Uric acid and cardiovascular disease

Clinica Chimica Acta 484 (2018) 150–163

Contents lists available at ScienceDirect

Clinica Chimica Acta journal homepage: www.elsevier.com/locate/cca

Review

Uric acid and cardiovascular disease Gjin Ndrepepa

T

⁎

Department of Adult Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany

A R T I C LE I N FO

A B S T R A C T

Keywords: Arterial hypertension Atrial fibrillation Coronary heart disease Congestive heart failure Mortality Stroke Uric acid

Uric acid (UA) is an end product of purine metabolism in humans and great apes. UA acts as an antioxidant and it accounts for 50% of the total antioxidant capacity of biological fluids in humans. When present in cytoplasm of the cells or in acidic/hydrophobic milieu in atherosclerotic plaques, UA converts into a pro-oxidant agent and promotes oxidative stress and through this mechanism participates in the pathophysiology of human disease including cardiovascular disease (CVD). Most epidemiological studies but not all of them suggested the existence of an association between elevated serum UA level and CVD, including coronary heart disease (CHD), stroke, congestive heart failure, arterial hypertension and atrial fibrillation as well as an increased risk for mortality due to CVD in general population and subjects with confirmed CHD. Evidence available also suggests an association between elevated UA and traditional cardiovascular risk factors, metabolic syndrome, insulin resistance, obesity, non-alcoholic fatty liver disease and chronic kidney disease. Experimental and clinical studies have evidenced several mechanisms through which elevated UA level exerts deleterious effects on cardiovascular health including increased oxidative stress, reduced availability of nitric oxide and endothelial dysfunction, promotion of local and systemic inflammation, vasoconstriction and proliferation of vascular smooth muscle cells, insulin resistance and metabolic dysregulation. Although the causality in the relationship between UA and CVD remains unproven, UA may be pathogenic and participate in the pathophysiology of CVD by serving as a bridging mechanism mediating (enabling) or potentiating the deleterious effects of cardiovascular risk factors on vascular tissue and myocardium.

1. A short historical perspective Uric acid (UA; 7,9-hihydro-1H-purine-2,6,8(3H)-trione; empiric formula C5H4N4O3; molecular weight of 168.11 Da) is a heterocyclic organic compound and an end product of purine metabolism in humans and great apes. Historical records show that UA crystals were first described by Antoni van Leeuwenhoek in 1679 in gouty tophus and, 50 years later, by William Stukeley in a tophaceous joint, although the chemical composition of the crystals at that time was unknown [1]. UA was first isolated in 1776 from urinary calculi by Swedish chemist Karl Wilhelm Scheele [2] who named the isolated substance lithic acid (from the Greek lithos meaning stone or rock). In 1798 George Pearson [3] isolated UA from 200 urinary stones and suggested the name ouric or uric oxide. The first chemical structure of UA was proposed by Ludwig Medicus [4] in 1875. In 1897 the German chemist H. Emil Fischer [5,6] - the 1902 Noble laureate for Chemistry - performed for the first time chemical synthesis of UA proving the accuracy of Medicus' proposed structure. Sir Alfred Garrod [7] provided the first evidence that gout was associated with increased UA levels in blood and he was the first to describe a method for UA measurement in serum or urine, which

⁎

probably represents the first chemical test ever undertaken [1]. The link between elevated UA level and cardiovascular disease (CVD) or arterial hypertension was suggested nearly 140 years ago by Frederick A. Mohamed [8], who addressing the Bright's disease and its symptoms, wrote in Lancet: “Yet another class of individuals fail through the arteries. These, I am inclined to think, are more especially the gouty and syphilitic ones. Atheroma is their great enemy; it may attack their aorta or large vessels so badly that they get aneurism, and fall victims to this disease.” Ten years later, in 1889, Haig and Oxon [9] wrote in British Medical Journal, “…that, caeteris paribus [other things equal], arterial tension varies with the amount of uric acid that is circulating in the blood.” In 1951, Gertler et al. [10] found higher UA levels in patients with premature coronary heart disease (CHD) compared with normal population and suggested for the first time to consider UA as a potential risk factor for CHD. In the same year UA was included in the protocols of the Framingham study to be investigated as a potential risk factor for CVD [11]. In 1967, a seminal publication by Kannel et al. [12] reported the results of a 12-year follow-up of a large cohort (n = 5127 participants) in the setting of Framingham Study noting that elevated serum UA was associated with the risk of CHD in

Corresponding author at: Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 München, Germany. E-mail address: [email protected].

https://doi.org/10.1016/j.cca.2018.05.046 Received 29 March 2018; Accepted 23 May 2018 Available online 24 May 2018 0009-8981/ © 2018 Elsevier B.V. All rights reserved.

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

increases the demand for purine elimination via UA production. Coffee and vitamin C may reduce this demand [31]. Although purine degradation pathway involves many enzymes [21], XOR is a critical and rate-limiting or house-keeping enzyme in purine metabolism. XOR, isolated first from bovine milk by Schardinger [32] as aldehyde reductase in 1902, is found across a wide range of species from prokaryotes to plants and animals. XOR has a relatively wide specificity and can oxidize a variety of endogenous or exogenous compounds including aldehydes, purines (like adenine, 6-mercaptopurine), a number of pyrimidines, pterines, azopurines, hetorocyclic compounds and various xenobiotics including antiviral and antineoplastic drugs and allopurinol [15]. Purified human XOR is a dimer of two identical subunits of ∼150 kDa. Each subunit consists of three domains: a N-terminal 20 kDa, a middle 40-kDa and a C-terminal 85 kDa domen. The 1st, 2nd and the 3rd domains contain 2 nonidentical Fe-S centers, a flavine adenine dinucleotide (FAD) cofactor and a 1 molybdopterin (Mo-pt) cofactor, respectively. Catalysis involves the sequential transfer of 2 electrons to the molybdenum atom (IV), FeS centers and FAD which is subsequently oxidized by molecular oxygen or nicotinamide adenine dinucleotide (NAD+) [21,33,34]. In mammals, XOR is present in 2 interconvertible forms: xanthine dehydrogenase (XDH) which prefers NAD+ and XOR which prefers molecular oxygen as acceptor of electrons. XOR reaction is associated with production of large amounts of highly cytotoxic oxygen reactive species (ROS), superoxide anion (O2−) and hydrogen peroxide (H2O2). XOR is constitutively expressed as XDH which is converted (reversibly) to XOR through oxidation of sulfhydryl groups (to form -S-S- bridges) or limited proteolysis (irreversibly) [33]. Conversion from XHD to XOR is favored by reduced O2 tension and lower pH, tissue hypoxia or ischemia, ischemia/reperfusion cycle, glutathione depletion and presence of oxidizing agents such as hydrogen peroxide [15,35,36]. XOR is one of the most important ROS producers. ROS are important mediators participating in a wide range of cellular processes from cellular signaling (physiological role), to inflammation, aging, cancer, diabetes and CVD (pathophysiological role). Allopurinol inhibits XOR after being oxidized by the enzyme to oxypurinol which binds tightly to the molybdenum center. It has been suggested that in the presence of low NAD+ concentrations, XDH may reduce (transfer electrons to) oxygen and produce ROS [21]. The human gene for XOR is located on the short arm of chromosome 22 (2p22) and contains 36 exons and 35 introns spanning at least 60 kb corresponding to a 1333 amino acid residue polypeptide [37]. Highest activity of XOR has been detected in liver, intestine and vascular endothelium whereas other human organs show a very low activity of the enzyme [21]. Of note, circulating XOR can bind to the surface of endothelial cells through glucosaminoglycans leading to increased oxidative stress and endothelial dysfunction [38]. This may explain “metastatic” damage by the activated enzyme in organs or tissues remote from the primary activation site. The expression of XOR gene in humans is lower compared with other mammals potentially due to promoter suppression [39] and is strict under regulatory control at transcriptional and post-transcriptional level (recently reviewed in [16]). The enzyme can be inhibited pharmacologically by drugs like allopurinol and febuxostat [40,41]. Since UA does not move freely across the cellular membranes, specific transporters enable UA transport across plasma membranes and play a crucial role in UA homeostasis. Although UA transporters have been detected in many types of cells, kidney and intestine harbor a large number of them consistent with their role as UA excretion routes. About 70% of UA is excreted by kidneys and the remaining 30% by gastrointestinal tract [42]. Kidney plays a crucial role in maintaining plasma UA levels and UA homeostasis in general, through complex and incompletely understood molecular mechanisms. A series of transmemebrane proteins in epithelial cells serve as UA transporters enabling a balanced UA secretion/re-absorption. It should be noted that virtually all circulating UA is filtered in glomerulus and 90–95% of filtered UA load is re-absorbed, mostly in proximal tubules with the remaining

men 30–59 years of age, alongside elevated cholesterol. In the following years, the association between UA and CVD has been extensively investigated but the nature of the relationship between UA and CVD remains debatable. Difficulties in determining whether UA acts as a risk marker or a risk factor for CHD may be explained by its frequent association and intricate relationship with other cardiovascular risk factors, the possibility of reverse causation and conflicting findings from epidemiological or clinical studies undertaken to investigate the association of UA with atherosclerosis or CHD. A hypothesis that UA elevation may represent an adaptive change to protect from atherosclerosis due to its antioxidant properties has also been proposed [13]. The interest on UA has recently resurrected. The primary focus of this review is to summarize the current status of knowledge regarding the association of UA with CVD and discuss mechanisms of its involvement in the cardiovascular pathophysiology. Although, UA is intrinsically linked with xanthine oxidoreductase (XOR) enzyme, the association of this enzyme with CVD was not the focus of this review. This issue has been extensively reviewed [14–16]. Likewise CVD in the setting of gout was not addressed. 2. Basics of UA metabolism UA, a weak organic acid with a pKa of 5.75 (diprotic acid with 2 dissociable protons with pKa1 of 5.4 and pKa2 of 10.3, respectively), is present principally (~99%) as monosodium urate at physiological pH values. Normal UA levels in serum are 2.6–5.7 mg/dl (155–339 μmol/L) in premenopausal women and 3.5–7.0 mg/dl (208–416 μmol/L) in men and postmenopausal women [17–19]. Solubility of UA in water is low and the UA concentration in blood close to solubility limit is 6.8 mg/dl. The total body pool of exchangeable UA is estimated to be ~600 mg in adult women and up to ~1200 mg in men. However, it may increase up to values ranging from 18,000 mg to 30,000 mg in patients with gout [20]. The basics of UA metabolism is covered in Fig. 1. In humans, UA is an end-product of catabolism of purine nucleotides arising from endogenous (nucleic acids and internal pool of purine nucleotides, mostly adenosine triphosphate [ATP], or their derivatives) and exogenous (dietary purines) sources. At the stage of monophosphate esters, nucleotidase enzymes act on adenosine monophosphate (AMP) and guanosine monophosphate (GMP), remove phosphate moiety and produce, adenosine and guanosine, respectively. Adenosine and guanosine products are further degraded via distinct pathways to produce hypoxanthine and xanthine, respectively. Hypoxanthine is further oxidized by xanthine dehydrogenase/oxidase to form xanthine which is further oxidized by the same enzyme to form UA as a final product of purine catabolism in humans and great apes [21]. In most other mammals, such as rats and mice, UA is further degraded by enzyme uricase to produce allantoin [22], which is 100 times more water-soluble than UA and consequently has more efficient urinary excretion route than UA [19,23]. However, in humans and higher primates, purine catabolism is stopped at UA stage due to the lack of functional uricase gene and consequently active uricase enzyme (see below). Mammals that have a functional uricase enzyme, typically display UA levels in the 1–2 mg/dl range, whereas humans and great apes have 3 to 10 times higher UA levels at least partly explainable by loss of functional uricase gene in the early Miocene era [24,25]. Although, XOR activity is detected in many tissues almost throughout the body [26–28], endogenous UA synthesis occurs mostly in liver, intestines, muscle including myocardium, kidney, mammary gland, corneal epithelium and vascular endothelium [29]. Exogenous purine pool varies with diet. Animal products such as red meat (particularly liver, kidney and sweetbreads), fatty poultry, high-fat dairy, seafood products and alcohol (particularly beer from the yeast) have high amounts of purines [23,30]. Increased cell turnover in the setting of many pathological processes (hemolysis, tumor growth or large tumor lysis syndrome) may increase the breakdown of nucleic acids leading to production of large amounts of purines which, in turn, 151

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

Fig. 1. Basics of uric acid metabolism. ABCG2 = ATP-binding cassette, subfamily 2; AMP = adenosine monophosphate; ATP = adenosine triphosphate; Dicarb = dicarboxylates; Glut9 = glucose transporter 9; GMP = guanosine monophosphate; GTP = guanosine triphosphate; MRP4 = multidrug resistance protein 4; NPT = Na+/phosphate transporter; OAT = organic anion transporter; UA = uric acid; URAT = urate transporter.

