© 2008 European Society of Cardiology
Uric acid in chronic heart failure—current pathophysiological concepts
Division of Applied Cachexia Research, Department of Cardiology, Campus Virchow -Medical Center, Charitè Medical School Berlin, Germany
Cardiovascular Division, University Hospital Zurich Switzerland
Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee UK
* Corresponding author. Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Medical Center, Augustenburger Platz 1, 13353 Berlin, Germany. Tel.: +49 30 450 553 507; fax +49 450 553 951. E-mail address: wolfram.doehner{at}charite.de.
To the editor
In their recent article [1] Alcaino and colleagues report a beneficial effect of hyperuricaemia in preventing oxidative stress and improving endothelial function in chronic heart failure (CHF). The conclusions from this observational correlation study in 38 patients with CHF are opposite to a substantial body of evidence. We would like to discuss these surprising results and put the findings in perspective with other data and current thinking.
Based on the background presented by the authors to support their study hypothesis, we believe that the authors have a misconception of the character of hyperuricaemia in CHF and its pathophysiologic meaning. Several studies are cited to support the role of uric acid (UA) as antioxidant preventing oxidative damage and endothelial dysfunction. All of these studies tested the impact of administration of exogenous uric acid, but not endogenous physiologically derived UA. There are two major differences between exogenous and endogenous UA. Firstly, UA levels after exogenous UA infusion are generally higher than endogenous UA levels. Secondly, and even more importantly, endogenous UA is produced by xanthine oxidase (XO), which in parallel is a predominant source of oxygen free radicals in human physiology. It has been shown by direct assessment of XO that elevated XO activity is the major cause of hyperuricaemia in CHF [2]. For each oxidative step two electrons are transferred to XO and the fully reduced XO6e– yields the production of two H2O2 and two O2– [3]. Hyperuricaemia in CHF hence implies increased oxygen radical accumulation rather than an improved anti-oxidative state.
The suggestion by the authors that elevated (endogenous) UA levels may exert a beneficial effect on endothelial function and prognosis opposes a large number of studies on vascular function [2,4,5] and mortality [6] in CHF, in other cardiovascular patient populations as in general populations [7].
Similarly, the interpretation of UA as a risk marker in early CHF, but as a beneficial factor at advanced stages does not agree with the observed linear association of UA with disease severity [4,5] and mortality. Furthermore, UA reduction by allopurinol in patients who are sickest (and have highest UA levels) produced beneficial effects [8].
The discussion of whether uric acid itself is an active contributor or mere marker of XO activity is not fully resolved as interventional studies with allopurinol are unable to separate the effects of UA from those of XO. However, the proposition by the authors that hyperuricaemia in CHF could be beneficial is not backed up by the existing data [9,10]. In fact, a recent study using uricase to decrease UA levels showed no effect on endothelial function [11].
Further, the authors claim that the association between uric acid, SOD activity and endothelial function has not been examined before whereas several papers have done so [2,4]. Notably, these previous studies showed opposite results to Alcaino et al., but these discrepancies were not discussed.
Regardless of substantial evidence in full contrast to the presented data, the findings by Alcaino et al. need to be explained. One factor may rest with the pre-specified selection of patients all with significantly reduced endothelial function, which means that only a limited spread of patients has been studied. Looking at this limited part of the spectrum may result in distortion and bias. This was only a relatively small observational study showing only correlations, which makes causal interpretations not possible.
It must be concluded that the findings and interpretation of the data by Alcaino et al. are diametrically opposed to most existing data and to current pathophysiological concepts. The shortcoming of discussing these discrepancies is unfortunate.
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- Alcaino H., Greig D., Chiong M., et al. Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure. Eur J Heart Fail (2008) 10:646–651.
[Abstract/Free Full Text] - Landmesser U., Spiekermann S., Dikalov S., et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation (2002) 106:3073–3078.
[Abstract/Free Full Text] - Hille R., Massey V. Studies on the oxidative half-reaction of xanthine oxidase. J Biol Chem (1981) 256:9090–9095.
[Abstract/Free Full Text] - Doehner W., Rauchhaus M., Florea V.G., et al. Uric acid in cachectic and non-cachectic CHF patients — relation to leg vascular resistance. Am Heart J (2001) 141:792–799.[CrossRef][Web of Science][Medline]
- Maxwell A.J., Bruinsma K.A. Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol (2001) 38:1850–1858.
[Abstract/Free Full Text] - Anker S.D., Doehner W., Rauchhaus M., et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation (2003) 107:1991–1997.
[Abstract/Free Full Text] - Meisinger C., Koenig W., Baumert J., Döring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol (2008) 28:1186–1192.
[Abstract/Free Full Text] - Doehner W., Anker S.D. Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart (2005) 91:707–709.
[Abstract/Free Full Text] - Doehner W., von Haehling S., Anker S.D. Uric acid as a prognostic marker in acute heart failure — new expectations from an old molecule. Eur J Heart Fail (2007) 9:437–439.
[Free Full Text] - Gullu H., Erdogan D., Caliskan M., et al. Elevated serum uric acid levels impair coronary microvascular function in patients with idiopathic dilated cardiomyopathy. Eur J Heart Fail (2007) 9:466–468.
[Abstract/Free Full Text] - Waring W.S., McKnight J.A., Webb D.J., Maxwell S.R. Lowering serum urate does not improve endothelial function in patients with type 2 diabetes. Diabetologia (2007) 50:2572–2579.[CrossRef][Web of Science][Medline]
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