not observed when the UA concentration was obtained by treatment with an uricosuric drug (benzbromarone)91 or oxypurinol.92

The US Food and Drug Administration approved a non-purine XO inhibitor, febuxostat, for the treatment of gout. Experimental data have shown that febuxostat may reduce the development of LVH and the amount of cardiac collagen content, thus improving systolic function.93 In a small study, 141 cardiac surgery patients with CKD were randomised to treatment with allopurinol or febuxostat: superior antioxidant and anti-inflammatory effects and a more favourable change in renal dysfunction were observed during treatment with febuxostat than with allopurinol.94

New data are needed to establish the clinical benefit of treatment with different XO inhibitors in patients with hyperuricaemia, with and without UA deposits, and HF

Conclusion

From the available epidemiological data it is clear that hyperuricaemia is associated with a greater risk of target organ damage and of CV morbidity and mortality.

The increase in risk is stronger in patients at high CV risk and in patients with SUA levels >6 mg/dl. Deleterious effects are substantially independent of the presence of urate crystals in the joints.

No strong evidence is available to show that lowering SUA is associated with a decreased incidence of CV events in patients without gout; the use of ULDs is not approved in patients with asymptomatic hyperuricaemia. Large controlled trials are ongoing to assess the effect of SUA-lowering drugs on CV events.95

