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Hyperuricemia and cardiovascular disease risk Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 01/10/15 For personal use only.

Expert Rev. Cardiovasc. Ther. 12(10), 1219–1225 (2014)

Claudio Borghi*, Federico Maria Verardi, Ilenia Pareo, Crescenzio Bentivenga and Arrigo FG Cicero Department of Medical and Surgical Science, S. Orsola-Malpighi University Hospital, University of Bologna, Via Albertoni 15 - Pad. 2, 40138 Bologna, Italy *Author for correspondence: Tel.: +39 51 636 3243 Fax: +39 51 391320 [email protected]

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Uric acid (UA) is the final end product of purine catabolism and is formed from xanthines and hypoxanthines. Hyperuricemia can be secondary to either an exaggerated production of UA that follows high cellular turnover conditions or, most frequently, to a low renal excretion in patients with impaired renal function. Recent data suggest that serum UA (SUA) at high–normal level is associated with cardiovascular disease risk factors and cardiovascular disease, often being a predictor of incident events. Preliminary data suggest that the reduction of SUA level in subjects with normal–high SUA could prevent at least a part of target-organ damage related to high SUA, especially when xanthine oxidase is selectively inhibited. KEYWORDS: allopurinol • cardiovascular disease risk • epidemiology • febuxostat • pathophysiology • serum uric acid • xanthine-oxidase inhibitors

Uric acid (UA) is the final end product of purine catabolism and is formed from xanthines and hypoxanthines mainly in the liver and the intestine. While this metabolic pathway has been well preserved during evolution in most of the living species, man as well as apes, Dalmatian dogs and some birds have lost the functionality of the degradation pathway of UA, which therefore tends to accumulate in serum [1]. An increase in serum UA (SUA) concentrations higher than 4.5 mg/dl in women and 5.5 mg/dl in men requires a careful evaluation, while plasma concentrations higher than 7 mg/dl identify a condition of overt hyperuricemia. From the biochemical standpoint, a scarce solubility is the main reason of tissue accumulation of UA leading to the formation of crystalline deposits of monosodium urate [2], which triggers the outset of an inflammatory state. This is particularly pronounced in kidneys and joints leading to nephrolithiasis and gout in some predisposed patients. In terms of pathophysiology, SUA levels are influenced by many mechanisms, both endogenous and exogenous. Hyperuricemia can be secondary to either an exaggerated production of UA that follows high cellular turnover conditions or, most frequently, to a low renal excretion in patients with impaired renal function [3]. Since the kidney is the main route of UA clearance, the integrity of renal function is essential for the maintenance of normal UA levels, while small bowel excretion 10.1586/14779072.2014.957675

contributes to only a small percentage. In the past years, the increased interest in the renal molecular mechanisms responsible for UA clearance has led to the discovery of different urate transport systems located in the proximal tubule. These proteins are involved in the processes of secretion and reabsorption of UA, and their loss-of-function mutations associated with some specific polymorphisms may contribute to the development of hyperuricemia [4]. Lifestyle and dietary habits also have a large influence on serum urate levels. For example, alcohol consumption >15 g/day leads to a high risk of hyperuricemia, particularly for beer drinkers [5], with a 93% relative risk of experiencing a gout attack compared to nonalcohol consumers [6]. Sugar-sweetened (fructose-sweetened) soft drinks have also been associated to an increase in serum levels of UA and incidence of gout [7], even though this finding has been recently contradicted in subjects with isocaloric feeding conditions [8]. However, according to epidemiological studies, the main exogenous source of UA is the consumption of meat and seafood with high purine content [9]. Among the possible causes of elevated SUA levels, it is important to consider the role of pharmacological treatment, particularly in patients with cardiovascular (CV) comorbidities. Loop diuretics and thiazides cause an increase in SUA. In fact, the proximal tubule is the major site of urate handling; both secretion and reabsorption occur


