Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle
© Hayden and Tyagi; licensee BioMed Central Ltd. 2004
Received: 23 August 2004
Accepted: 19 October 2004
Published: 19 October 2004
The topical role of uric acid and its relation to cardiovascular disease, renal disease, and hypertension is rapidly evolving. Its important role both historically and currently in the clinical clustering phenomenon of the metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), atheroscleropathy, and non-diabetic atherosclerosis is of great importance.
Uric acid is a marker of risk and it remains controversial as to its importance as a risk factor (causative role). In this review we will attempt to justify its important role as one of the many risk factors in the development of accelerated atherosclerosis and discuss its importance of being one of the multiple injurious stimuli to the endothelium, the arterial vessel wall, and capillaries. The role of uric acid, oxidative – redox stress, reactive oxygen species, and decreased endothelial nitric oxide and endothelial dysfunction cannot be over emphasized.
In the atherosclerotic prooxidative environmental milieu the original antioxidant properties of uric acid paradoxically becomes prooxidant, thus contributing to the oxidation of lipoproteins within atherosclerotic plaques, regardless of their origins in the MS, T2DM, accelerated atherosclerosis (atheroscleropathy), or non-diabetic vulnerable atherosclerotic plaques. In this milieu there exists an antioxidant – prooxidant urate redox shuttle.
Elevations of uric acid > 4 mg/dl should be considered a "red flag" in those patients at risk for cardiovascular disease and should alert the clinician to strive to utilize a global risk reduction program in a team effort to reduce the complications of the atherogenic process resulting in the morbid – mortal outcomes of cardiovascular disease.
While the topicality of serum uric acid (SUA) being a risk factor is currently controversial [1, 2], there is little controversy regarding its association as a risk marker associated with cardiovascular (CVD) and renal disease (especially in patients with hypertension, diabetes, and heart failure). SUA seems to be a graded marker of risk for the development of coronary heart disease (CHD) or cerebrovascular disease and stroke compared with patients with normal uric acid levels and especially those in the lower 1/3 of its normal physiological range [1, 3–13].
LK Niskanen's et al. recently published article has demonstrated new information regarding this subject. They were able to demonstrate that elevations of SUA levels were independent of variables commonly associated with gout or the metabolic syndrome in association with CVD mortality in middle aged men .
In 1951, Gertler MM and White PD et al. sat out to determine the clinical aspects of premature coronary heart disease in 100 male patients 40 years old and younger. Their findings were increased mesomorphic body build, shorter stature, increased anterior posterior chest wall diameter, and increased cholesterol and uric acid (5.13 +/- .11 vs. 4.64 +/-.06) as compared to the normal population .
A much larger trial (1967) confirmed the initial interest in SUA and CVD with the publication of the early, large (5,127 participants), epidemiologic, seminal Framingham study. This classical paper by Kannel et al. noted an elevated SUA was also associated with an increased risk of coronary heart disease for men aged 30–59 . In addition to the important finding of elevations in lipoproteins (specifically cholesterol levels greater than 250 mg/100 ml) being associated with CHD, there also appeared a definite association of elevated SUA, which was associated with an increase in the incidence rate of CHD. The above authors also noted that subjects in this study with evidence of impaired carbohydrate metabolism or disordered purine metabolism could be assumed to have accelerated atherogenesis .
A-FLIGHT-U ACRONYM Identification of multiple metabolic toxicities and injurious stimuli responsible for reactive oxygen species production. (figure 2)
Angiotensin II (also induces PKC-β isoform)
Amylin (hyperamylinemia) / amyloid toxicity
AGEs/AFEs (advanced glycosylation/fructosylation endproducts)
Antioxidant reserve compromised
Absence of antioxidant network
ADMA (Asymmetrical DiMethyl Arginine)
Free fatty acid toxicity: Obesity toxicity: Triad
Lipotoxicity – Hyperlipidemia – Obesity toxicity: Triad
Insulin toxicity (endogenous hyperinsulinemia-hyperproinsulinemia)
Glucotoxicity (compounds peripheral insulin resistance) reductive stress
Pseudohypoxia (increased NADH/NAD ratio)
Triglyceride toxicity: Obesity toxicity: Triad
Uric Acid toxicity: Antioxidant early in physiological range and a conditional prooxidant late when elevated through the paradoxical (antioxidant → prooxidant)
URATE REDOX SHUTTLE
Endothelial cell dysfunction with eNOS uncoupling, decreased eNO and increased ROS.
Vulnerable atherosclerotic plaque milieu of being acidic, proinflammatory, excess metal ions (Fe) (Cu) from vasa vasorum rupture and red blood cell plasma membranes due to intraplaque hemorrhage and plaque thrombus formation.
Hyperuricemia: clinical clusters at cardiovascular risk
Patients with CVD
Congestive heart failure
Increased apoptosis – necrosis of the arterial vessel wall and capillary resulting in increased purine metabolism and hyperuricemia.
Increased oxidative – redox stress
Antioxidant – Prooxidant Paradox:
Urate Redox Shuttle
Patients with (T2DM)
Acting through obesity and insulin resistance.
Accelerated atherosclerosis with increased vascular cell apoptosis and inflammatory necrosis with increased purine metabolism resulting in hyperuricemia and increased oxidative stress through ischemia-reperfusion and xanthine oxidase.
Additional reductive stress associated with glucotoxicity and pseudohypoxia.
Increased oxidative-redox stress
Antioxidant – Prooxidant Paradox:
Urate Redox Shuttle
Obesity – Insulin resistance
Hyperinsulinemia – Insulin toxicity
Metabolic Syndrome (figure 1):
Hyperlipidemia dyslipidemia, obesity
Leptin may induce hyperuricemia.
Insulin increases sodium reabsorption and is tightly linked to urate reabsorption.
Increased oxidative – redox stress
Antioxidant – Prooxidant Paradox:
Urate Redox Shuttle
Men and Postmenopausal females
Estrogen is uricosuric
Decreases in GFR increases uric acid levels
Urate reabsorption increased in setting of increased renal vascular resistance, microvascular disease predisposes to tissue ischemia that leads to increased urate generation (excess purine metabolism) and reduced excretion (due to lactate competing with urate transporter in the proximal tubule).
