Zurich Open Repository and Archive. Uric acid in chronic heart failure - current pathophysiological concepts

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1 University of Zurich Zurich Open Repository and Archive Winterthurerstr. 190 CH-8057 Zurich Year: 2008 Uric acid in chronic heart failure - current pathophysiological concepts Doehner, W; Springer, J; Landmesser, U; Struthers, A D; Anker, S D Doehner, W; Springer, J; Landmesser, U; Struthers, A D; Anker, S D (2008). Uric acid in chronic heart failure - current pathophysiological concepts. European Journal of Heart Failure, 10(12): Postprint available at: Posted at the Zurich Open Repository and Archive, University of Zurich. Originally published at: European Journal of Heart Failure 2008, 10(12):

2 Letter to the Editor Letter Title: Uric acid in chronic heart failure: looking at the elephants tails. Re Article: Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure By Alcaino et al Eur J Heart Failure 10; 2008: Authors: Wolfram Doehner, MD, PhD [1] Jochen Springer, PhD [1] Ulf Landmesser [2] Stefan D Anker, MD, PhD [1] Affiliation: [1] Division of Applied Cachexia Research, Department of Cardiology, Campus Virchow -Medical Center, Charité Medical School, Berlin, Germany [2] Klinik für Kardiologie, UniversitätsSpital Zürich and Kardiovaskuläre Forschung, Institut für Physiologie, Universität Zürich Corresponding author: Wolfram Doehner, MD, PhD, Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Medical Center, Augustenburger Platz 1, Berlin, Germany Tel.: ; Fax ; wolfram.doehner@charite.de We confirm there is no conflict of interest, financial or otherwise, in our submission of the manuscript.

3 To the Editor In their recent article Alcaino et colleagues report a beneficial effect of hyperuricaemia in patients with chronic heart failure towards prevention of oxidative stress and improved endothelium function. The conclusions from this observational study in 38 patients with CHF are opposite to a substantial body of evidence. Therefore, we would like to make up for the authors shortfall to discuss these discrepancies and put the findings in perspective to current data. Most importantly, based on the presented background the hypothesis of the study reveals a serious misconception of the character of hyperuricaemia in CHF pathophysiology. Several studies are cited to support the role of UA as antioxidant to prevent oxidative damage including endothelium dysfunction. All these studies, however, tested the impact of administration of exogenous uric acid not the impact of endogenous physiologically derived uric acid. While exogenous uric acid may indeed function to scavenge free oxygen radicals, it is of utmost importance to appreciate the origin of elevated UA levels in CHF. It has sufficiently been shown by direct assessment of xanthine oxidase XO [i] as well as indirectly from allopurinol therapy studies [ii] that elevated XO activity the predominant cause of hyperuricaemia in CHF. Importantly, the uric acid generating enzyme XO is one of the major sources of oxygen free radicals in human physiology. In fact, as early as 1968 the cytosolic XO was the first documented biological generator of oxygen derived free radicals [iii]. It seems an indefensible hypothesis to suggest hyperuricaemia as an adaptive process in response to the increased ROS accumulation if the UA and ROS are generated in parallel by up-regulated XO. Moreover, the suggestion that this process in CHF is leading to a raise in ecsod activity and thus preserving endothelial function has clearly been disproved as SOD and endothelium dysfunction are decreased in CHF well in parallel to disease severity. The idea that elevated (endogenous) UA levels may exert a beneficial effect on endothelium function and prognosis as discussed by the authors is in contrast to a large number of studies on vascular function [i, ii, iv, v] and mortality [vi, vii, viii] in heart failure patients and several 2

4 other cardiovascular diseases including stroke [ix], cardiovascular risk [x], hypertension and renal disease [xi] as well as in normal populations [xii, xiii, xiv, xv]. Any attempt to include a representative number of all papers that provide data and conclusions that are opposite to the paper by Alcaino et al. would be stopped short due to limitation of space. Similarly the interpretation of UA as a risk marker at early CHF but as beneficial factor at advanced stages does not withstand reality as studies show linear associations of UA with disease severity [iv, xvi, xvii], mortality and impaired vascular function [v]. While the ongoing scientific discussion regarding the role of uric acid as active contributor vs passive marker is indeed ongoing, Alcaino et al slipped in the misinterpretation of the absence of evidence as evidence of absence: If previous studies using allopurinol treatment could not prove a detrimental effect of UA itself this may by no means allow to conclude for a compensatory (i.e. beneficial) role of uric acid. The references quoted by Alcaino et al in support of their view are at least in part [xviii, xix] neither stating nor intending this message. In fact, a recent study to test the effect of UA lowering without XO inhibition using uricase has shown no effect on endothelial function [xx]. Alcaino et al seemingly base their study on the theory by Reyes that diuretic dependent increase in UA conveys improved prognosis in cardiovascular patients [xxi]. Whether the rise of uric acid caused by diuretic treatment may exert beneficial effect on antioxidant capacity is, however, the wrong question to ask and resembles the attempt to describe an elephant from looking at its tail. The potential contribution of this particular cause to elevated UA cannot be looked at separately from other mechanisms to increase UA in CHF. Elevated UA levels in CHF result likely from a combination of increased XO activity (i.e. overproduction, see above) and to some degree impaired excretion following impaired renal function and diuretic use. The isolated effect of the diuretic dependent UA increase in this context is, however, negligible as only the effect of total UA elevation may - or may not be clinically relevant. The theory by Reyes that diuretic dependent increase in UA conveys improved prognosis in cardiovascular patients has previously been challenged [xxii] an is convincingly refuted by a multitude of studies that show 3

