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Uric acid: is it a risk factor for cardiovascular disease?
Uric Acid: Is It A Risk Factor for Cardiovascular Disease? Michael W. Rich, he importance of serum uric acid as a risk factor for cardiovascular disease has been debated for T nearly 50 years. However, in recent months the debate has intensified as a result of renewed interest in identifying treatable targets for the prevention of coronary heart disease, and in light of several new studies with seemingly conflicting results. The objectives of this editorial review are to discuss potential mechanisms by which uric acid might contribute to the development of atherosclerosis, and to summarize currently available evidence regarding the relation between uric acid and cardiovascular disease. Ever since Gertler et al1 first suggested the possibility of a complex interaction between uric acid and coronary heart disease, virtually all studies have shown that higher uric acid levels are associated with increased cardiovascular risk (Tables I and II).2–22 The question, then, is not whether such an association exists (it does), but whether uric acid is causally related to atherosclerosis, or if it merely serves as a readily identifiable serum marker for other, more fundamental risk factors. This distinction is critically important, because if uric acid is indeed a primary risk factor, then therapies directed at lowering serum acid levels have the potential for significantly reducing cardiovascular risk. It has been well documented that uric acid levels correlate with many of the traditional and some of the more recently identified cardiovascular risk factors, including older age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and the insulin-resistance/hyperinsulinemia syndrome.20,23,24 In addition, uric acid levels increase as renal function declines.25 These relations suggest that the observed association between uric acid levels and cardiovascular disease may represent an epiphenomenon, reflecting the complex interaction between uric acid and other risk factors. At the same time, they greatly confound efforts to establish the “independence” of uric acid as a cardiovascular risk factor using conventional statistical techniques. Apart from the interactions between uric acid and other risk factors, there are several plausible mechanisms whereby uric acid may have a direct effect on atherogenesis or on the clinical course of cardiovascular disease. First, there is evidence that increased uric acid levels promote oxygenation of low density From the Washington University School of Medicine, St. Louis, Missouri. Manuscript received October 25, 1999; revised manuscript received and accepted November 8, 1999. Address for reprints: Michael W. Rich, MD, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St. Louis, Missouri 63110.
1018
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 April 15, 2000
MD
lipoprotein cholesterol and facilitate lipid perioxidation.26 In addition, increased uric acid levels are associated with increased production of oxygen free radicals,27 and each of these factors is known to play a pivotal role in the progression of atherosclerosis. Moreover, it has been suggested that elevated uric acid levels are associated with increased platelet adhesiveness,28 and this effect could potentiate thrombus formation in patients with acute coronary syndromes. Although additional research is required to further delineate the precise role of uric acid in each of these putative mechanisms, it is clear that these effects of uric acid provide a potential basis for uric acid as a primary cardiovascular risk factor. Another potential role of uric acid is as a mediator for the development of other risk factors, particularly systemic hypertension. Although hyperuricemia and hypertension are clearly linked, the mechanisms underlying this relation are uncertain.29 Whereas hypertensive renal dysfunction could account for increased uric acid levels,25 it is also conceivable that hyperuricemia itself may predispose to the development of hypertension or play a role either in the rate of blood pressure progression or in the effects of hypertension on other organs, including the kidney, heart, brain, or vascular endothelium. Indeed, as discussed below, there have been at least 2 studies implicating uric acid as a risk factor for incident hypertension.5,6 In summary, although it is certainly possible that the relation between uric acid and cardiovascular disease is mediated entirely through other risk factors, there are also several potential mechanisms whereby uric acid could exert a direct effect in promoting atherogenesis or in adversely affecting the clinical manifestations of patients with established atherosclerosis. The difficulty in sifting out the independent effects of uric acid amid a constellation of confounding variables is reflected in discordant results from a multitude of very large and well-respected epidemiologic and clinical studies (Tables I and II).2–22 Although space does not permit an exhaustive review of all of these reports, some brief comments are in order. First, it is noteworthy that the relation between uric acid and cardiovascular disease has been examined in at least 16 large trials involving ⬎100,000 subjects. Clearly the lack of a definitive answer to this question is not due to insufficient numbers. Second, 10 of the 16 studies (62.5%) found a significant independent association between uric acid levels and clinical events, either overall or in at least 1 major subgroup (e.g., women), whereas 6 studies concluded that any relation between uric acid and clinical outcomes could 0002-9149/00/$–see front matter PII S0002-9149(99)00922-4
TABLE I Studies Implicating Uric Acid as an Independent Cardiovascular Risk Factor Study and Year
No.
Comments
Chicago Heart Association Detection Project in Industry, 19792,3
24,997
Hypertension Detection and Followup Program, 19854
10,940
In women, uric acid was an independent predictor of all-cause mortality. In men, uric acid was associated with all-cause mortality but was not an independent predictor. Baseline uric acid ⱖ7 mg/dl was associated with significantly higher 5-year mortality in both men and women independent of other risk factors. Baseline uric acid was a strong independent predictor of incident hypertension, with a quintile V: quintile I relative risk of 2.19. Baseline uric acid was the strongest independent predictor of incident hypertension, with a 1-mg/dl increment being associated with a 23% increase in risk. In women, uric acid was an independent predictor of all-cause and coronary mortality, and a 1-mg/dl increment was associated with a 48% increase in risk. In men, uric acid was associated with coronary mortality but was not an independent risk factor. Uric acid was an independent risk factor for cardiovascular events among hypertensive patients, and diuretic-induced increases in uric acid attenuated the benefits of antihypertensive treatment. Among middle-aged diabetics, hyperuricemia was a strong independent risk factor for incident stroke. Uric acid ⱖ7 mg/dl was an independent risk factor for adverse cardiac effects among African-American and Hispanic hypertensives. A uric acid level ⱖ6 mg/dl was an independent risk factor for coronary heart disease and a level ⱖ7 mg/dl was an independent risk factor for stroke. Elevated uric acid (quartile IV vs quartile I) was associated with an independent 32% increase in cardiovascular events overall, and an 86% increase in white men. An increase in uric acid of 1 mg/dl from baseline to 12 months was associated with a 72% increase in the risk of cardiovascular events.
Kaiser Permanente Multiphasic Health Checkup, 19905
Olivetti Heart Study, 19946
2,062
547
National Health and Nutrition Examination Survey I, 19957
5,421
Alderman et al, 19998
7,978
Lehto et al, 19989
1,017
Community Hypertension Intervention Project, 199910
718
National Health and Nutrition Examination Survey III, 199911
16,025
Systolic Hypertension in the Elderly Program, 199912,13
4,327
be accounted for by the interaction between uric acid and other risk factors. Third, in only 1 of the studies, involving ⬍1,000 subjects, was there no apparent relation between uric acid and clinical events by either bivariate or multivariate analysis.18 As mentioned previously, 2 of the studies examined uric acid as a risk factor for incident hypertension. In the Olivetti Heart Study, the baseline serum uric acid level was the strongest independent predictor of new-onset hypertension among 547 middle-aged men, and a 1-mg/dl increment in serum uric acid was associated with a 23% increase in the risk of developing hypertension during a 12-year follow-up period.6 Similarly, in a case-control study involving ⬎2,000 participants in the Kaiser Permanente Multiphasic Health Checkup, there was a progressive increase in the risk of incident hypertension as a function of baseline uric acid quintile, with subjects in the fifth quintile (roughly corresponding to a uric acid level of ⱖ7 mg/dl) experiencing a 2.19-fold greater risk of developing hypertension compared with persons in the first quintile (uric acid level ⬍4 mg/dl).5 Although the mechanism underlying the relation between uric acid and hypertension remains undefined, these studies suggest that an elevated uric acid level may predispose to the development of hypertension. If this is indeed the case, then the use of hypertension as a covariate in the multivariate analyses of uric acid
and cardiovascular disease may be inappropriate, because it would tend to minimize the strength of the association. Alternatively, the uric acid level may simply be a marker for persons who are at increased risk for developing hypertension, and not a primary risk factor per se. The Framingham Heart Study is perhaps the most widely cited analysis that failed to demonstrate an independent association between hyperuremia and cardiovascular disease.20,21 However, even in Framingham, men with gout had a 60% greater incidence of coronary heart disease independent of other risk factors, suggesting that patients with the highest uric acid levels or with the greatest impairment in uric acid metabolism are at substantially increased risk for cardiovascular events.22 Similarly, although the uric acid level was not found to be an independent risk factor in the Honolulu Heart Program,16 among alcohol abstainers (36% of the population), elevated serum uric acid was associated with a 40% increase in coronary risk independent of all other covariates.17 Rather than refuting the uric acid hypothesis, these findings from the Framingham and Honolulu studies imply that, at the very least, there are important subgroups of the population for whom elevated uric acid is an important independent risk factor for cardiovascular disease. As with all risk factors, epidemiologic associations, no matter how strong, do not prove causality. Is EDITORIALS
1019
TABLE II Studies Not Supporting Uric Acid as an Independent Cardiovascular Risk Factor Study and Year
No.
