Uric Acisd in Chronic Heart Failure—Current Pathophysiological Concepts

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.