Uric acid: is it a risk factor for cardiovascular disease?

T importance of serum uric acid as a risk factor for cardiovascular disease has been debated for 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 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 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.