Increased oxidative – redox stress
Antioxidant – Prooxidant Paradox:
Urate Redox Shuttle
Unknown (assumed genetic causes as yet unidentified)
Volume contraction promotes urate reabsorption
Alcohol use (in excess)
Increases urate generation and decreased urate excretion
Uric acid, MS, T2DM, and atheroscleropathy
The importance of hyperuricemia and the clustering phenomenon of the metabolic syndrome were first described by Kylin in 1923 when he described the clustering of three clinical syndromes: hypertension, hyperglycemia, and hyperuricemia . In 1988, Reaven GM described the important central role of insulin resistance in the seminal Banting lecture where he described Syndrome X, which has now become known as the metabolic syndrome (MS) and/or the insulin resistance syndrome (IRS) . Seven decades after the clustering phenomenon was reported by Kylin (1993), Reaven GM and Zavaroni I et al. suggested that hyperuricemia be added to the cluster of metabolic and hemodynamic abnormalities associated with insulin resistance and/or hyperinsulinemia of Syndrome X .
The four major players in the MS are hyperinsulinemia, hypertension, hyperlipidemia, and hyperglycemia. Each member of this deadly quartet has been demonstrated to be an independent risk factor for CHD and capable of working together in a synergistic manner to accelerate both non-diabetic atherosclerosis and the atheroscleropathy associated with MS, PD, and T2DM.
In a like manner, hyperuricemia, hyperhomocysteinemia, ROS, and highly sensitive C- reactive protein (hsCRP) each play an important role in expanding the original Syndrome X described by Reaven in the atherosclerotic process. The above quartet does not stand alone but interacts in a synergistic manner resulting in the progression of accelerated atherosclerosis and arterial vessel wall remodeling along with the original players and the A-FLIGHT-U toxicities (table 1). The MS of clinical clustering has been renamed multiple times over the past 16 years indicating its central importance to cardiovascular disease and was included in the recent National Cholesterol Educational Program – Adult Treatment Panel III (NCEP ATP III) clinical guidelines in order to assist the clinician in using this important tool to evaluate additional cardiovascular risk [16–19].
Hyperinsulinemia and Hyperamylinemia
Deleterious effects of hyperinsulinemia (HI)
HI, hyperproinsulinemia, and hyperamylinemia synergistically activate RAS with subsequent increase in Ang II, renin, and aldosterone.
HI promotes Na+ and H2O retention, which increases blood volume and pressure. In turn this activates the reabsorption of uric acid resulting in elevation of SUA. In turn increased SUA has been shown to increase tubular reabsorption of Na+.
HI increases membrane cation-transport increasing intracellular Ca++, which increases tone and pressure.
HI activates the sympathetic nervous system.
HI stimulates vSMC proliferation and migration and remodeling.
HI increases the number of AT-1 receptors.
HI creates cross talk between the insulin receptor and AT-1 receptor, resulting in a more profound Ang II effect.
HI promotes PI3 kinase Akt-MAP kinase Shunt. Impairing the metabolic (PI3 kinase-AKT pathway while promoting the MAPkinase remodeling pathway.
HI induces Ang II, which promotes the MAP kinase pathway and remodeling.
HI induces Ang II, which is the most potent stimulus for production of NAD(P)H oxidase with reactive oxygen species generation (superoxide production) and resultant vascular oxidative stress.
Hypertension is strongly associated with hyperuricemia. SUA levels are elevated in hypertension and are present in 25% of untreated hypertensive subjects, 50% of subjects taking diuretics, and greater than 75% of patients with malignant hypertension . Potential mechanisms involved with the association of hyperuricemia and hypertension include the following: 1. Decreased renal blood flow (decreased GFR) stimulating urate reabsorption, 2. Microvascular (capillary) disease resulting in local tissue ischemia. 3. Ischemia with associated increased lactate production that blocks urate secretion in the proximal tubule and increased uric acid synthesis due to increased RNA-DNA breakdown and increased purine (adenine and guanine) metabolism, which increases uric acid and ROS through the effect of xanthine oxidase (XO). 4. Ischemia induces increased XO production and increased SUA and ROS. These associations with ischemia and XO induction may help to understand why hyperuricemia is associated with preeclampsia and congestive heart failure.
Because endothelial dysfunction, local oxidant generation, elevated circulating cytokines, and a proinflammatory state are common in patients with cardiovascular disease and hypertension there is an increased level of oxidative – redox stress within vascular tissues. Oxidative – redox stress results in impaired endothelium-dependent vasodilation with quenching of endothelial nitric oxide (eNO) and allows the endothelium to become a net producer of ROS specifically superoxide as the endothelial nitric oxide synthase (eNOS) enzyme uncouples to produce superoxide instead of eNO. This similar mechanism applies equally well to that associated with type 2 diabetes and congestive heart failure [11, 19]. It is important to note that allopurinol and oxypurinol (XO inhibitors) are capable of reversing the impaired eNO production in both heart failure [23–25] and type 2 diabetes mellitus (T2DM) .
Lin KC et al. were able to demonstrate that blood pressure levels were predictive for cardiovascular disease incidence synergistically with serum uric acid level . Two separate laboratories have demonstrated the development of systemic hypertension in a rat model of hyperuricemia developed with a uricase inhibitor (oxonic acid) after several weeks of treatment [28, 29]. This hypertension was associated with increased renin and a decrease in neuronal nitric oxide synthase in the juxtaglomerular apparatus. Prevention of this hypertension was accomplished by an ACE inhibitor and to a lesser extent L-arginine. These findings indicate an interacting role of the renin- angiotensin system and the NOS enzyme. Hypertension, neural nitric oxide synthase (nNOS) and renin changes were also prevented by maintaining uric acid levels in the normal range with allopurinol or benziodarone (a uricosuric).
