Serum uric acid levels and cardiovascular disease: the Gordian knot

Serum uric acid levels and cardiovascular disease: the Gordian knot

Efrén Martínez-Quintana1, Antonio Tugores2, Fayna Rodríguez-González3

1Cardiology Service, Insular-Materno Infantil University Hospital, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain;2Research Unit, Insular-Materno Infantil University Hospital, Las Palmas de Gran Canaria, Spain;3Dr. Negrín University Hospital of Gran Canaria, Las Palmas de Gran Canaria, Spain

Correspondence to: Efrén Martínez-Quintana. Servicio de Cardiología, Complejo Hospitalario Universitario Insular Materno Infantil, Avd. Marítima del Sur s/n. 35016 Las Palmas de Gran Canaria, Spain. Email:

Abstract: Hyperuricemia is defined as serum uric acid level of more than 7 mg/dL and blood levels of uric acid are causally associated with gout, as implicated by evidence from randomized clinical trials using urate lowering therapies. Uric acid as a cardiovascular risk factor often accompanies metabolic syndrome, hypertension, diabetes, dyslipidemia, chronic renal disease, and obesity. Despite the association of hyperuricemia with cardiovascular risk factors, it has remained controversial as to whether uric acid is an independent predictor of cardiovascular disease. To settle this issue, and in the absence of large randomized controlled trials, Mendelian randomization analysis in which the exposure is defined based on the presence or absence of a specific allele that influences a risk factor of interest have tried to shed light on this.

Keywords: Hyperuricemia; cardiovascular risk factors; coronary artery disease; mendelian randomization

Submitted Sep 30, 2016. Accepted for publication Nov 04, 2016.

doi: 10.21037/jtd.2016.11.39

Serum concentrations of uric acid, the end product of the metabolism of purine compounds, above 7 mg/dL result in hyperuricemia, causally associated with gout as evidenced in randomized clinical trials using urate lowering therapies (1). All or nearly all urate is filtrated out at the glomerulus, and decreased efficiency of renal uric acid excretion is responsible for about 85 to 90 percent of primary or secondary hyperuricemia. Hyperuricemia may also occur, but to a lesser degree, by the overproduction of uric acid due to the intake of purine-rich food, alcohol abuse or by conditions associated with high cellular turnover (large destruction of tumor cells, psoriasis, etc.). Also, numerous drugs, used frequently in patients with heart disease, such as losartan, diuretics, beta-blockers or acetylsalicylic acid may favor an increase on serum uric acid (2). In the same way genetic variation may contribute to serum uric acid levels through regulation of uric acid synthesis, excretion, or reabsorption (3).

Hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. The atherosclerotic plaque contains a considerable amount of uric acid which may increase platelet adhesiveness and potentiate thrombus formation (4). Increased serum uric acid levels may favor microvascular diseases stimulating vascular smooth muscle cell proliferation, the production of low-grade inflammatory and pro-oxidative states and the generation of vasoconstrictive substances, ultimately leading to growth, instability, and rupture of atherosclerotic plaques and facilitation of thrombosis. It is believed that the action of serum urate is elicited through the action, among other factors, of xanthine oxidase, a powerful oxygen radical-generating system in human physiology (5,6), and by altering the equilibrium the renin-angiotensin system (7), thus influencing arterial hypertension. As a support of the causative role of uric acid in the development of hypertension, two randomized trials have shown that hypertension in adolescents is preventable by lowering uric acid with either xanthine oxidase inhibitors or uricosuric agents (8,9). Meanwhile, benefits on blood pressure in adults are less significant (10). In this context, a meta-analysis of 18 prospective cohort studies of subjects who were normotensive at baseline (n=55,607) found that hyperuricemia was associated with an increased risk for incident hypertension being this finding most striking in younger individuals and women.

There is also increasing evidence that elevated serum uric acid levels may predict the development of type 2 diabetes. Biologically, uric acid plays an important role in worsening the insulin resistance phenotype in animal models by inhibiting the bioavailability of nitric oxide, which is essential for insulin-stimulated glucose uptake (11). On the other hand hyperinsulinemia, as a consequence of insulin resistance, causes an increase in serum uric acid concentration by both reducing renal uric acid secretion (12) and the accumulation of substrates required for uric acid production (13). In this context, Kodama et al. (14) found, in a meta-analysis of 11 cohort studies (42,834 participants) which included 3,305 incident cases of type 2 diabetes, that hyperuricemia was positively associated with the development of type 2 diabetes.