Comments
Klein et al, 197314
2,530
Reunanen et al, 198215
6,355
Honolulu Heart Program, 198416,17
7,705
Uric acid was associated with increased prevalence of coronary heart disease, but not as an independent risk factor on multivariate analysis. Total mortality at 5 years was increased in men and women with hyperuricemia, but not independent of other risk factors. Increased uric acid was associated with increased risk of coronary heart disease but not independent of other risk factors. Among alcohol abstainers, elevated uric acid (quartile IV vs quartile I) was associated with an independent 40% increase in coronary risk. No relation between baseline uric acid and either total or cardiovascular mortality.
factors that are easily measured and highly prevalent in the general population. Hyperuricemia is 1 such potential risk factor, but substantially more research is needed at both the basic science and clinical levels before widespread screening for and treatment of elevated serum uric acid levels can be recommended.
1. Gertler MM, Garn SM, Levine SA. Serum uric acid in relation to age and physique in health and in coronary heart disease. Ann Intern Med 1951;34:1421–1431. 2. Persky VW, Dyer AR, Idris-Soven E, Stamler J, Shekelle RB, Schoenberger JA, Berkson DM, Lindberg HA. Uric acid: a risk factor for coronary heart disease? Circulation 1979;59:969 –977. 3. Levine W, Dyer AR, Shekelle RB, Schoenberger JA, European Working Party 822 Stamler J. Serum uric acid and 11.5-year mortality of on High Blood middle-aged women: findings of the Chicago Heart Pressure in the Elderly, Association Detection Project in Industry. J Clin Epi18 demiol 1989;42:257–267. 1991 4. The Hypertension Detection, and Follow-up Program Wannamethee et al, 7,688 Uric acid was associated with increased Cooperative Research Group. Mortality findings for 199719 coronary risk after adjusting for lifestyle stepped-care and referred-care participants in the Hyfactors and disease indicators, but the pertension Detection and Follow-up Program, stratified relation was nonsignificant after by other risk factors. Prev Med 1985;14:312–335. including diastolic blood pressure and 5. Selby JV, Friedman GD, Quesenberry CP. Precurtotal cholesterol in the multivariate sors of essential hypertension: pulmonary function, model. heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 1990;131:1017–1027. Framingham Heart Study, 6,763 Age-adjusted risk for coronary heart 20–22 6. Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, 1999 disease, cardiovascular death, and allGalasso R, Mancini M, Trevisan M. Serum uric acid cause mortality increased with increasing and hypertension: the Olivetti Heart Study. J Hum uric acid levels in women but not in men, Hypertens 1994;8:677– 681. but the effect was not significant after 7. Freedman DS, Williamson DF, Gunter EW, Byers T. adjusting for other risk factors. However, Relation of serum uric acid to mortality and ischemic men with gout had a 60% greater risk of heart disease. The NHANES I Epidemiologic Folincident coronary disease independent of low-up Study. Am J Epidemiol 1995;141:637– 644. 8. Alderman MH, Cohen H, Madhavan S, Kinlighn S. other risk factors. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999; 34:144 –150. there any evidence that uric acid–lowering therapies 9. Lehto S, Niskanen L, Ro¨nnemaa T, Laakso M. Serum uric acid is a strong are associated with a reduction in cardiovascular predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke 1998;29:635– 639. events? Unfortunately, such data are extremely sparse. 10. San Diego R, Pan D, Morisky D, Enonmoh A, Fong R, Ward H. Elevated In experimental animals, treatment with allopurinol serum uric acid levels are associated with increased hypertension morbidity in the has been shown to reduce ischemia, infarct size, and minority population (abstr). Am J Hypertens 1999;12(suppl A):13A. 11. Waddington C. Elevated uric acid can raise risk for CHD. Cardiol Today reperfusion injury, presumably by reducing the pro- 1999;2(7):15. duction of oxygen free radicals.30,31 However, despite 12. Franse LV, Pahor M, DiBari M, Shorr RI, Wan JY, Somes GW, Applegate these apparently encouraging findings, there have WB. Serum uric acid and cardiovascular events in older persons with isolated been very few studies in humans. In 1 study, Johnson systolic hypertension. J Am Geriatr Soc 1999;47:S10. 