Uric Acid: Role in Cardiovascular Disease and Effects of Losartan

Michael Alderman; Kala J. V. Aiyer

Disclosures

Curr Med Res Opin. 2004;20(3) 

In This Article

Summary and Introduction

Summary

A substantial body of epidemiological and experimental evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes. However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease. At the very least, it should be carefully considered when evaluating overall cardiovascular risk.

Introduction

Nearly 120 years have elapsed since serum uric acid was first described as a potential factor in the development of cardiovascular disease.[1] Much, but not all, epidemiological research identifies hyperuricemia as an independent risk factor for the development of cardiovascular and renal disease, particularly in patients with hypertension or congestive heart failure, and in women.[2,3,4,5,6,7,8,9]

Hyperuricemia (usually defined as serum uric acid levels > 6.5 mg/dL in men and > 6.0mg/dL in women) is frequently encountered in hypertensive patients and is often due to a defect in renal urate clearance.[5,10] Commonly encountered in hypertensive patients without overt evidence of renal insufficiency, it may reflect subclinical renal disease. Gout and uric acid kidney stones are traditionally considered to be the major complications of hyperuricemia, but mounting evidence suggests that hyperuricemia is also an independent risk factor for cardiovascular (CV) and renal disease.[2,7,11,12] Elevated serum uric acid levels can be lowered by inhibiting xanthine oxidase (e.g., allopurinol), a key enzyme involved in the terminal stages of uric acid synthesis, or by increasing the rate of excretion of uric acid in renal tubules (e.g., probenecid, sulfinpyrazone, benzbromarone, benziodarone).[13,14,15,16]

Whether a reduction in serum uric acid levels in hypertensive patients impacts the overall risk of CV disease is uncertain. However, recent findings from the LIFE study are consistent with a role for uric acid in the development of CV disease. In this study, up to one third of the CV benefit of losartan-versus atenololbased therapy could be ascribed to differences in effect of these agents on serum uric acid levels.[17]

This paper will review the evidence that uric acid is an independent risk factor for CV disease, summarize the potential pathophysiological mechanisms that link uric acid with hypertension and cardiorenal disease, and explore the potential clinical implications of lowering serum acid levels in the management of hypertensive patients with hyperuricemia.

Articles included in this review were identified using a MEDLINE search for studies published between 1990 and 2003 and included the search terms uric acid, cardiovascular disease, renal disease, hypertension, and angiotensin II antagonists. Articles describing major clinical trials, new data, or new mechanisms were selected for review.

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