Uric acid in chronic heart failure - ResearchGate

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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):1269-1270.
Postprint available at:
http://www.zora.uzh.ch
Posted at the Zurich Open Repository and Archive, University of Zurich.
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Originally published at:
European Journal of Heart Failure 2008, 10(12):1269-1270.

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: 646-651
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,
13353 Berlin, Germany
Tel.: +49 30 450 553 507; Fax +49 450 553 951;
E-mail: wolfram.doehner@charite.de
We confirm there is no conflict of interest, financial or otherwise, in our submission of the
manuscript.

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
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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
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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

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;106:3073-3078.
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: 2619-2624
iii McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem. 1968;
243: 5753-5760.
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;141:792-799
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;38:1850-8.
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;107:1991-1997
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;9:518-24.
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;115:151-5.
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;71:1120-7.
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;58:623-30.
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;41:1183-90.
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;59:1276-82.
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;96:1576-8.
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;54:273-84.
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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;28:1186-92.
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;18:858-65.
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;114:211-5.
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;9:437-9.
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;9:466-8.
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;50:2572-9.
xxi Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be beneficial in
heart failure. Eur J Heart Fail. 2005;7:461-7.
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;106:221-6.
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;114:2508-16.
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