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Uric Acid Level As a Risk Factor for Cardiovascular and All-Cause Mortality in Middle-Aged Men a Prospective Cohort Study

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Uric Acid Level As a Risk Factor for Cardiovascular and All-Cause Mortality in Middle-Aged Men a Prospective Cohort Study ORIGINAL INVESTIGATION Uric Acid Level as a Risk Factor for Cardiovascular and All-Cause Mortality in Middle-aged Men A Prospective Cohort Study Leo K. Niskanen, MD, PhD; David E. Laaksonen, MD, PhD, MPH; Kristiina Nyysso¨nen, PhD; Georg Alfthan, PhD; Hanna-Maaria Lakka, MD, PhD; Timo A. Lakka, MD, PhD; Jukka T. Salonen, MD, PhD Background: Despite abundant epidemiologic evi- gout increased the relative risk to 3.73. Further adjust- dence, the role of elevated serum uric acid level as a car- ment for factors related to the metabolic syndrome strength- diovascular risk factor is controversial. We assessed the ened the risk to 4.77. Excluding the 53 men using diuret- predictive value of serum uric acid levels for cardiovas- ics did not alter the results. In age-adjusted analyses, men cular and overall mortality. with serum uric acid levels in the upper third were 1.7- fold more likely to die of any cause than men with levels Methods: A population-based prospective cohort study in the lower third. Adjustment for further risk factors was performed of 1423 middle-aged Finnish men ini- strengthened the association somewhat. tially without cardiovascular disease, cancer, or diabe- tes. The main outcome measure was death from cardio- Conclusions: Serum uric acid levels are a strong pre- vascular disease and any cause. dictor of cardiovascular disease mortality in healthy middle-aged men, independent of variables commonly Results: The mean follow-up was 11.9 years. There were associated with gout or the metabolic syndrome. Serum 157 deaths during follow-up, of which 55 were cardio- uric acid measurement is an easily available and inex- vascular. In age-adjusted analyses, serum uric acid levels pensive risk marker, but whether its relationship to car- in the upper third were associated with a greater than 2.5- diovascular events is circumstantial or causal remains to fold higher risk of death from cardiovascular disease than be answered. levels in the lower third. Taking into account cardiovas- cular risk factors and variables commonly associated with Arch Intern Med. 2004;164:1546-1551 HE ROLE OF URIC ACID AS AN and reduced insulin sensitivity,15-19 all of From the Department of independent marker of car- which are components of the metabolic or 20 Medicine, Kuopio University diovascular risk has been insulin resistance syndrome. Moreover, Hospital, Kuopio, Finland controversial for decades. there are other features of atherosclero- (Drs Niskanen and Laaksonen); At physiologic pH values, sis, such as inflammation,21 oxidative Research Institute of Public Tserum monoanionic uric acid is the ma- stress,22 and endothelial dysfunction,23 that Health, Kuopio (Drs Nyysso¨nen jor product of purine metabolism in hu- have also been associated with increased and Salonen); Biomarker mans and higher primates and is formed serum uric acid levels. Furthermore, clini- Laboratory, Department of from xanthine, a reaction catalyzed by xan- cal ischemic heart,24 cerebrovascular,25 and Health and Functional thine dehydrogenase/oxidase.1,2 Several even mild renal26 disease are all associ- Capacity, National Public Health Institute, Helsinki, epidemiologic studies have shown el- ated with increased uric acid levels. Finland (Dr Alfthan); evated uric acid levels to predict in- Recently, the massive 16.4-year fol- 3-12 Pennington Biomedical creased risk of cardiovascular events, al- low-up of the National Health and Nutri- Research Center, Louisiana though lack of an independent relationship tion Examination Survey I (NHANES I),11 State University, Baton Rouge has also been found.3,10 consisting of 5926 subjects, has convinc- (Drs H.-M. Lakka and It is conceivable that the interpreta- ingly established the role of serum uric acid T. A. Lakka); Department of tion of the “independent” role of uric acid as an independent predictor of cardiovas- Public Health and General is further complicated by the use of di- cular mortality in subjects older than 45 Practice, University of Kuopio uretics and by the very close correlation years regardless of sex, menopausal sta- (Drs H.