Despite the association of hyperuricemia with cardiovascular risk factors, it has remained controversial as to whether uric acid is an independent predictor of cardiovascular disease, with many studies in favour (15-19) and others against (20,21). One example of the latter is the study of the Framingham Heart Study cohort (20), which did not reveal a significant association between uric acid levels and the incidence of coronary heart disease or cardiovascular mortality after adjustment for cardiovascular risk factors. The authors indicated that the observed lack of association was likely because of the close association between uric acid and known risk factors such as decreased glomerular filtration rate, the use of diuretics and insulin resistance. Similarly, some meta-analyses have not reached an agreement about the utility of uric acid as a cardiovascular risk factor per se (22,23). Also, hypoxaemia, body mass index, and C-reactive protein concentrations have been demonstrated to be higher in hyperuricemic congenital heart disease patients, although no significant differences were seen in mortality between congenital heart disease patients with high and low serum uric acid concentrations (24). By contrast, other authors have found that high uric acid levels may predict the risk for stroke (25) and heart failure (26) besides being predictive of symptom status and prognosis (27). Likewise, some authors have detected an increased risk of both cardiac and total mortality with increasing serum uric acid levels (28). Nonetheless, establishing whether serum uric acid is an independent risk factor has been complicated by interactions between serum uric acid levels, cardiovascular risk factors and kidney function.

Intervention studies are needed to determine whether serum uric acid levels and cardiovascular disease are indeed associated but, up to date, there has only been a randomized, double-blind, placebo-controlled, crossover trial in patients with angina pectoris which concluded that the uric acid lowering drug allopurinol is a useful, well tolerated, and safe anti-ischaemic treatment option in patients with angina (29). The mechanism of the anti-ischaemic effect of allopurinol, a xanthine oxidase inhibitor, might be related to the improvement in the peripheral endothelial function. Nonetheless, while the results of this study showed a benefit of allopurinol, the overall effects were modest and the study population small (n=65).

Being faced by this Gordian knot and, in the absence of costly randomized controlled trials, considered the gold standard since they provide the highest level of statistical evidence, some authors have turned to Mendelian randomization analysis. This is the case of Keenan et al. (30), who tried to assess whether serum urate levels were causally relevant in type 2 diabetes mellitus, coronary heart disease, ischemic stroke, and heart failure. Twenty eight single nucleotide polymorphisms known to be associated with serum urate levels were examined in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms, exclusively associated with serum urate levels, were used in a genetic risk score to detect associations with cardiometabolic diseases. Their results revealed no evidence to support a causal role of circulating serum urate levels in type 2 diabetes mellitus, coronary heart disease, ischemic stroke, or heart failure. Moreover, they state that decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.

A lack of association between individual genetic variants associated with serum urate levels and hypertension, glucose, lipids, and coronary artery diseases has been also reported by others (3,31,32). Yang et al. (33) used Mendelian randomization to establish a genetic urate risk score based on the analysis of eight genetic loci (SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, SLC17A1) that showed genome-wide significant association with urate levels in a meta-analysis. This score explained, in average, 6.0% of serum urate variance, compared to an average of 0.8% when individual SNPs were considered. As in the study of Keenan et al. (30), they did not observe an association between the genetic urate score, fasting glucose levels or coronary heart disease. Pfister et al. (34) established a risk score based on eight serum-uric-acid-raising common allelic variants, identified in genome-wide association studies and evaluated the association of this score with type 2 diabetes in several case-control studies including 7,504 diabetes patients and 8,560 non-diabetic controls. Their results did not support a causal relationship between uric acid and the development of type 2 diabetes, limiting the expectations that uric-acid-lowering drugs would be effective in the prevention of type 2 diabetes. Similarly, Palmer et al. (35) conducted a Mendelian randomization analysis and found no strong evidence for causal associations between a variant at the SLC2A9 gene (rs7442295), associated with uric acid levels, and ischaemic heart disease or blood pressure. Another large meta-analysis, including over 28,000 participants, showed no association between nine different loci associated to serum uric acid levels and the risk of coronary artery disease (36). In this context, Keenan et al. (30), by examining a much larger cohort of coronary heart disease cases than in previous studies (33-36) obtained a similar result.

Because the association between genes and disease is not generally subject to confounding by environmental factors or reverse causality, causal inferences between exposure and disease can be examined more specifically using Mendelian randomization (37,38). This methodology is inspired by Mendel’s second law, which states that unlinked or distantly linked segregating gene pairs assort independently at meiosis. In other words, gene transfer from parent to child is a chance occurrence, similar to the random assignment into different experimental groups as in a randomized controlled trial (39). However, we may find several scenarios violating the Mendelian randomization assumptions, such as inadequate phenotype definition, time-varying exposures, the presence of gene-environment interaction, the existence of measurement error, the possibility of reverse causation, deviations in the expected allelic frequencies due to several causes (population stratification, existence of linkage disequilibrium phenomena, pleotropic activity of some genes, etc.), the existence of an appropriate instrument (simple or multiple polymorphism, or genetic risk scores) for the study of interest, the lack of compliance with the conditions that should be met by instrumental variables, or problems with sample size (39-41).

The Gordian knot, according to prophecy, was to be undone only by the person who was to rule Asia, and that was cut, rather than untied, by Alexander the Great. Only large, randomized controlled trials will be able to disentangle the role of hyperuricemia in cardiovascular disease, undoing the knot rather than cutting it.




Provenance: This is an invited Perspective commissioned by the Section Editor Haiyun Yuan (Department of Cardiovascular Surgery, Guangdong Provincial Cardiovascular Institute, Guangdong General Hospital, Dongchuan Road, Guangzhou, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Keenan T, Zhao W, Rasheed A, et al. Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. J Am Coll Cardiol 2016;67:407-16.