References

  1. Kang DH, Ha SK. Uric Acid Puzzle: Dual Role as Anti-oxidant and Pro-oxidant. Electrolyte Blood Press 2014;12:1–6
    Crossref | PubMed
  2. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des 2005;11 :4145–51.
    Crossref | PubMed
  3. Waring WC, Webb DJ, Maxwell SR. Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers. J Cardiovasc Pharmacol 2001;38:365–71.
    Crossref | PubMed
  4. George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114:2508–16.
    Crossref | PubMed
  5. Sánchez-Lozada LG, Tapia E, Soto V, 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;23:1179–85.
    Crossref | PubMed
  6. Borghi C, Rosei EA, Bardin T, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens 2015;33:1729–41. 
    Crossref | PubMed
  7. Haig A. On uric acid and arterial tension. BMJ 1889;1 : 288–91.
    Crossref | PubMed
  8. Huchard H. Arteriolosclerosis: Including its cardiac form. JAMA 1909;53:1129–32.
  9. Niskanen LK, Laaksonen DE, Nyyssonen K, 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;164:1546–51. 
    Crossref | PubMed
  10. Zhang W, Doherty M, Bardin T, et al. EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312–24.
    Crossref | PubMed
  11. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:1431–46.
    Crossref | PubMed
  12. Feig DI, Rang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21.
    Crossref | PubMed
  13. Culleton BF, Larson MG, Kannel WB, et al. Serum acid uric and risk of cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131 :7–13.
    Crossref | PubMed
  14. Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham Study. J Clin Epidemiol 1988;41 :237–42. 
    Crossref | PubMed
  15. Lottmann K, Chen X, Schädlich PK. Association Between Gout and All-Cause as well as Cardiovascular Mortality: A Systematic Review. Curr Rheumatol Rep 2012;14:195–203.
    Crossref | PubMed
  16. Kanbay M, Segal M, Afsar B, et al. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013;99:759–66.
    Crossref | PubMed
  17. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adoles-cents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008;300:924–32. 
    Crossref | PubMed
  18. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 2012;60:1148–56. 
    Crossref | PubMed
  19. Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary artery disease. Am J Cardiol 2001;87:1411–4. 
    Crossref | PubMed
  20. Crouse JR, Toole JF, McKinney WM, et al. Risk factors for extracranial carotidartery atherosclerosis. Stroke 1987;18:990–6.
    Crossref | PubMed
  21. Nieto FJ, Iribarren C, Gross MD, et al. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131–9.
    Crossref | PubMed
  22. Iribarren C, Folsom AR, Eckfeldt JH, et al. Correlates of uric acid andits association with asymptomatic carotid atherosclerosis: the ARIC Study. Atherosclerosis risk in communities. Ann Epidemiol 1996;6:331–40.
    Crossref | PubMed
  23. Mutluay R, Deger SM, Bahadir E, et al. Uric acid is an important predictor for hypertensive early atherosclerosis. Adv Ther 2012;29:276–86.
    Crossref | PubMed
  24. Cicero AF, Salvi P, D’Addato S, et al. for the Brisighella Heart Study group. Association between serum uric acid, hypertension, vascular stiffness and subclinical atherosclerosis: data from the Brisighella Heart Study. J Hypertens 2014;32:57–64.
    Crossref | PubMed
  25. Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocytechemo attractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41 :1287–93.
    Crossref | PubMed
  26. Kang DH, Park SK, Lee IK, et al. Uric acid-induced C-reactive protein expression:implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005;16:3553–62. 
    Crossref | PubMed
  27. Corry DB, Eslami P, Yamamoto K, et al. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269–75.
    Crossref | PubMed
  28. Suarna C, Dean RT, May J, et al. Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of alpha-tocopherol and ascorbate. Arterioscler Thromb Vasc Biol 1995;15:1616–24. 
    Crossref | PubMed
  29. Ginsberg MH, Kozin F, O’Malley M, et al. Release of platelet constituents by monosodium urate crystals. J Clin Invest 1977;60:999–1007.
    Crossref | PubMed
  30. George J, Struthers AD. The role of urate and xanthine oxidase inhibitors in cardiovascular disease. Cardiovasc Ther 2008;26:59–64.
    Crossref | PubMed
  31. Viazzi F, Parodi D, Leoncini G, et al. Serum uric acid and target organ damage in primary hypertension. Hypertension 2005;45:991–6.
    Crossref | PubMed
  32. Kurata A, Shigematsu Y, Higaki J. Sex-related differences in relations of uric acid to left ventricular hypertrophy and remodeling in Japanese hypertensive patients. Hypertens Res 2005;28:133–9.
    Crossref | PubMed
  33. Matsumura K, Ohtsubo T, Oniki H, et al. Gender-related association of serum uric acid and left ventricular hypertrophy in hypertension. Circ J 2006;70:885–8.