These above models have provided the first challenging evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease .
Leptin levels are elevated and associated with insulin resistance in MS and early T2DM. Bedir A et al. have recently discussed the role of leptin as possibly being a regulator of SUA concentrations in humans and even suggested that leptin might be one of the possible candidates for the missing link between obesity and hyperuricemia . Furthermore, hypertriglyceridemia and free fatty acids are related to hyperuricemia independently of obesity and central body fat distribution [30, 33] (table 1: (T): Triglyceride toxicity and (F): Free fatty acid toxicity).
Hyperglycemia: Impaired glucose tolerance: Type 2 Daibetes Mellitus (T2DM)
Glucotoxicity places an additional burden of redox stress on the arterial vessel wall and capillary endothelium. Hyperglycemia induces both an oxidative stress (glucose autoxidation and advanced glycosylation endproducts (AGE) – ROS oxidation products) and a reductive stress through pseudohypoxia with the accumulation of NADH and NAD(P)H in the vascular intima [19, 35, 36].
Antioxidants: enzymatic – nonenzymatic inactivation of free radicals.
SUPER OXIDE DISMUTASE (SOD)
Reactions catalyzed: [O2- + SOD → H2O2 + O2]
Various isoforms: ecSOD (extracellular); Mn-SOD (mitochondrial); Cu/Zn-SOD (intracellular)
CATALASE – Location: peroxisome.
Reaction catalyzed: [2 H2O2 + catalase → 2 H2O + O2]
GLUTATHIONE PEROXIDASE – Location: mitochondrion, cytosol, and systemic circulation.
Glutathione (GSH or glutamyl-cysteinyl-glycine tripeptide): the reduced -SH of GSH is oxidized to disulfide GSSG.
Glutathione peroxidase-catalyzed reation: [GSH + 2 H2O2 → GSSG + H2O + O2]
Glutathione reductase-catalyzed reaction: [GSSG → GSH] at the expense of [NADH → NAD+] and/or [NAD(P)H → NAD(P)+]
ENZYMATIC – NONENZYMATIC INACTIVATION OF FREE RADICALS. NITRIC OXIDE SYNTHASE Location: membrane.
eNOS (endothelial): good
nNOS (neuronal): good
iNOS (inducible-inflammatory): bad
O2- and nitric oxide (NO) are consumed in this process with the creation of reactive nitrogen species (RNS).
O2- + NO → ONOO-(peroxynitrite) + tyrosine → nitrotyrosine.
Nitrotyrosine reflects redox stress and leaves a measurable footprint.
NO the good; O2• the bad; ONOO- the ugly *
Vitamins (A, C, and E):
Thiols: Sulfhydryl (-SH)-containing molecules.
Albumin: Is an antioxidant because of it is a thiol-containing macromolecule.
Apoproteins: Ceruloplasmin and transferrin. Bind copper and iron in forms, which cannot participate in the Fenton reaction.
Uric acid: Early on in the atherosclerotic process in physiologic ranges: antioxidant.
PARADOX: Late in elevated range prooxidant with loss of supporting antioxidants above and in a milieu of oxidative – redox stress within the atherosclerotic intima. In MS, T2DM and advanced vulnerable atherosclerotic plaques SOD, Catalase, and GPX are depleted. The Urate Redox Shuttle.
PARADOX: antioxidants may become prooxidant in a certain milieu.
A direct relation between homocysteine levels and SUA levels is known to occur in patients with atherosclerosis. Not only do these two track together (possibly reflecting an underlying elevated tension of redox stress) but also may be synergistic in creating an elevated tension of redox stress, especially in the rupture prone, vulnerable atherosclerotic plaque with depletion of local occurring antioxidants [39–41] (figure 1).
Atherosclerosis and Atheroscleropathy
In MS and T2DM there is an observed increased thrombogenecity, hyperactive platelets, increased PAI-1 (resulting in impaired fibrinolysis), and increased fibrinogen in the atherosclerotic milieu associated with the dysfunctional endothelial cell. Additionally, the vulnerable atherosclerotic plaque includes increased tissue factor, which increases the potential for thrombus formation when the plaque ruptures and exposes its contents to the lumen [19, 42, 43].
Uric acid as one of the multiple injurious stimuli to the endothelium of the arterial vessel wall and capillary
Origin, enzymatic pathways of reactive oxygen species, and their oxidized products.
[Origin and Location]
Oxidized lipids and proteins:
Oxidized lipids, proteins, nucleic acids, and autoxidation byproducts
Advanced lipoxidation endproducts (ALE)
Nitric Oxide Synthase (iNOS)
Large bursts – uncontrolled
Nitric Oxide Synthase (NOS)
eNOS → NO
nNOS → NO
Small bursts – controlled
NO + O 2 • → ONOO•
NO The GOOD *
Natural-occurring, local-occurring, chain-breaking, antioxidant
O 2 • The BAD *
Toxic effects of ROS on proteins, lipid, nucleic acids
ONOO • The UGLY *
Toxic effects of ROS on proteins, lipid, nucleic acids
HCLO The UGLY *
Toxic effects of ROS on proteins, lipid, nucleic acids
Restoration of eNO
Via the eNOS reaction
Prevention of the toxic effects of ROS
The simple concept that SUA in patients with CVD, MS, T2DM, hypertension, and renal disease may reflect a compensatory mechanism to counter oxidative stress is intriguing. However, this does not explain why higher SUA levels in patients with these diseases are generally associated with worse outcomes .
An antioxidant – prooxidant urate redox shuttle
SUA in the early stages of the atherosclerotic process is known to act as an antioxidant and may be one of the strongest determinates of plasma antioxidative capacity .
The ANAi acronym
We have devised an acronym, to better understand the increase in SUA synthesis within the accelerated atherosclerotic plaque termed: ANAi. A – apoptosis, N – necrosis, A – acidic atherosclerotic plaque, angiogenesis (both induced by excessive redox stress), i – inflammation, intraplaque hemorrhage increasing red blood cells – iron and copper transition metal ions within the plaque.
This acronym describes the excess production of purines: (A) adenine and (G) guanine base pairs from RNA and DNA breakdown due to apoptosis and necrosis of vascular cells in the vulnerable – accelerated atherosclerotic plaques; allowing SUA to undergo the antioxidant – prooxidant urate redox shuttle (figure 3).
Reactions involving transitional metal ions such as copper and iron are important to the oxidative stress within atherosclerotic plaques. Reactions such as the Fenton and Haber- Weiss reactions and similar reactions with copper lead to an elevated tension of oxidative – redox stress.
Fe 2+ + H 2 O 2 → Fe 3+ + OH • + OH -
Fe 3+ + H 2 O 2 → Fe 2+ + OOH • + H +
HABER – WEISS REACTION:
H 2 O 2 + O 2 - → O2 + OH - + OH
H 2 O 2 + OH - → H 2 O + O 2 - + H +
The hydroxyl radicals can then proceed to undergo further reactions with the production of ROS through addition reactions, hydrogen abstraction, electron transfer, and radical interactions. Additionally, copper (Cu3+ - Cu2+ - Cu1+) metal ions can undergo similar reactions with formation of lipid peroxides and ROS. This makes the leakage of iron and copper from ruptured vasa vasorum very important in accelerating oxidative damage to the vulnerable accelerated atherosclerotic plaques, as well as, providing a milieu to induce the SUA antioxidant – prooxidant switch within these plaques .
These same accelerated – vulnerable plaques now have the increased substrate of SUA through apoptosis and necrosis of vascular cells (endothelial and vascular smooth muscle cells) and the inflammatory cells (primarily the macrophage and to a lesser extent the lymphocyte).
Endothelial function and endothelial nitric oxide (eNO)
The endothelium is an elegant symphony responsible for the synthesis and secretion of several biologically active molecules. It is responsible for regulation of vascular tone, inflammation, lipid metabolism, vessel growth (angiogenesis – arteriogenesis), arterial vessel wall – capillary sub endothelial matrix remodeling, and modulation of coagulation and fibrinolysis. One particular enzyme system seems to act as the maestro: The endothelial nitric oxide synthase (eNOS) enzyme and its omnipotent product: endothelial nitric oxide (eNO) (figure 2).
The positive effects of eNOS and eNO
• Promotes vasodilatation of vascular smooth muscle.
• Counteracts smooth muscle cell proliferation.
• Decreases platelet adhesiveness.
• Decreases adhesiveness of the endothelial layer to monocytic WBCs (the "teflon effect").
• Anti-inflammatory effect.
• Anti-oxidant effect. It scavenges reactive oxygen species locally, and acts as a chain-breaking antioxidant to scavenge ROS.
• Anti-fibrotic effect. When NO is normal or elevated, MMPs are quiescent; conversely if NO is low, MMPs are elevated and active.
MMPs are redox sensitive.
• No inhibits prooxidant actions of uric acid during copper-mediated LDL oxidation.
• NO has diverse anti-atherosclerotic actions on the arterial vessel wall including antioxidant effects by direct scavenging of ROS – RNS acting as chain-breaking antioxidants and it also has anti-inflammatory effects.
There are multiple causes for endothelial uncoupling in addition to hyperuricemia and the antioxidant – prooxidant urate redox shuttle: A-FLIGHT -U toxicities, ROS, T2DM, prediabetes, T1DM, insulin resistance, MS, renin angiotensin aldosterone activation, angiotensin II, hypertension, endothelin, dyslipidemia – hyperlipidemia, homocysteine, and asymmetrical dimethyl arginine (ADMA) [19, 39, 43].
Xanthine oxidase – oxioreductase (XO) has been shown to localize immunohistochemically within atherosclerotic plaques allowing the endothelial cell to be equipped with the proper machinery to undergo active purine metabolism at the plasma membrane surface, as well as, within the cytoplasm and is therefore capable of overproducing uric acid while at the same time generating excessive and detrimental ROS  (figure 3,4). To summarize this section:
The healthy endothelium is a net producer of endothelial nitric oxide (eNO).
The activated, dysfunctional endothelium is a net producer of superoxide (O2-) associated with MS, T2DM, and atheroscleropathy .
Uric acid and inflammation
Uric acid and highly sensitive C reactive protein (hsCRP) each now share a respected inclusion as two of the novel risk markers – risk factors associated with the metabolic syndrome. It is not surprising that these two markers of risk track together within the MS. If there is increased apoptosis and necrosis of vascular cells and inflammatory cells in accelerated – vulnerable atherosclerotic plaques as noted in the above section then one would expect to see an increase in the metabolic breakdown products of RNA and DNA with arginine and guanine to its end product of uric acid. SUA elevation may indeed be a sensitive marker for underlying vascular inflammation and remodeling within the arterial vessel wall and capillary interstitium.
Is it possible that SUA levels could be as similarly predictive as hsCRP since it is a sensitive marker for underlying inflammation and remodeling within the arterial vessel wall and the myocardium .
Should the measurement of SUA be part of the national cholesterol educational program adult treatment panel III and future IV (NCEP ATPIII or the future NCEP ATPIV) clinical guidelines (especially in certain ethnic groups such as females and in the African Americans)?
Uric acid is known to induce the nuclear transcription factor (NF-kappaB) and monocyte chemoattractant protein-1 (MCP-1) . Regarding TNF alpha it has been shown that SUA levels significantly correlate with TNF alpha concentrations in congestive heart failure and as a result Olexa P et al. conclude that SUA may reflect the severity of systolic dysfunction and the activation of an inflammatory reaction in patients with congestive heart failure . Additionally, uric acid also stimulates human mononuclear cells to produce interleukin-1 beta, IL-6, and TNF alpha .
Tamakoshi K et al. have shown a statistically significant positive correlation between CRP and body mass index (BMI), total cholesterol, triglycerides, LDL-C, fasting glucose, fasting insulin, uric acid, systolic blood pressure, and diastolic blood pressure and a significant negative correlation of CRP with HDL-C in a study of 3692 Japanese men aged 34–69 years of age. They conclude that there are a variety of components of the MS, which are associated with elevated CRP levels in a systemic low-grade inflammatory state .