13. Franse LV, Pahor M, DiBari M, Shorr RI, Wan JY, Somes GW, Applegate et al32 randomized 169 patients to allopurinol or pla- WB. Serum uric acid, its change with diuretic use and risk of cardiovascular cebo before coronary bypass surgery. Cardiac perfor- events in the Systolic Hypertension in the Elderly Program (SHEP) (abstr). Am J mance was improved and mortality was lower in the Hypertens 1999;12(suppl A):13A. 14. Klein R, Klein BE, Cornoni JC, Maready J, Cassel JC, Tyroler HA. Serum allopurinol group, but nonfatal complications were uric acid. Its relationship to coronary heart disease risk factors and cardiovascular more common with allopurinol. Clearly, there is a disease, Evans County, Georgia. Arch Intern Med 1973;132:401– 410. need for additional studies assessing the effects of uric 15. Reunanen A, Takkunen H, Knekt P, Aromaa A. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand (Suppl) 1982;668:49 –59. acid–lowering therapies on major clinical outcomes in 16. Yano K, Reed DM, McGee DL. Ten-year incidence of coronary heart disease persons at risk for cardiovascular events. in the Honolulu Heart Program. Relationship to biologic and lifestyle characterBased on the above overview, it appears that the istics. Am J Epidemiol 1984;119:653– 666. preponderance of epidemiologic data supports a po- 17. Iribarren C, Sharp DS, Curb JD, Yano K. High uric acid: a metabolic marker of coronary heart disease among alcohol abstainers? J Clin Epidemiol 1996;49: tential role for serum uric acid as an independent risk 673– 678. factor for cardiovascular disease. However, the pre- 18. Staessen J, for members of the European Working Party on High Blood cise mechanisms underlying such an association re- Pressure in the Elderly. The determinants and prognostic significance of serum acid in elderly patients of the European Working Party on High Blood main uncertain, and the value of therapies aimed at uric Pressure in the Elderly trial. Am J Med 1991;90(suppl 3A):50S-54S. lowering uric acid levels is unproven. Given that ath- 19. Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of erosclerotic cardiovascular disease remains rampant major coronary heart disease events. Heart 1997;78:147–153. FN, McGee DL, Kannel WB, Stokes J, Castelli WP. Hyperuricemia as despite the widespread availability of highly effective a20.riskBrand factor of coronary heart disease: The Framingham Study. Am J Epidemiol therapies for hyperlipidemia and hypertension, there is 1985;121:11–18. a pressing need to identify additional treatable risk 21. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for
1020 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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APRIL 15, 2000
cardiovascular disease and death: The Framingham Heart Study. Ann Intern Med 1999;131:7–13. 22. Abbott RD, Brand FN, Kannel WB, Castelli WP. Gout and coronary heart disease: The Framingham Study. J Clin Epidemiol 1988;41:237– 42. 23. Bonora E, Targher G, Zenere MB, Saggiani F, Cacciatori 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. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes 1996;20:975–980. 24. Rathmann W, Funkhouser E, Dyer AR, Roseman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: The CARDIA Study. Ann Epidemiol 1998;8:250 –261. 25. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 1999;33:225–234.
26. Ward HJ. Uric acid as an independent risk factor in the treatment of
hypertension. Lancet 1998;352:670 – 671. 27. DeScheeder IK, van de Kraay AM, Lamers JM, Koster JF, deJong JW,
Serruys PW. Myocardial malodialdehyde and uric acid release after short-lasting coronary occlusions during angioplasty: potential mechanisms for free radical generation. Am J Cardiol 1991;68:392–395. 28. Ginsberg MH, Kozin F, O’Malley M, McCarty DJ. Release of platelet constituents by monosodium urate crystals. J Clin Invest 1997;60:999 –1007. 29. Breckenridge A. Hypertension and hyperuricemia. Lancet 1966;1:15–18. 30. DeWall RA, Vasko KA, Stanley EL, Kezdi P. Responses of the ischemic myocardium to allopurinol. Am Heart J 1971;82:362–370. 31. Bando K, Tago M, Teramoto S. Prevention of free radical-induced myocardial injury by allopurinol. Experimental study in cardiac preservation and transplantation. J Thorac Cardiovasc Surg 1988;95:465– 473. 32. Johnson WD, Kayser KL, Brenowitz JB, Saedi SF. A randomized controlled trial of allopurinol in coronary bypass surgery. Am Heart J 1991;121:20 –24.