  1. Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Febuxostat for treating chronic gout. Cochrane Database Syst Rev 2012;11:CD008653. [PubMed]
  2. Borghi C, Rosei EA, Bardin T, et al. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens 2015;33:1729-41; discussion 1741.
  3. Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008;40:437-42. [Crossref] [PubMed]
  4. Suarna C, Dean RT, May J, et al. Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of alpha-tocopherol and ascorbate. Arterioscler Thromb Vasc Biol 1995;15:1616-24. [Crossref] [PubMed]
  5. Doehner W, Landmesser U. Xanthine oxidase and uric acid in cardiovascular disease: clinical impact and therapeutic options. Semin Nephrol 2011;31:433-40. [Crossref] [PubMed]
  6. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004;555:589-606. [Crossref] [PubMed]
  7. Corry DB, Eslami P, Yamamoto K, et al. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269-75. [Crossref] [PubMed]
  8. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008;300:924-32. [Crossref] [PubMed]
  9. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 2012;60:1148-56. [Crossref] [PubMed]
  10. Kanbay M, Huddam B, Azak A, et al. A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin J Am Soc Nephrol 2011;6:1887-94. [Crossref] [PubMed]
  11. Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67:1739-42. [Crossref] [PubMed]
  12. Quiñones Galvan A, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans. Am J Physiol 1995;268:E1-5. [PubMed]
  13. Fox IH. Metabolic basis for disorders of purine nucleotide degradation. Metabolism 1981;30:616-34. [Crossref] [PubMed]
  14. Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32:1737-42. [Crossref] [PubMed]
  15. Høieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65:1041-9. [Crossref] [PubMed]
  16. 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. [Crossref] [PubMed]
  17. Alderman MH, Cohen H, Madhavan S, et al. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999;34:144-50. [Crossref] [PubMed]
  18. Krishnan E, Baker JF, Furst DE, et al. Gout and the risk of acute myocardial infarction. Arthritis Rheum 2006;54:2688-96. [Crossref] [PubMed]
  19. Bos MJ, Koudstaal PJ, Hofman A, et al. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 2006;37:1503-7. [Crossref] [PubMed]
  20. Culleton BF, Larson MG, Kannel WB, et al. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7-13. [Crossref] [PubMed]
  21. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart disease events. Heart 1997;78:147-53. [Crossref] [PubMed]
  22. Wheeler JG, Juzwishin KD, Eiriksdottir G, et al. 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. [Crossref] [PubMed]
  23. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2010;62:170-80. [PubMed]
  24. Martínez-Quintana E, Rodríguez-González F. Hyperuricaemia in congenital heart disease patients. Cardiol Young 2015;25:29-34. [Crossref] [PubMed]
  25. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 2009;61:885-92. [Crossref] [PubMed]
  26. Ekundayo OJ, Dell'Italia LJ, Sanders PW, et al. Association between hyperuricemia and incident heart failure among older adults: a propensity-matched study. Int J Cardiol 2010;142:279-87. [Crossref] [PubMed]
  27. Leyva F, Anker SD, Godsland IF, et al. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 1998;19:1814-22. [Crossref] [PubMed]
  28. Stack AG, Hanley A, Casserly LF, et al. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM 2013;106:647-58. [Crossref] [PubMed]
  29. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010;375:2161-7. [Crossref] [PubMed]
  30. Keenan T, Zhao W, Rasheed A, et al. Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization. J Am Coll Cardiol 2016;67:407-16. [Crossref] [PubMed]
  31. Caulfield MJ, Munroe PB, O'Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008;5:e197. [Crossref] [PubMed]
  32. Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008;3:e1948. [Crossref] [PubMed]
  33. Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010;3:523-30. [Crossref] [PubMed]
  34. Pfister R, Barnes D, Luben R, et al. No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach. Diabetologia 2011;54:2561-9. [Crossref] [PubMed]
  35. Palmer TM, Nordestgaard BG, Benn M, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. BMJ 2013;347:f4262. [Crossref] [PubMed]
  36. Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009;4:e7729. [Crossref] [PubMed]
  37. Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133-63. [Crossref] [PubMed]
  38. Smith GD, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22. [Crossref] [PubMed]
  39. Iturrieta-Zuazo I, Walter S.. Mendelian randomization: present and future of epidemiological studies in cardiology. Rev Esp Cardiol (Engl Ed) 2015;68:87-91. [Crossref] [PubMed]
  40. VanderWeele TJ, Tchetgen Tchetgen EJ, Cornelis M, et al. Methodological challenges in mendelian randomization. Epidemiology 2014;25:427-35. [Crossref] [PubMed]
  41. Freeman G, Cowling BJ, Schooling CM. Power and sample size calculations for Mendelian randomization studies using one genetic instrument. Int J Epidemiol 2013;42:1157-63. [Crossref] [PubMed]
Cite this article as: Martínez-Quintana E, Tugores A, Rodríguez-González F. Serum uric acid levels and cardiovascular disease: the Gordian knot. J Thorac Dis 2016;8(11):E1462-E1466. doi: 10.21037/jtd.2016.11.39