Uric Acid and Cardiovascular Disease: Chicken or the Egg? Animal and Human Data Suggest Possible Direct Pathogenic Role of Urate

Special Report

Theodore R. Fields, MD, FACP

Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College

Over the last half century, rheumatologists have generally agreed that the chief risks of uric acid elevation were gout and kidney stones. We have known for many years that uric acid levels are associated with cardiovascular disease, hypertension, obesity, and renal disease, but have tended to assume that the hyperuricemia was due to one of these other conditions.

All prior studies have found a correlation between uric acid level and cardiac risk. Studies differed as to whether urate was an independent cardiac risk factor, or whether it was just a marker of elevated GFR or hypertension. The implications for causality are great, since they could alter our approach to asymptomatic hyperuricemia. We need to know if hyperuricemia is the chicken, or the egg.

Prior studies not showing urate to be an independent risk for cardiovascular disease may have been the result of urate causing the other risk factor, such as hypertension, renal insufficiency or cardiovascular disease and, therefore, not appearing to be independent of these factors. Lack of "independence," therefore, does not necessarily mean lack of "causality." The importance of separating "independence" from "causality" is nicely reviewed by Johnson et al[1].

Prior data has found uric acid increased in 25% of those with untreated hypertension, in 50% taking diuretics, in over 75% with malignant hypertension, in pre-eclampsia and in congestive heart failure. See Table 1 for the pathophysiology of these correlations.

Hyperuricemia also predicts cardiac disease in patients with hypertension, as shown in a number of studies, such as the PIUMA study[2]. In that study, after correcting for age, gender, diabetes, cholesterol, creatinine, left ventricular hypertrophy, level of hypertension, and use of diuretics, uric acid level predicted cardiovascular events and all-cause mortality. However, the authors noted that they were "unable to answer the question of whether urate exerts direct toxic effects."

Studies have also shown that hypertension predicts cardiac complications in patients with pre-existing cardiovascular disease; stroke in diabetic and non-diabetic patients; and the development of hypertension and renal disease in the general population. These studies were variable as to whether urate was independent risk.

Until recently, most reviews have concluded that hyperuricemia is benign unless associated with gout or renal stones (despite non-independence not proving non-causality).

A 2005 meta-analysis of the data on uric acid and cardiovascular risk concluded that uric acid was in fact and independent risk factor[4]. More recent data has confirmed elevated uric acid to be an independent risk factor for all-cause and cardiovascular mortality[5], adverse outcomes in patients presenting to an emergency room with dyspnea[6], the metabolic syndrome[7], type II diabetes mellitus[8], increased myocardial infarction and stroke[9], In patients given high doses of fructose, which raises the uric acid, those pre-treated with allopurinol did not get blood pressure elevation while those not given allopurinol did raise their blood pressure[10].
Animal studies, likewise, suggest an independent risk status of urate[3]. Rat data in this study suggested that urate appears to be pathogenic of hypertension, arteriolar wall thickening, and endothelial dysfunction. Mild induced hyperuricemia (using a uricase inhibitor which does not lead to crystal deposition in the kidney and preserves renal function) causes hypertension in the rat within several weeks, with stimulation of the renin-angiotensin system and inhibition of NO synthase (and renal injury and fibrosis).

In this model, blood pressure changes were prevented if allopurinol was given early. Chronically hyperuricemic rats showed salt-sensitivity and thickening of the afferent artery of the glomerulus and tubulointerstitial inflammation and fibrosis - which did not reverse if allopurinol was given late. Hyperuricemia stimulated rat vascular smooth muscle cell proliferation and induced endothelial dysfunction.

May this model apply to the human situation? Human study has shown that 24-40% of gout patients have some degree of renal insufficiency -- the majority with histologic injury. Also, soluble urate is pro-inflammatory, inducing cytokines (e.g. TNFalpha) which may be atherogenic. The renal lesion in gouty patients shows arteriolosclerosis, glomerulosclerosis, interstitial fibrosis, and urate deposits in the outer medulla. These changes are more than what can easily be explained by hypertension or aging. Human studies have had variable results with regard to urate lowering leading to improved renal function. (It may be "too late" if rat model also applies to humans.) There is variable human data on whether urate is a risk factor for worsening in established renal disease. Urate infusion into humans has been shown to induce endothelial dysfunction in the forearm. Complicating the picture is that urate also has antioxidant properties, and it is unclear which effects dominate in the human situation. It has been shown that allopurinol improves endothelial dysfunction in CHF and diabetes.