5–10% of filtered UA finally excreted [43]. It has recently been suggested that in humans, UA tubular secretion plays a negligible role and the final amount of excreted UA depends on glomerular filtration and subsequent tubular reabsorption [44]. Many UA transporters have been identified and reviewed [45–47]. Genome-wide association studies have shown an association between UA concentration and single nucleotide polymorphisms for several UA transporter genes such as SLC2A9 (GLUT9 [glucose transporter]), ABCG2 (ATP-binding cassette, subfamily 2, also named BCRP [breast cancer resistance protein]), SLC17A1 (NPT1 [Na+/phosphate transporter]), SLC17A3 (NPT4), SLC17A4 (NTP5), SLC22A11 (OAT4 [organic anion transporter]), SLC22A12 (URAT1 [urate transporter]) and SLC16A9 (MCT9 [monocarboxylate transporter]) [47]. However, main transporters responsible for UA tubular reabsorption are URAT1 which is predominantly expressed on the apical side of kidney tubular cells and GLUT9 which is widely expressed and located on the basolateral side of tubular cells. URAT1 is 12-transmembrane domain protein that transports UA in exchange for Cl− or organic anions [45]. The use of URAT1 inhibitors like probenecid is associated with reduced serum UA levels. Human GLUT9 has 2 alternatively spliced variants encoding different N-terminal cytoplasmic tails [48]. Human GLUT9a protein has 540 amino acid residues and is encoded by a 12-exon gene, whereas GLUT9b protein has 512 amino acid residues and is encoded by a 13-exon gene [45]. GLUT9 is mostly present in distal convoluted tubule, whereas URAT1 is mostly located in the proximal tubule [45]. GLUT9a is mostly expressed

in the basolateral membrane of cells in kidney (epithelial tubular cells) and liver, whereas GLUT9b is expressed on the apical pole of cells across a wide range of tissues including liver, intestine, kidney, leukocytes and chondrocytes [48,49]. Impaired UA hemostasis is substantially more severe in GLUT9−/− than in URAT1−/−, OAT1−/− or OAT3−/− variants in mice [50] indicating that GLUT9 transporter is a major regulator of UA homeostasis [45]. Recently a genome-wide association study of > 140,000 individuals confirmed 10 previously described loci and described 18 new ones affecting serum UA concentration [51]. However, none of the newly described loci were related to UA transporters but instead were related to glucose, glycolysis, insulin or pyruvic acid, indicating an impact of de novo purine synthesis on UA production, and consequently UA circulating level [31]. Although URAT1 has been shown to be genetically associated with UA levels, no genetic association between URAT1 and gout has been demonstrated [52,53]. GLUT9 and ABCG2 (expressed in renal and extra-renal tissues) are responsible for 4% and 1% variance in circulating UA level, respectively [52,53]. It has been established that serum UA has an evident heritable component with an overall heritability of 40–60% [54]. However, all known genetic variants identified so far contribute little (7%) to serum UA variance [51]. Approximately 30% of UA is excreted via gastrointestinal tract. This route of UA excretion is poorly understood. Many UA transporters have been identified in intestine and involved in UA excretion [45,47]. In particular, ABCG2 transporter is expressed on the luminal surface of 152

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

activate the inflammasome participating in innate immunity and initiation of inflammation [75]. However, it should be noted that knowledge for most of above-mentioned functions remains incomplete.

intestinal cells and suggested to play a major role in UA intestinal excretion [45,47,55]. Expression of intestinal ABCG2 is increased in nephrectomy rats [56] whereas a decrease in the ABCG2 function is associated with hyperuricemia and increased UA urinary UA excretion [57]. These and other studies [58] point out to the importance of intestinal UA excretion route and the role of ABCG2 transporter in the UA homeostasis. Two developments are important for understanding why contemporary humans have particularly high UA levels: first, a stepwise loss of uricase activity - an enzyme that degrades UA to allantoin - due to mutations in uricase gene occurring approximately 15 million years ago (mid Miocene) in hominid ancestors [24,25], and second, diet and lifestyle changes that took place over the last century that contributed to an increase in serum UA level from 3.5 mg/dl in 1920s to > 6.0 mg/ dl in 1970s [59]. There are at least 2 hypotheses to explain the loss of uricase gene (pseudogenization): one hypothesis involves slowly decreased uricase transcription via mutations in the uricase promoter before the pseudogenization [24], whereas the alternative hypothesis implicates mutations within the gene itself which slowly diminished enzymatic activity before pseudogenization events [60]. Detection of uricase mRNA in human liver cells being nonfunctional due to premature stop codons [25] seems to support the latter hypothesis. The first event is considered to have been advantageous due to UA antioxidant properties and might have been key to the survival of our ancestors during the unfavorable climate changes that occurred during the mid Myocene and later [22]. However, the marked increase in UA level cannot be explained by the loss of uricase gene only. The low UA levels measured in the Yanomamo Indians living in southern Venezuela who likely live in conditions similar to prehistoric ancestors may point out to the role of diet (or life-style) related UA elevation in contemporary humans [22]. In particular, fructose is known to raise UA level via several mechanisms, including ATP depletion [61], increased amounts of adenosine di- and mono-phosphates used for UA synthesis, activation of AMP-deaminase [62] increasing the rate of purine degradation, and suppression of renal [63] and intestinal [64] UA excretion. Thus Western diet containing high amounts of purine-rich foods and fructose has greatly contributed to current UA levels and has helped to transform UA from a beneficial adaptive factor to a risk contributor to arterial hypertension, obesity, metabolic syndrome and CVD. As elegantly articulated by Johnson et al. [22], UA may represent a physiological alarm signal gone awry in Western society. Physiological functions of UA remain poorly understood. Serving as a vehicle enabling elimination of purine waste from the body is undoubtedly important, but highly likely, is not the only function of this metabolite. The presence of UA transporters across a wide range of cells in different tissues and complex and strictly controlled renal handling of UA suggest that UA may also have other physiological functions. The antioxidant role is best known and widely accepted function of UA supported by strong evidence from experimental studies. It has been estimated that UA accounts for 50% of the total antioxidant capacity of biological fluids in humans [65,66]. The adaptive advantages of UA elevation due to loss of functional uracase gene are at least partially attributable to UA antioxidant properties. It has been also suggested that the loss of uricase gene and subsequent UA elevation may have occurred to compensate for reduced plasma antioxidant activity after the loss of ascorbate synthesis [67,68]. Higher UA levels have been related to higher intelligence, better reaction time and ability to control blood pressure at lower salt intake, albeit these effects remain poorly grounded and speculative [69,70]. Demonstration of lower UA levels in several neurodegenerative diseases like multiple sclerosis, Parkinson's and Alzheimer's disease has fueled the hypothesis that UA may be neuroprotective [71–73]. Experimental evidence suggests that UA may serve as an immunity stimulator. Studies in mice showed that UA is released from injured somatic cells and functions as an innate immunity enhancer by stimulating the maturation of dendritic cells and antigenpresenting cells to endogenous antigens [74]. Monosodium UA crystals

3. UA and cardiovascular disease Epidemiological evidence suggests that prevalence of hyperuricemia and gout are on the rise worldwide [76,77]. Many factors have been suggested to explain the rise in the prevalence of hyperuricemia including dietary (and life-style) changes, increased life expectancy, aging of the population and increased prescription of antihypertensive drugs. 3.1. UA and coronary heart disease (CHD) stroke and mortality The association between UA and CHD or mortality has been extensively investigated [78]. However, epidemiological evidence on the association between UA and CHD or mortality remains controversial with studies supporting [79–83] or refuting [84–86] such an association. The First National Health and Nutrition Examination Survey (NHANES I) study - a cross-sectional population-based study of 5926 subjects 25–74 years of age followed up for a mean of 16.4 years – showed that increased serum UA was associated with CHD-related mortality in men and women with a risk ratio (RR) = 1.77 [1.08–3.98] in men and RR = 3.00 [1.45–6.28] in women for 4th vs. 1st UA quartiles. After adjustment, for each 59.48 μmol/L higher UA level, the risk for cardiovascular and CHD-related mortality increased by 9.0% and 17.0% in men and 26.0% and 30.0% in women [79]. The Apolipoprotein MOrtality RISk (AMORIS) study tested the association between serum UA and the risk for nonfatal myocardial infarction, stroke or congestive heart failure (CHF) in 417,734 men and women from health check-ups in the Stockholm area, over 11.8 years of follow-up (range 7–17 years). There was a gradual increase in the risk for acute myocardial infarction, stroke or CHF over time. Women showed a stronger relationship between UA and acute myocardial infarction or ischemic stroke than men. The association between UA and hemorrhagic stroke was U-shaped in both genders. UA showed a stronger and less-affected by adjustment association with CHF than with myocardial infarction or stroke [80]. Other studies showed also a positive and independent association between UA and cardiovascular events, mortality or stroke [81–83]. Several other studies failed to demonstrate a significant association between elevated UA level and cardiovascular events or mortality. In the Framingham Study which included 6763 participants (mean age, 47 years), 617 CHD events, 429 CVD deaths, and 1460 deaths from all causes occurred during a follow-up of 117,376 person-years. In men, after adjustment for age, elevated UA level was not associated with the risk for adverse events. In women, after adjustment for age, UA was associated with increased risk of CHD (P = 0.002) and cardiovascular (P = 0.009) or all-cause (P = 0.03) mortality. After further adjustment for cardiovascular disease risk factors, UA was no longer associated with any of these outcomes. Notably, diuretic use was identified as the covariate responsible for the attenuation of the association between UA and adverse outcomes [84]. The prospective Reykjavik study, assessed the association between serum UA and the risk for CHD using baseline values of serum UA in 2456 incident CHD cases and 3962 age and sexmatched controls, plus paired serum UA measurements taken at baseline and, on average, 12 years later in 379 participants. Subjects in the top third of UA level had an age- and sex-adjusted odds ratio [OR] for CHD of 1.39 [1.23–1.58] which was attenuated to 1.12 [0.97–1.30] after adjustment for smoking and other established risk factors. In addition, a meta-analysis of 15 prospective studies conducted in general population with 9458 cases and 155,084 controls (embedded in the same publication) showed an OR = 1.13 [1.07–1.20] for an association between UA and CHD which fell to 1.02 [0.91–1.14] after adjustment [85]. The recently published (NHANES) III study – a cohort study of 153

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

11,009 adults followed up over 14.5 years (median) – showed that serum UA was not associated with cardiovascular (adjusted hazard ratio [HR] = 1.06, 95% confidence interval [CI] 0.96–1.16; P = 0.27) or CHD-related (adjusted HR = 1.06 [0.94–1.19]; P = 0.32) mortality. Of note, adding UA to prediction models with traditional cardiovascular risk factors did not result in significant increments of C-statistic, receiver-operating characteristics (ROC) – area under curve or net reclassification index (NRI) showing that UA did not provide prognostic information beyond that provided by traditional cardiovascular risk factors with respect to prediction of CHD-related deaths [86]. Two large studies in Asian population reported significant associations between UA and CHD or mortality [87,88]. A prospective cohort study of 41,879 men and 48,514 women (> 35 years of age) followed over a mean of 8.2 years, showed that hyperuricemia (serum UA > 7 mg/dl) was associated with a significant 16%, 39% and 35% increase in the adjusted risk for all-cause mortality, total CVD or stroke, respectively. After adjustment, the risk of stroke in men was attenuated [87]. The other Asian study that included 128,569 adults (≥20 years of age) followed over 7.33 years (mean) showed an increased risk for incident CHD in men (adjusted HR = 1.25 [1.11–1.40]) and women (adjusted HR = 1.19 [1.02–1.38]) with hyperuricemia (UA ≥ 7 mg/dl) [88]. A large cohort of 83,683 Austrian men (mean age, 41.6 years) followed over a median of 13.6 years, showed that UA was associated with the risk of mortality from stroke (adjusted HR = 1.59 [1.23–2.04]; P < 0.001) or CHF (HR = 1.51 [1.03–2.22]; P = 0.03, with both risk estimates calculated for highest quintile vs. lowest UA quintile) but not with the risk of mortality from acute, subacute or chronic forms of CHD (P = 0.12) [89]. Another cohort study of 28613 Austrian women (mean age, 62.3 years), followed-up over 15.2 years (median), showed that UA was an independent correlate of all forms of death from CVD including acute, subacute and chronic forms of CHD, CHF or stroke [90]. The Tromsø Study - a population-based prospective cohort study of 2696 men and 3004 women with a 15-year follow-up - showed an association between serum UA and all-cause mortality in men (HR = 1.11 [1.02–1.20]) and women (HR = 1.16 [1.05–1.29]) and stroke in men (HR = 1.31 [1.14–1.50]) but not in women (HR = 1.13 [0.94–1.36]) calculated for 1 standard deviation (87 μmol/L) increase in UA level. No independent association between UA and the risk of myocardial infarction was observed [91]. A longitudinal Taiwanese cohort study of 127,771 adults (≥65 years of age) reported a U-shaped relationship between UA and all-cause or CVD mortality with higher mortality rates for UA levels < 4 mg/dl (HR = 1.16 [1.07–1.25]) and ≥ 8 mg/dl (HR = 1.13 [1.06–1.21]) compared to reference UA level of 4 to < 5 mg/dl over a median follow-up of 5.8 years. Likewise, CVD mortality was higher for UA levels < 4 mg/dl (HR = 1.19 [1.00–1.40]) and ≥ 7 mg/dl (HR = 1.17 [1.04–1.32]). Among subjects with low UA level (< 4 mg/dl) only malnourished subjects had greater all-cause or CVD-related mortality [92]. Another cross-sectional study of 8144 subjects undergoing general health screening showed an independent association between UA and prevalence of carotid plaques in men without metabolic syndrome [93]. Likewise, in the National Heart, Lung, and Blood Institute Family Heart Study that included 4866 participants, serum UA was associated with carotid atherosclerotic plaques (assessed by ultrasound imaging) in men, regardless of the presence of cardiovascular risk factors [94]. An association between UA and the risk for carotid atherosclerosis has been reported even in children and adolescents [95]. A small study has suggested an association between UA and carotid intima–media thickness independent of arterial hypertension [96]. Some studies [97–99] but not all of them [100] showed an association between elevated UA level and presence or severity of coronary artery calcification, an equivalent of coronary atherosclerosis. In one study, UA level predicted progression of coronary artery calcium in postmenopausal women [101]. Previous meta-analyses reached opposite conclusions with respect to the association between UA and CVD events or mortality [85,102,103]. Recent meta-analyses, however, confirmed a significant,

albeit modest, association between UA and CVD or mortality. A 2016 meta-analysis by Braga et al. [20] identified 12 population-based studies (457,915 subjects; 53.7% males) testing the association between UA and incident CHD and 7 studies (237,433 subjects; 66.3% males) investigating the association between UA and CHD mortality. Overall RR was 1.206 [1.066–1.364] (P = 0.003) for CHD incidence and 1.209 [1.003–1.457] (P = 0.047) for CHD mortality. Subgroup analysis showed a marginal and not significant association between hyperuricemia and CHD incidence or mortality, respectively, in men, but an increased risk for CHD incidence and mortality in hyperuricemic women (RR = 1.446 [1.323–1.581]; P < 0.0001, and RR = 1.830 [1.066–3.139], P = 0.028, respectively). The risk markedly increased for UA levels > 7.0 mg/dl. However, the meta-analysis has come under criticism for not assessing the validity of included studies and not accounting for residual confounding which may have distorted the association between UA and CHD or CHD mortality [104]. In another recent meta-analysis by Li et al. [78] that included 29 prospective cohort studies with 958,410 participants, hyperuricemia was associated with increased risk of CHD morbidity (adjusted RR = 1.13 [1.05–1.21]) and mortality (adjusted RR = 1.27 [1.16–1.39]). For each 1 mg/dl increase in UA level, the risk of CHD mortality increased by 13% (adjusted RR = 1.13 [1.06–1.20]). Dose-response analysis showed that for each 1 mg/dl increase in UA level, the risk of CHD mortality increased in women (RR = 2.44 [1.69–3.54]) but not in men (RR = 1.02 [0.84–1.24]) without heterogeneity in analyses. The meta-analysis showed that hyperuricemia may increase the risk of CHD events, particularly CHD-related mortality in women [78]. A 2009 meta-analysis by Kim et al. [105] that included 16 studies showed that hyperuricemia was associated with increased risk of stroke (RR = 1.41 [1.05–1.76]) and mortality (RR = 1.36 [1.03–1.69]). Both associations remained significant after adjustment for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol and adjusted risk estimates did not differ according to sex. A large recent Mendelian randomization study assessed genetic risk associated with UA based on 14 single nucleotide polymorphisms exclusively associated with serum UA levels. The study did not support a causal role of circulating serum UA in type 2 diabetes, CHD, ischemic stroke or CHF [106]. Notably, the study also suggested that decreasing serum UA levels may not translate into risk reductions for cardiometabolic conditions. In the same vein, an umbrella review of observational studies, randomized controlled trials, and Mendelian randomization studies exploring 136 unique health outcomes, found convincing evidence for a clear role of UA in gout and nephrolithiasis but not in CVD [107]. UA-lowering therapy has been used for putative beneficial effects in terms of reduction of CHD events and as an instrument to investigate causality relationship between UA and CHD. A recent meta-analysis of randomized controlled trials of patients with gout showed that UAlowering therapy did not reduce the composite of CVD death, non-fatal myocardial infarction or non-fatal stroke (RR = 1.47 [0.49–4.40]; P = 0.49) or all-cause mortality (RR = 1.45 [0.35–5.77, P = 0.60]) compared with placebo. There was no significant difference between febuxostat or allopurinol in terms of CVD events (RR = 1.69 [0.54–5.34]; P = 0.37). Of note, CVD events did not decrease over time in long-term studies with febuxostat vs. allopurinol and more CVD events occurred with febuxostat treatment [108]. The latter finding seems to be corroborated by a recent randomized trial which reported higher rates of all-cause (7.8% vs. 6.4%; HR = 1.22 [1.01–1.47]; P = 0.04) and cardiovascular (4.3% vs. 3.2%; HR = 1.34 [1.03–1.73]; P = 0.03) mortality with febuxostat than allopurinol over 32 months (median) of follow-up [109]. In aggregate, epidemiological evidence linking UA with CHD disease or mortality remains controversial. The association between UA level and the risk of stroke appears to be better supported. Although UA appears to be associated with higher risk of CHD or mortality in both sexes, the association seems to be stronger in women than men. Studies 154

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

the association between UA and cardiac or all-cause mortality showed a J-shaped pattern with lowest mortality observed in UA levels between 5.17 mg/dl and 6.76 mg/dl. A sex-by-UA interaction was observed showing a stronger association between UA and mortality in women than men (P for interaction = 0.019 for all-cause mortality and 0.059 for cardiac mortality) [119]. A recent meta-analysis that included 9 studies with 25,229 subjects with confirmed or suspected CHD showed that UA was associated with the risk of cardiovascular pooled RR = 2.09 [1.45–3.02] and all-cause mortality RR = 1.80 [1.39–2.34] after adjustment for potential confounders in a random effects model (with risk estimates calculated for highest vs. lowest UA categories). Moreover, each 1 mg/ml increase in UA level was associated with 12% and 20% increase in the risk for cardiovascular and all-cause mortality, respectively [120]. Several studies assessed the association between UA and outcome in patients with acute coronary syndromes, mostly acute myocardial infarction. Kojima et al. [121] showed that UA level correlated closely with Killip class and predicted the development of CHF and short- and long-term mortality. After adjustment, UA remained significantly associated with the increased risk of long-term mortality (HR = 3.716 [1.417–9.741]; P = 0.00765 for highest vs. lowest UA quartile). Lazzeri et al. [122] investigated the association between UA and in-hospital mortality in 466 patients with ST-segment elevation myocardial infarction. Increased UA levels (> 6.5 mg/dl) were observed in 21.5% of the patients. Higher UA levels were associated with higher in-hospital mortality (9.0% vs. 2.5%; OR = 3.9 [1.5–10.2]). After correction for sex, the presence of chronic obstructive pulmonary disease, Killip class, and diuretic use, UA remained independently associated with in-hospital mortality (OR = 2.02 [1.47–2.78]; P < 0.001). In another study of 856 patients with ST-elevation myocardial infarction, the same group of researchers showed that UA was independently associated with the risk of complications in intensive coronary care unit (OR = 1.11 [1.01–1.21] P = 0.03 for each 1 mg/dl higher UA level). Although UA was associated with the risk for mortality (OR = 1.24 [1.03–1.51]; P = 0.025), the significance was lost after adjustment for troponin I (a measure of myocardial damage) and renal dysfunction (assessed by estimated glomerular filtration rate) [123]. Our group assessed the association between UA and 1-year mortality in 5124 patients with acute coronary syndromes treated with percutaneous coronary intervention. Patients with ST-segment elevation myocardial infarction had significantly lower levels of UA compared with patients presenting with non-ST-segment elevation myocardial infarction or unstable angina. In patients with UA in the 1st, 2nd, 3rd and 4th UA quartiles, the KaplanMeier estimates of mortality were 6.4%, 6.2%, 5.6%, and 17.4%, respectively (adjusted HR = 1.12 [1.06–1.18]; P < 0.001 for each 1 mg/ dl higher UA level). Of note, when added in the multivariable model, UA improved prediction of mortality (absolute and relative integrated discrimination improvement 0.008 and 4.0%, respectively P = 0.005) [124]. A recent study that included 1039 asymptomatic individuals and 772 patients with acute myocardial infarction, showed no association between UA and coronary artery calcium and significantly higher UA levels in patients with type 2 myocardial infarction than type 1 myocardial infarction [125]. Since different pathophysiological mechanisms trigger type 1 (atherosclerotic plaque rupture leading to coronary occlusion) and type 2 (a supply/demand imbalance in myocardium) myocardial infarction, this study [125] and a previous one that showed lower UA levels in patients with ST-segment myocardial infarction compared with other presentations [124] seem to downplay the role of UA in atherosclerotic plaque rupture and subsequent acute coronary events. This issue, however, requires further research. In conclusion, evidence available suggests an independent association between elevated UA level and the risk of mortality in patients with confirmed CHD. However, in the absence of comparative studies in subjects with and without CHD, the question whether the association between UA and mortality is stronger in subjects with CHD, remained unanswered.

that have used contemporary discriminatory tests (like C-statistic, adjusted ROC curve analysis or net-reclassification index) did not show an improvement in outcome prediction when UA was added in prediction models alongside traditional cardiovascular risk factors. Thus, the question whether UA is a risk factor or simply a correlate (epiphenomenon) of cardiovascular risk clustered in subjects with elevated UA level remains unanswered. 3.2. UA and outcome in subjects with CHD Previous studies suggested that the presence of CHD may strengthen the association between UA and mortality [110,111]. UA and XOR activity have been identified in atherosclerotic plaques and involved in the etiology of atherosclerosis [112]. An association between UA level and severity of angiographic CHD (progressive increase in UA level in patients with 1, 2 and 3-vessel CHD disease) has been demonstrated in both sexes, which was attenuated after adjustment for cardiovascular risk factors [113,114]. The close association and intrinsic relationship between UA and cardiovascular risk factors and evidence from experimental studies indicating a possible role of UA in atherosclerotic plaque build-up and (in)stability (to be discussed later in this review) may suggest a particularly deleterious effect of elevated UA in patients with confirmed CHD. In 1017 patients with angiography-proven CHD (coronary stenoses with > 30% of lumen narrowing), Bickel et al. [115] reported a 5-fold (17.1% vs. 3.4%) increase in mortality in patients with UA in the highest quartile (> 7.1 mg/dl) vs. those with UA in the lowest quartile (< 5.1 mg/dl) over a 2.2-year follow-up. Both sexes showed an increased risk of death with increasing UA levels after adjustment for age (HR = 1.30 [1.14–1.49]; P < 0.001 in women and HR = 1.39 [1.21–1.59], P < 0.001 in men). After adjustment for 12 variables, UA remained significantly associated with all-cause mortality (adjusted HR = 1.23 [1.11–1.36]; P < 0.001). In 8832 patients with severe (≥75% lumen narrowing) coronary stenoses, Okura et al. [116] showed a significant and independent association between UA and combined cardiovascular events and mortality over a 3-year follow-up. The incidence rate of all events was significantly different among UA quartiles (58.3, 56.5, 61.2, 76.3 per 1000 patient-years, respectively; P < 0.001). The association remained significant after adjustment (HR = 1.25 [1.07–1.45], P < 0.01 for highest UA quartile) and propensity matching (HR = 1.25 [1.06–1.43]; P < 0.001). The group with an increase in UA level ≥ 1.0 mg/dl after 6 months had a significantly higher event rate than the group in which UA did not increase (70.6 vs. 58.8 per 1000 patient-years, P = 0.042). A retrospective cohort study of 1916 patients treated with percutaneous coronary intervention showed a strong trend toward an association between UA and mortality (HR = 1.25 [0.98–1.59; P = 0.07]) but no association between UA and the risk of major adverse cardiovascular events (P = 0.71) or myocardial infarction (P = 0.20) over a 7-year follow-up [117]. The LUdwigshafen RIsk and Cardiovascular health (LURIC) study assessed the association between UA and all-cause mortality, cardiovascular mortality, and sudden cardiac death in 3245 individuals referred for coronary angiography over 7.3 ± 2.3 years. After adjusting for sex and age, subjects in the 4th UA quartile had increased all-cause (HR of 1.68; P < 0.001), cardiovascular (HR of 2.00; P < 0.001) or sudden cardiac (HR of 2.27; P < 0.001) death. The associations remained significant after further adjustment for cardiovascular risk factors and severity of atherosclerosis; however, adjustment for medications abolished the association between the serum UA and all-cause mortality [118]. Our group assessed the association between serum UA and mortality in 13,273 patients with angiography-proven CHD. After adjustment for cardiovascular risk factors, C-reactive protein, renal function and left ventricular ejection fraction, UA remained significantly associated with cardiac (HR = 1.20 [1.08–1.34]; P = 0.001) and all-cause (HR = 1.19 [1.08–1.30]; P < 0.001) mortality (with both risk estimates calculated per standard deviation increase in the logarithmic UA scale). Notably, 155

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

degradation in the setting of CHF due to hypoxia, up-regulation of catabolic pathways, insulin resistance, increased rates of cell death and tissue wasting (particularly development of sarcopenia and cachexia at end stages of the disease) [137] and impaired renal excretion [140]. Despite these associations and proposed mechanisms involving UA in pathophysiology of CHF, it has been suggested that UA is simply a marker of increased XOR activity and excessive amounts of ROS rather than UA per se are responsible for cardiovascular dysfunction and increased risk [14,141]. Furthermore, the close association between UA and XOR activity [14], arterial hypertension [142] and atrial fibrillation [143], the latter two being major risk factors for CHF, points out to the difficulties in defining the true role of UA in CHF. As already mentioned, Mendelian randomization studies did not prove causality in the UA-CHF relationship [106]. UA-lowering therapy with XOR inhibitors (mostly allopurinol) has been extensively used to improve outcomes of patients with CHF. XOR inhibition repeatedly showed beneficial effects over a range of surrogate markers including myocardial mechanical efficiency [144], energy balance and increased concentration of high-energy phosphates [145], left ventricular ejection fraction [146], cardiac remodeling [147], peripheral blood flow [148], endothelial dysfunction [149] and reduced natriuretic peptide levels [150]. However, UA-lowering agents like benzbromarone [151] or probenecid [152], failed to improve hemodynamic parameters of CHF severity including echocardiographic dimensions, left ventricular ejection fraction or B-type natriuretic peptide level [151] or improve endothelial dysfunction [152] despite a significant reduction of UA levels comparable to those achieved by allopurinol. All direct UA-lowering drugs failed to improve endothelial dysfunction or other clinical parameters in patients with CHF [137]. Stimulated by results using surrogate endpoints in patients with CHF, interventional UA-lowering studies with hard clinical endpoints have been undertaken. However, the results of these studies have been mostly disappointing. The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) study randomized 405 patients with moderate to severe systolic CHF to receive XOR inhibitor oxypurinol (600 mg daily) or placebo for 24 weeks. Oxypurinol reduced serum UA by ~2 mg/dl. Treatment with oxypurinol was not associated with any significant effect on the primary endpoint of clinical status (percentage of patients characterized as improved, unchanged, or worsened clinical status) or with the composite endpoint of CHF, morbidity, mortality, and quality of life [153]. Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) trial randomized 253 patients with symptomatic CHF, left ventricular ejection fraction ≤40%, and serum UA levels≥9.5 mg/dl to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. Although, UA levels were significantly reduced with allopurinol compared to placebo, there were no changes in clinical status (worsened or improved) or left ventricular ejection fraction between allopurinol and placebo groups at 24 weeks of follow-up [154]. The study failed to show a benefit of UA lowering therapy with XOR inhibitor allopurinol in patients with symptomatic CHF and elevated UA level. In conclusion, epidemiological evidence supports an association between serum UA and incident CHF in general population. UA level correlates with severity of disease and increased risk of mortality in patients with CHF. The lack of association between UA and the risk of CHF in Mendelian randomization studies and failure of UA-lowering therapy to improve hard clinical outcomes despite marked reduction of UA levels do not support a causal relationship between UA and CHF. This, however, does not negate a pathogenic role of UA in in this clinical syndrome.

3.3. UA and congestive heart failure Elevated UA level is common in patients with CHF. A number of longitudinal studies [80,126–129] and meta-analyses [130,131] investigated the association between UA and incidence, severity or prognosis after CHF. The Framingham Offspring cohort study assessed the association between UA and incident CHF in 4912 participants (mean age at baseline 36 years; 52% women) over a 29-year median follow-up. The incidence rates of CHF were nearly 6-fold higher among those at the highest UA quartile of (> 6.3 mg/dl) compared with those at the lowest quartile (< 3.4 mg/dl). After adjusting for sex, age, smoking, body mass index, renal dysfunction, diuretic drugs, systolic blood pressure, valvular heart disease, diabetes, alcohol, and antihypertensive medications, the adjusted HR for incident CHF was 2.1 [1.04–4.22] for the highest vs. the lowest serum UA quartile. The association between hyperuricemia and CHF was found in participants without metabolic syndrome [126]. A propensity matching analysis of subjects with (baseline serum UA ≥6 mg/dl for women and ≥ 7 mg/dl for men) or without hyperuricemia in the setting of Cardiovascular Health Study (community-dwelling older adults ≥65 years without HF at baseline) reported a 30% higher risk of CHF (21% vs. 18%; HR = 1.30 [1.05–1.60]; P = 0.015) in participants with hyperuricemia during a 8.1-year follow-up. The association between hyperuricemia and incident CHF was significant only in subgroups with normal kidney function, and those without hypertension, thiazide diuretic drugs or hyperinsulinemia. Each 1 mg/dl increase in serum UA was associated with a 12% increase in the risk for incident CHF (HR = 1.12[1.03–1.22]; P = 0.006). In this study, hyperuricemia had no association with acute myocardial infarction or all-cause mortality [127]. A 2014 meta-analysis that included 28 studies reported that hyperuricemia was associated with increased risk of incident CHF (HR = 1.65 [1.41–1.94]), all-cause mortality (HR = 2.15 [1.64–2.83]), cardiovascular mortality (HR = 1.45 [1.18–1.78]) and composite of death or cardiac events (HR = 1.39 [1.18–1.63]) in patients with CHF. For every 1 mg/dl increase in serum UA, the risk of CHF increased by 19% (HR = 1.19 [1.17–1.21]) and the risk of all-cause mortality or composite endpoint in CHF patients increased by 4% (HR = 1.04 [1.02–1.06]) and 28% (HR = 1.28 [0.97–1.70]), respectively [131]. The British Regional Heart Study (3440 men, aged 60–79 years with no history of myocardial infarction or CHF and with and without hypertensive treatment) reported 260 incident CHF cases over a 15-year mean follow-up. Raised serum UA was associated with significantly increased risk of CHF in men on antihypertensive treatment but not in those without (P for interaction = 0.003). Treated hypertensive men with UA levels > 410 μmol/L showed an increased risk of CHF of > 2fold compared with those on treatment with UA levels < 350 μmol/L even after adjustment for lifestyle characteristics and risk factors (adjusted HR = 2.26 [1.23–4.15]). Of note, UA improved prediction for CHF beyond conventional risk factors (P = 0.02 for improvement in Cstatistics) [129]. In patients with established CHF, UA is associated with disease severity. Increased UA levels correlated with echocardiographic markers of myocardial or diastolic dysfunction [132,133], NYHA class and exercise capacity [134], impaired oxidative metabolism and oxygen consumption [135], impaired hemodynamic profile including higher right atrial and pulmonary arterial and capillary wedge pressure, higher pulmonary vascular resistance index and lower cardiac index [136], cachexia or endothelial dysfunction [134,135]. The association of UA with all-cause or cardiovascular mortality in patients with CHF was already mentioned. [131] Because of strong association between serum UA and CHF severity or prognosis, UA has been included in several outcome prediction models in patients with CHF [137]. Many factors leading to UA elevation and hyperuricemia in patients with CHF have been proposed [137]. The source of UA is likely multifactorial and includes increased production from ischemia-induced up-regulation of XOR activity in failing heart [14,138,139], increased purine

3.4. UA and arterial hypertension Epidemiological, clinical and experimental evidence supports an association between elevated UA level and the risk of arterial hypertension. A 2008 review by Feig et al. [59] listed 16 longitudinal 156

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

elevated UA and arterial hypertension. However, causality in the relationship between UA and arterial hypertension remains unproven and there is inconclusive evidence with respect to the use of UA-lowering agents to treat arterial hypertension.

studies showing that hyperuricemia increased the risk for arterial hypertension within 5 years, independent of other risk factors. Numerous subsequent studies further emphasized an increased risk for arterial hypertension associated with elevated UA level [155]. Although the relationship between hyperuricemia and hypertension is mutual, the observation that hyperuricemia precedes the development of hypertension indicates that it is not simply a consequence of hypertension per se. Hyperuricemia is more common in primary hypertension than in secondary hypertension and 25%–60% of subjects with untreated hypertension have hyperuricemia [59]. An UA level exceeding 5.5 mg/dl was observed in 90% of adolescents with essential arterial hypertension [156]. A cohort study of 12 to 17-year old adolescents in the US showed that high UA levels were independently associated with future development of arterial hypertension, independent of other risk factors [157]. Mean arterial blood pressure correlated with serum UA, cholesterol and XOR activity [158]. Experimental studies showed that raising the UA level results in elevated blood pressure mimicking arterial hypertension in humans. Tungsten-rich diets, which inactivate XOR, decreased blood pressure in salt-sensitive [159] or spontaneously hypertensive [160] rats suggesting a role of XOR in blood pressure elevation. UA levels also correlated with blood pressure in rats with mild hyperuricemia induced by oxonic acid - an urate oxidase inhibitor - and blood pressure elevation was preventable by treatment with allopurinol or an uricosuric agent [161]. The latter study suggested that high blood pressure was attributable to UA and not XOR. Renal biopsies from low-salt rats with oxonic acid-induced glomerular and systemic hypertension showed afferent arteriolar thickening; however both hypertension and renal findings were preventable with allopurinol [162]. Nevertheless, it remains unknown whether renal alterations were due to UA or arterial hypertension. Finally, clinical studies showed that reducing UA level with XOR inhibitors lowers blood pressure in subjects with arterial hypertension. A randomized, placebo-controlled study of hypertensive adolescents showed that allopurinol significantly reduced blood pressure and normalized blood pressure values in 20 of 30 participants [163]. Another randomized double-blinded, placebo-controlled trial tested the efficacy of allopurinol, probenecid (an uricosuric agent) versus placebo in reducing blood pressure in prehypertensive obese adolescents, 11–17 years of age. The study showed a significant reduction in blood pressure by UA-lowering therapy (systolic and diastolic blood pressure fell by 10.2 mmHg and 9.0 mmHg, respectively). UA-lowering therapy significantly reduced systemic vascular resistance, as well [164]. A 2013 meta-analysis that included 10 trials with 738 participants showed that compared with control group, allopurinol reduced blood pressure by 3.3 mmHg and diastolic blood pressure by 1.3 mmHg [165]. Despite this evidence, the benefits of UA lowering in hypertensive patients remain debatable and a recent Cochrane review concluded that there is insufficient evidence for the use of allopurinol or other UA lowering drugs as the initial treatment of arterial hypertension [166]. The change in serum UA level has been shown to predict the response to antihypertensive therapy in patients with hypertension. In the Systolic Hypertension in the Elderly (SHEP) trial – a study of 4327 men and women ≥60 years of age with isolated systolic hypertension and randomized to chlorthalidone or placebo - an increase of serum UA < 0.06 mmol/l (median change) in the active treatment group was associated with a 42% reduction in the rate of coronary events compared with those with a serum UA increase ≥0.06 mmol/l [167]. Likewise, the Losartan Intervention for Endpoint reduction (LIFE) study found losartan to be superior to atenolol in reducing cardiovascular events and mortality in patients with hypertension [168] which was at least partly attributable to uricosuric effect of losartan via inhibition of UA transporter URAT1 [169]. Mechanisms through which UA mediates blood pressure elevation and arterial hypertension are discussed later in this review. In conclusion, evidence from epidemiological, clinical, experimental and UA-lowering interventional studies suggests an association between

3.5. UA and atrial fibrillation Several studies have suggested an association between elevated UA and the risk for atrial fibrillation. In the Atherosclerosis Risk in Communities (ARIC) study – a multiethnic, community-based study – increasing UA levels were associated with higher risk of atrial fibrillation with a HR = 1.16 [1.06–1.26] per quartile of baseline UA level. The association was stronger in back population and women [170]. A higher risk of atrial fibrillation in diabetic patients with elevated UA level has also been reported [171]. A large study in Japanese population including 285,882 consecutive subjects showed a significant and independent association between UA level and the risk for atrial fibrillation with adjusted OR of 1.19 [1.14–1.24] < 0.0001 in men and OR of 1.44 [1.34–1.55] < 0.0001 in women [172]. A recent metaanalysis supports an association between elevated UA level and the risk for atrial fibrillation. In cross-sectional studies, median UA level was 6.2 (range 5.4–6.4) mg/dl in subjects with atrial fibrillation versus 5.1 (4.9–5.7) mg/dl in those without atrial fibrillation. In cohort studies, the RR of having AF was 1.67 [1.23–2.27] for those with high serum UA level (> 7 mg/dl) compared with those with low serum UA level [143]. Although, mechanisms for the association between UA and the risk for atrial fibrillation remain unclear, the association of elevated UA with cardiovascular risk factors (particularly arterial hypertension) and UAinduced oxidative stress, endothelial dysfunction and inflammation have been suggested as factors increasing the risk for atrial fibrillation [173]. An electrophysiological hypothesis suggesting that UA may increase susceptibility to atrial fibrillation has also been proposed. According to this hypothesis, UA enters atrial cells via UA transporters and induces the expression of Kv1.5 protein leading to increased activity of Kv1.5 ion and channel/Ikur current which shortens the action potential duration of atrial cardiomyocytes predisposing for atrial fibrillation [173]. Thus evidence available suggests an association between elevated UA and the risk for atrial fibrillation but many aspects of this association remain unclear. 4. Pathophysiological mechanisms of UA involvement in CVD Putative mechanisms through which UA participates in CVD are summarized in Fig. 2. In principle, these mechanisms may belong to 3 categories. First, UA is correlated closely with almost all known cardiovascular risk factors [89], insulin resistance [174,175], metabolic syndrome [95,176], obesity [177], non-alcoholic fatty liver disease [178] and chronic kidney disease [179,180]. In many instances, there is a mutual relationship between UA and these conditions and teasing out the individual contribution of each factor has proven difficult. In this regard, an elevated UA level may be seen as a correlate of cardiovascular risk or an epiphenomenon of co-existing cardio-metabolic risk factors (a risk marker). Second, UA is a product of XOR, which is known to be one of the most important courses of ROS in organism. Elevated UA level may be a marker or a consequence of up-regulated or increased XOR activity and increased oxidative stress. XOR per se has far reaching implications in CVD mostly but not entirely related to ROS generation and increased oxidative stress [14–16]. XOR is closely related with another major ROS producer, the enzyme NADPH oxidase (ROS produced by XOR activate NADPH oxidase and vice versa) [16]. Third, UA per se exerts a plethora of deleterious effects in cells and thus it may be directly involved in the pathophysiology of CVD. In general, pro-oxidant activity, depletion of nitric oxide (NO) and endothelial dysfunction, promotion of inflammation and potentiation of 157

