Hyperuricemia in heart failure: coincidence or cause?

Elevated uric acid levels have been found in various hypoxic states, including obstructive airways disease, fetal and neonatal hypoxia, and cyanotic heart disease. There is increasing evidence that uric acid may also be a major culprit in cardiovascular disease. Several cross-sectional studies, including in a large population with chronic heart failure, have shown uric acid to be an independent predictor of mortality. Hyperuricemia is a recurrent finding in both acute and chronic heart failure, possibly due to the reduced tissue availability of oxygen, regardless of pathogenesis. No differences in xanthine oxidase activity, and hence uric acid levels, were observed in chronic heart failure, whether due to coronary heart disease or dilated cardiomyopathy.

Explanations for the association between hyperuricemia and heart failure include:

• Overproduction of uric acid.

• Impaired renal function causing decreased urate excretion.

• Direct stimulation of cytokine-dependent xanthine oxidase activity.

• Metabolic effect of hyperinsulinemia and insulin resistance: the combined effects of hypoxia and insulin resistance may decrease uric acid excretion, while hypoxia and insulin resistance affect glycolytic enzyme activity, thus encouraging uric acid production.

• Thiazide and loop diuretics dose-dependently increase uric acid levels by increasing tubular resorption during volume depletion.

Xanthine oxidase, which converts xanthine or hypo-xanthine to uric acid, is an important mediator in the inflammatory response and cell damage in ischemia-reperfusion injury, rheumatic and renal disease, and exercise-induced muscle inflammation. Its activation by reduced tissue oxygen availability releases free radicals and triggers chronic inflammation, as suggested by elevations in circulating cytokines, their soluble receptors, and soluble adhesion molecules. Leyva et al have observed that the ability of xanthine oxidase to generate superoxide free radicals is an important stimulus of leukocyte adhesion molecule expression and leukocyte activation and adhesion to damaged endothelium. They have also shown that xanthine oxi-dase-derived free radicals play an important part in endothelial injury. Recent observations also suggest that xanthine oxidase is involved in endothelial dysfunction in chronic heart failure. A small double-blind crossover study by Farquharson et al showed that the xanthine oxidase inhibitor, allopurinol, is an antioxidant and enhances endothelium-dependent vasodilatation in heart failure. Exposure of endothelial cells to tumor necrosis factor-oc converts xanthine dehydrogenase to xanthine oxidase, releasing superoxide anion and hydrogen peroxide. These reactive oxygen species are critical causes of endothelial stress and impaired endothelium-dependent nitric oxide (NO)-mediated vasodilatation in chronic heart failure. Experimental studies suggest that endothelial NO synthase (eNOS)-derived NO production lowers myocardial oxygen consumption and limits left ventricular remodeling. The ability of xanthine oxidase inhibition to improve endothelial function and myocardial efficiency in heart failure correlates with the ability to preserve NO synthase bioactivity, in addition to its efficacy as a radical scavenger.

In summary, impaired oxidative metabolism may be the pathogenetic link between chronic heart failure, especially if severe, and its marker, hyperuricemia. On this basis, allopurinol could become a novel addition to the therapeutic arsenal in chronic heart failure. In a retrospective cohort study, Struthers et al observed sig-

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biochemistry; uric acid; hyperuricemia; etiology; xanthine oxidase; NO; oxidative metabolism; allopurinol

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