Could urate be a causal factor in human cardiovascular disease? If urate causes cardiovascular disease via hypertension or renal disease, then it would be understandable that urate would not always have appeared as an "independent risk factor" because it was actually causing another factor -- that factor being clearly and strongly an independent risk. The antioxidant effect of urate may mediate the damage it causes, leading to urate not always being seen as an independent risk factor.

Conclusions: Rat data[3] raises the challenging question of the "chicken and the egg" with regard to uric acid and cardiovascular and renal adverse outcomes. Perhaps the uric acid is causing, or contributing to, the hypertension, renal and cardiovascular disease from which it could not previously be shown to be "independent."

Johnson et al postulate that even if the net effects of hyperuricemia were negative, the mutation which caused humans to lack the enzyme uricase (which occurred in the great apes in the Eocene era) may have persisted because hyperuricemia was protective against hypotension in low-salt situations and because of the antioxidant properties of urate. For our era, however, with plentiful salt, the net effect of hyperuricemia may be a clear negative. In balance, urate may be a risk factor for cardiovascular disease and hypertension. The hyperuricemic rats get hypertension, intra-renal vascular disease, renal dysfunction, and vascular inflammation, and some or all of these may play a role in human cardiovascular and renal disease.

Implications: There is no evidence, as yet, that treating urate reverses the vascular changes, but a question remains: would allopurinol given early in hyperuricemia have a protective effect? Once the renal changes occur, it may be too late to reverse them with allopurinol - so prevention may be much more effective. There are as yet no human studies on hypertension response to allopurinol, and it is too early to recommend allopurinol for this indication. Johnson, et al, suggest that further studies might focus on short-duration hyperuricemia, e.g. children with hyperuricemia, or patients just starting on cyclosporine or diuretics. Based on the pathophysiology in the rat model, we might consider especially aggressive salt restriction in hypertensive gout patients, as salt retention may be a major mechanism of hyperuricemia-induced hypertension.

No one questions that a number of pathophysiologic factors lead to hyperuricemia (See Table 1). An important question, re-opened by recent important animal studies, is whether hyperuricemia itself may be a cause of many of these very same conditions. If so, we may ultimately find ourselves being much more aggressive with the asymptomatic hyperuricemic patient. Further studies will be of great interest. Hyperuricemia, in at least some patients, may be “the chicken,” and be directly contributing to cardiovascular and renal adverse outcomes.

[1] Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M: Is there a pathogenetic role for uric Acid in hypertension and cardiovascular and renal disease? Hypertension. 2003 Jun;41(6):1183-90.

[2] Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension. 2000 Dec;36(6):1072-8.

[3] Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.Hypertension. 2001 Nov;38(5):1101-6.

[4] Baker et al: Serum uric acid and cardiovascular disease: Recent developments, and where do they leave us? Am J Med, 118:816-26, 2005.

[5] Kuo C-F et al: Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology, 10.1093, October. 2009.

[6] Reichlin T et al: Diagnostic and Prognostic Value to Uric Acid in Patients with Acute Dyspnea. Am J Med, 122, 1054e7-0154e14, 2009.

[7] Choi HK et al: Prevalence of the metabolic syndrome in patients with gout: the Thrid National Health and Nutrition Examination Survey. Arthritis Rheum, 57: 109-115, 2007.

[8] Bennett M et al:  Hyperuricemia as An Early Marker for Type 2 Diabetes Among Young Adults, Presentation #2033, American College of Rheumatology, Philadelphia PA, 11/21/09.

[9] Bos et al: Uric acid as a risk factor for myocardial infarction and stroke (The Rotterdam study). Stroke, 37:1503-7, 2006.

[10] Johnson R and Touyz R: Fructose-induced hypertension prevented by allopurinol. American Heart Association’s 63rd High Blood Pressure Research Conference, 9/23/09

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