    Crossref | PubMed
  34. Xaplanteris P, Vlachopoulos C, Vyssoulis G, et al. Uric acid levels, left ventricular mass and geometry in newly diagnosed, never treated hypertension. J Hum Hypertens 2011;25:340–2.
    Crossref | PubMed
  35. Cuspidi C, Valerio C, Sala C, et al. Lack of association between serum uric acid and organ damage in a never-treated essential hypertensive population at low prevalence of hyperuricemia. Am J Hypertens 2007;20:678–85.
    Crossref | PubMed
  36. Iwashima Y, Horio T, Kamide K, et al. Uric acid, left ventricular mass index, and risk of cardiovascular disease in essential hypertension. Hypertension 2006;47:195–202.
    Crossref | PubMed
  37. Corry DB, Eslami P, Yamamoto K, et al. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin–angiotensin system. J Hypertens 2008;26:269–75.
    Crossref | PubMed
  38. Yu MA, Sanchez-Lozada LG, Johnson RJ, et al. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid induced endothelial dysfunction. J Hypertens 2010;28:1234– 42.
    PubMed
  39. Cheng TH, Lin JW, Chao HH, et al. Uric acid activates extracellular signal-regulated kinases and thereafter endothelin-1 expression in rat cardiac fibroblasts. Int J Cardiol 2010;139:42–9.
    Crossref | PubMed
  40. Vlachopoulos C, Xaplanteris P, Vyssoulis G. Association of serum uric acid level with aortic stiffness and arterial wave reflections in newly diagnosed, never-treated hypertension. Am J Hypertens 2011;24:33–9.
    Crossref | PubMed
  41. Krishnan E, Hariri A, Dabbous O, et al. Hyperuricemia and the echocardiographic measures of myocardial dysfunction. Congest Heart Fail 2012;18:138–43.
    Crossref | PubMed
  42. Huang H, Huang B, Li Y, Huang Y, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 2014;16:15–24. 
    Crossref | PubMed
  43. Krishnan E. Hyperuricemia and incident heart failure. Circ Heart Fail 2009;2:556–62.
    Crossref | PubMed
  44. Høieggen A, Alderman MH, Kjeldsen SE, et al. LIFE Study Group. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65:1041–9.
    Crossref | PubMed
  45. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). Circ J 2013;77:2043–9.
    Crossref | PubMed
  46. Kao MP, Ang DS, Gandy SJ, et al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 2011;22:1382–9. 
    Crossref | PubMed
  47. Fang, J, Alderman MH. Serum Uric Acid and Cardiovascular Mortality. The NHANES I Epidemiologic Follow-up Study, 1971–1992. JAMA 2000;283:2404–10.
    Crossref | PubMed
  48. Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888–97.
    Crossref | PubMed
  49. Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystalindependent mechanism. Hypertension 2001 ;38:1101 –6.
    Crossref | PubMed
  50. Sanchez-Lozada LG, Tapia E, Soto V, et al. Effect of febuxostat on the progression of renal disease in 5/6 nephrectomy rats with and without hyperuricemia. Nephron Physiol 2008;108:p69–p78. 
    Crossref | PubMed
  51. Badve SV, Brown F, Hawley CM, et al. Challenges of conducting a trial of uric-acid-lowering therapy in CKD. Nat Rev Nephrol 2011;7:295–300.
    Crossref | PubMed
  52. Jalal DI, Chonchol M, Chen W, et al. Uric acid as a target of therapy in CKD. Am J Kidney Dis 2013;61 :134–46.
    Crossref | PubMed
  53. Bose B, Badve SV, Hiremath SS, et al. Effects of uric acidlowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 2014;29:406–13.
    Crossref | PubMed
  54. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 2000;283:2404–10. 
    Crossref | PubMed
  55. Freedman DS, Williamson DF, Gunter EW, et al. Relation of serum uric acid to mortality and ischemic heart disease: the NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1995;141 :637–44.
    Crossref | PubMed
  56. Bos MJ, Koudstaal PJ, Hofman A, et al. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 2006;37:1503–7. 
    Crossref | PubMed
  57. Kuo CF, See LC, Yu KH, et al. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality. Rheumatology 2013;52:127–34.
    Crossref | PubMed
  58. Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population. Follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) Study. Circulation 2005;111 :1777–83.
    Crossref | PubMed
  59. Bombelli M, Ronchi I, Volpe M, et al. Prognostic value of serum uric acid: new-onset in and out-of-office hypertension and long-term mortality. J Hypertens 2014;32:1237–44. 
    Crossref | PubMed
  60. Klein R, Klein BE, Cornoni JC, et al. Serum uric acid: its relationship to coronary heart disease risk factors and cardiovascular disease, Evans County, Georgia. Arch Intern Med 1973;132:401–10.
    Crossref | PubMed
  61. Verdecchia P, Schillaci G, Reboldi GP, et al. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension: the PIUMA study. Hypertension 2000;36:1072–8.
    Crossref | PubMed
  62. Alderman H, Cohen H, Madhavan S, et al. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144–50.
    Crossref | PubMed
