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Uric acid in CHF: Marker or player in a metabolic disease?
International Journal of Cardiology 115 (2007) 156 – 158 www.elsevier.com/locate/ijcard
Editorial
Uric acid in CHF: Marker or player in a metabolic disease? Wolfram Doehner a,⁎, Stephan von Haehling b , Stefan D. Anker a,b a
Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany b Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College, London, UK Received 24 May 2006; accepted 26 May 2006 Available online 17 July 2006
Cardiovascular medicine is a story of success in many aspects, especially with regard to improved outcome in acute cardiovascular events. An immediate consequence is of course a growing prevalence of cardiovascular diseased patients. A wealth of epidemiological data from recent decades highlights the fact that we are confronted with an epidemic development in CHF. Indeed, the prevalence of CHF has been estimated at 4.8 million in the United States alone. To meet this challenge, much research has focused on understanding the complex pathophysiology of CHF. This has led to deduce that CHF is much more than mere pump failure. Neuroendocrine activation, for example, has been recognised as a cornerstone in CHF pathophysiology and has become a major target in the treatment of CHF patients. On the other hand, immune activation [1] and, more recently, hormonal and metabolic derangement [2], have emerged as significant contributors to CHF morbidity and mortality. Importantly, hyperuricaemia has been established as a characteristic feature in CHF with both symptomatic and prognostic significance. In this issue of International Journal of Cardiology, Jankowska et al. report the significance of hyperuricaemia to predict survival in patients with CHF [3]. This study is in line with earlier reports showing uric acid (UA) as a strong and independent prognostic marker in moderate to severe CHF [4]. Jankowska et al. expand the previous data on prognostic value of UA to a broader patient population such as patients with mild to moderate CHF (mean NYHA class 2.3, 63% in NYHA class I and II, mean LVEF 32%). The investigators observed that more consistent adherence to beta blocker ⁎ Corresponding author. Tel.: +49 30 450 553507; fax: +49 30 450 553951. E-mail address: [email protected] (W. Doehner). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.05.003
therapy (82%) did not affect the prognostic value of elevated UA levels compared to the previous report by Anker et al. [4]. Importantly, the authors show that even a mild elevation in UA levels (≥ 6.5 mg/dl) indicate significantly impaired survival. The study from our group found the best cut-off value at 9.5 mg/dl. Thus, UA is a parameter with robust prognostic significance over a broad range of CHF severity, which remains unaffected by different test settings. Notably, the association between UA and outcome was independent of kidney function, which confirms a number of previous reports [4,5]. Impaired renal function is the leading mechanism of hyperuricaemia in patients suffering from gout, and renal insufficiency is a common co-morbidity in CHF. Nevertheless, the predominant mechanism of elevated UA levels in CHF seems to be overproduction rather than underexcretion of UA. Overactivation of the xanthine oxidase (XO) metabolic system has been regularly observed in CHF [6,7]. This may distinguish hyperuricaemia in CHF from gout. Accordingly, gout is not recognised as a common comorbidity in CHF although substantial increases in UA are present in up to 35% of patients with CHF [4]. Furthermore, the initiation of allopurinol treatment (300 mg once daily) in hyperuricaemic patients with CHF has yielded a 40% reduction in UA levels after only 1 week [8]. Such rapid treatment effects are not usually observed in patients with gout. The oxygen radical generating capacity of the XO pathway forms the basis of the pathophysiologic potential of this metabolic system. In fact, in 1968, cytosolic XO was the first documented biological generator of oxygen derived free radicals [9]. The XO pathway has since emerged as a major source of free oxygen radical production in humans. In this context it is interesting to note that although purine
W. Doehner et al. / International Journal of Cardiology 115 (2007) 156–158
157
Fig. 1. Therapeutic UA lowering by XO inhibition improves surrogate markers in CHF. An association with elevated UA has been shown for a number of surrogate markers of CHF (left). Lowering UA by XO inhibition has been observed to improve the respective feature of CHF pathophysiology (right).