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

Fig. 2. Putative mechanisms of participation of uric acid in cardiovascular disease. Cox2 = cyclooxygenase-2; CRP=C-reactive protein; IL = interleukin; TNF = tumor necrosis factor; eNOS = ethothelial nitric oxide synthase; LDL = low-density lipoprotein; MAPK = mitogen-activated protein kinase; MCP1 = monocyte chemoattractant protein-1; NADPH = nicotinamide adenine dinucleotide phosphate; NAFLD = non-alcoholic fatty liver disease; NF-kB = nuclear factor kappa b; NO = nitric oxide; OxLDL = oxidized LDL; ROS = reactive oxygen species; VEGF = vascular endothelial growth factor; VSMC = vascular smooth muscle cell. Plus sign means stimulation; minus sign means inhibition (or reduction).

reacts direct with NO in a rapid and irreversible reaction resulting in production of 6-aminouracil and nitric oxide depletion [187]. Moreover, UA blocks insulin and vascular endothelial growth factor (VEGF)mediated eNOS and NO release [188,189], blocks uptake [190] and stimulates degradation [191] of amino acid L-arginine (the substrate used by eNOS to produce NO). Since endothelium-derived NO, controls vascular tone, prevents platelet adhesion and aggregation and reduce intima proliferation, reduced NO availability is a major cause of endothelial dysfunction and increased vascular risk associated with hyperuricemia [192]. Population-based studies have shown that elevated serum UA level was associated with white blood cell count, neutrophils, C-reactive protein, interleukin (IL)-6, IL-6 receptor antagonist, IL-10, IL18 and tumor-necrosis factor-α [23,193,194]. UA stimulates human mononuclear cells to produce IL-1ß, IL-6 and TNF-α [195] and smooth muscle cells to produce monocyte chemoattractant protein-1 (MCP-1) [195], known to play a major role in the initiation of atherosclerotic lesions. It is believes that the pathway leading to MCP-1 expression by UA involves the nuclear factor kappa b (NF-kB) and mitogen-activated protein-kinase (MAPK) pathway [195]. Moreover, UA may serve as an internal danger signal that stimulates innate immune response [196], known to play a major role in atherosclerosis, arterial hypertension, CHF and renal disease. Experimental studies showed that UA promotes vasoconstriction

vasoconstrictor and proliferative vascular stimuli are the most accepted mechanisms of UA involvement in the pathophysiology of CVD. UA acts as antioxidant and has an important physiological role in protection against oxidative stress. UA reacts and neutralizes several oxidants including singlet oxygen, superoxide, peroxyl and hydroxyl radicals and protects vascular endothelium from external oxidative stress [140]. UA also prevents peroxynitrite-induced protein nitrasation, lipid and protein peroxidation, inactivation of tetrahydrobiopterin - a cofactor for endothelial nitric oxide synthase (eNOS) - and Cu2+-mediated lowdensity lipoprotein oxidation [45]. However, depending on the surrounding chemical milieu, UA may convert to pro-oxidant in cytoplasm or atherosclerotic plaques. In the presence of transition metals, UA may further oxidize, partially oxidized (preformed lipid hydroperoxides) low-density lipoproteins [181,182] leading to deeper low-density lipoprotein oxidation. The reaction of UA with peroxynitrites produces several radicals including aminocarbonyl and triuretcarbonyl radicals and products with alkylating activity [183,184] which could propagate the pro-oxidant state [45]. If this reaction takes place in plasma, these products are rapidly neutralized by ascorbic acid [185]. Of note, UA is present in atherosclerotic plaques and according to redox shuttle theory acts as prooxidant in hydrophobic/acidic milieu [186]. Reduced NO availability is one of the most important and accepted pathophysiological mechanism through which UA promotes CVD. UA 158

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

Conflicts of interest

and vascular smooth muscle cell proliferation. It has been shown that UA increases the expression of angiotensin II in vascular endothelial cells [197] and activates intrarenal renin-angiotensin system in humans [198]. Human studies demonstrated an association between serum UA and renin activity in patients with arterial hypertension [199] and oxonic acid induced hyperuricemia elevates plasma aldosterone in rats with experimental renal insufficiency [200]. However, in one recently published randomized study UA-lowering therapy had no effect on kidney-specific or systemic renin-angiotensin system or on mean systolic blood pressure after 8 weeks of therapy with probenecid or allopurinol [201]. UA stimulates the expression of endothelin-1 in human aortic smooth muscle cells [202] and rat cardiac fibroblasts [203]. Hyperuricemic rats showed increased renal renin and cyclooxygenase-2 (COX-2) expression suggesting a critical role of UA-mediated COX-2 generated thromboxane A2 in vascular smooth muscle cell proliferation, increased blood pressure and renal disease [204]. In vitro studies in rats showed that UA enters vascular smooth muscle cells via UART1 transporter [205] and stimulates their proliferation with increased expression of platelet-derived growth factor (PDGF), COX-2, and MCP-1 [206,207]. UA enters adipocytes via URAT1 transporters [208] and increases oxidative stress in these cells leading to inflammation, insulin resistance and a decrease in adiponectin synthesis [208]. Serum UA is independently associated with serum leptin concentration in diabetic patients [209]. UA inhibits AMP-activated protein kinase stimulating gluconeogenesis and glucose production in diabetes and starvation [210] and growth of pancreatic beta cells [211] contributing to glucose metabolism dysregulation. These and a multitude of dysmetabolic effects produced by elevated XOR activity [15] supposed to parallel elevated UA level may contribute to metabolic syndrome, known to be intrinsically linked to hyperuricemia.

None. Funding None. References [1] G. Nuki, P.A. Simkin, A concise history of gout and hyperuricemia and their treatment, Arthritis Res. Ther. 8 (Suppl. 1) (2006), http://dx.doi.org/10.1186/ ar1906. [2] K.W. Scheele, Examen chemicum calculi urinarii [A chemical examination of kidney stones], Opuscula 2 (1776) 73–79. [3] G. Pearson, Experiments and observations, tending to show the composition and properties of urinary concretions, Phil. Trans. R. Soc. London 88 (1798) 15–46. [4] L. Medicus, Zur Constitution der Harnsäuregruppe, Justus Liebigs Ann. Chem 175 (1875) 230–251. [5] E. Fischer, Ueber die Constitution des Caffeins, Xanthins, Hypoxanthins und Verwandter Basen, Ber. Dtsch. Chem. Ges. 30 (1897) 549–559. [6] E. Fischer, Synthesen in der Puringruppe, Ber. Dtsch. Chem. Ges. 32 (1899) 435–504. [7] A.B. Garrod, Observations on certain pathological conditions of the blood and urine in gout, rheumatism and Bright's disease, Trans. Med. Chir. Soc. Edinb. 31 (1848) 83–97. [8] F.A. Mohamed, On Bright's disease, and its essential symptoms, Lancet 1 (1879) 399–401. [9] A. Haig, M.D. Oxon, On uric acid and arterial tension, BMJ 1 (1889) 288–291. [10] M.M. Gertler, S.M. Garn, S.A. Levine, Serum uric acid in relation to age and physique in health and in coronary heart disease, Ann. Intern. Med. 34 (1951) 1421–1431. [11] T.R. Dawber, G.F. Meadors, F.E. Moore Jr., Epidemiological approaches to heart disease: the Framingham study, Am. J. Public Health Nation Health 41 (1951) 279–281. [12] W.B. Kannel, W.P. Castelli, P.M. McNamara, The coronary profile: 12-year followup in the Framingham study, J. Occup. Med. 9 (1967) 611–619. [13] K.J. Davies, A. Sevanian, S.F. Muakkassah-Kelly, P. Hochstein, Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid, Biochem. J. 235 (1986) 747–754. [14] C.E. Berry, J.M. Hare, Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications, J. Physiol. 555 (2004) 589–606. [15] M.G. Battelli, L. Polito, A. Bolognesi, Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress, Atherosclerosis 237 (2014) 562–567. [16] M.G. Battelli, A. Bolognesi, L. Polito, Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme, Biochim. Biophys. Acta 1842 (2014) 1502–1517. [17] Y. Zhu, B.J. Pandya, H.K. Choi, Prevalence of gout and hyperuricemia in the US general population: the National Health and nutrition examination survey 20072008, Arthritis Rheum. 63 (2011) 3136–3141. [18] D. Khanna, J.D. Fitzgerald, P.P. Khanna, S. Bae, M.K. Singh, T. Neogi, 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) 64 (2012) 1431–1446. [19] G. Desideri, G. Castaldo, A. Lombardi, M. Mussap, A. Testa, R. Pontremoli, et al., Is it time to revise the normal range of serum uric acid levels? Eur. Rev. Med. Pharmacol. Sci. 18 (2014) 1295–1306. [20] F. Braga, S. Pasqualetti, S. Ferraro, M. Panteghini, Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis, Clin. Chem. Lab. Med. 54 (2016) 7–15. [21] J. Maiuolo, F. Oppedisano, S. Gratteri, C. Muscoli, V. Mollace, Regulation of uric acid metabolism and excretion, Int. J. Cardiol. 213 (2016) 8–14. [22] R.J. Johnson, Y.Y. Sautin, W.J. Oliver, C. Roncal, W. Mu, L. Gabriela SanchezLozada, et al., Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? J. Comp. Physiol. B. 179 (2009) 67–76. [23] C. Chen, J.M. Lu, Q. Yao, Hyperuricemia-related diseases and xanthine oxidoreductase (XOR) inhibitors: an overview, Med. Sci. Monit. 22 (2016) 2501–2512. [24] M. Oda, Y. Satta, O. Takenaka, N. Takahata, Loss of urate oxidase activity in hominoids and its evolutionary implications, Mol. Biol. Evol. 19 (2002) 640–653. [25] X.W. Wu, D.M. Muzny, C.C. Lee, C.T. Caskey, Two independent mutational events in the loss of urate oxidase during hominoid evolution, J. Mol. Evol. 34 (1992) 78–84. [26] Y. Hellsten-Westing, Immunohistochemical localization of xanthine oxidase in human cardiac and skeletal muscle, Histochemistry 100 (1993) 215–222. [27] J. Cejkova, T. Ardan, M. Filipec, A. Midelfart, Xanthine oxidoreductase and xanthine oxidase in human cornea, Histol. Histopathol. 17 (2002) 755–760. [28] N. Linder, J. Rapola, K.O. Raivio, Cellular expression of xanthine oxidoreductase protein in normal human tissues, Lab. Investig. 79 (1999) 967–974. [29] K. Chaudhary, K. Malhotra, J. Sowers, A. Aroor, Uric acid - key ingredient in the recipe for cardiorenal metabolic syndrome, Cardiorenal Med. 3 (2013) 208–220. [30] H.K. Choi, K. Atkinson, E.W. Karlson, W. Willett, G. Curhan, Purine-rich foods,

5. Concluding remarks Despite nearly 140 years of research, the association of UA with CVD remains contentious. The association between elevated UA and increased risk for CVD is undisputable, yet causality in the UA-CVD relationship remains unproven. Thus there is no definitive answer to the question whether elevated UA is directly and independently involved in the pathophysiology of CVD (risk factor) or it is a correlate or epiphenomenon of increased cardiovascular risk (risk marker). Difficulties in determining whether UA acts as a risk marker or a risk factor for CVD may be explained by its frequent association and intricate relationship with other cardiovascular risk factors, possibility of reverse causation and conflicting findings from epidemiological and clinical studies undertaken to investigate the association of UA with CVD. Mendelian randomization studies and intervention studies with UA-lowering therapy – commonly seen as research tools to (dis)prove the causality relationship –have offered no evidence to support a causal relationship between elevated UA and CVD thus far. However, since causality in genetic studies is seldom deterministic but probabilistic [212], Mendelian randomization studies are not gold standard to make causality conclusions. Furthermore, high-quality intervention studies with epidemiological credentials to assess causality (powered for CVD outcomes and of sufficient duration) are missing. A bidirectional and intrinsic relationship between elevated UA and CVD risk factors may imply that UA is not merely a bystander or an epiphenomenon of these conditions but it may play a causal (direct or by proxy) role in the pathophysiology CVD. The latter possibility is strongly supported by experimental studies that have evidenced a plethora of mechanisms through UA exerts its deleterious effects on molecular and cellular level. Thus if not causal, UA may be pathogenic by serving as a bridging mechanism mediating or potentiating the deleterious effects of cardiovascular risk factors on vascular tissue and myocardium [213]. UA is a metabolite of distinction and the clarification of its role in CVD will remain a fascinating research field in the foreseeable future. 159

