The other important event of 1776 was the first isolation of uric acid from kidney stones by the Swedish pharmacist Carl Wilhelm Scheele.1 About 70 years later, Garrod2 published the first account of the relationship between gout and levels of uric acid in the blood. Since then, our understanding of the role of uric acid in human disease has been largely confined to gout, until recently when it was also shown to be related to the development of hypertension and increased cardiovascular morbidity and mortality. This new role of uric acid has been intensively investigated, but 3 main questions remain. Is the serum uric acid concentration a passive biomarker for cardiovascular disease, or is there a clear causal relationship? If there is, what is the mechanism? Does lowering the uric acid level reduce cardiovascular risk?
Is the serum uric acid concentration a passive biomarker for cardiovascular disease, or is there a clear causal relationship? The multicenter, multinational INTERHEART study of acute myocardial infarction (MI) in 52 countries identified 9 potentially modifiable risk associations, namely dyslipidemia, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits and vegetables, regular alcohol consumption, and regular physical activity. These collectively accounted for 90% of the population-attributable risk (PAR) of a first MI in men and 94% in women at all ages and in all regions of the world.3 Of note in this study, hypertension accounted for 18% of the PAR of a first MI. Added to this list should be chronic kidney disease. Most of the biomarkers that we associate with increased CV risk can be subsumed into these risk factors. Such biomarkers include high-sensitivity C-reactive protein (hs-CRP), brain natriuretic peptide, N-terminal pro-atrial natriuretic peptide, aldosterone, renin, fibrinogen, plasminogen activator inhibitor-1, d-dimer, homocysteine, apolipoprotein A and A-1, lipoprotein (a), and lipoprotein-associated phospholipase A2. To this formidable list can be added uric acid, now well established as a risk marker, and for which we also have some tentative understanding of the mechanism.
We now have solid epidemiological evidence of an association between elevated serum uric acid levels and increased coronary heart disease and cardiovascular mortality.4–8 There are also data to suggest that high uric acid levels are associated with impaired prognosis in patients with moderate to severe chronic heart failure.9
In this issue of the journal, results are presented from a single-center, cross-sectional study that sought to evaluate the possible relationship between circadian blood pressure rhythm and serum uric acid levels in patients with newly diagnosed hypertension.10 The study included 112 newly diagnosed essential hypertensive patients who, based on 24-hour ambulatory blood pressure monitoring, were categorized as “dippers” (n=60), with a normal nocturnal reduction in blood pressure, vs “nondippers” (n=52), those who did not have this circadian variation. They also included 50 healthy, nonhypertensive control patients. The main finding was significantly higher uric acid and hs-CRP levels in the nondippers compared with the dippers or controls. There are some caveats (aren’t there always?) including the fact that this was a single-center, cross-sectional study, with uric acid and hs-CRP levels measured once only at the start, with gout as an exclusion criterion for no clear reason, no control of concurrent medications, and some potentially confounding differences in high-density lipoprotein cholesterol, serum creatinine, and smoking incidence between the groups. However, the study was well done and the results are interesting, but in itself really does not answer our first question of association vs causality.
Causality is supported by reports that elevated uric acid often precedes obesity,11 diabetes,12 or hypertension.11,12 However, the temporal sequence of the appearance of elevated uric acid followed by obesity, diabetes, and hypertension does not unequivocally prove causality. There may simply be a difference in the rate of expression of these variables, which could be linked by a common upstream metabolic stimulus. One suggestion in this regard is fructose. There has been a huge increase in the consumption of fructose, from high-fructose corn syrup, used in a wide variety of food processing as an artificial sweetener. Fructose ingestion acutely raises uric acid levels and can also be included on the list of bad actors causing obesity and all of its attendant ills.13
If there is a causal relationship between uric acid concentration and cardiovascular disease, what is the mechanism? Oxonic acid is an inhibitor of uricase, the enzyme that degrades uric acid to allantoin in virtually all animals (except humans and other primates, who lack uricase). Rats treated with oxonic acid elevate their uric acid levels and also their blood pressure. The mechanism of this effect is a decrease in nitric oxide synthase in the macula densa of the kidney, a decrease of endothelial nitric oxide, and stimulation of the renin-angiotensin system.14 Other studies showed renal damage by the elevated uric acid levels caused by glomerular hypertension and thromboxane-induced tubular ischemia, resulting in glomerular hypertrophy, renal fibrosis, and glomerulosclerosis.15,16
Another mechanism of both the elevated uric acid and the cardiovascular damage may be through the upregulation of xanthine oxidase, which generates nitric oxide and is also one of the major sources of oxygen-derived free radicals.17
Does lowering the uric acid level reduce cardiovascular risk? In patients with hyperuricemia, xanthine oxidase inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.18
Lowering uric acid improves endothelial dysfunction in type 2 diabetes with hypertension,19 in heart failure,20,21 and in heavy smokers22; improves exercise tolerance in patients with stable angina23; and slows the rate of decline of renal function in patients with chronic kidney disease.24
What is lacking, however, is a good prospective study of uric acid lowering with hard endpoints, such as cardiovascular mortality, MI, and stroke. Until we have that, it would be premature to suggest adding drug-based uric acid lowering to the list of interventions for reducing cardiovascular risk. How about population-based strategies for lowering uric acid levels, as well as reducing obesity and the metabolic syndrome, such as lowering fructose intake or (dare I say it?) persuading the food industry to reduce the fructose content of processed foods? There is, alas, not much hope of that. It may be easier to persuade patients to reduce their consumption of fructose-sweetened drinks and food.
The other dietary source of uric acid, purines, are impossible to regulate, but high-risk individuals with hyperuricemia or possibly even high normal uric acid levels might reasonably be advised to avoid purine-rich foods, such as liver, sweetbreads, kidneys, beef, pork, seafood, sardines, several other meats and fish, and some legumes. Not much left to satisfy the gourmet palate, but that may be the price some of us need to pay for better cardiovascular health.