  63. Grassi G, Cifkova R, Laurent S, et al. Blood pressure control and cardiovascular risk profile in hypertensive patients from central and Eastern European countries: results of the BP-CARE study. Eur Heart J 2011;32:218–25.
    Crossref | PubMed
  64. Rathmann W, Hauner H, Dannehl K, Gries FA. Association of elevated serum uric acid with coronary heart disease in diabetes mellitus. Diabete Metab 1993;19:159–66.
    PubMed
  65. Lehto S, Niskanen L, Ronnemaa T, et al. Serum uric acid is a strong predictor of stroke in patients with non-insulindependent diabetes mellitus. Stroke 1998;29:635–9.
    Crossref | PubMed
  66. Yu MA, Sanchez-Lozada LG, Johnson RJ, et al. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acidinduced endothelial dysfunction. J Hypertens 2010;28:1234– 42.
    PubMed
  67. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013;62:3307–15.
    Crossref | PubMed
  68. Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies. Atherosclerosis 2013;231 :61–8.
    Crossref | PubMed
  69. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and coronary heart disease: a systematic review and metaanalysis. Arthritis Care Res 2010;62:170–80.
    Crossref | PubMed
  70. Carnes CA, Chung MK, Nakayama T, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res 2001;89:E32–E38.
    Crossref | PubMed
  71. Gonzalez DR, Treuer A, Sun QA, et al. S-nitrosylation of cardiac ion channels. J Cardiovasc Pharmacol 2009;54: 188–95.
    Crossref | PubMed
  72. Gill JS, McKenna WJ, Camm AJ. Free radicals irreversibly decrease Ca2+ currents in isolated guinea-pig ventricular myocytes. Eur J Pharmacol 1995;292:337–40.
    Crossref | PubMed
  73. Shimano M, Shibata R, Inden Y, et al. Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation. Heart Rhythm 2009;6:935–40.
    Crossref | PubMed
  74. Letsas KP, Korantzopoulos P, Filippatos GS, et al. Uric acid elevation in atrial fibrillation. Hellenic J Cardiol 2010;51 : 209–13.
    PubMed
  75. Charles BA, Shriner D, Doumatey A, et al. A genome-wide association study of serum uric acid in African Americans. BMC Med Genomics 2011;4:17.
    Crossref | PubMed
  76. Liu T, Zhang X, Korantzopoulos P, et al. Uric acid levels and atrial fibrillation in hypertensive patients. Intern Med 2011;50:799–803.
    Crossref | PubMed
  77. Tamariz L, Hernandez F, Bush A, et al. Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2014;11 :1102–8.
    Crossref | PubMed
  78. Bhole V, Krishnan E. Gout and the heart. Rheum Dis Clin North Am 2014;40:125–43.
    Crossref | PubMed
  79. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003;107:1991–7. 
    Crossref | PubMed
  80. Ekundayo OJ, Dell’Italia LJ, Sanders PJ, et al. Association between hyperuricemia and incident heart failure among older adults: a propensity-matched study. Int J Cardiol 2010;142:279–87.
    Crossref | PubMed
  81. Tamariz L, Harzand A, Palacio A, et al. Uric acid as a predictor of all-cause mortality in heart failure: a meta-analysis. Congest Heart Fail 2011;17:25–30.
    Crossref | PubMed
  82. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170:1358–64.
    Crossref | PubMed
  83. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004;43:589–99.
    Crossref | PubMed
  84. Culleton BF. Uric acid and cardiovascular disease: a renal-cardiac relationship? Curr Opin Nephrol Hypertens 2001;10:371–5. 
    Crossref | PubMed
  85. Pascual-Figal DA, Hurtado-Martinez JA, Redondo B, et al. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail 2007;9:518–24.
    Crossref | PubMed
  86. Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M, et al. Hyperuricemia predicts adverse outcomes in patients with heart failure. Int J Cardiol 2011;151 :143–7.
    Crossref | PubMed
  87. Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure. Eur J Heart Fail 2005;7:461–7.
    Crossref | PubMed
  88. Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest 2014;44:573–8.
    Crossref | PubMed
  89. Farquharson CA, Butler R, Hill A, et al. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002;106:221–6.
    Crossref | PubMed
  90. Doehner W, Schoene N, Rauchhaus M, 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;105:2619–24.
    Crossref | PubMed
  91. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010;3:73–81.
    Crossref | PubMed
  92. Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPTCHF study. J Am Coll Cardiol 2008;51 :2301–9.
    Crossref | PubMed
  93. Xu X, Hu X, Lu Z, et al. Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice. J Card Fail 2008;14:746–53.
    Crossref | PubMed
  94. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients with chronic kidney disease (NU-FLASH trial for CKD). J Cardiol 2015;66:298–303. 
    Crossref | PubMed
  95. White W, Chohan S, Dabholkar A, et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J 2012;164:14–20.
    Crossref | PubMed
Previous Volume Article Next Volume Article