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] [41] [42] [43]

[44] [45] [46] [47] [48]

[49]

[50]

[51]

[52]

[53]

[54] [55] [56]

[57]

[58]

[59] [60]

[61]

dairy and protein intake, and the risk of gout in men, N. Engl. J. Med. 350 (2004) 1093–1103. D. Gustafsson, R. Unwin, The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality, BMC Nephrol. 14 (2013) 164. F. Schardinger, Über das Verhalten der Kuhmilch gegen Methyleneblau und seine Verwendung zur Unterscheidung von ungekochter und gekochter Milch, Z Untersuch Nahrungs Genussmittel 5 (1902) 1113–1121. T. Nishino, K. Okamoto, B.T. Eger, E.F. Pai, T. Nishino, Mammalian xanthine oxidoreductase - mechanism of transition from xanthine dehydrogenase to xanthine oxidase, FEBS J. 275 (2008) 3278–3289. C.M. Harris, V. Massey, The reaction of reduced xanthine dehydrogenase with molecular oxygen reaction kinetics and measurement of superoxide radical, J. Biol. Chem. 272 (1997) 8370–8379. M. Saksela, R. Lapatto, K.O. Raivio, Irreversible conversion of xanthine dehydrogenase into xanthine oxidase by a mitochondrial protease, FEBS Lett. 443 (1999) 117–120. N. Cantu-Medellin, E.E. Kelley, Xanthine oxidoreductase-catalyzed reactive species generation: a process in critical need of reevaluation, Redox Biol. 1 (2013) 353–358. T. Iwasaki, K. Okamoto, T. Nishino, J. Mizushima, H. Hori, Sequence motif-specific assignment of two [2Fe-2S] clusters in rat xanthine oxidoreductase studied by site-directed mutagenesis, J. Biochem. 127 (2000) 771–778. R. Radi, H. Rubbo, K. Bush, B.A. Freeman, Xanthine oxidase binding to glycosaminoglycans: kinetics and superoxide dismutase interactions of immobilized xanthine oxidase-heparin complexes, Arch. Biochem. Biophys. 339 (1997) 125–135. P. Xu, P. LaVallee, J.R. Hoidal, Repressed expression of the human xanthine oxidoreductase gene E-box and TATA-like elements restrict ground state transcriptional activity, J. Biol. Chem. 275 (2000) 5918–5926. C.D. Brondino, M.J. Romao, I. Moura, J.J. Moura, Molybdenum and tungsten enzymes: the xanthine oxidase family, Curr. Opin. Chem. Biol. 10 (2006) 109–114. N. Schlesinger, New agents for the treatment of gout and hyperuricemia: febuxostat, puricase, and beyond, Curr. Rheumatol. Rep. 12 (2010) 130–134. P. Richette, T. Bardin, Gout, Lancet 375 (2010) 318–328. X. Zhou, L. Matavelli, E.D. Frohlich, Uric acid: its relationship to renal hemodynamics and the renal renin-angiotensin system, Curr. Hypertens. Rep. 8 (2006) 120–124. G. Bellomo, Uric acid and chronic kidney disease: a time to act? World J. Nephrol. 2 (2013) 17–25. A. So, B. Thorens, Uric acid transport and disease, J. Clin. Invest. 120 (2010) 1791–1799. I.A. Bobulescu, O.W. Moe, Renal transport of uric acid: evolving concepts and uncertainties, Adv. Chronic Kidney Dis. 19 (2012) 358–371. X. Xu, C. Li, P. Zhou, T. Jiang, Uric acid transporters hiding in the intestine, Pharm. Biol. 54 (2016) 3151–3155. R. Augustin, M.O. Carayannopoulos, L.O. Dowd, J.E. Phay, J.F. Moley, K.H. Moley, Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking, J. Biol. Chem. 279 (2004) 16229–16236. A. Mobasheri, H. Dobson, S.L. Mason, F. Cullingham, M. Shakibaei, J.F. Moley, et al., Expression of the GLUT1 and GLUT9 facilitative glucose transporters in embryonic chondroblasts and mature chondrocytes in ovine articular cartilage, Cell Biol. Int. 29 (2005) 249–260. M. Hosoyamada, K. Ichida, A. Enomoto, T. Hosoya, H. Endou, Function and localization of urate transporter 1 in mouse kidney, J. Am. Soc. Nephrol. 15 (2004) 261–268. A. Kottgen, E. Albrecht, A. Teumer, V. Vitart, J. Krumsiek, C. Hundertmark, et al., Genome-wide association analyses identify 18 new loci associated with serum urate concentrations, Nat. Genet. 45 (2013) 145–154. M. Kolz, T. Johnson, S. Sanna, A. Teumer, V. Vitart, M. Perola, et al., Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations, PLoS Genet. 5 (2009) e1000504. Q. Yang, A. Kottgen, A. Dehghan, A.V. Smith, N.L. Glazer, M.H. Chen, et al., Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors, Circ. Cardiovasc. Genet. 3 (2010) 523–530. E. Krishnan, C.N. Lessov-Schlaggar, R.E. Krasnow, G.E. Swan, Nature versus nurture in gout: a twin study, Am. J. Med. 125 (2012) 499–504. A. Hosomi, T. Nakanishi, T. Fujita, I. Tamai, Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2, PLoS ONE 7 (2012) e30456. H. Yano, Y. Tamura, K. Kobayashi, M. Tanemoto, S. Uchida, Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease, Clin. Exp. Nephrol. 18 (2014) 50–55. K. Ichida, H. Matsuo, T. Takada, A. Nakayama, K. Murakami, T. Shimizu, et al., Decreased extra-renal urate excretion is a common cause of hyperuricemia, Nat. Commun. 3 (2012) 764. H. Matsuo, T. Tsunoda, K. Ooyama, M. Sakiyama, T. Sogo, T. Takada, et al., Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2, Sci. Rep. 6 (2016) 31003. D.I. Feig, D.H. Kang, R.J. Johnson, Uric acid and cardiovascular risk, N. Engl. J. Med. 359 (2008) 1811–1821. J.T. Kratzer, M.A. Lanaspa, M.N. Murphy, C. Cicerchi, C.L. Graves, P.A. Tipton, et al., Evolutionary history and metabolic insights of ancient mammalian uricases, Proc. Natl. Acad. Sci. U. S. A. 111 (2014) 3763–3768. G. van den Berghe, M. Bronfman, R. Vanneste, H.G. Hers, The mechanism of

[62]

[63]

[64]

[65] [66] [67] [68]

[69] [70]

[71]

[72]

[73]

[74] [75] [76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

160

adenosine triphosphate depletion in the liver after a load of fructose. A kinetic study of liver adenylate deaminase, Biochem. J. 162 (1977) 601–609. R.J. Johnson, S.E. Perez-Pozo, Y.Y. Sautin, J. Manitius, L.G. Sanchez-Lozada, D.I. Feig, et al., Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr. Rev. 30 (2009) 96–116. T. Nakagawa, H. Hu, S. Zharikov, K.R. Tuttle, R.A. Short, O. Glushakova, et al., A causal role for uric acid in fructose-induced metabolic syndrome, Am. J. Physiol. Ren. Physiol. 290 (2006) F625–F631. C. Kaneko, J. Ogura, S. Sasaki, K. Okamoto, M. Kobayashi, K. Kuwayama, et al., Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation, Biochim. Biophys. Acta 1861 (2017) 559–566. G.K. Glantzounis, E.C. Tsimoyiannis, A.M. Kappas, D.A. Galaris, Uric acid and oxidative stress, Curr. Pharm. Des. 11 (2005) 4145–4151. B. Alvarez-Lario, J. Macarron-Vicente, Is there anything good in uric acid? QJM 104 (2011) 1015–1024. P. Proctor, Similar functions of uric acid and ascorbate in man? Nature 228 (1970) 868. B.N. Ames, R. Cathcart, E. Schwiers, P. Hochstein, Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis, Proc. Natl. Acad. Sci. U. S. A. 78 (1981) 6858–6862. J.A. Sofaer, A.E. Emery, Genes for super-intelligence? J. Med. Genet. 18 (1981) 410–413. S. Watanabe, D.H. Kang, L. Feng, T. Nakagawa, J. Kanellis, H. Lan, et al., Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity, Hypertension 40 (2002) 355–360. G. Toncev, B. Milicic, S. Toncev, G. Samardzic, Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction, Eur. J. Neurol. 9 (2002) 221–226. C.F. Kuo, K.H. Yu, S.F. Luo, Y.S. Ko, M.S. Wen, Y.S. Lin, et al., Role of uric acid in the link between arterial stiffness and cardiac hypertrophy: a cross-sectional study, Rheumatology (Oxford) 49 (2010) 1189–1196. M.C. Irizarry, R. Raman, M.A. Schwarzschild, L.M. Becerra, R.G. Thomas, R.C. Peterson, et al., Plasma urate and progression of mild cognitive impairment, Neurodegener. Dis. 6 (2009) 23–28. Y. Shi, J.E. Evans, K.L. Rock, Molecular identification of a danger signal that alerts the immune system to dying cells, Nature 425 (2003) 516–521. F. Martinon, V. Petrilli, A. Mayor, A. Tardivel, J. Tschopp, Gout-associated uric acid crystals activate the NALP3 inflammasome, Nature 440 (2006) 237–241. K.L. Wallace, A.A. Riedel, N. Joseph-Ridge, R. Wortmann, Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population, J. Rheumatol. 31 (2004) 1582–1587. T.R. Mikuls, J.T. Farrar, W.B. Bilker, S. Fernandes, H.R. Schumacher Jr., K.G. Saag, Gout epidemiology: results from the UK general practice research database, 19901999, Ann. Rheum. Dis. 64 (2005) 267–272. M. Li, X. Hu, Y. Fan, K. Li, X. Zhang, W. Hou, et al., Hyperuricemia and the risk for coronary heart disease morbidity and mortality a systematic review and dose-response meta-analysis, Sci. Rep. 6 (2016) 19520. J. Fang, M.H. Alderman, Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and nutrition examination survey, JAMA 283 (2000) 2404–2410. I. Holme, A.H. Aastveit, N. Hammar, I. Jungner, G. Walldius, Uric acid and risk of myocardial infarction, stroke and congestive heart failure in 417,734 men and women in the apolipoprotein MOrtality RISk study (AMORIS), J. Intern. Med. 266 (2009) 558–570. C. Meisinger, W. Koenig, J. Baumert, A. Doring, Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1186–1192. L.K. Niskanen, D.E. Laaksonen, K. Nyyssonen, G. Alfthan, H.M. Lakka, T.A. Lakka, 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. 164 (2004) 1546–1551. M.J. Bos, P.J. Koudstaal, A. Hofman, J.C. Witteman, M.M. Breteler, Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study, Stroke 37 (2006) 1503–1507. B.F. Culleton, M.G. Larson, W.B. Kannel, D. Levy, Serum uric acid and risk for cardiovascular disease and death: the Framingham heart study, Ann. Intern. Med. 131 (1999) 7–13. J.G. Wheeler, K.D. Juzwishin, G. Eiriksdottir, V. Gudnason, J. Danesh, Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis, PLoS Med. 2 (2005) e76. S.K. Zalawadiya, V. Veeranna, S. Mallikethi-Reddy, C. Bavishi, A. Lunagaria, A. Kottam, et al., Uric acid and cardiovascular disease risk reclassification: findings from NHANES III, Eur. J. Prev. Cardiol. 22 (2015) 513–518. J.H. Chen, S.Y. Chuang, H.J. Chen, W.T. Yeh, W.H. Pan, Serum uric acid level as an independent risk factor for all-cause, cardiovascular, and ischemic stroke mortality: a Chinese cohort study, Arthritis Rheum. 61 (2009) 225–232. S.Y. Chuang, J.H. Chen, W.T. Yeh, C.C. Wu, W.H. Pan, Hyperuricemia and increased risk of ischemic heart disease in a large Chinese cohort, Int. J. Cardiol. 154 (2012) 316–321. A. Strasak, E. Ruttmann, L. Brant, C. Kelleher, J. Klenk, H. Concin, et al., Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83,683 Austrian men, Clin. Chem. 54 (2008) 273–284. A.M. Strasak, C.C. Kelleher, L.J. Brant, K. Rapp, E. Ruttmann, H. Concin, et al., Serum uric acid is an independent predictor for all major forms of cardiovascular

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110] [111]

[112]

[113]

[114]

[115]