5 that (global) hyperuricaemia is a strong marker of disease severity and impaired prognosis (see above). Further, the assertion of the authors to address a previously not investigated association between UA, SOD activity and endothelium function is in negation of several papers that particularly evaluated these interactions [i, ii, v]. Notably, the findings on the impact of UA in CHF in these previous studies were opposite to the results by Alcaino. Unfortunately, these discrepancies were not discussed. The authors comment that UA levels in their study were within normal limits in the majority of patients, however, not such data is presented. In the studied CHF patient group UA levels were abnormally elevated (7.3±2.3 mg/dl) and the comparison with the control subjects revealed significantly elevated UA levels in CHF patients (p<0.04). Moreover, the references to underscore conformity with the other CHF populations are not applicable in this context [xxiii, xxiv]. Notable, elevated uric acid levels are a common finding in CHF with increasing UA in parallel to CHF severity [iv, xvi, xvii]. Despite the overwhelming evidence from previous studies against the conclusion by Alcaino et al, the current data need to be explained. On factor may rest with the small size of the study population and the statistical possibility of 5% to observe random associations. More importantly, the pre-specified selection of patients with significantly reduced endothelium function prevents a realistic reflection of the association over the normal pathophysiological range of patient. Looking at the limited part of the spectrum may results in a distorted association. It can be concluded that the findings and interpretation of the data by Alcaino are diametrically opposed to the current pathophysiological concepts. The lack of discussing the discrepancy with the vast body of evidence against these data is dissatisfactory particularly given the nature of this study as a small observational study showing mere correlations that do not allow for causal interpretations. The lack of relating the hypothesis and findings of the study to recent literature together with insufficient and in part incorrect referencing with previous studies 4

6 highlight of course the responsibility of the Journal to ensure a thorough and high quality peer reviewing process. A rope is a rope is a rope. To recognise the shape and nature of the elephant might not be possible from the isolated gaze at its tail but requires an integrative inter-coordinated and repeatedly verified approach. REFERENCES i Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, Harrison DG, Hornig B, Drexler H. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation. 2002;106: ii Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJS, Anker SD, Rainer Hambrecht. The effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure results from two placebo controlled studies. Circulation. 2002; 105: iii McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem. 1968; 243: iv Doehner W, Rauchhaus M, Florea VG, Sharma R, Bolger AP, Davos, CH, Coats AJS, Anker SD. Uric acid in cachectic and non-cachectic CHF patients - relation to leg vascular resistance. Am Heart J. 2001;141: v Maxwell AJ, Bruinsma KA. Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease. J Am Coll Cardiol. 2001;38: vi Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJ. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003;107: vii Pascual-Figal DA, Hurtado-Martínez JA, Redondo B, Antolinos MJ, Ruiperez JA, Valdes M. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail. 2007;9: viii Jankowska EA, Ponikowska B, Majda J, Zymlinski R, Trzaska M, Reczuch K, Borodulin-Nadzieja L, Banasiak W, Ponikowski P. Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol. 2007;115: ix Karagiannis A, Mikhailidis DP, Tziomalos K, Sileli M, Savvatianos S, Kakafika A, Gossios T, Krikis N, Moschou I, Xochellis M, Athyros VG. Serum uric acid as an independent predictor of early death after acute stroke. Circ J. 2007;71: x Ioachimescu AG, Brennan DM, Hoar BM, Hazen SL, Hoogwerf BJ. Serum uric acid is an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiology information system (PreCIS) database cohort study. Arthritis Rheum. 2008;58: xi 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;41: xii Erdogan D, Gullu H, Caliskan M, Yildirim E, Bilgi M, Ulus T, Sezgin N, Muderrisoglu H. Relationship of serum uric acid to measures of endothelial function and atherosclerosis in healthy adults. Int J Clin Pract. 2005;59: xiii Kato M, Hisatome I, Tomikura Y, Kotani K, Kinugawa T, Ogino K, Ishida K, Igawa O, Shigemasa C, Somers VK. Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol. 2005;96: xiv Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, Diem G, Pfeiffer K, Ulmer H; VHM&PP Study Group. Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83,683 Austrian men. Clin Chem. 2008;54:

7 xv 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: xvi Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997;18: xvii Olexa P, Olexová M, Gonsorcík J, Tkác I, Kisel'ová J, Olejníková M. Uric acid--a marker for systemic inflammatory response in patients with congestive heart failure? Wien Klin Wochenschr. 2002;114: xviii Doehner W, von Haehling S, Anker SD. Uric acid as a prognostic marker in acute heart failure--new expectations from an old molecule. Eur J Heart Fail. 2007;9: xix Gullu H, Erdogan D, Caliskan M, Tok D, Kulaksizoglu S, Yildirir A, Muderrisoglu H. Elevated serum uric acid levels impair coronary microvascular function in patients with idiopathic dilated cardiomyopathy. Eur J Heart Fail. 2007;9: xx Waring WS, McKnight JA, Webb DJ, Maxwell SR. Lowering serum urate does not improve endothelial function in patients with type 2 diabetes. Diabetologia. 2007;50: xxi Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure. Eur J Heart Fail. 2005;7: xxii Srinivas TR, Herrera-Acosta J, Feig DI, Kang DH, Segal MS, Johnson RJ. Diuretic-induced hyperuricemia does not decrease cardiovascular risk. J Hypertens. 2004;22:1415-7; xxiii Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002;106: xxiv George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114: