Q J Med 2000; 93:707±713Review QJM Uric acid as a risk factor for cardiovascular disease W.S. WARING, D.J. WEBB and S.R.J. MAXWELL From the Clinical Pharmacology Unit and Research Centre, Department of Medical Sciences, University of Edinburgh, Edinburgh, UK Introduction Over recent years there has been renewed debate about the nature of the association between raised serum uric acid concentration and cardiovascular disease.1 Several large studies have identified the value, in populations, of serum uric acid concentration in predicting the risk of cardiovascular events, such as myocardial infarction. This has directed research towards the potential mechanisms by which uric acid might have direct or indirect effects on the cardiovascular system. It has been difficult to identify the specific role of elevated serum uric acid because of its association with established cardiovascular risk factors such as hypertension, diabetes mellitus, hyperlipidaemia and obesity.2,3 Indeed, it is not even clear at this stage whether uric acid has a damaging or protective effect in these circumstances. Increased understanding of the mechanisms underlying these associations may allow a clearer interpretation of the importance of elevated serum uric acid concentrations, and the potential value of specific urate-lowering treatment on cardiovascular disease. Uric acid synthesis Purines arise from metabolism of dietary and endogenous nucleic acids, and are degraded ultimately to uric acid in man, through the action of the enzyme xanthine oxidase (Figure 1). Uric acid is a weak acid (pKa 5.8), distributed throughout the extracellular fluid compartment as sodium urate, and cleared from the plasma by glomerular filtration.4 Around 90% of filtered uric acid is reabsorbed from the proximal renal tubule, while active secretion into the distal tubule by an ATPase-dependent mechanism contributes to overall clearance.5 Serum uric acid concentration within the population has a Gaussian distribution, with a typical reference range (95% CI) of 120±420 mmol/l. For an individual, urate concentration is determined by a combination of the rate of purine metabolism (both endogenous and exogenous) and the efficiency of renal clearance. Purine metabolism is influenced by dietary, as well as genetic factors regulating cell turnover. Uric acid is sparingly soluble in aqueous media, and persistent exposure to high serum levels predisposes to urate crystal deposition within soft tissues.4 All species apart from man and higher apes express urate oxidase, an enzyme responsible for further metabolism of uric acid to allantoin (a more soluble waste product) prior to excretion.6 In man, the urate oxidase gene located on chromosome 1 is not expressed due to two non-sense mutations.7 Loss of uric oxidase activity appears to have developed under evolutionary pressure,7 suggesting that higher serum uric acid concentrations, or reduced urate oxidase may confer important advantages in man. Uric acid as a risk factor for cardiovascular disease An epidemiological link between elevated serum uric acid and an increased cardiovascular risk has Address correspondence to Dr W.S. Waring, Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2LH. e-mail:
[email protected] ß Association of Physicians 2000 09±1. Figure 1.17 Indeed.3.11. been recognized for many years. 95%CI 1.14 Among patients with established hypertension. interestingly. elevated serum uric acid concentration has been associated with a significantly increased cardiovascular risk during a mean 6.29) or systolic blood pressure (1. 95%CI 1. asymptomatic hyperuricaemia predicts future development of hypertension. responsible for conversion of uric acid to more soluble excretory products.D.2 mmol/l) was 1.00±1.12 About one quarter of hypertensive patients have co-existent hyperuricaemia13 and. fasting and post-carbohydrate plasma insulin concentrations.18.10.8. Waring et al. irrespective of renal function. 95%CI 1.02±1. indicating a possible causal relationship.708 W. and its local vasodilatating action may preserve blood flow and prevent tissue ischaemia.09.2 However. whereas other species express uric oxidase.S.15 The proportional hazard ratio for one SD elevation of uric acid (29.22 (95%CI 1.19).35). cholesterol (1. hyperuricaemia is also associated with possible confounding factors including elevated serum triglyceride and cholesterol concentrations.9 Observational studies show that serum uric acid concentrations are higher in patients with established coronary heart disease compared with healthy controls. Uric acid is the end-product of purine metabolism in man. Thiazide diuretics confer unequivocal benefits in treatment of hypertensive patients.16 Persistence of the relationship between elevated serum uric acid concentration and increased cardiovascular risk among thiazidetreated patients has prompted speculation that uric acid elevation may attenuate some of their potential benefits. blood glucose. and cause a significant reduction in cardiovascular and allcause mortality.10 Elevated serum uric acid concentrations are also found in healthy offspring of parents with coronary artery disease.6-year follow-up period.19).11±1. waist-hip ratio and body mass index. the US National Health and Nutrition Survey (NHANES) III showed that ageadjusted rates of myocardial infarction and stroke . Adenosine