EDITORIALS
1021
1018
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 April 15, 2000
MD
lipoprotein cholesterol and facilitate lipid perioxidation.26 In addition, increased uric acid levels are associated with increased production of oxygen free radicals,27 and each of these factors is known to play a pivotal role in the progression of atherosclerosis. Moreover, it has been suggested that elevated uric acid levels are associated with increased platelet adhesiveness,28 and this effect could potentiate thrombus formation in patients with acute coronary syndromes. Although additional research is required to further delineate the precise role of uric acid in each of these putative mechanisms, it is clear that these effects of uric acid provide a potential basis for uric acid as a primary cardiovascular risk factor. Another potential role of uric acid is as a mediator for the development of other risk factors, particularly systemic hypertension. Although hyperuricemia and hypertension are clearly linked, the mechanisms underlying this relation are uncertain.29 Whereas hypertensive renal dysfunction could account for increased uric acid levels,25 it is also conceivable that hyperuricemia itself may predispose to the development of hypertension or play a role either in the rate of blood pressure progression or in the effects of hypertension on other organs, including the kidney, heart, brain, or vascular endothelium. Indeed, as discussed below, there have been at least 2 studies implicating uric acid as a risk factor for incident hypertension.5,6 In summary, although it is certainly possible that the relation between uric acid and cardiovascular disease is mediated entirely through other risk factors, there are also several potential mechanisms whereby uric acid could exert a direct effect in promoting atherogenesis or in adversely affecting the clinical manifestations of patients with established atherosclerosis. The difficulty in sifting out the independent effects of uric acid amid a constellation of confounding variables is reflected in discordant results from a multitude of very large and well-respected epidemiologic and clinical studies (Tables I and II).2–22 Although space does not permit an exhaustive review of all of these reports, some brief comments are in order. First, it is noteworthy that the relation between uric acid and cardiovascular disease has been examined in at least 16 large trials involving ⬎100,000 subjects. Clearly the lack of a definitive answer to this question is not due to insufficient numbers. Second, 10 of the 16 studies (62.5%) found a significant independent association between uric acid levels and clinical events, either overall or in at least 1 major subgroup (e.g., women), whereas 6 studies concluded that any relation between uric acid and clinical outcomes could 0002-9149/00/$–see front matter PII S0002-9149(99)00922-4
TABLE I Studies Implicating Uric Acid as an Independent Cardiovascular Risk Factor Study and Year
No.
Comments
Chicago Heart Association Detection Project in Industry, 19792,3
24,997
Hypertension Detection and Followup Program, 19854
10,940
In women, uric acid was an independent predictor of all-cause mortality. In men, uric acid was associated with all-cause mortality but was not an independent predictor. Baseline uric acid ⱖ7 mg/dl was associated with significantly higher 5-year mortality in both men and women independent of other risk factors. Baseline uric acid was a strong independent predictor of incident hypertension, with a quintile V: quintile I relative risk of 2.19. Baseline uric acid was the strongest independent predictor of incident hypertension, with a 1-mg/dl increment being associated with a 23% increase in risk. In women, uric acid was an independent predictor of all-cause and coronary mortality, and a 1-mg/dl increment was associated with a 48% increase in risk. In men, uric acid was associated with coronary mortality but was not an independent risk factor. Uric acid was an independent risk factor for cardiovascular events among hypertensive patients, and diuretic-induced increases in uric acid attenuated the benefits of antihypertensive treatment. Among middle-aged diabetics, hyperuricemia was a strong independent risk factor for incident stroke. Uric acid ⱖ7 mg/dl was an independent risk factor for adverse cardiac effects among African-American and Hispanic hypertensives. A uric acid level ⱖ6 mg/dl was an independent risk factor for coronary heart disease and a level ⱖ7 mg/dl was an independent risk factor for stroke. Elevated uric acid (quartile IV vs quartile I) was associated with an independent 32% increase in cardiovascular events overall, and an 86% increase in white men. An increase in uric acid of 1 mg/dl from baseline to 12 months was associated with a 72% increase in the risk of cardiovascular events.
