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Uric acid marker for Cardiovascular diease & deaths   


July 26, 2004  The JAMA Network, Internal Medicine, Citations 391

Uric Acid Level as a Risk Factor for Cardiovascular and All-Cause Mortality in Middle-aged Men  A Prospective Cohort Study



Background  Despite abundant epidemiologic evidence, the role of elevated serum uric acid level as a cardiovascular risk factor is controversial. We assessed the predictive value of serum uric acid levels for cardiovascular and overall mortality.

Methods  A population-based prospective cohort study was performed of 1423 middle-aged Finnish men initially without cardiovascular disease, cancer, or diabetes. The main outcome measure was death from cardiovascular disease and any cause.

Results  The mean follow-up was 11.9 years. There were 157 deaths during follow-up, of which 55 were cardiovascular. In age-adjusted analyses, serum uric acid levels in the upper third were associated with a greater than 2.5-fold higher risk of death from cardiovascular disease than levels in the lower third. Taking into account cardiovascular risk factors and variables commonly associated with gout increased the relative risk to 3.73. Further adjustment for factors related to the metabolic syndrome strengthened the risk to 4.77. Excluding the 53 men using diuretics did not alter the results. In age-adjusted analyses, men with serum uric acid levels in the upper third were 1.7-fold more likely to die of any cause than men with levels in the lower third. Adjustment for further risk factors strengthened the association somewhat.

Conclusions  Serum uric acid levels are a strong predictor of cardiovascular disease mortality in healthy middle-aged men, independent of variables commonly associated with gout or the metabolic syndrome. Serum uric acid measurement is an easily available and inexpensive risk marker, but whether its relationship to cardiovascular events is circumstantial or causal remains to be answered.

The role of uric acid as an independent marker of cardiovascular risk has been controversial for decades. At physiologic pH values, serum monoanionic uric acid is the major product of purine metabolism in humans and higher primates and is formed from xanthine, a reaction catalyzed by xanthine dehydrogenase/oxidase.1,2 Several epidemiologic studies have shown elevated uric acid levels to predict increased risk of cardiovascular events,312although lack of an independent relationship has also been found.3,10

It is conceivable that the interpretation of the "independent" role of uric acid is further complicated by the use of diuretics and by the very close correlation of uric acid levels with established cardiovascular risk factors such as hypertension,13,14 obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, hyperinsulinemia, and reduced insulin sensitivity,1519 all of which are components of the metabolic or insulin resistance syndrome.20 Moreover, there are other features of atherosclerosis, such as inflammation,21oxidative stress,22 and endothelial dysfunction,23 that have also been associated with increased serum uric acid levels. Furthermore, clinical ischemic heart,24 cerebrovascular,25and even mild renal26 disease are all associated with increased uric acid levels.

Recently, the massive 16.4-year follow-up of the National Health and Nutrition Examination Survey I (NHANES I),11 consisting of 5926 subjects, has convincingly established the role of serum uric acid as an independent predictor of cardiovascular mortality in subjects older than 45 years regardless of sex, menopausal status, diuretic use, presence of cardiovascular disease (CVD), or race. However, NHANES I did not adjust for the essential components of the metabolic syndrome, like waist circumference and levels of glucose, insulin, high-density lipoprotein cholesterol, and triglycerides. Furthermore, the baseline serum creatinine level was unknown in 60% of the participants.

As determination of serum uric acid is widely available and inexpensive, a better understanding of its role as a risk factor is certainly warranted. Therefore, we studied the predictive role of uric acid levels in a population-based sample of 1423 healthy (free of CVD, diabetes, or cancer) middle-aged men with respect to 12-year cardiovascular and total mortality.


The unadjusted Kaplan-Meier hazard curves for serum uric acid levels categorized into thirds (tertile limits, 5.04 and 5.88 mg/dL [299.78 and 349.74 Ámol/L])… In age-adjusted Cox proportional hazards analyses, serum uric acid levels in the 2 upper thirds were associated with 2.7-fold higher risk of death from CVD than uric acid levels in the lower third.  Further adjustment for factors related to the metabolic syndrome (dyslipidemia, insulin and glucose levels, leisure-time physical activity, and cardiorespiratory fitness) additionally strengthened the risk (relative risk for the upper third vs lower third, 4.77).  ddition of white blood cell count and serum fibrinogen concentrations to the models as measures of inflammation did not weaken the association (data not shown). Excluding the 53 men who were using diuretics at baseline had little effect on the results. Men with uric acid concentrations in the upper third were also more likely to die of coronary heart disease, but the association only tended to significance (32 deaths; relative risk, 3.12 [95% confidence interval, 0.92-10.6]; model 2). Likewise, men in the upper third had an increased risk of death from stroke (52 deaths; relative risk, 5.52 [95% confidence interval, 1.09-28.0]; model 2).  Excluding the 53 men who used diuretics had little effect on the results.  [Another example of pharma attacking an off patent drug as dangerous.] ….; The relationship between uric acid and cardiovascular risk may therefore not be wholly linear, but whether this is so and at what point the curve steepens has yet to be established. [Intermediate range was at higher risk than the top 5th or top 3rd.]


Elevated levels of serum uric acid may be due to increased dietary intake of purines, increase in uric acid production, or decrease in its excretion. Differences in alcohol consumption, exercise, or dietary purine intake may have caused transient hyperuricemia.42 Adjustment for alcohol consumption, leisure-time physical activity, or cardiorespiratory fitness did not attenuate the association of hyperuricemia with cardiovascular mortality. Dietary purines are also unlikely to explain the association.

[As of 2004] the mechanisms by which hyperuricemia is associated with atherosclerotic vascular disease remain to be clarified. It is not even established whether hyperuricemia is a risk factor on its own, requiring treatment, or an innocent bystander in proximity to vascular accidents, merely reflecting an adverse risk factor pattern; or ev en whether, as a major endogenous antioxidant, it could play a protective role in this respect.

With regard to the first possibility, there are no convincing data to show that treatment of hyperuricemia reduces cardiovascular events. Second, many associations of hyperuricemia have been reported, but during the past decade hyperuricemia has also been linked to reduced insulin sensitivity.1619 

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