CRP and IL-6 are important confounders in the relationship between SUA and overall mortality in elderly persons, thus when evaluating this association the potential confounding effect of underlying inflammation and other risk factors should be considered .
Uric acid and chronic renal disease
Hyperuricemia can be the consequence of increased uric acid production or decreased excretion. Any cause for decreased glomerular filtration, tubular excretion or increased reabsorption would result in an elevated SUA. Increased SUA has been found to predict the development of renal insufficiency in individuals with normal renal function . In T2DM hyperuricemia seems to be associated with MS and with early onset or increased progression to overt nephropathy, whereas hypouricemia was associated with hyperfiltration, and a later onset or decreased progression to overt nephropathy . An elevated SUA could be advantageous information for the clinician when examining the global picture of T2DM in order to detect those patients who might gain from more aggressive global risk reduction to delay or prevent the transition to overt nephropathy. Elevated SUA contributes to endothelial dysfunction and increased oxidative stress within the glomerulus and the tubulo-interstitium with associated increased remodeling fibrosis of the kidney and as noted earlier in this discussion to be pro-atherosclerotic and proinflammatory. This would have a direct effect on the vascular supply affecting macrovessels, particularly the afferent arterioles. The glomeruli would be affected also through the effect of uric acid on the glomerular endothelium with endothelial dysfunction due to oxidative – redox stress and result in glomerular remodeling. SUA's effect on hypertension would have an additional affect on the glomeruli and the tubulo-interstitium with remodeling changes and progressive deterioration of renal function. Increased ischemia – ischemia reperfusion would activate the xanthine oxidase mechanism and contribute to an increased production of ROS through H2O2 generation and oxidative stress within the renal architecture with resultant increased remodeling. Hyperuricemia could increase the potential for urate crystal formation and in addition to elevated levels of soluble uric acid could induce inflammatory and remodeling changes within the medullary tubulo-interstitium.
A recent publication by Hsu SP et al. revealed a J-shaped curve association with SUA levels and all-cause mortality in hemodialysis patients . They were able to demonstrate that decreased serum albumin, underlying diabetic nephropathy, and those in the lowest and highest quintiles of SUA had higher all-cause mortality. It is interesting to note that almost all of the large trials with SUA and cardiovascular events have demonstrated this same J shaped curve regarding all-cause mortality with the nadir of risk occurring in the second quartile .
Johnson RJ et al. have speculated that the increased risk for the lowest quartile reflects a decreased antioxidant activity, while the increased risk at higher levels reflects the role of uric acid in inducing vascular disease and hypertension through the mechanism of the previously discussed antioxidant prooxidant urate redox shuttle. This would suggest that treatment with xanthine oxidase inhibitors (allopurinol) should strive to bring levels to the 3–4 mg/dl range and not go lower .
Nutritional support for hyperuricemia
Nutritional guidelines for hyperuricemia
Caloric restriction to induce weight loss in order to decrease insulin resistance of the MS.
Exercise to aid in weight reduction by increased energy expenditure, also to increase eNOS and eNO, as well as, increase HDL-C with its antioxidant – anti-inflammatory effects. Both will result in REDOX STRESS REDUCTION
Avoidance and or moderation. Especially beer with the increased purines from hops and barley. Also improve the liver antioxidant potential.
REDOX STRESS REDUCTION
Low purine diet (moderation)
Moderation in meats and seafood's, especially shrimp and barbeque ribs (all you can eat specials).
Vegetables and fruits higher in purine should not be completely avoided as they provide fiber and naturally occurring antioxidants.
Lists should be provided to demonstrate the vegetables and fruits that are higher in purines to allow patients healthier choices
REDOX STRESS REDUCTION
Emphasize the importance of fiber in the diet as fiber helps to bind excess purines in the gastrointestinal track.
REDOX STRESS REDUCTION
Moderation is the key element in any diet approaching hyperuricemia. The nutritional "gold standard" for the treatment of hyperuricemia has been "the low purine diet". This traditional diet has recently come into question as it may limit the intake of high purine vegetables and fruits. Vegetables and fruits are important for the fiber they supply in addition to naturally occurring antioxidants. Recently, of greater importance is controlling obesity through generalized caloric restriction and increased exercise to combat the overnutrition and underexercise of our modern-day society, as well as, controlling the consumption of alcohol .
Nutritional support by the nutritionist and the diabetic educator (an integral part of the health care team) is of utmost importance when dealing with the metabolic syndrome, T2DM, and the cardiovascular atherosclerotic afflicted patients in order to obtain global risk reduction, because we are what we eat.
The RAAS Acronym: GLOBAL RISK REDUCTION
Reductase inhibitors (HMG-CoA). Decreasing modified LDL-cholesterol, i.e., oxidized, acetylated LDL-cholesterol. Decreasing triglycerides and increasing HDL-cholesterol.
Improving endothelial cell dysfunction. Restoring the abnormal Lipoprotein fractions.
Thus, decreasing the redox and oxidative stress to the arterial vessel wall and myocardium.
Redox stress reduction
AngII inhibition or receptor blockade:
ACEi-prils. ARBs-sartans. Both inhibiting the effect of angiotensin-II locally as well as systemically. Affecting hemodynamic stress through their antihypertensive effect as well as the deleterious effects of angiotensin II on cells at the local level – injurious stimuli -decreasing the stimulus for O2• production. Decreasing the A-FLIGHT toxicities. The positive effects on microalbuminuia and delaying the progression to end stage renal disease. Plus the direct-indirect antioxidant effect within the arterial vessel wall and capillary. Antioxidant effects.
Aspirin antiplatelet, anti-inflammatory effect on the diabetic hyperactive platelet.
Adrenergic (non-selective blockade) in addition to its blockade of prorenin → renin conversion.