Kaiser Permanente Multiphasic Health Checkup, 19905
Olivetti Heart Study, 19946
2,062
547
National Health and Nutrition Examination Survey I, 19957
5,421
Alderman et al, 19998
7,978
Lehto et al, 19989
1,017
Community Hypertension Intervention Project, 199910
718
National Health and Nutrition Examination Survey III, 199911
16,025
Systolic Hypertension in the Elderly Program, 199912,13
4,327
be accounted for by the interaction between uric acid and other risk factors. Third, in only 1 of the studies, involving ⬍1,000 subjects, was there no apparent relation between uric acid and clinical events by either bivariate or multivariate analysis.18 As mentioned previously, 2 of the studies examined uric acid as a risk factor for incident hypertension. In the Olivetti Heart Study, the baseline serum uric acid level was the strongest independent predictor of new-onset hypertension among 547 middle-aged men, and a 1-mg/dl increment in serum uric acid was associated with a 23% increase in the risk of developing hypertension during a 12-year follow-up period.6 Similarly, in a case-control study involving ⬎2,000 participants in the Kaiser Permanente Multiphasic Health Checkup, there was a progressive increase in the risk of incident hypertension as a function of baseline uric acid quintile, with subjects in the fifth quintile (roughly corresponding to a uric acid level of ⱖ7 mg/dl) experiencing a 2.19-fold greater risk of developing hypertension compared with persons in the first quintile (uric acid level ⬍4 mg/dl).5 Although the mechanism underlying the relation between uric acid and hypertension remains undefined, these studies suggest that an elevated uric acid level may predispose to the development of hypertension. If this is indeed the case, then the use of hypertension as a covariate in the multivariate analyses of uric acid
and cardiovascular disease may be inappropriate, because it would tend to minimize the strength of the association. Alternatively, the uric acid level may simply be a marker for persons who are at increased risk for developing hypertension, and not a primary risk factor per se. The Framingham Heart Study is perhaps the most widely cited analysis that failed to demonstrate an independent association between hyperuremia and cardiovascular disease.20,21 However, even in Framingham, men with gout had a 60% greater incidence of coronary heart disease independent of other risk factors, suggesting that patients with the highest uric acid levels or with the greatest impairment in uric acid metabolism are at substantially increased risk for cardiovascular events.22 Similarly, although the uric acid level was not found to be an independent risk factor in the Honolulu Heart Program,16 among alcohol abstainers (36% of the population), elevated serum uric acid was associated with a 40% increase in coronary risk independent of all other covariates.17 Rather than refuting the uric acid hypothesis, these findings from the Framingham and Honolulu studies imply that, at the very least, there are important subgroups of the population for whom elevated uric acid is an important independent risk factor for cardiovascular disease. As with all risk factors, epidemiologic associations, no matter how strong, do not prove causality. Is EDITORIALS
1019
TABLE II Studies Not Supporting Uric Acid as an Independent Cardiovascular Risk Factor Study and Year
No.
Comments
Klein et al, 197314
2,530
Reunanen et al, 198215
6,355
Honolulu Heart Program, 198416,17
7,705
Uric acid was associated with increased prevalence of coronary heart disease, but not as an independent risk factor on multivariate analysis. Total mortality at 5 years was increased in men and women with hyperuricemia, but not independent of other risk factors. Increased uric acid was associated with increased risk of coronary heart disease but not independent of other risk factors. Among alcohol abstainers, elevated uric acid (quartile IV vs quartile I) was associated with an independent 40% increase in coronary risk. No relation between baseline uric acid and either total or cardiovascular mortality.
factors that are easily measured and highly prevalent in the general population. Hyperuricemia is 1 such potential risk factor, but substantially more research is needed at both the basic science and clinical levels before widespread screening for and treatment of elevated serum uric acid levels can be recommended.