release is increased during hypoxia. elevation of blood glucose (1. which was higher than for one S.8. To unravel this association. which may serve as an important regulatory mechanism for restoring blood flow and limiting the ischaemia31 (Figure 1). since competitive antagonism at the adenosine receptor by methylxanthines. particularly serum cholesterol concentration.3) and cardiovascular death of 2. diuretic use. and a significant elevation of serum uric acid.29 Under conditions of hypoxia and tissue ischaemia.36 These findings are also consistent with the inverse relation between baseline serum uric acid concentration and maximal .27 In summary.8).7 (95%CI 0. and therefore elevated serum uric acid may act as a marker of underlying tissue ischaemia. The Gothenburg prospective study of 1462 women aged 38 to 60 years also found a significant relationship between serum uric acid concentration and total mortality during 12-year follow-up. blood pressure and age. it is important to understand the mechanisms by which hyperuricaemia relates to other risk factors. vascular dysfunction and cardiovascular disease. which undergoes rapid efflux to the vascular lumen due to low intracellular pH and negative membrane potential.24±2. The Coronary Drug Project Research Group studied 2789 men.35 Study of tourniquet-induced lower limb exsanguination in patients undergoing surgery shows a five-fold increase in systemic vascular xanthine oxidase activity during reperfusion.23 Similar findings have been reported from the Social Insurance Institution of Finland Study24 and Framingham Heart Study. smoking habit. diabetes mellitus is a very powerful risk factor for cardiovascular disease. vascular adenosine synthesis and release are upregulated. caused by transient coronary artery occlusion. Multivariate analysis of data from the MONICA cohort of 1044 males showed a significant association between raised serum uric acid and cardiovascular mortality. It remains unclear whether uric acid is an independent predictor of poor cardiovascular outcome. causing significantly increased circulating concentrations. independent of body mass index.94) of fatal or non-fatal stroke during 7-year follow-up. and found that the association between increased cardiovascular risk and elevated serum uric acid concentration was not significant after consideration of other risk factors. The British Regional Heart Study of 7688 men aged 40 to 59 years showed a significant association between elevated serum uric acid and fatal and non-fatal coronary disease over a mean 16. leads to an increase in the local circulating concentration of uric acid.22 However. this relationship disappeared after correcting for other risk factors. Adenosine synthesized locally by vascular smooth muscle in cardiac tissue is rapidly degraded by the endothelium to uric acid. hypoxia. which was independent of body mass index.8±3. such as theophylline.20 Uric acid also has a predictive role in high-risk patient groups.91 (95%CI 1.2 (95%CI 1.21 In contrast to these findings. In the human coronary circulation. several studies have suggested that the relationship between elevated serum uric acid and cardiovascular risk does not persist after correcting for other risk factors. Uric acid as a marker of subclinical ischaemia Adenosine is synthesized and released by cardiac and vascular myocytes.0±4. alcohol intake and smoking habits. hypertension. although there is overwhelming evidence that elevated serum uric acid concentrations are strongly associated with increased cardiovascular risk and poor outcome. the Honolulu Heart Program 709 found that elevated serum uric acid was not an independent risk factor for the presence at autopsy of aortic or coronary atherosclerosis in Japanese men.Uric acid and cardiovascular disease are higher across increasing serum uric acid quartiles among male and female hypertensive patients. We shall now consider these relationships in more detail.19 Comparison of those individuals within the highest serum uric acid quartile (0373 mmol/l) versus those in the lowest quartile ((319 mmol/l) gave an adjusted risk of myocardial infarction of 1.26 Similarly. Binding to specific adenosine receptors causes relaxation of vascular smooth muscle and arteriolar vasodilatation.30 Cardiac and visceral ischaemia promote generation of adenosine. and a prospective study of 1017 non-insulin-dependent patients showed that serum uric acid concentration )295 mmol/l conferred a hazard ratio of 1.32 Xanthine oxidase activity33 and uric acid synthesis34 are increased in vivo under ischaemic conditions. and when thiazide diuretic use was considered.25 The Atherosclerosis Risk in Communities study of 11 488 healthy men and women showed an apparent association between serum uric acid concentration and early carotid artery atherosclerosis.18 Some studies have suggested that the importance of uric acid may be independent of confounding risk factors. which was dependent of other coronary risk factors. prospective population studies are often confounded by co-existent risk factors. serum lipid concentrations. serum cholesterol concentration. aged 30 to 64 years.8 years. reduce blood flow response to ischaemia in the forearm vascular bed. which persists for at least 2 h. For instance.28 Adenosine makes a small contribution to normal resting vascular tone. 14 even in