[116]

death in 28,613 elderly women: a prospective 21-year follow-up study, Int. J. Cardiol. 125 (2008) 232–239. H.M. Storhaug, J.V. Norvik, I. Toft, B.O. Eriksen, M.L. Lochen, S. Zykova, et al., Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from the Tromso study, BMC Cardiovasc. Disord. 13 (2013) 115. W.C. Tseng, Y.T. Chen, S.M. Ou, C.J. Shih, D.C. Tarng, Taiwan Geriatric kidney disease research, U-shaped association between serum uric acid levels with cardiovascular and all-cause mortality in the elderly: the role of malnourishment, J. Am. Heart Assoc. (2018) 7. N. Ishizaka, Y. Ishizaka, E. Toda, R. Nagai, M. Yamakado, Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 1038–1044. T. Neogi, R.C. Ellison, S. Hunt, R. Terkeltaub, D.T. Felson, Y. Zhang, Serum uric acid is associated with carotid plaques: the National Heart, Lung, and Blood Institute family heart study, J. Rheumatol. 36 (2009) 378–384. L. Pacifico, V. Cantisani, C. Anania, E. Bonaiuto, F. Martino, R. Pascone, et al., Serum uric acid and its association with metabolic syndrome and carotid atherosclerosis in obese children, Eur. J. Endocrinol. 160 (2009) 45–52. Y. Tavil, M.G. Kaya, S.O. Oktar, N. Sen, K. Okyay, H.U. Yazici, et al., Uric acid level and its association with carotid intima-media thickness in patients with hypertension, Atherosclerosis 197 (2008) 159–163. H. Wang, D.R. Jacobs Jr., A.L. Gaffo, M.D. Gross, D.C. Goff Jr., J.J. Carr, Longitudinal association between serum urate and subclinical atherosclerosis: the coronary artery risk development in young adults (CARDIA) study, J. Intern. Med. 274 (2013) 594–609. C. Grossman, J. Shemesh, N. Koren-Morag, G. Bornstein, I. Ben-Zvi, E. Grossman, Serum uric acid is associated with coronary artery calcification, J. Clin. Hypertens. (Greenwich) 16 (2014) 424–428. H. Kim, S.H. Kim, A.R. Choi, S. Kim, H.Y. Choi, H.J. Kim, et al., Asymptomatic hyperuricemia is independently associated with coronary artery calcification in the absence of overt coronary artery disease: a single-center cross-sectional study, Medicine (Baltimore) 96 (2017) e6565. T. Neogi, R. Terkeltaub, R.C. Ellison, S. Hunt, Y. Zhang, Serum urate is not associated with coronary artery calcification: the NHLBI family heart study, J. Rheumatol. 38 (2011) 111–117. R.Y. Calvo, M.R. Araneta, D. Kritz-Silverstein, G.A. Laughlin, E. Barrett-Connor, Relation of serum uric acid to severity and progression of coronary artery calcium in postmenopausal white and Filipino women (from the Rancho Bernardo study), Am. J. Cardiol. 113 (2014) 1153–1158. S.Y. Kim, J.P. Guevara, K.M. Kim, H.K. Choi, D.F. Heitjan, D.A. Albert, Hyperuricemia and coronary heart disease: a systematic review and meta-analysis, Arthritis Care Res. 62 (2010) 170–180. G. Zhao, L. Huang, M. Song, Y. Song, Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies, Atherosclerosis 231 (2013) 61–68. A. Battaggia, A. Scalisi, L. Puccetti, Hyperuricemia does not seem to be an independent risk factor for coronary heart disease, Clin. Chem. Lab. Med. 56 (2018) e59-e62. S.Y. Kim, J.P. Guevara, K.M. Kim, H.K. Choi, D.F. Heitjan, D.A. Albert, Hyperuricemia and risk of stroke: a systematic review and meta-analysis, Arthritis Rheum. 61 (2009) 885–892. T. Keenan, W. Zhao, A. Rasheed, W.K. Ho, R. Malik, J.F. Felix, et al., Causal assessment of serum urate levels in Cardiometabolic diseases through a Mendelian randomization study, J. Am. Coll. Cardiol. 67 (2016) 407–416. X. Li, X. Meng, M. Timofeeva, I. Tzoulaki, K.K. Tsilidis, J.P. Ioannidis, 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 357 (2017) j2376. T. Zhang, J.E. Pope, Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis, Rheumatology (Oxford) 56 (2017) 1144–1153. W.B. White, K.G. Saag, M.A. Becker, J.S. Borer, P.B. Gorelick, A. Whelton, et al., Cardiovascular safety of Febuxostat or allopurinol in patients with gout, N. Engl. J. Med. 378 (2018) 1200–1210. M. Torun, S. Yardim, B. Simsek, S. Burgaz, Serum uric acid levels in cardiovascular diseases, J. Clin. Pharm. Ther. 23 (1998) 25–29. A.G. Ioachimescu, D.M. Brennan, B.M. Hoar, S.L. Hazen, B.J. Hoogwerf, Serum uric acid is an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiology information system (PreCIS) database cohort study, Arthritis Rheum. 58 (2008) 623–630. P. Patetsios, M. Song, W.P. Shutze, C. Pappas, W. Rodino, J.A. Ramirez, et al., Identification of uric acid and xanthine oxidase in atherosclerotic plaque, Am. J. Cardiol. 88 (2001) 188–191 (A6). G. Ndrepepa, S. Braun, L. King, M. Hadamitzky, H.U. Haase, K.A. Birkmeier, et al., Association of uric acid with mortality in patients with stable coronary artery disease, Metabolism 61 (2012) 1780–1786. G. Ndrepepa, S. Cassese, S. Braun, M. Fusaro, L. King, T. Tada, et al., A genderspecific analysis of association between hyperuricaemia and cardiovascular events in patients with coronary artery disease, Nutr. Metab. Cardiovasc. Dis. 23 (2013) 1195–1201. C. Bickel, H.J. Rupprecht, S. Blankenberg, G. Rippin, G. Hafner, A. Daunhauer, et al., Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease, Am. J. Cardiol. 89 (2002) 12–17. T. Okura, J. Higaki, M. Kurata, J. Irita, K. Miyoshi, T. Yamazaki, et al., Elevated serum uric acid is an independent predictor for cardiovascular events in patients

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

[126] [127]

[128]

[129]

[130]

[131] [132]

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141] [142]

[143]

[144]

[145]

161

with severe coronary artery stenosis: subanalysis of the Japanese coronary artery disease (JCAD) study, Circ. J. 73 (2009) 885–891. D.B. Spoon, A. Lerman, A.D. Rule, A. Prasad, R.J. Lennon, D.R. Holmes, et al., The association of serum uric acid levels with outcomes following percutaneous coronary intervention, J. Interv. Cardiol. 23 (2010) 277–283. G. Silbernagel, M.M. Hoffmann, T.B. Grammer, B.O. Boehm, W. Marz, Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography, Nutr. Metab. Cardiovasc. Dis. 23 (2013) 46–52. G. Ndrepepa, S. Braun, L. King, M. Fusaro, T. Tada, S. Cassese, et al., Uric acid and prognosis in angiography-proven coronary artery disease, Eur. J. Clin. Investig. 43 (2013) 256–266. R. Wang, Y. Song, Y. Yan, Z. Ding, Elevated serum uric acid and risk of cardiovascular or all-cause mortality in people with suspected or definite coronary artery disease: a meta-analysis, Atherosclerosis 254 (2016) 193–199. S. Kojima, T. Sakamoto, M. Ishihara, K. Kimura, S. Miyazaki, M. Yamagishi, et al., Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study), Am. J. Cardiol. 96 (2005) 489–495. C. Lazzeri, S. Valente, M. Chiostri, A. Sori, P. Bernardo, G.F. Gensini, Uric acid in the acute phase of ST elevation myocardial infarction submitted to primary PCI: its prognostic role and relation with inflammatory markers a single center experience, Int. J. Cardiol. 138 (2010) 206–209. C. Lazzeri, S. Valente, M. Chiostri, C. Picariello, G.F. Gensini, Uric acid in the early risk stratification of ST-elevation myocardial infarction, Intern. Emerg. Med. 7 (2012) 33–39. G. Ndrepepa, S. Braun, H.U. Haase, S. Schulz, S. Ranftl, M. Hadamitzky, et al., Prognostic value of uric acid in patients with acute coronary syndromes, Am. J. Cardiol. 109 (2012) 1260–1265. T.R. Larsen, O. Gerke, A.C.P. Diederichsen, J. Lambrechtsen, F.H. Steffensen, N.P. Sand, et al., The association between uric acid levels and different clinical manifestations of coronary artery disease, Coron. Artery Dis. 29 (2018) 194–203. E. Krishnan, Hyperuricemia and incident heart failure, Circ. Heart Fail. 2 (2009) 556–562. O.J. Ekundayo, L.J. Dell'Italia, P.W. Sanders, D. Arnett, I. Aban, T.E. Love, et al., Association between hyperuricemia and incident heart failure among older adults: a propensity-matched study, Int. J. Cardiol. 142 (2010) 279–287. R.V. Desai, M.I. Ahmed, G.C. Fonarow, G.S. Filippatos, M. White, I.B. Aban, et al., Effect of serum insulin on the association between hyperuricemia and incident heart failure, Am. J. Cardiol. 106 (2010) 1134–1138. S.G. Wannamethee, O. Papacosta, L. Lennon, P.H. Whincup, Serum uric acid as a potential marker for heart failure risk in men on antihypertensive treatment: the British regional heart study, Int. J. Cardiol. 252 (2018) 187–192. L. Tamariz, A. Harzand, A. Palacio, S. Verma, J. Jones, J. Hare, Uric acid as a predictor of all-cause mortality in heart failure: a meta-analysis, Congestive Heart Fail. 17 (2011) 25–30. H. Huang, B. Huang, Y. Li, Y. Huang, J. Li, H. Yao, et al., Uric acid and risk of heart failure: a systematic review and meta-analysis, Eur. J. Heart Fail. 16 (2014) 15–24. E. Krishnan, A. Hariri, O. Dabbous, B.J. Pandya, Hyperuricemia and the echocardiographic measures of myocardial dysfunction, Congestive Heart Fail. 18 (2012) 138–143. M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, et al., Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy, Am. Heart J. 143 (2002) 1107–1111. W. Doehner, M. Rauchhaus, V.G. Florea, R. Sharma, A.P. Bolger, C.H. Davos, et al., Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance, Am. Heart J. 141 (2001) 792–799. F. Leyva, S. Anker, J.W. Swan, I.F. Godsland, C.S. Wingrove, T.P. Chua, et al., Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure, Eur. Heart J. 18 (1997) 858–865. M.M. Kittleson, M.E. St John, V. Bead, H.C. Champion, E.K. Kasper, S.D. Russell, et al., Increased levels of uric acid predict haemodynamic compromise in patients with heart failure independently of B-type natriuretic peptide levels, Heart 93 (2007) 365–367. W. Doehner, E.A. Jankowska, J. Springer, M. Lainscak, S.D. Anker, Uric acid and xanthine oxidase in heart failure - emerging data and therapeutic implications, Int. J. Cardiol. 213 (2016) 15–19. H. Sakai, T. Tsutamoto, T. Tsutsui, T. Tanaka, C. Ishikawa, M. Horie, Serum level of uric acid, partly secreted from the failing heart, is a prognostic marker in patients with congestive heart failure, Circ. J. 70 (2006) 1006–1011. A. Boueiz, M. Damarla, P.M. Hassoun, Xanthine oxidoreductase in respiratory and cardiovascular disorders, Am. J. Phys. Lung Cell. Mol. Phys. 294 (2008) L830–L840. M. Kanbay, M. Segal, B. Afsar, D.H. Kang, B. Rodriguez-Iturbe, R.J. Johnson, The role of uric acid in the pathogenesis of human cardiovascular disease, Heart 99 (2013) 759–766. A.H. Wu, J.D. Gladden, M. Ahmed, A. Ahmed, G. Filippatos, Relation of serum uric acid to cardiovascular disease, Int. J. Cardiol. 213 (2016) 4–7. A. Gluba, A. Bielecka-Dabrowa, D.P. Mikhailidis, N.D. Wong, S.S. Franklin, J. Rysz, et al., An update on biomarkers of heart failure in hypertensive patients, J. Hypertens. 30 (2012) 1681–1689. L. Tamariz, F. Hernandez, A. Bush, A. Palacio, J.M. Hare, Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis, Heart Rhythm. 11 (2014) 1102–1108. T. Ukai, C.P. Cheng, H. Tachibana, A. Igawa, Z.S. Zhang, H.J. Cheng, et al., Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure, Circulation 103 (2001) 750–755. G.A. Hirsch, P.A. Bottomley, G. Gerstenblith, R.G. Weiss, Allopurinol acutely

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155] [156] [157]

[158]

[159]

[160]

[161]

[162]

[163]

[164] [165]

[166] [167]

[168]

[169]

[170]

[171]

[172]

[173]

