ARTHRITIS & RHEUMATISM Vol. 58, No. 2, February 2008, pp 623–630 DOI 10.1002/art.23121 © 2008, American College of Rheumatology Serum Uric Acid Is an Independent Predictor of All-Cause Mortality in Patients at High Risk of Cardiovascular Disease A Preventive Cardiology Information System (PreCIS) Database Cohort Study Adriana G. Ioachimescu, Danielle M. Brennan, Brian M. Hoar, Stanley L. Hazen, and Byron J. Hoogwerf Objective. Uric acid is a product of the activity of xanthine oxidase, an enzyme linked to oxidative stress, endothelial dysfunction, and heart failure. It is unclear whether adding uric acid levels to the assessment of cardiovascular risk might contribute to the improved ability to stratify cardiovascular risk. The purpose of this study was to evaluate the prognostic value of serum uric acid levels in a large cohort of men and women at high risk of cardiovascular disease. Methods. Serum uric acid levels were determined in all patients seen for primary/secondary cardiovascu- lar disease prevention at the Cleveland Clinic Section of Preventive Cardiology and Rehabilitation between 1998 and 2004, and all data were entered into the Preventive Cardiology Information System (PreCIS) database. Vi- tal status of the patients was determined through the Social Security Death Index. Death from all causes was summarized across quartiles of uric acid values. Results. A total of 3,098 patients (age range 18–87 years) were identified in the database, among whom 43% had cardiovascular disease. There were 156 deaths (5%) during the 14,262 person-years of followup. For each 1-mg/dl increase in the serum uric acid level, there was a 39% increase in the risk of death (by Cox regression analysis). After adjusting for age, sex, smok- ing status, alcohol consumption, weight, body mass index, waist circumference, blood pressure, history of cardiovascular disease, estimated glomerular filtration rate, levels of cholesterol fractions, and plasma glucose levels, the serum uric acid level continued to predict the risk of death (hazard ratio  1.26 [95% confidence interval 1.15–1.38], P < 0.001). This association was present regardless of diuretic use. Concordance index (C statistic) analyses showed that uric acid significantly improved the predictive accuracy of a model that in- cluded Framingham Heart Study score factors, meta- bolic syndrome components, and fibrinogen levels. Conclusion. Serum uric acid levels are an inde- pendent predictor of death in patients at high risk of cardiovascular disease. Further studies are warranted to evaluate its prognostic implications and potential utility in the monitoring of therapy. Uric acid (urate) is a product of the activity of xanthine oxidase, an enzyme increasingly implicated as a mechanistic participant in oxidant stress and cardiovas- cular disease. Xanthine oxidase activity is increased during ischemia and heart failure, and treatment with xanthine oxidase inhibitors has favorable effects on myocardial oxygen consumption and endothelium- dependent vascular function (1,2). Hyperuricemia has also been linked to multiple proatherogenic processes, including increased oxidative stress (3,4), vascular smooth muscle cell proliferation (5), leukocyte activa- tion (6), and crystal formation within coronary athero- sclerotic plaques (7). Although numerous studies have noted an asso- Dr. Hazen’s work was supported by the NIH (grant P01-HL- 076491). Adriana G. Ioachimescu, MD, PhD, Danielle M. Brennan, MS, Brian M. Hoar, Stanley L. Hazen, MD, PhD, Byron J. Hoogwerf, MD: Cleveland Clinic, Cleveland, Ohio. Address correspondence and reprint requests to Byron J. Hoogwerf, MD, Cleveland Clinic, Department of Endocrinology, Diabetes, and Metabolism, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: hoogweb@ccf.org. Submitted for publication April 20, 2007; accepted in revised form October 19, 2007. 623