the presence of normal creatinine clearance and plasma glucose concentrations. Elevated serum uric acid concentrations predict subsequent development of diabetes mellitus42 and hypertension. thus promoting vasodilatation and reducing the potential for peroxynitrite-induced oxidative damage.40.50. Uric acid can also stimulate granulocyte adherence to the endothelium.38 through activation of several pathways including the sympathetic nervous system.710 W. and raised body mass index and waist-hip ratio. causing reduced sodium and uric acid clearance. platelet aggregation.43 Reduction of nitric oxide bioavailability is an important early step in the development of atherosclerosis.60 Direct study of the actions of uric acid on endothelial function. and contributes about 60% of free radical scavenging activity in human serum. where cardiovascular risk is mediated by other factors. while uric acid appears to make a significant contribution to serum anti-oxidant capacity. hypercholesterolaemia and smoking.49 Thus.58 These crystals may contribute to local inflammation and plaque progression. Thus. a potent vasodilator.51 and these effects are inhibited by vitamin C52 indicating an important interaction between aqueous anti-oxidants. and serum triglyceride concentration. vessel wall elasticity and autonomic cardiovascular regulation is required so that its effects on the cardiovascular system and in cardiovascular disease can be determined. interestingly.55±57 Uric acid traverses dysfunctional endothelial cells and accumulates as crystal within atherosclerotic plaques.44. and therefore may be a subtle.48 Uric acid interacts with peroxynitrite to form a stable nitric oxide donor. which disrupts synthesis and accelerates degradation of nitric oxide. uric acid could be expected to protect against oxidative stresses.45 Thus increased oxidative stress appears to have an important role in development and progression of atherosclerosis and is a characteristic finding associated with its major risk factors. a key step in the progression of atherosclerosis.39 Elevated serum uric acid is a consistent feature of the insulin resistance syndromes. a consistent relationship has been noted between elevated serum uric acid concentration and circulating inflammatory markers. However.44 So-called endothelial dysfunction.53 and peroxide and superoxide free radical liberation.59 This effect may have been due to an increase in recorded serum antioxidant capacity. which are also characterized by elevated plasma insulin level (fasting and postcarbohydrate).37 In conclusion therefore. hyperuricaemia may arise as a consequence of enhanced renal insulin activity. hypertension. sensitivity to the renal effects persists. Conclusions Raised serum uric acid concentrations are a powerful predictor of cardiovascular risk and poor . Study of the direct effects of uric acid on vascular function has been hampered by its poor solubility. where higher concentrations could predict subclinical ischaemia. it could also lead directly or indirectly to vascular injury.59 although the effect of uric acid was not considered. elevated serum uric acid may be a marker of local or systemic tissue ischaemia and provides one possible explanation for a non-causal associative link between hyperuricaemia and cardiovascular disease.46 Serum uric acid possesses antioxidant properties. Direct impact of uric acid on vascular function The endothelium plays a central role in maintaining vascular tone through synthesis and release of nitric oxide.2.S. Waring et al. blood glucose concentration.47.54 Therefore uric acid may have a deleterious effect on the endothelium through leukocyte activation and. such as diabetes mellitus. associated with impaired endothelium-dependent vasodilatation may arise from excessive free radical activity.40 Despite blunting of the action of insulin on glucose metabolism. Thus a link between elevated serum uric acid concentration and cardiovascular disease may arise through its non-causal relationship with insulin resistance syndromes.32.3 Insulin has a physiological action on renal tubules.41 Because plasma insulin concentration is characteristically elevated. lower limb blood flow in patients with cardiac failure. uric acid has been found to promote low-density lipoprotein (LDL) oxidation in vitro. Uric acid as a marker of insulin resistance Insulin resistance syndromes result in attenuation of insulin-mediated glucose utilization and confer a substantial increase in cardiovascular risk.53. early marker of peripheral insulin resistance syndromes. and we speculate that crystal accumulation may be greater in patients with elevated serum uric acid concentration. It is interesting to note that treatment of chronic cardiac failure patients with allopurinol (a xanthine oxidase inhibitor) restored endothelial function. although this has been overcome recently. Kohn PM. Waldman GT. 34:78±84. Circulation 1980. Kao FT. Hewitt D. 334:445±51. Yardim S. Several potential explanations have been put forward to explain the apparent association between hyperuricaemia and cardiovascular risk. The management of gout. Lancet 1991. Doring A. Tykarski A. 118:241±9. Lee CC. Branzi P. Bonora E. Beard JT. Agamah ES. Uric acid as an independent risk factor in the treatment of hypertension. JAMA 1959. 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