degradation occurs ubiquitously, a the selective distribution of XO is found in humans. Indeed, XO is primarily located in endothelial cells of capillary wall [10] with its highest activity detected in capillaries of the intestine [11]. This suggests that XO has a specific function in this particular vascular system. Given the capacity to generate free oxygen radicals, XO may have a role in bactericidal defence mechanisms [12], especially at the barrier between the intestinal lumen and other tissues. A substantial body of evidence has accumulated to suggest a pathophysiologic involvement of elevated XO activity in CHF (Fig. 1). Consequently, XO inhibition by allopurinol has been shown to yield improvements in a range of surrogate markers in CHF pathophysiology (Fig. 1). In view of the aforementioned data it is surprising, that a recent study by Gavin and Struthers failed to find an improvement of exercise capacity on maximum exercise level or on submaximal level following allopurinol treatment in CHF patients [13]. Some aspects in the trial setting likely explain the neutral results in this trial, such as unselected enrolment of patients with normal UA levels, i.e. no up-regulated XO activity [14]. The therapeutic concept of allopurinol in CHF, however, suffered some controversy. An important fact has recently been highlighted when it became apparent that the conversion of the prodrug allopurinol to its active metabolite oxypurinol is itself accompanied by superoxide generation [15]. Only the latter compound then fully inhibits free radical formation by irreversible inhibition of XO. Consequently, oxypurinol seems preferable over allopurinol to inhibit the XO-derived oxygen radical accumulation. This approach is recently tested in the OPT-CHF trial, a multi-centre, doubleblind, placebo-controlled randomized trial adding oxypurinol to standard therapy in 400 patients with CHF [16]. In this trial, however, UA – the indicator of increased XO activity in CHF – seems not to be assessed as obligatory inclusion criterion. This is surprising as in patients with
normal UA levels (i.e. no XO activation), a measurable therapeutic effect of XO inhibition is unlikely to be found. On comparison, treatment of anaemia would not be considered if assessment of haemoglobin levels indicated absence of anaemia. Accordingly, previous studies failed to observe therapeutic affects of allopurinol in CHF patients if unselected patients with normal UA levels were studied [14]. The concept of tailored treatment only of those patients eligible for the therapeutic concept might prevent neutral results as in the study by Gavin and Struthers. Whether oxypurinol or newer compounds such as the non-purine selective XO inhibitor Febuxostat (previously known as TMX-67) [17] are a better option for targeted metabolic therapy in CHF awaits further studies. Whether UA itself in this context should be viewed as a mere reflection of XO activity or is actively involved, needs to be clarified. This, however, does not call the value of UA assessment as prognostic marker into question. The discussion of whether or not UA itself contributes to cardiovascular pathophysiology is still ongoing. UA has been identified as an endogenous danger signal that mediates immune response following cell injury [18]. Moreover, UA infusion in a mouse model caused increased tumor necrosis factor-α production upon endotoxin challenge indicating immune activation [19]. Recognition of CHF as a metabolic illness is increasing, however, no metabolic therapy is available at present. Further studies are needed to establish whether XO inhibition is a useful advance in therapy for CHF patients. References [1] Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart 2004;90-:464–70. [2] Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997;96-:526–34.
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W. Doehner et al. / International Journal of Cardiology 115 (2007) 156–158
[3] Jankowska EA, Ponikowska B, Majda J, et al. Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol 2007;115-:151–5. [4] Anker SD, 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-:1991–7. [5] Doehner W, Rauchhaus M, Florea VG, et al. Uric acid in cachectic and non-cachectic CHF patients – relation to leg vascular resistance. Am Heart J 2001;141-:792–9. [6] 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-:3073–8. [7] Doehner W, Tarpey MT, Pavitt DV, et al. Elevated plasma xanthine oxidase activity in chronic heart failure: source of increased oxygen radical load and effect of allopurinol in a placebo controlled, double blinded treatment study. J Am Coll Cardiol 2003;42(Suppl 207A). [8] Doehner W, Schoene N, Rauchhaus M, et al. 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-:2619–24. [9] McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem 1968;243-:5753–60. [10] Jarasch ED, Grund C, Bruder G, Heid HW, Keenan TW, Franke WW. Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium. Cell 1981;25-:67–82.