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in this segment, with the net effect being reabsorption of most of the filtered urate. Urate enters the proximal tubular cell from peritubular capillary blood through organic anion transporters 1 and 3 (OAT1 and OAT3) located on the basolateral membrane, and is secreted from the cell into the tubular fluid through solute carrier (SLC) family members SLC17A1 and SLC17A3, multidrug resistance protein 4 and ATP-binding cassette G2 located on the luminal membrane. Urate reabsorption from the tubular fluid into the cell is mediated by urate transporter 1, OAT4 and OAT10, located on the luminal membrane, and from the cell back to the peritubular capillary blood through glucose transporter 9 located on the basolateral membrane. Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion. Aspirin can also reduce urate secretion at the tubular level by inhibiting the synthesis of specific prostaglandins [10]. What is UA & how does it work?

While UA was initially considered as a substance devoid of any biological effect, only as late as the 90s its antioxidant effect was thought to be mainly directed against hydroxyl radicals and peroxynitrite [11]. This suggested some authors that this beneficial property could be the reason why, during the course of human evolution, the processes of UA reabsorption in the renal tubule have been conserved [12]. In fact, low concentrations of UA contribute to prevention of oxidative inactivation of endothelial enzymes as cyclooxygenase and angiotensin converting enzyme and to preservation of NO production [13], which is strategic for endothelial vasodilatation [14]. UA is also implied in neuroprotection, preventing lipid peroxidation in brain cells, with decreased levels demonstrated in people affected by neurological diseases such as multiple sclerosis [15] and Parkinson’s disease [16] compared to controls. The burden starts when UA levels increase. In fact, under hyperuricemic conditions, benefits are replaced by deleterious effects, consisting of NO reduction, endothelial dysfunction [17], oxygen radical promotion and increased proinflammatory marker production, such as IL-1, IL-6, IL-10, TNF-a [18]. Moreover, increased SUA levels stimulate smooth muscle cell proliferation via the mitogen-activated protein kinase pathway and angiotensin 1 and 2 expression [19], inducing a microvascular disease that can benefit from the use of renin-angiotensin system blockade [20]. On the light of these pathophysiological features, the inflammatory state promoted by UA has been thought to be related to the development of several clinical comorbidities in addition to gout, which was first identified almost two centuries ago. The basis of this hypothesis can be easily understood during clinical practice: hyperuricemic patients are often affected by comorbidities such as hypertension, metabolic syndrome, diabetes or CV disease. Hyperuricemia & CV comorbidities

CV disease (CVD) is the leading cause of death worldwide [21]. A link between elevated uricemia and increased CV risk has 1220

