Background: Serum uric acid

While the topicality of serum uric acid (SUA) being a risk factor is currently controversial [1, 2], there is little controversy regarding its association as a risk marker associated with cardiovascular (CVD) and renal disease (especially in patients with hypertension, diabetes, and heart failure). SUA seems to be a graded marker of risk for the development of coronary heart disease (CHD) or cerebrovascular disease and stroke compared with patients with normal uric acid levels and especially those in the lower 1/3 of its normal physiological range [1,3-13].LK Niskanen's et al. recently published article has demonstrated new information regarding this subject. They were able to demonstrate that elevations of serum uric acid levels were independent of variables commonly associated with gout or the metabolic syndrome in association with cardiovascular disease (CVD) mortality in middle aged men [3].

In 1951, Gertler MM and White PD et al. sat out to determine the clinical aspects of premature coronary heart disease in 100 male patients 40 years old and younger. Their findings were increased mesomorphic body build, shorter stature, increased anterior posterior chest wall diameter, and increased cholesterol and uric acid (5.13 +/- .11 vs. 4.64 +/-.06) as compared to the normal population [14].A much larger trial (1967) confirmed the initial interest in serum uric acid (SUA) and cardiovascular disease with the publication of the early, large (5,127 participants), epidemiologic, seminal Framingham study. This classical paper by Kannel et al. noted an elevated serum uric acid was also associated with an increased risk of coronary heart disease for men aged 30–59 [15].

In addition to the important finding of elevations in lipoproteins (specifically cholesterol levels greater than 250 mg/100 ml) being associated with CHD, there also appeared a definite association of elevated serum uric acid (SUA), which was associated with an increase in the incidence rate of CHD. The above authors also noted that subjects in this study with evidence of impaired carbohydrate metabolism or disordered purine metabolism could be assumed to have accelerated atherogenesis [15].This controversy regarding serum uric acid being a risk factor or a risk marker is not as important as understanding its overall role in the association with endothelial cell damage, dysfunction, decreased endothelial nitric oxide (eNO) bioavailability, and how serum uric acid interacts with other substrate toxicities and increased reactive oxygen species (ROS) of the A-FLIGHT-U acronym, which result in accelerated atherosclerosis (table 1). Johnson RJ et al. have nicely demonstrated that hyperuricemia predicts cardiovascular events in the general population, the hypertensive population, and patients with pre-existing cardiovascular disease. Furthermore hyperuricemia predicts the development of future hypertension [11].

There are certain clinical clustering groups with increased cardiovascular risk, which have associated hyperuricemia (table 2). Non-diabetic patient groups with accelerated atherosclerosis, T2DM patient groups with accelerated atherosclerosis (atheroscleropathy), congestive heart failure patient groups with ischemic cardiomyopathy, metabolic syndrome patient groups (with hyperinsulinemia, hypertension, dyslipidemia, impaired glucose tolerance, and obesity), renal disease patient groups, hypertensive patient groups, African American patient groups, patient groups taking diuretics, and patient groups with excessive alcohol usage. Each of these clustering groups has metabolic mechanisms that may help to explain why serum uric acid may be elevated (table 2). In addition to the recurring finding of an elevated tension of oxidative- redox stress and ROS in many of the groups is the importance of the MS and insulin resistance.

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