[11] Sarnesto A, Linder N, Raivio KO. Organ distribution and molecular forms of human xanthine dehydrogenase/xanthine oxidase protein. Lab Invest 1996;74-:48–56. [12] Tubaro E, Lotti B, Cavallo G, Croce C, Borelli G. Liver xanthine oxidase increase in mice in three pathological models. A possible defence mechanism. Biochem Pharmacol 1980;29-:1939–43. [13] Gavin AD, Struthers AD. Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure. Heart 2005;91-:749–53. [14] Doehner W, Anker SD. Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart 2005;91-:707–9. [15] Galbusera C, Orth P, Fedida D, Spector T. Superoxide radical production by allopurinol and xanthine oxidase. Biochem Pharmacol 2006 [Epub ahead of print]. [16] Freudenberger RS, Schwarz Jr RP, Brown J, et al. Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III–IV congestive heart failure. Expert Opin Investig Drugs 2004;13-:1509–16. [17] Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353-:2450–61. [18] Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516–21. [19] Netea MG, Kullberg BJ, Blok WL, et al. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood 1997;89-:577–82.
Editorial
Uric acid in CHF: Marker or player in a metabolic disease? Wolfram Doehner a,⁎, Stephan von Haehling b , Stefan D. Anker a,b a
Division of Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany b Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College, London, UK Received 24 May 2006; accepted 26 May 2006 Available online 17 July 2006
Cardiovascular medicine is a story of success in many aspects, especially with regard to improved outcome in acute cardiovascular events. An immediate consequence is of course a growing prevalence of cardiovascular diseased patients. A wealth of epidemiological data from recent decades highlights the fact that we are confronted with an epidemic development in CHF. Indeed, the prevalence of CHF has been estimated at 4.8 million in the United States alone. To meet this challenge, much research has focused on understanding the complex pathophysiology of CHF. This has led to deduce that CHF is much more than mere pump failure. Neuroendocrine activation, for example, has been recognised as a cornerstone in CHF pathophysiology and has become a major target in the treatment of CHF patients. On the other hand, immune activation [1] and, more recently, hormonal and metabolic derangement [2], have emerged as significant contributors to CHF morbidity and mortality. Importantly, hyperuricaemia has been established as a characteristic feature in CHF with both symptomatic and prognostic significance. In this issue of International Journal of Cardiology, Jankowska et al. report the significance of hyperuricaemia to predict survival in patients with CHF [3]. This study is in line with earlier reports showing uric acid (UA) as a strong and independent prognostic marker in moderate to severe CHF [4]. Jankowska et al. expand the previous data on prognostic value of UA to a broader patient population such as patients with mild to moderate CHF (mean NYHA class 2.3, 63% in NYHA class I and II, mean LVEF 32%). The investigators observed that more consistent adherence to beta blocker ⁎ Corresponding author. Tel.: +49 30 450 553507; fax: +49 30 450 553951. E-mail address: [email protected] (W. Doehner). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.05.003
therapy (82%) did not affect the prognostic value of elevated UA levels compared to the previous report by Anker et al. [4]. Importantly, the authors show that even a mild elevation in UA levels (≥ 6.5 mg/dl) indicate significantly impaired survival. The study from our group found the best cut-off value at 9.5 mg/dl. Thus, UA is a parameter with robust prognostic significance over a broad range of CHF severity, which remains unaffected by different test settings. Notably, the association between UA and outcome was independent of kidney function, which confirms a number of previous reports [4,5]. Impaired renal function is the leading mechanism of hyperuricaemia in patients suffering from gout, and renal insufficiency is a common co-morbidity in CHF. Nevertheless, the predominant mechanism of elevated UA levels in CHF seems to be overproduction rather than underexcretion of UA. Overactivation of the xanthine oxidase (XO) metabolic system has been regularly observed in CHF [6,7]. This may distinguish hyperuricaemia in CHF from gout. Accordingly, gout is not recognised as a common comorbidity in CHF although substantial increases in UA are present in up to 35% of patients with CHF [4]. Furthermore, the initiation of allopurinol treatment (300 mg once daily) in hyperuricaemic patients with CHF has yielded a 40% reduction in UA levels after only 1 week [8]. Such rapid treatment effects are not usually observed in patients with gout. The oxygen radical generating capacity of the XO pathway forms the basis of the pathophysiologic potential of this metabolic system. In fact, in 1968, cytosolic XO was the first documented biological generator of oxygen derived free radicals [9]. The XO pathway has since emerged as a major source of free oxygen radical production in humans. In this context it is interesting to note that although purine
W. Doehner et al. / International Journal of Cardiology 115 (2007) 156–158
157
Fig. 1. Therapeutic UA lowering by XO inhibition improves surrogate markers in CHF. An association with elevated UA has been shown for a number of surrogate markers of CHF (left). Lowering UA by XO inhibition has been observed to improve the respective feature of CHF pathophysiology (right).