been demonstrated in several epidemiological studies over the years [22,23]. However, elevated SUA is also associated with several coexistent CV risk factors, many of which are part of the metabolic syndrome, including serum triglyceride levels, hip circumference ratio, BMI, HDL cholesterol, LDL cholesterol, preexisting coronary heart disease (CHD), insulin level and plasma glucose [24–27]. The matter is whether UA represents merely a marker in a complex metabolic pathway or plays an independent role in the development of CV diseases such as hypertension, coronary artery disease or heart failure (HF) and, therefore, it might become a potential screening and therapeutic target. Hypertension is a very common CV disease that significantly increases the risk of myocardial infarction, stroke, congestive HF, peripheral vascular disease and end-stage renal disease [28]. The first correlation between hyperuricemia and hypertension was described in 1879 in patients with gout [29]. In the past 50 years, several clinical and laboratory studies have suggested that UA may play an important role in the development of primary hypertension in humans. UA has been demonstrated to be an independent risk factor for the development of hypertension [30–33]. Consistent with these results, a recent meta-analysis of 18 prospective cohort studies, including data from more than 55,000 patients, showed an increased risk reduction for incident hypertension in subjects with hyperuricemia, especially in younger adults and women, independent of other known risk factors [34]. The overall risk increased by 13% per 1 mg/dl increase in serum SUA, suggesting a linear relationship between hypertension and hyperuricemia levels. At the beginning of this century, Mazzali et al. carried out some experiments on rats to clarify the underlying pathogenetic mechanism. They induced mild uricemia in rats by providing an uricase inhibitor in the diet (oxonic acid), demonstrating a significant increase in systolic blood pressure within 3 weeks, which correlated with UA levels and the development of tubulointerstitial injury. The administration of a xanthine oxidase inhibitor, allopurinol, or an uricosuric agent could prevent the development of both hypertension and renal damage [35]. The same study demonstrated an abnormal activation of the renin-angiotensin system and a decrease in Nitrix Oxid Synthetase 1 expression in the macula densa, which could be prevented with use of angiotensin-converting enzyme inhibitors and L-arginine administration. In another study, hyperuricemic rats were found to develop vascular disease, particularly of the afferent arteriole of the renal microvasculature, independent of blood pressure and because of a direct stimulation of the vascular smooth muscle cells by UA [36]. Furthermore, these changes in preglomerular arterioles could lead to an increase in salt sensitivity during the first phases of hypertension [37]. As for humans, it is important to underline that the association between high SUA levels and prehypertension [38,39] is more evident in younger subjects and children [40–43]. Feig and Johnson found that the vast majority of children with primary hypertension (89%) had SUA levels >5.5 mg/dl, in contrast to 30% of children with secondary hypertension and none with white-coat hypertension or controls [40]. In a recent Expert Rev. Cardiovasc. Ther. 12(10), (2014)

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Hyperuricemia & CVD risk

cross-sectional Italian study involving 501 children between 6 and 18 years, after adjusting for puberty, gender, BMI z-score, homeostasis model assessment index and renal function, SUA was found to be directly related to systolic and diastolic blood pressure. When normotensive children were used for comparison, the risk of prehypertension or hypertension increased by at least 50% for each 1 mg/dl SUA increase [44]. In older subjects, the correlation between SUA and blood pressure progressively decreases [45]. These results, both on rats and humans, are consistent with the hypothesis that UA might have a role in the early pathogenesis of primary hypertension. Considering this, it was demonstrated that, in this short-term crossover study of 30 adolescents with newly diagnosed hypertension, a 4-week therapy with a xanthine oxidase inhibitor such as allopurinol led to lower blood pressure values in office and 24-h ambulatory blood pressure measurements compared with placebo [46]. More clinical trials with longer followup periods are needed to determine the safety and efficacy of urate-lowering therapies such as allopurinol in hypertension. While UA seems to play an independent role in the development of hypertension, mainly in the first phases of the disease, its association with other CV diseases as an independent risk factor is conflicting. In data examinations of the Framingham Heart Study, SUA predicted the development of CHD. However, in multivariate analysis including age, systolic blood pressure, relative weight, cigarette smoking and serum cholesterol, the independent relationship between SUA levels and CHD lost statistical relevance [47]. A similar result was obtained in 1997 by Wannamethee et al. In this prospective cohort study of 7688 men, a nonsignificant association between SUA and CHD after adjustment for diastolic blood pressure and serum total cholesterol was found, concluding that elevated SUA is only part of a cluster of risk factors associated with the insulin resistance syndrome [27]. On the other hand, the early NHANES I study showed an independent relationship between SUA and mortality from CHD, but only in women [48]. For each 1 mg/dl increase in uricemia among women, there was an increased rate of 1.48 (95% CI: 1.3–1.7). The Honolulu Heart Study demonstrated a consistent independent relationship between SUA levels and CHD at all points in the follow-up [49]. Data from the Preventive Cardiology Information System (PreCIS) database, including UA levels from 3098 patients at high CV risk and therefore examined for primary and secondary CV disease prevention, showed that, by using Cox regression analysis, each 1 mg/dl increase in SUA level corresponded to a 39% increase in death risk [50]. It has to be highlighted that, regardless of diuretic use, after adjusting for age, sex, smoking status, alcohol consumption, weight, BMI, waist circumference, blood pressure, history of CVD, estimated glomerular filtration rate, levels of cholesterol fractions and plasma glucose levels, SUA levels continue to predict the risk of death (hazard ratio 1.26; 95% CI: 1.15–1.38; p < 0.001). The association between SUA and CVD in a healthy population without diabetes or previous CVD was also demonstrated, and it was stronger in women than in men [51]. Another gender-dependent informahealthcare.com

