COMMENTARIES

Uric Acid and Cardiovascular Disease: Risk Factor or Risk Marker?

Thais Coutinho, M.D.1 and Iftikhar Kullo, M.D. 2, 1Department of Internal Medicine and 2Division of Cardiovascular Diseases,
Mayo Clinic
Rochester
MN

Thais Coutinho Iftikhar Kullo

Introduction

Whether serum uric acid (UA) has an etiologic role in cardiovascular disease continues to be a matter of debate. Whereas several investigators have suggested that UA contributes to the pathogenesis of atherosclerosis [1,2], hypertension [2], and inflammation [3-5], others have hypothesized that elevation of serum UA is a consequence, not a cause, of vascular disease since UA is a free radical scavenger, and therefore its elevation could represent a physiologic response to increased vascular oxidative stress [6].

          Several reports describe an independent association of UA with coronary heart disease (CHD) and cerebrovascular disease [7-10], but numerous others have failed to confirm such an association [11-13]. In this commentary we discuss the relationship of UA with risk factors for atherosclerosis, endothelial function, and sub-clinical atherosclerosis.

 
Serum Uric Acid, Conventional Risk Factors, Metabolic Syndrome, and Inflammation

Higher levels of UA have been associated with hypertension, diabetes, higher low density lipoprotein (LDL) cholesterol, lower high-density lipoprotein (HDL) cholesterol, elevated serum triglycerides, increased adiposity, and smoking [13,14], and the relationship between UA and CHD may be confounded by these risk factors. We and others have shown that individuals with the metabolic syndrome have significantly higher UA levels than individuals without the syndrome [14,15]. Furthermore, UA levels increase with the increased number of metabolic syndrome components [14]. A possible mechanism for increased UA levels in the metabolic syndrome, a hyperinsulinemic state, may be that insulin stimulates sodium and urate reabsorption in the proximal tubule [16].

          Several studies suggest that increased UA levels may represent a systemic inflammatory state. We and others have shown that serum UA is significantly associated with plasma levels of C-reactive protein (CRP), a marker of systemic inflammation, independent of potential confounders such as the conventional CHD risk factors [14,17]. In addition, UA has been shown to have pro-inflammatory effects in vitro, including stimulation of production of interleukin-1β, interleukin-6, and tumor necrosis factor-alpha (TNF-α) by human mononuclear cells, and CRP by cultured human vascular cells [4]. However, because serum urate serves as a free-radical scavenger and has anti-oxidant properties [6], elevation of serum UA in the setting of inflammation may be a reactive phenomenon and not a cause of the inflammatory process.

Serum Uric Acid, Endothelial Function, and Hypertension

Previous studies investigating the relationship between UA and flow-mediated dilation, a marker of endothelial function in conduit arteries, have not yielded consistent results. While some reported a significant association [18,19], others suggested that the association of UA and flow-mediated dilation is not independent of the conventional CHD risk factors [20]. We too noted a lack of association between UA and flow-mediated dilation of the brachial artery in adults with hypertension [21]. However, UA was independently associated with reactive forearm hyperemic flow, a measure of endothelial function of the microvasculature [21]. We speculate that the association may be due to the increase in UA production in the microcirculation in the setting of ischemia. During periods of ischemia, xanthine oxidase activity in the endothelial microvasculature leads to formation of oxygen free radicals and UA which in turn may impair post-ischemic hyperemia [22,23]. This has motivated investigation of the effects of xanthine oxidase inhibitors on microvascular endothelial function. Recently, high dose allopurinol (600 mg) was shown to significantly improve forearm endothelial function, assessed by venous occlusion plethysmography, when compared to lower dose allopurinol (300 mg) and placebo [24].

          Serum UA has also been implicated in the development of hypertension given its reported role in the activation of the renin-angiotensin system [25], induction of pre-glomerular arteriolopathy and salt sensitivity [2], and proliferation of vascular smooth muscle [26]. Moreover, it has been show that allopurinol administration can prevent development of hypertension in animal models [27]. Such an association has also been demonstrated in a population-based cohort study performed by Shankar et al. [28], who showed increasing risk of developing hypertension with increasing quartiles of serum uric acid.

Serum Uric Acid and Sub-Clinical Atherosclerosis

The association of serum UA with measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (IMT) and coronary artery calcification, is also controversial. While Iribarren et al. [29] observed that UA was not independently associated with carotid IMT in 11,488 patients from the Atherosclerosis Risk in Communities (ARIC) study, Kawamoto et al. found an independent association in elderly patients [30]. We recently studied the association of serum UA with sub-clinical coronary atherosclerosis (defined by presence and quantity of coronary calcium measured by electron beam computer tomography), in 1,107 asymptomatic non-Hispanic whites belonging to sibships ascertained on the basis of essential hypertension [31]. Serum UA was associated with presence and quantity of coronary artery calcium after adjustment for age and sex, but not after further adjustment for the conventional CHD risk factors.