1. Gertler MM, Garn SM, Levine SA. Serum uric acid in relation to age and physique in health and in coronary heart disease. Ann Intern Med 1951;34:1421–1431. 2. Persky VW, Dyer AR, Idris-Soven E, Stamler J, Shekelle RB, Schoenberger JA, Berkson DM, Lindberg HA. Uric acid: a risk factor for coronary heart disease? Circulation 1979;59:969 –977. 3. Levine W, Dyer AR, Shekelle RB, Schoenberger JA, European Working Party 822 Stamler J. Serum uric acid and 11.5-year mortality of on High Blood middle-aged women: findings of the Chicago Heart Pressure in the Elderly, Association Detection Project in Industry. J Clin Epi18 demiol 1989;42:257–267. 1991 4. The Hypertension Detection, and Follow-up Program Wannamethee et al, 7,688 Uric acid was associated with increased Cooperative Research Group. Mortality findings for 199719 coronary risk after adjusting for lifestyle stepped-care and referred-care participants in the Hyfactors and disease indicators, but the pertension Detection and Follow-up Program, stratified relation was nonsignificant after by other risk factors. Prev Med 1985;14:312–335. including diastolic blood pressure and 5. Selby JV, Friedman GD, Quesenberry CP. Precurtotal cholesterol in the multivariate sors of essential hypertension: pulmonary function, model. heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 1990;131:1017–1027. Framingham Heart Study, 6,763 Age-adjusted risk for coronary heart 20–22 6. Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, 1999 disease, cardiovascular death, and allGalasso R, Mancini M, Trevisan M. Serum uric acid cause mortality increased with increasing and hypertension: the Olivetti Heart Study. J Hum uric acid levels in women but not in men, Hypertens 1994;8:677– 681. but the effect was not significant after 7. Freedman DS, Williamson DF, Gunter EW, Byers T. adjusting for other risk factors. However, Relation of serum uric acid to mortality and ischemic men with gout had a 60% greater risk of heart disease. The NHANES I Epidemiologic Folincident coronary disease independent of low-up Study. Am J Epidemiol 1995;141:637– 644. 8. Alderman MH, Cohen H, Madhavan S, Kinlighn S. other risk factors. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999; 34:144 –150. there any evidence that uric acid–lowering therapies 9. Lehto S, Niskanen L, Ro¨nnemaa T, Laakso M. Serum uric acid is a strong are associated with a reduction in cardiovascular predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke 1998;29:635– 639. events? Unfortunately, such data are extremely sparse. 10. San Diego R, Pan D, Morisky D, Enonmoh A, Fong R, Ward H. Elevated In experimental animals, treatment with allopurinol serum uric acid levels are associated with increased hypertension morbidity in the has been shown to reduce ischemia, infarct size, and minority population (abstr). Am J Hypertens 1999;12(suppl A):13A. 11. Waddington C. Elevated uric acid can raise risk for CHD. Cardiol Today reperfusion injury, presumably by reducing the pro- 1999;2(7):15. duction of oxygen free radicals.30,31 However, despite 12. Franse LV, Pahor M, DiBari M, Shorr RI, Wan JY, Somes GW, Applegate these apparently encouraging findings, there have WB. Serum uric acid and cardiovascular events in older persons with isolated been very few studies in humans. In 1 study, Johnson systolic hypertension. J Am Geriatr Soc 1999;47:S10. 13. Franse LV, Pahor M, DiBari M, Shorr RI, Wan JY, Somes GW, Applegate et al32 randomized 169 patients to allopurinol or pla- WB. Serum uric acid, its change with diuretic use and risk of cardiovascular cebo before coronary bypass surgery. Cardiac perfor- events in the Systolic Hypertension in the Elderly Program (SHEP) (abstr). Am J mance was improved and mortality was lower in the Hypertens 1999;12(suppl A):13A. 14. Klein R, Klein BE, Cornoni JC, Maready J, Cassel JC, Tyroler HA. Serum allopurinol group, but nonfatal complications were uric acid. Its relationship to coronary heart disease risk factors and cardiovascular more common with allopurinol. Clearly, there is a disease, Evans County, Georgia. Arch Intern Med 1973;132:401– 410. need for additional studies assessing the effects of uric 15. Reunanen A, Takkunen H, Knekt P, Aromaa A. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand (Suppl) 1982;668:49 –59. acid–lowering therapies on major clinical outcomes in 16. Yano K, Reed DM, McGee DL. 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