Heart J. 57 (2016) 395–399. [174] E. Krishnan, B.J. Pandya, L. Chung, A. Hariri, O. Dabbous, Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study, Am. J. Epidemiol. 176 (2012) 108–116. [175] Y. Zhu, Y. Hu, T. Huang, Y. Zhang, Z. Li, C. Luo, et al., High uric acid directly inhibits insulin signalling and induces insulin resistance, Biochem. Biophys. Res. Commun. 447 (2014) 707–714. [176] E.S. Ford, C. Li, S. Cook, H.K. Choi, Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents, Circulation 115 (2007) 2526–2532. [177] H. Mangge, S. Zelzer, P. Puerstner, W.J. Schnedl, G. Reeves, T.T. Postolache, et al., Uric acid best predicts metabolically unhealthy obesity with increased cardiovascular risk in youth and adults, Obesity (Silver Spring) 21 (2013) E71–E77. [178] S. Petta, C. Camma, D. Cabibi, V. Di Marco, A. Craxi, Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease, Aliment. Pharmacol. Ther. 34 (2011) 757–766. [179] J.E. Lee, Y.G. Kim, Y.H. Choi, W. Huh, D.J. Kim, H.Y. Oh, Serum uric acid is associated with microalbuminuria in prehypertension, Hypertension 47 (2006) 962–967. [180] K. Iseki, S. Oshiro, M. Tozawa, C. Iseki, Y. Ikemiya, S. Takishita, Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects, Hypertens. Res. 24 (2001) 691–697. [181] M. Bagnati, C. Perugini, C. Cau, R. Bordone, E. Albano, G. Bellomo, When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced lowdensity lipoprotein oxidation: a study using uric acid, Biochem. J. 340 (Pt 1) (1999) 143–152. [182] R.A. Patterson, E.T. Horsley, D.S. Leake, Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDL: important role of uric acid, J. Lipid Res. 44 (2003) 512–521. [183] C. Gersch, S.P. Palii, W. Imaram, K.M. Kim, S.A. Karumanchi, A. Angerhofer, et al., Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress, Nucleosides Nucleotides Nucleic Acids 28 (2009) 118–149. [184] W. Imaram, C. Gersch, K.M. Kim, R.J. Johnson, G.N. Henderson, A. Angerhofer, Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry, Free Radic. Biol. Med. 49 (2010) 275–281. [185] N. Kuzkaya, N. Weissmann, D.G. Harrison, S. Dikalov, Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase, Biochem. Pharmacol. 70 (2005) 343–354. [186] M.R. Hayden, S.C. Tyagi, Uric acid: a new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle, Nutr. Metab. (Lond.) 1 (2004) 10. [187] C. Gersch, S.P. Palii, K.M. Kim, A. Angerhofer, R.J. Johnson, G.N. Henderson, Inactivation of nitric oxide by uric acid, Nucleosides Nucleotides Nucleic Acids 27 (2008) 967–978. [188] U.M. Khosla, S. Zharikov, J.L. Finch, T. Nakagawa, C. Roncal, W. Mu, et al., Hyperuricemia induces endothelial dysfunction, Kidney Int. 67 (2005) 1739–1742. [189] Y.J. Choi, Y. Yoon, K.Y. Lee, T.T. Hien, K.W. Kang, K.C. Kim, et al., Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis, FASEB J. 28 (2014) 3197–3204. [190] E.D. Rosen, B.M. Spiegelman, Molecular regulation of adipogenesis, Annu. Rev. Cell Dev. Biol. 16 (2000) 145–171. [191] S. Zharikov, K. Krotova, H. Hu, C. Baylis, R.J. Johnson, E.R. Block, et al., Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells, Am. J. Phys. Cell Phys. 295 (2008) C1183–C1190. [192] P. Puddu, E. Cravero, L. Vizioli, A. Muscari, Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications, J. Cardiol. 59 (2012) 235–242. [193] C. Ruggiero, A. Cherubini, A. Ble, A.J. Bos, M. Maggio, V.D. Dixit, et al., Uric acid and inflammatory markers, Eur. Heart J. 27 (2006) 1174–1181. [194] T. Lyngdoh, P. Marques-Vidal, F. Paccaud, M. Preisig, G. Waeber, M. Bochud, et al., Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study, PLoS ONE 6 (2011) e19901. [195] R.J. Johnson, D.H. Kang, D. Feig, S. Kivlighn, J. Kanellis, S. Watanabe, et al., Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41 (2003) 1183–1190. [196] L. Liu, H. Inoue, H. Nakayama, R. Kanno, M. Kanno, The endogenous danger signal uric acid augments contact hypersensitivity responses in mice, Pathobiology 74 (2007) 177–185. [197] M.A. Yu, L.G. Sanchez-Lozada, R.J. Johnson, D.H. Kang, 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. 28 (2010) 1234–1242. [198] T.S. Perlstein, O. Gumieniak, P.N. Hopkins, L.J. Murphey, N.J. Brown, G.H. Williams, et al., Uric acid and the state of the intrarenal renin-angiotensin system in humans, Kidney Int. 66 (2004) 1465–1470. [199] I. Saito, T. Saruta, K. Kondo, R. Nakamura, T. Oguro, K. Yamagami, et al., Serum uric acid and the renin-angiotensin system in hypertension, J. Am. Geriatr. Soc. 26 (1978) 241–247. [200] A. Eraranta, V. Kurra, A.M. Tahvanainen, T.I. Vehmas, P. Koobi, P. Lakkisto, et al., Oxonic acid-induced hyperuricemia elevates plasma aldosterone in experimental renal insufficiency, J. Hypertens. 26 (2008) 1661–1668. [201] C.J. McMullan, L. Borgi, N. Fisher, G. Curhan, J. Forman, Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: a

increases adenosine triphospate energy delivery in failing human hearts, J. Am. Coll. Cardiol. 59 (2012) 802–808. H.E. Cingolani, J.A. Plastino, E.M. Escudero, B. Mangal, J. Brown, N.G. Perez, The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: la plata study, J. Card. Fail. 12 (2006) 491–498. N. Engberding, S. Spiekermann, A. Schaefer, A. Heineke, A. Wiencke, M. Muller, et al., Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug? Circulation 110 (2004) 2175–2179. W. Doehner, N. Schoene, M. Rauchhaus, F. Leyva-Leon, D.V. Pavitt, D.A. Reaveley, 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 105 (2002) 2619–2624. C.A. Farquharson, R. Butler, A. Hill, J.J. Belch, A.D. Struthers, Allopurinol improves endothelial dysfunction in chronic heart failure, Circulation 106 (2002) 221–226. A.D. Gavin, A.D. Struthers, Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure, Heart 91 (2005) 749–753. K. Ogino, M. Kato, Y. Furuse, Y. Kinugasa, K. Ishida, S. Osaki, et al., Uric acidlowering treatment with benzbromarone in patients with heart failure: a doubleblind placebo-controlled crossover preliminary study, Circ. Heart Fail 3 (2010) 73–81. J. George, E. Carr, J. Davies, J.J. Belch, A. Struthers, High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid, Circulation 114 (2006) 2508–2516. J.M. Hare, B. Mangal, J. Brown, C. Fisher Jr., R. Freudenberger, W.S. Colucci, et al., Impact of oxypurinol in patients with symptomatic heart failureResults of the OPT-CHF study, J. Am. Coll. Cardiol. 51 (2008) 2301–2309. M.M. Givertz, K.J. Anstrom, M.M. Redfield, A. Deswal, H. Haddad, J. Butler, 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 131 (2015) 1763–1771. M. Kuwabara, Hyperuricemia, cardiovascular disease, and hypertension, Pulse (Basel) 3 (2016) 242–252. D.I. Feig, R.J. Johnson, Hyperuricemia in childhood primary hypertension, Hypertension 42 (2003) 247–252. L.F. Loeffler, A. Navas-Acien, T.M. Brady, E.R. Miller 3rd, J.J. Fadrowski, Uric acid level and elevated blood pressure in US adolescents: national health and nutrition examination survey, 1999-2006, Hypertension 59 (2012) 811–817. M.A. Newaz, N.N. Adeeb, N. Muslim, T.A. Razak, N.N. Htut, Uric acid, xanthine oxidase and other risk factors of hypertension in normotensive subjects, Clin. Exp. Hypertens. 18 (1996) 1035–1050. A. Swei, F. Lacy, F.A. Delano, D.A. Parks, G.W. Schmid-Schonbein, A mechanism of oxygen free radical production in the dahl hypertensive rat, Microcirculation 6 (1999) 179–187. H. Suzuki, F.A. DeLano, D.A. Parks, N. Jamshidi, D.N. Granger, H. Ishii, et al., Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats, Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 4754–4759. M. Mazzali, J. Hughes, Y.G. Kim, J.A. Jefferson, D.H. Kang, K.L. Gordon, et al., Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism, Hypertension 38 (2001) 1101–1106. L.G. Sanchez-Lozada, E. Tapia, C. Avila-Casado, V. Soto, M. Franco, J. Santamaria, et al., Mild hyperuricemia induces glomerular hypertension in normal rats, Am. J. Physiol. Ren. Physiol. 283 (2002) F1105–F1110. D.I. Feig, B. Soletsky, R.J. Johnson, Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial, JAMA 300 (2008) 924–932. B. Soletsky, D.I. Feig, Uric acid reduction rectifies prehypertension in obese adolescents, Hypertension 60 (2012) 1148–1156. V. Agarwal, N. Hans, F.H. Messerli, Effect of allopurinol on blood pressure: a systematic review and meta-analysis, J. Clin. Hypertens. (Greenwich) 15 (2013) 435–442. P.H. Gois, E.R. Souza, Pharmacotherapy for hyperuricemia in hypertensive patients, Cochrane Database Syst. Rev. 1 (2013) (CD008652). L.V. Franse, M. Pahor, M. Di Bari, R.I. Shorr, J.Y. Wan, G.W. Somes, et al., Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP), J. Hypertens. 18 (2000) 1149–1154. A. Hoieggen, M.H. Alderman, S.E. Kjeldsen, S. Julius, R.B. Devereux, U. De Faire, et al., The impact of serum uric acid on cardiovascular outcomes in the LIFE study, Kidney Int. 65 (2004) 1041–1049. T. Hamada, K. Ichida, M. Hosoyamada, E. Mizuta, K. Yanagihara, K. Sonoyama, et al., Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients, Am. J. Hypertens. 21 (2008) 1157–1162. L. Tamariz, S. Agarwal, E.Z. Soliman, A.M. Chamberlain, R. Prineas, A.R. Folsom, et al., Association of serum uric acid with incident atrial fibrillation (from the Atherosclerosis Risk in Communities [ARIC] study), Am. J. Cardiol. 108 (2011) 1272–1276. F. Valbusa, L. Bertolini, S. Bonapace, L. Zenari, G. Zoppini, G. Arcaro, et al., Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus, Am. J. Cardiol. 112 (2013) 499–504. S. Kawasoe, T. Kubozono, S. Yoshifuku, S. Ojima, N. Oketani, M. Miyata, et al., Uric acid level and prevalence of atrial fibrillation in a Japanese general population of 285,882, Circ. J. 80 (2016) 2453–2459. N. Maharani, M. Kuwabara, I. Hisatome, Hyperuricemia and atrial fibrillation, Int.

162

Clinica Chimica Acta 484 (2018) 150–163

G. Ndrepepa

Hypertension 41 (2003) 1287–1293. [208] Y.Y. Sautin, T. Nakagawa, S. Zharikov, R.J. Johnson, Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress, Am. J. Phys. Cell Phys. 293 (2007) C584–C596. [209] B. Fruehwald-Schultes, A. Peters, W. Kern, J. Beyer, A. Pfutzner, Serum leptin is associated with serum uric acid concentrations in humans, Metabolism 48 (1999) 677–680. [210] C. Cicerchi, N. Li, J. Kratzer, G. Garcia, C.A. Roncal-Jimenez, K. Tanabe, et al., Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids, FASEB J. 28 (2014) 3339–3350. [211] Y. Zhang, T. Yamamoto, I. Hisatome, Y. Li, W. Cheng, N. Sun, et al., Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic beta cells, Mol. Cell. Endocrinol. 375 (2013) 89–96. [212] A.J. Marian, Genetic causality in complex traits: the case of uric acid, J. Am. Coll. Cardiol. 67 (2016) 417–419. [213] G. Ndrepepa, Elevated serum uric acid – a marker and mediator of increased stress on myocardium, Coron. Artery Dis. 29 (2018) 183–185.

randomized controlled trial, Clin. J. Am. Soc. Nephrol. 12 (2017) 807–816. [202] H.H. Chao, J.C. Liu, J.W. Lin, C.H. Chen, C.H. Wu, T.H. Cheng, Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells, Acta Pharmacol. Sin. 29 (2008) 1301–1312. [203] T.H. Cheng, J.W. Lin, H.H. Chao, Y.L. Chen, C.H. Chen, P. Chan, et al., Uric acid activates extracellular signal-regulated kinases and thereafter endothelin-1 expression in rat cardiac fibroblasts, Int. J. Cardiol. 139 (2010) 42–49. [204] D.H. Kang, T. Nakagawa, L. Feng, S. Watanabe, L. Han, M. Mazzali, et al., A role for uric acid in the progression of renal disease, J. Am. Soc. Nephrol. 13 (2002) 2888–2897. [205] K.L. Price, Y.Y. Sautin, D.A. Long, L. Zhang, H. Miyazaki, W. Mu, et al., Human vascular smooth muscle cells express a urate transporter, J. Am. Soc. Nephrol. 17 (2006) 1791–1795. [206] G.N. Rao, M.A. Corson, B.C. Berk, Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression, J. Biol. Chem. 266 (1991) 8604–8608. [207] J. Kanellis, S. Watanabe, J.H. Li, D.H. Kang, P. Li, T. Nakagawa, et al., Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2,

163