Summary

Serum UA is a marker of increased cardiovascular risk, however, given its associations with conventional cardiovascular risk factors and components of the metabolic syndrome, an independent correlation may not be easily demonstrated. An added complexity is the fact that UA has been shown to be involved in pathways of inflammation and also as a free radical scavenger. It is possible that UA plays a role in atherosclerosis and endothelial dysfunction by mediating some of the adverse effects of known risk factors, in which case pharmacologic lowering of UA may have beneficial effects. Randomized controlled trials using UA-lowering drugs will be necessary to confirm or refute this hypothesis.

References

  1.    Chapman PT, Yarwood H, Harrison AA, et al. Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: in vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 1997;40:955-65.
  2.    Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-90.
  3.    Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287-93.
  4.    Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol 2005;25:39-42.
  5.    Netea MG, Kullberg BJ, Blok WL, Netea RT, van der Meer JW. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood 1997;89:577-82.
  6.    Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131-39.
  7.    Liese AD, Hense HW, Lowel H, Doring 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. World Health Organization monitoring trends and determinants in cardiovascular diseases. Epidemiology 1999;10:391-97.
  8.    Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. JAMA 2000;283:2404-10.
  9.    Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med 2005;118:816-26.
  10.    Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144-50.
  11.    Wheeler JG, Juzwishin KD, Eiriksdottir G, Gudnason V, Danesh J. Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med 2005;2:e76.
  12.    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;131:7-13.
  13.    Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond WD. Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2000;10:136-43.
  14.    Coutinho Tde A, Turner ST, Peyser PA, Bielak LF, Sheedy PF 2nd, Kullo IJ. Associations of serum uric acid with markers of inflammation, metabolic syndrome, and subclinical coronary atherosclerosis. Am J Hypertens 2007;20:83-89.
  15.    Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M. Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol 2005;25:1038-44.
  16.    Galvan AQ, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol 1995;268:E1-E5.
  17.    Hashimoto K, Kasayama S, Yamamoto H, Kurebayashi S, Kawase I, Koga M. Strong association of C-reactive protein with body mass index and 2-h post-challenge glucose in non-diabetic, non-smoker subjects without hypertension. Diabet Med 2004;21:581-85.
  18.    Kato M, Hisatome I, Tomikura Y, et al. Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol 2005;96:1576-78.
  19.    Mercuro G, Vitale C, Cerquetani E, et al. Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. Am J Cardiol 2004;94:932-35.
  20.    Maxwell AJ, Bruinsma KA. Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol 2001;38:1850-58.
  21.    de ACT, Turner ST, Kullo IJ. Serum uric acid is associated with microvascular function in hypertensive individuals. J Hum Hypertens 2007;21:610-15.
  22.    Gerlach E, Nees S, Becker BF. The vascular endothelium: a survey of some newly evolving biochemical and physiological features. Basic Res Cardiol 1985;80:459-74.
  23.    Des Rosiers C, Nees S, Gerlach E. Purine metabolism in cultured aortic and coronary endothelial cells. Biochem Cell Biol 1989;67:8-15.
  24.    George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114:2508-16.
  25.    Sundstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005;45:28-33.
  26.    Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem 1991;266:8604-8.
  27.    Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101-6.
  28.    Shankar A, Klein R, Klein BE, Nieto FJ. The association between serum uric acid level and long-term incidence of hypertension: Population-based cohort study. J Hum Hypertens 2006;20:937-45.
  29.    Iribarren C, Folsom AR, Eckfeldt JH, McGovern PG, Nieto FJ. Correlates of uric acid and its association with asymptomatic carotid atherosclerosis: the ARIC Study. Atherosclerosis Risk in Communities. Ann Epidemiol 1996;6:331-40.
  30.    Kawamoto R, Tomita H, Oka Y, Kodama A, Ohtsuka N, Kamitani A. Association between uric acid and carotid atherosclerosis in elderly persons. Intern Med 2005;44:787-93.
  31.    Coutinho TD, Turner ST, Peyser PA, Bielak LF, Sheedy PF 2nd, Kullo IJ. Associations of serum uric acid with markers of inflammation, metabolic syndrome, and subclinical coronary atherosclerosis. Am J Hypertens 2007;20:83-89.

 

 

CLOSE THE WINDOW