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result was seen in a recent systematic review and meta-analysis of prospective cohort studies. Higher SUA levels were associated with a mild but significant increase in CHD incidence and mortality, independent of traditional risk factors. Subgroup analysis showed that this was true only in women [52]. The same group of authors carried out another systematic review and meta-analysis to assess the association between hyperuricemia and risk of stroke incidence and mortality [53]. Sixteen prospective cohort studies were collected with a follow-up time spread from 2.3 to 23 years, including data from 238,449 subjects. This review showed a slightly but statistically significant increased risk of stroke incidence and mortality in adults with elevated SUA levels, without a significant difference by sex. Regarding stroke, however, there are conflicting data, in particular about the role of UA in the outcome of patients with stroke. Some studies suggest that a better short-term outcome is associated with elevated SUA levels [54], while others indicate an association between elevated UA and poor long-term outcome [55–57]. Recently, a meta-analysis involving 33 studies has been carried out to identify the association between SUA and incidence and prognosis of HF. This meta-analyis concluded that subjects with hyperuricemia had an increased risk of HF incidence, CV mortality, all-cause mortality and the composite of death and cardiac events in HF patients [58]. SUA was also found to predict clinical outcomes in patients with moderate to severe HF, confirming that the xanthine-oxidase pathway and/or UA itself may be of pathophysiological importance in HF progression [59,60]. UA could be used in monitoring the metabolic status in these subjects and could play a role in the management of patients with HF. A similar finding about the capacity of UA in predicting clinical outcome in patients with established CVD has been demonstrated in subjects with recent myocardial infarction. Data from the GISSIPrevenzione trial showed that SUA improved the identification of patients at higher risk of CV events [61]. In another study, 5124 patients with acute coronary syndrome who underwent percutaneous coronary intervention were divided into quartiles according to their SUA levels. The unadjusted hazard ratio of 1-year mortality was 3.05 (95% CI: 2.54–3.67; p < 0.001) for fourth versus first quartile. Furthermore, after adjustment for traditional CV risk factors, renal function and inflammatory status, a 12% increase in the adjusted risk for 1-year mortality for every 1 mg/dl increase in the UA level remained [62]. Recent acquisitions have demonstrated that adding SUA measurement to CVD risk prediction algorithms, such as the Framingham CV risk score, improves the risk reclassification capacity in adults aged 75 years and older [63]. However, neither for older adults nor for younger subjects SUA is listed among CV risk factors in CV guidelines [64]. Treating hyperuricemia

About the possibility of using UA as a pharmacological target to reduce CV mortality, literature contains conflicting data. A very recent meta-analysis grouped data from 11 randomized trials, where SUA at baseline and at the end of follow-up was 1221

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reported. In each of these trials, an active drug treatment able to reduce UA serum levels versus placebo has been used. The results of the meta-analysis do not show changes in all-cause death and major CV events when SUA is reduced by pharmacological therapies [65]. We have already hinted at evidence suggesting that a drug treatment in experimental rats with induced hyperuricemia and in adolescents with newly diagnosed hypertension is able to lower blood pressure. In another experiment, rats with high-fructose diets were given thiazides, resulting in a reduction in blood pressure and an elevation in SUA. Adding the xanthine oxidase inhibitor allopurinol resulted in a lowering of SUA and a further reduction in blood pressure values [66]. An interesting point emerged from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. The authors first demonstrated that UA levels at baseline and intreatment were independently correlated with CV events. Then, beyond a similar impact on blood pressure, losartan is able to reduce SUA by interfering with urate reabsorption in the renal proximal tube, while the compared drug atenolol is not. It was then demonstrated that CV outcome improvement in patients treated with losartan may be partially related with the specific feature of reducing SUA levels [67]. However, the LIFE study was not designed to test this hypothesis. In fact, there are few randomized clinical trials evaluating the effects of SUA pharmacological reduction in CV disease. A trial has been performed to determine the high-dose allopurinol treatment effects on patients with chronic stable angina [68]: allopurinol produced some benefits, as a prolonged time to develop chest pain during exercise. These effects seem to be secondary to the reduction of oxidative stress and the improvement in endothelial function [69]. However, the study has no strong indication because the population was small [65] and the overall effects were modest. Conclusion

The relationship between UA and hypertension is well demonstrated. The association of SUA with CVD such as stroke, CHD and HF is clearly present. Whether UA may play an independent role in the prediction of these conditions and may be useful to predict clinical outcomes in established CVD, though, is still debated. Currently, conflicting data and the close relationship with a large number of risk factors do not allow UA to be listed in CV guidelines together with other CV risk factors. Therefore, further studies are needed to determine if UA might contribute to improve the ability to stratify CV risk. Even more, we need studies to assess if UA can become a therapeutic target to reduce CV mortality and extend prevention tools. Expert commentary

In our recent research experience we have observed, in agreement with other literature data, that a high–normal SUA level is associated to worse ejection fraction in HF patients [70], impaired stroke volume and cardiac output [71], cognitive function [72] and arterial stiffness [73] in overall healthy adult-elderly subjects. 1222

Moreover, recent meta-analyses have clearly demonstrated a linear association between SUA level and mortality: elevated SUA increased the risk of all-cause mortality (relative risk 1.24; 95% CI 1.09–1.42) and CV mortality (relative risk 1.37; 95% CI: 1.19–1.57) in the general population [74], and each 0.1 mmol/l increase in SUA resulted in a 28% increase in the risk of vascular complications and a 9% increase in the risk of mortality in Type 2 diabetes patients [75]. In this context, some scientists have already proposed to revise the guidelines to identify a lower level of abnormal SUA, the one that could be related to systemic vascular damage even if not related to gout risk [76]. Of course, from a therapeutic point of view, the first step of treatment would be the improvement of lifestyle aimed at the reduction of oxidative stress that is probably the main indirect cause of UA hyperproduction at levels lowers than the ones able to induce gout. In fact, SUA, as an endogenous antioxidant [11–20], should be hyperproduced in answer to oxidative stress, but over certain levels becoming per se a risk factor for CVD. However, available data also suggest that drug-induced decrease in SUA should be efficacious in reducing CVD risk. In particular, selective inhibition of xanthine oxidase (mainly by febuxostat) [77] appears to be a promising pharmacological tool to reduce SUA levels and CVD risk associated to high–normal SUA levels. The revision of available epidemiological data and of data derived from large intervention trials is advisable to check if high–normal SUA levels are associated to a different CV prognosis. Future trials are needed to clearly understand how the integration of SUA in CVD risk stratification charts will improve the early detection of subjects at high CVD risk and how SUA reduction will improve the risk. However, on the basis of the available data, we strongly suggest to measure SUA in subjects with known cardiovascular disease risk factors (hypertensives, smokers, dyslipidemic patients, diabetic patients, etc) and to consider them at even more increased CV risk if having high–normal SUA levels. Five-year view

A large number of researchers are concentrating their activity on in vitro and in vivo effects of SUA-reducing drugs on cells and arteries. Moreover, numerous clinicians are focusing their research on the relationship between SUA, its changes and vascular health. On the basis of the available evidence, it is highly probable that high–normal SUA will be included in the list of CVD risk factors by the main international guidelines. Moreover, it is highly probable that the normality cut-off for SUA will be reduced from the actual ones to lower ones to detect the subjects in whom high– normal SUA will increase CVD risk. The new research efforts on SUA as a potentially reversible risk factor for CVD are also largely justified by the fact that SUA dosage is largely standardized, very cheap and available in a large part of the developed and developing countries compared to other more innovative and expensive laboratory or instrumental biomarkers. On the other hand, several trials on selective inhibitors of xanthine oxidase such as febuxostat are planned and ongoing and their results should improve our confidence in reducing SUA to reduce CVD risk. Expert Rev. Cardiovasc. Ther. 12(10), (2014)

Hyperuricemia & CVD risk

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This

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includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Recent data suggest that high–normal serum uric acid (SUA) levels are often associated to a large number of known cardiovascular disease (CVD) risk factors. Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 01/10/15 For personal use only.

• High–normal SUA is also often associated to CVD and cognitive decline. • High–normal SUA also seems to be an independent risk factor for CVD and Type 2 diabetes. • Renin-angiotensin system activation seems at least partly responsible for SUA-related cardiovascular damage. • Preliminary data suggest that the reduction in SUA levels in subjects with normal–high SUA could prevent at least a part of target organ damage related to high SUA. • Selective inhibition of xanthine oxidase appears to be a promising pharmacological tool to reduce SUA levels and CVD risk associated to high–normal SUA levels. • Future trials are needed to understand how the integration of SUA in risk stratification charts will improve the early detection of subjects at high cardiovascular risk and how SUA reduction will decrease the risk.

serum uric acid vary among controlled dietary trials. J Nutr 2012;142(5):916-23

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Kanellis J, Johnson RJ. Editorial comment – elevated uric acid and ischemic stroke: accumulating evidence that it is injurious and not neuroprotective. Stroke 2003;34(8): 1956-7

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Weir CJ, Muir SW, Walters MR, Lees KR. Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003;34(8):1951-6

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Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res 2011; 63(1):102-10

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Savarese G, Ferri C, Trimarco B, et al. Changes in serum uric acid levels and cardiovascular events: a meta-analysis. Nutr Metab Cardiovasc Dis 2013;23(8):707-14

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A meta-analysis showing that uric acid reduction by nonselective xanthine-oxidase inhibitors does not seem to reduce cardiovascular event risk.

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Reungjui S, Roncal CA, Mu W, et al. Thiazide diuretics exacerbate fructose-induced metabolic syndrome. J Am Soc Nephrol 2007;18(10):2724-31

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of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis 2013; 231(1):61-8

patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010;375(9732):2161-7 69.

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Review

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Xu Y, Zhu J, Gao L, et al. Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients: a meta-analysis. PLoS One 2013;8(10):e78206

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Desideri G, Castaldo G, Lombardi A, et al. Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci 2014;18(9):1295-306

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Cicero AF, Salvi P, D’Addato S, et al. Association between serum uric acid, hypertension, vascular stiffness and subclinical atherosclerosis: data from the Brisighella Heart Study. J Hypertens 2014; 32(1):57-64

An interesting revision of the available literature supporting the lowering of the normality cut-off point for serum uric acid aimed at improving the early detection of patients at increased cardiovascular disease risk.

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Cicero AF, Rosticci M, Parini A, et al. Serum uric acid is inversely proportional to estimated stroke volume and cardiac output in a large sample of pharmacologically untreated subjects: data from the Brisighella Heart Study. Intern Emerg Med 2013. [Epub ahead of print]

Tausche AK, Christoph M, Forkmann M, et al. As compared to allopurinol, urate-lowering therapy with febuxostat has superior effects on oxidative stress and pulse wave velocity in patients with severe chronic tophaceous gout. Rheumatol Int 2014; 34(1):101-9

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One of the first trials directly demonstrating a positive effect of selective xanthine-oxidase inhibition on vascular health in humans.

Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest 2014;44(6):573-8 Cicero AF, Desideri G, Grossi G, et al. Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: data from the Brisighella Study. Intern Emerg Med 2014. [Epub ahead of print]

Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor

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