-M. Lakka and Salonen); and Inner Savo of uric acid levels with established cardio- tus, diuretic use, presence of cardiovas- Health Center, Suonenjoki, vascular risk factors such as hyperten- cular disease (CVD), or race. However, 13,14 Finland (Dr Salonen). The sion, obesity, low levels of high- NHANES I did not adjust for the essen- authors have no relevant density lipoprotein cholesterol, tial components of the metabolic syn- financial interest in this article. hypertriglyceridemia, hyperinsulinemia, drome, like waist circumference and lev- (REPRINTED) ARCH INTERN MED/ VOL 164, JULY 26, 2004 WWW.ARCHINTERNMED.COM 1546 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 els of glucose, insulin, high-density lipoprotein ASCERTAINMENT OF cholesterol, and triglycerides. Furthermore, the base- ALL-CAUSE AND CVD DEATHS line serum creatinine level was unknown in 60% of the participants. Deaths were ascertained by computer linkage to the national death As determination of serum uric acid is widely avail- registry by means of the Finnish social security number. There were no losses to follow-up. All deaths that occurred between able and inexpensive, a better understanding of its role study entry (from March 1, 1984, to December 31, 1989) and as a risk factor is certainly warranted. Therefore, we stud- December 31, 1998, were included. Deaths coded with the In- ied the predictive role of uric acid levels in a population- ternational Classification of Diseases, Ninth Revision, codes 390 based sample of 1423 healthy (free of CVD, diabetes, or to 459 were considered CVD deaths. Death codes as coronary cancer) middle-aged men with respect to 12-year car- heart disease (CHD) (410-414) or stroke (430-436) were all vali- diovascular and total mortality. dated according to the international criteria adopted by the World Health Organization MONICA (Monitoring of Trends and De- 38-40 METHODS terminants of Cardiovascular Disease) Project. The prov- ince of Kuopio participated in the multinational MONICA project 39 The Kuopio Ischaemic Heart Disease Risk Factor Study is a pro- between 1982 and 1992, during which CHD deaths were de- 40 spective population-based study.27 The study population com- termined by the FINMONICA coronary registry group. Data prised a random age-stratified sample of 2682 men living in east- on fatal acute coronary events between January 1, 1993, and De- ern Finland who were 42, 48, 54, or 60 years old at baseline cember 31, 1998, were obtained by computer linkage to the na- between 1984 and 1989. The University of Kuopio Research tional computerized hospital discharge registry. Diagnostic in- Ethics Committee approved the study. All subjects gave their formation was collected from hospitals and classified by one 41 written informed consent. internist (T.A.L.) using identical diagnostic criteria. For the present study, 1123 men with a history of CVD (excluding hypertension), cancer, or diabetes mellitus at base- STATISTICAL ANALYSIS line were excluded. Men with missing measurements of se- rum uric acid were also excluded (n=136), leaving 1423 men The associations of clinical, biochemical, anthropometric, and for the analyses. lifestyle variables with cardiovascular and all-cause mortality Body mass index was computed as weight in kilograms were assessed with univariate Cox proportional hazards mod- divided by the square of height in meters. Blood pressure was els. Associations of serum uric acid levels categorized into thirds measured with a random-zero mercury sphygmomanometer with cardiovascular and overall mortality were also analyzed (Hawksley & Sons Ltd, Lancing, England). Waist circumfer- with forced Cox proportional hazards models, with adjust- ence was calculated as the average of one measurement taken ment for age (model 1); adjusted for age, examination year, after inspiration and one taken after expiration at the level of smoking (cigarettes per day), low-density lipoprotein choles- middistance between the bottom of the rib cage and the top of terol level, family history of CHD, systolic blood pressure, use ␤ the iliac crest. The protocol for blood pressure measurement of diuretics, use of -blockers, use of other blood pressure medi- included, after supine rest of 5 minutes, 3 measurements while cations, body mass index, alcohol intake, serum creatinine level, supine, 1 while standing, and 2 while sitting at 5-minute in- and adult socioeconomic class (model 2); and fasting serum tervals. The mean of all 6 measurements was used as the sys- insulin, triglyceride, and high-density lipoprotein cholesterol tolic and diastolic blood pressure. Hypertension was defined concentrations, fasting blood glucose levels, conditioning ex- as blood pressure of 140/90 or greater, or use of blood pres- ercise (kilocalories per day), and cardiorespiratory fitness in sure medication.28-30 addition to the covariates in model 2 (model 3). Triglyceride Subjects were asked to fast and refrain from smoking for and insulin concentrations and alcohol intake were corrected 12 hours and to avoid alcohol intake for 3 days before blood sam- for skewing by means of log transformation but are presented pling. Blood glucose was measured at baseline by means of a glu- with untransformed values. Significance was considered to be Ͻ cose dehydrogenase method after precipitation of proteins by tri- P .05. All statistical analyses were performed with SPSS 11.0 chloroacetic acid. Diabetes was defined as a fasting blood glucose for Windows (SPSS Inc, Chicago, Ill). level of 110 mg/dL (6.1 mmol/L) or greater, or a clinical diag- 31,32 nosis of diabetes with dietary, oral, or insulin treatment. RESULTS The serum samples for insulin determination were stored at −80°C. Serum insulin level was determined with a radioim- The mean follow-up was 11.9 years (range of follow-up munoassay kit (Novo Nordisk; Novo Biolabs, Bagsvaerd, for survivors from baseline to the end of follow-up, 9.1- Denmark).
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