Amlodipine – Felodipine with calcium channel blocking antihypertensive effect, in addition to their direct antioxidant effects.
Redox stress reduction
Aggressive control of diabetes to HbA1c of less than 7. This usually requires combination therapy with the use of insulin secretagogues, insulin sensitizers (PPAR-gamma agonists), biguanides, alpha-glucosidase inhibitors, and ultimately exogenous insulin.
Decreasing modified LDL cholesterol, i.e., glycated-glycoxidated LDL cholesterol. Improving endothelial cell dysfunction. Also decreasing glucotoxicity and the oxidative-redox stress to the intima and pancreatic islet.
Aggressive control of blood pressure, which usually requires combination therapy, including thiazide diuretics to attain JNC 7 guidelines.
Aggressive control of homocysteine with folic acid with its associated additional positive effect on re-coupling the eNOS enzyme reaction by restoring the activity of the BH4 cofactor to run the eNOS reaction via a folate shuttle mechanism and once again produce eNO.
Aggressive control of uric acid levels with xanthine oxidase inhibitors (allopurinol and oxypurinol) should be strongly considered in view of the prevailing literature in order to achieve more complete: Global Risk Reduction
Redox stress reduction
Statins. Improving plaque stability (pleiotropic effects) independent of cholesterol lowering. Improving endothelial cell dysfunction. Moreover, the direct/indirect antioxidant anti-inflammatory effects within the islet and the arterial vessel wall promoting stabilization of the unstable, vulnerable islet and the arterial vessel wall.
Style. Lifestyle modification (weight loss, exercise, and change eating habits).
Redox stress reduction
SUA may or may not be an independent risk factor especially since its linkage to other risk factors is so strong, however there is not much controversy regarding its role as a marker of risk, or that it is clinically significant and relevant.
Regarding the MS and epidemiologic evaluations: A multivariate model could well eliminate hyperuricemia as an independent risk factor even if it were contributing to the overall phenotypic risk of the syndrome. Additionally, we must remember that it was Reaven that called for the inclusion of hyperuricemia to Syndrome X we now call MS – insulin resistance syndrome -IRS in 1993 .
A quote by Johnson RJ and Tuttle KR is appropriate for the concluding remarks:
"The bottom line is that measuring uric acid is a useful test for the clinician, as it carries important prognostic information. An elevation of uric acid is associated with an increased risk for cardiovascular disease and mortality, especially in women" .
Serum uric acid
coronary heart disease
endothelial nitric oxide
endothelial nitric oxide synthase
endothelial nitric oxide
reactive oxygen species
insulin resistance syndrome
nicotine adenine dinucleotide phosphate oxidase reduced NA
type 2 diabetes mellitus
angiotensin converting enzyme
advanced glycosylation endproducts
plasminogen activator inhibitor
low density lipoprotein cholesterol
asymmetrical dimethyl arginine
highly sensitive C reactive protein
- NCEP ATPIII:
national cholesterol educational program adult treatment panel III
nuclear transcription factor
monocyte chemoattractant protein-1
- TNF alpha:
tumor necrosis factor alpha
interleukin one beta
body mass index
high density lipoprotein
free fatty acids
A part of this study was supported by NIH grants HL-71010 and HL-74185.
The authors would like to acknowledge Dr. Charles Kilo and Dr. Joe Williamson of Washington University School of Medicine for their devotion to teaching medical students, residents, fellows and patients with diabetes in the pursuit of knowledge regarding diabetes. Their research and 31 years of providing CME exposure through a nationally recognized annual CME Diabetes Symposium have been an inspiration to all interested in delivering the best diabetic care possible to their patients.
- Culleton BF, Larson MG, Kannel WB, Levy D: Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999, 131 (1): 7-13.View ArticleGoogle Scholar
- Fang J, Alderman MH: Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA. 2000, 283 (18): 2404-2410. 10.1001/jama.283.18.2404.View ArticleGoogle Scholar
- Niskanen LK, Laaksonen DE, Nyyssonen K, Alfthan G, Lakka HM, Lakka TA, Salonen JT: Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med. 2004, 164 (14): 1546-1551. 10.1001/archinte.164.14.1546.View ArticleGoogle Scholar
- Freedman DS, Williamson DF, Gunter EW, Byers T: Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1995, 141: 637-644.Google Scholar
- Alderman MH: Uric acid and cardiovascular risk. Curr Opin Pharmacol. 2002, 2 (2): 126-130. 10.1016/S1471-4892(02)00143-1.View ArticleGoogle Scholar
- Verdecchia P, Schillaci G, Reboldi GP, Santeusanio F, Porcellati C, Brunetti P: Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. Hypertension. 2000, 36: 1072-1078.View ArticleGoogle Scholar
- Liese AD, Hense HW, Löwel H, Döring A, Tietze M, Keil U: Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. Epidemiology. 1999, 10: 391-397. 10.1097/00001648-199907000-00006.View ArticleGoogle Scholar
- Brand FN, McGee DL, Kannel WB, Stokes J, Castelli WP: Hyperuricemia as a risk factor of coronary heart disease: the Framingham study. Am J Epidemiol. 1985, 121: 11-18.Google Scholar
- Wannamethee SG, Shaper AG, Whincup PH: Serum urate and the risk of major coronary heart disease events. Heart. 1997, 78 (2): 147-153. (Part of the cluster not independent)View ArticleGoogle Scholar
- Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB: Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens. 2000, 18 (8): 1149-1154. 10.1097/00004872-200018080-00021.View ArticleGoogle Scholar
- Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M: Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?. Hypertension. 2003, 41 (6): 1183-1190. 10.1161/01.HYP.0000069700.62727.C5.View ArticleGoogle Scholar
- Alderman M, Aiyer KJ: Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin. 2004, 20 (3): 369-379.View ArticleGoogle Scholar
- Wang JG, Staessen JA, Fagard RH, Birkenhager WH, Gong L, Liu L: Prognostic significance of serum creatinine and uric acid in older Chinese patients with isolated systolic hypertension. Hypertension. 2001, 37 (4): 1069-1074.View ArticleGoogle Scholar
- Gertler MM, Driskell MM, Bland EF, Garn SM, Learman J, Levine SA, Sprague HB, White PD: Clinical aspects of coronary heart disease; an analysis of 100 cases in patients 23 to 40 years of age with myocardial infarction. J Am Med Assoc. 1951, 146 (14): 1291-1295.View ArticleGoogle Scholar
- Kannel WB, Castelli WP, McNamara PM: The coronary profile: 12-year follow-up in the Framingham study. J Occup Med. 1967, 9 (12): 611-619.Google Scholar
- Kylin E: Studien ueber das Hypertonie-Hyperglyka "mie-Hyperurika" miesyndrom. Zentralblatt fuer Innere Medizin. 1923, 44: 105-127.Google Scholar
- Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988, 37 (12): 1595-1607.View ArticleGoogle Scholar
- Zavaroni I, Mazza S, Fantuzzi M, Dall'Aglio E, Bonora E, Delsignore R, Passeri M, Reaven GM: Changes in insulin and lipid metabolism in males with asymptomatic hyperuricaemia. J Intern Med. 1993, 234 (1): 25-30.View ArticleGoogle Scholar
- Hayden MR, Tyagi SC: Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. Cardiovasc Diabetol. 2002, 1 (1): 3-10.1186/1475-2840-1-3.View ArticleGoogle Scholar
- Griendling KK, Sorescu D, Ushio-Fukai M: NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000, 86: 494-501.View ArticleGoogle Scholar
- Hayden MR: Global risk reduction of reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy. Medical Hypotheses and Research. 2004, 1 (2–3): 171-185.Google Scholar
- Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH: Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966, 275 (9): 457-464.View ArticleGoogle Scholar
- Oxipurinol: alloxanthine, Oxyprim, oxypurinol. Drugs R D. 2004, 5 (3): 171-175.
- Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD: Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002, 106 (2): 221-226. 10.1161/01.CIR.0000022140.61460.1D.View ArticleGoogle Scholar
- Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R: Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002, 105 (22): 2619-2624. 10.1161/01.CIR.0000017502.58595.ED.View ArticleGoogle Scholar
- Butler R, Morris AD, Belch JJ, Hill A, Struthers AD: Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000, 35 (3): 746-751.View ArticleGoogle Scholar
- Lin KC, Tsao HM, Chen CH, Chou P: Hypertension was the major risk factor leading to development of cardiovascular diseases among men with hyperuricemia. J Rheumatol. 2004, 31 (6): 1152-1158.Google Scholar
- Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C, Jones P, Bradley A, Caskey CT: Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc Natl Acad Sci U S A. 1994, 91 (2): 742-746.View ArticleGoogle Scholar
- Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001, 38 (5): 1101-1106.View ArticleGoogle Scholar
- Conen D, Wietlisbach V, Bovet P, Shamlaye C, Riesen W, Paccaud F, Burnier M: Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health. 2004, 4 (1): 9-10.1186/1471-2458-4-9.View ArticleGoogle Scholar
- Ogura T, Matsuura K, Matsumoto Y, Mimura Y, Kishida M, Otsuka F, Tobe K: Recent trends of hyperuricemia and obesity in Japanese male adolescents, 1991 through 2002. Metabolism. 2004, 53 (4): 448-453. 10.1016/j.metabol.2003.11.017.View ArticleGoogle Scholar
- Pan WH, Flegal KM, Chang HY, Yeh WT, Yeh CJ, Lee WC: Body mass index and obesity-related metabolic disorders in Taiwanese and US whites and blacks: implications for definitions of overweight and obesity for Asians. Am J Clin Nutr. 2004, 79 (1): 31-39.Google Scholar
- Bonora E, Targher G, Zenere MB, Saggiani F, Cacciatoryi V, Tosi F, Travia D, Zenti MG, Branzi P, Santi L, Muggeo M: Relationship of uric acid concentration to cardiovascular risk factors in young men. The role of obesity and central fat distribution, The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord. 1996, 20: 975-980.Google Scholar
- Bedir A, Topbas M, Tanyeri F, Alvur M, Arik N: Leptin might be a regulator of serum uric acid concentrations in humans. Jpn Heart J. 2003, 44 (4): 527-536. 10.1536/jhj.44.527.View ArticleGoogle Scholar
- Williamson JR, Kilo C, Ido Y: The role of cytosolic reductive stress in oxidant formation and diabetic complications. Diabetes Res Clin Pract. 1999, 45: 81-82. 10.1016/S0168-8227(99)00034-0.View ArticleGoogle Scholar
- Aronson D, Rayfield EJ: How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol. 2002, 1 (1): 1-10.1186/1475-2840-1-1.View ArticleGoogle Scholar
- Santos CX, Anjos EI, Augusto O: Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch Biochem Biophys. 1999, 372 (2): 285-294. 10.1006/abbi.1999.1491.View ArticleGoogle Scholar
- Abuja PM: Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. FEBS Lett. 1999, 446 (2–3): 305-308. 10.1016/S0014-5793(99)00231-8.View ArticleGoogle Scholar
- Hayden MR, Tyagi SC: Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: The pleiotropic effects of folate supplementation. Nutr J. 2004, 3 (1): 4-10.1186/1475-2891-3-4.View ArticleGoogle Scholar
- Evers S, Koch HG, Grotemeyer KH, Lange B, Deufel T, Ringelstein EB: Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol. 1997, 54 (10): 1276-1282.View ArticleGoogle Scholar
- Hong YS, Lee MJ, Kim KH, Lee SH, Lee YH, Kim BG, Jeong B, Yoon HR, Nishio H, Kim JY: The C677 mutation in methylene tetrahydrofolate reductase gene: correlation with uric acid and cardiovascular risk factors in elderly Korean men. J Korean Med Sci. 2004, 19 (2): 209-213.View ArticleGoogle Scholar
- Hayden MR, Tyagi SC: Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation. Cardiovasc Diabetol. 2004, 3 (1): 1-10.1186/1475-2840-3-1.View ArticleGoogle Scholar
- Hayden MR, Tyagi SC: Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Cardiovasc Diabetol. 2003, 2 (1): 2-10.1186/1475-2840-2-2.View ArticleGoogle Scholar
- Jurgens G, Hoff HF, Chisolm GM, Esterbauer H: Modification of human serum low density lipoprotein by oxidation – characterization and pathophysiological implications. Chem Phys Lipids. 1987, 45 (2–4): 315-336. 10.1016/0009-3084(87)90070-3.View ArticleGoogle Scholar
- Hazell LJ, Arnold L, Flowers D, Waeg G, Malle E, Stocker R: Presence of hypochlorite-modified proteins in human atherosclerotic lesions. J Clin Invest. 1996, 97 (6): 1535-1544.View ArticleGoogle Scholar
- Heinecke JW: Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis. Am J Cardiol. 2003, 91 (3A): 12A-16A. 10.1016/S0002-9149(02)03145-4.View ArticleGoogle Scholar
- Darley-Usmar VM, Hogg N, O'Leary VJ, Wilson MT, Moncada S: The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic Res Commun. 1992, 17 (1): 9-20.View ArticleGoogle Scholar
- Hogg N, Darley-Usmar VM, Graham A, Moncada S: Peroxynitrite and atherosclerosis. Biochem Soc Trans. 1993, 21 (2): 358-362.View ArticleGoogle Scholar
- Daugherty A, Dunn JL, Rateri DL, Heinecke JW: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest. 1994, 94 (1): 437-444.View ArticleGoogle Scholar
- Kuhn H, Belkner J, Suzuki H, Yamamoto S: Oxidative modification of human lipoproteins by lipoxygenases of different positional specificities. J Lipid Res. 1994, 35 (10): 1749-1759.Google Scholar
- Bagnati M, Perugini C, Cau C, Bordone R, Albano E, Bellomo G: When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid. Biochem J. 1999, 340 (Pt 1): 143-152. 10.1042/0264-6021:3400143.View ArticleGoogle Scholar
- Patterson RA, Horsley ET, Leake DS: Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDL: important role of uric acid. J Lipid Res. 2003, 44 (3): 512-521. 10.1194/jlr.M200407-JLR200.View ArticleGoogle Scholar
- Nyyssonen K, Porkkala-Sarataho E, Kaikkonen J, Salonen JT: Ascorbate and urate are the strongest determinants of plasma antioxidative capacity and serum lipid resistance to oxidation in Finnish men. Atherosclerosis. 1997, 130 (1–2): 223-233. 10.1016/S0021-9150(96)06064-9.View ArticleGoogle Scholar
- Naghavi M, John R, Naguib S, Siadaty MS, Grasu R, Kurian KC, van Winkle WB, Soller B, Litovsky S, Madjid M, Willerson JT, Casscells W: pH Heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque. Atherosclerosis. 2002, 164 (1): 27-35. 10.1016/S0021-9150(02)00018-7.View ArticleGoogle Scholar
- Sanguinetti SM, Batthyany C, Trostchansky A, Botti H, Lopez GI, Wikinski RL, Rubbo H, Schreier LE: Nitric oxide inhibits prooxidant actions of uric acid during copper-mediated LDL oxidation. Arch Biochem Biophys. 2004, 423 (2): 302-308. 10.1016/j.abb.2003.12.034.View ArticleGoogle Scholar
- Vickers S, Schiller HJ, Hildreth JE, Bulkley GB: Immunoaffinity localization of the enzyme xanthine oxidase on the outside surface of the endothelial cell plasma membrane. Surgery. 1998, 124 (3): 551-560. 10.1067/msy.1998.89892.View ArticleGoogle Scholar
- Ridker PM, Wilson PW, Grundy SM: Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk?. Circulation. 2004, 109 (23): 2818-2825. 10.1161/01.CIR.0000132467.45278.59.View ArticleGoogle Scholar
- Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ: Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003, 41 (6): 1287-1293. 10.1161/01.HYP.0000072820.07472.3B.View ArticleGoogle Scholar
- Olexa P, Olexova M, Gonsorcik J, Tkac I, Kisel'ova J, Olejnikova M: Uric acid – a marker for systemic inflammatory response in patients with congestive heart failure?. Wien Klin Wochenschr. 2002, 114 (5–6): 211-215.Google Scholar
- Tamakoshi K, Yatsuya H, Kondo T, Hori Y, Ishikawa M, Zhang H, Murata C, Otsuka R, Zhu S, Toyoshima H: The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state. Int J Obes Relat Metab Disord. 2003, 27 (4): 443-449. 10.1038/sj.ijo.0802260.View ArticleGoogle Scholar
- Hu P, Seeman TE, Harris TB, Reuben DB: Is serum uric acid level associated with all-cause mortality in high-functioning older persons: MacArthur studies of successful aging?. J Am Geriatr Soc. 2001, 49 (12): 1679-1684. 10.1046/j.1532-5415.2001.t01-1-49279.x.View ArticleGoogle Scholar
- Bo S, Cavallo-Perin P, Gentile L, Repetti E, Pagano G: Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest. 2001, 31 (4): 318-321. 10.1046/j.1365-2362.2001.00812.x.View ArticleGoogle Scholar
- Hsu SP, Pai MF, Peng YS, Chiang CK, Ho TI, Hung KY: Serum uric acid levels show a 'J-shaped' association with all-cause mortality in haemodialysis patients. Nephrol Dial Transplant. 2004, 19 (2): 457-462. 10.1093/ndt/gfg563.View ArticleGoogle Scholar
- Lyu LC, Hsu CY, Yeh CY, Lee MS, Huang SH, Chen CL: A case-control study of the association of diet and obesity with gout in Taiwan. Am J Clin Nutr. 2003, 78 (4): 690-701.Google Scholar
- Johnson RJ, Tuttle KR: Much ado about nothing, or much to do about something? The continuing controversy over the role of uric acid in cardiovascular disease. Hypertension. 2000, 35 (3): E10-View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.