degradation occurs ubiquitously, a the selective distribution of XO is found in humans. Indeed, XO is primarily located in endothelial cells of capillary wall [10] with its highest activity detected in capillaries of the intestine [11]. This suggests that XO has a specific function in this particular vascular system. Given the capacity to generate free oxygen radicals, XO may have a role in bactericidal defence mechanisms [12], especially at the barrier between the intestinal lumen and other tissues. A substantial body of evidence has accumulated to suggest a pathophysiologic involvement of elevated XO activity in CHF (Fig. 1). Consequently, XO inhibition by allopurinol has been shown to yield improvements in a range of surrogate markers in CHF pathophysiology (Fig. 1). In view of the aforementioned data it is surprising, that a recent study by Gavin and Struthers failed to find an improvement of exercise capacity on maximum exercise level or on submaximal level following allopurinol treatment in CHF patients [13]. Some aspects in the trial setting likely explain the neutral results in this trial, such as unselected enrolment of patients with normal UA levels, i.e. no up-regulated XO activity [14]. The therapeutic concept of allopurinol in CHF, however, suffered some controversy. An important fact has recently been highlighted when it became apparent that the conversion of the prodrug allopurinol to its active metabolite oxypurinol is itself accompanied by superoxide generation [15]. Only the latter compound then fully inhibits free radical formation by irreversible inhibition of XO. Consequently, oxypurinol seems preferable over allopurinol to inhibit the XO-derived oxygen radical accumulation. This approach is recently tested in the OPT-CHF trial, a multi-centre, doubleblind, placebo-controlled randomized trial adding oxypurinol to standard therapy in 400 patients with CHF [16]. In this trial, however, UA – the indicator of increased XO activity in CHF – seems not to be assessed as obligatory inclusion criterion. This is surprising as in patients with
normal UA levels (i.e. no XO activation), a measurable therapeutic effect of XO inhibition is unlikely to be found. On comparison, treatment of anaemia would not be considered if assessment of haemoglobin levels indicated absence of anaemia. Accordingly, previous studies failed to observe therapeutic affects of allopurinol in CHF patients if unselected patients with normal UA levels were studied [14]. The concept of tailored treatment only of those patients eligible for the therapeutic concept might prevent neutral results as in the study by Gavin and Struthers. Whether oxypurinol or newer compounds such as the non-purine selective XO inhibitor Febuxostat (previously known as TMX-67) [17] are a better option for targeted metabolic therapy in CHF awaits further studies. Whether UA itself in this context should be viewed as a mere reflection of XO activity or is actively involved, needs to be clarified. This, however, does not call the value of UA assessment as prognostic marker into question. The discussion of whether or not UA itself contributes to cardiovascular pathophysiology is still ongoing. UA has been identified as an endogenous danger signal that mediates immune response following cell injury [18]. Moreover, UA infusion in a mouse model caused increased tumor necrosis factor-α production upon endotoxin challenge indicating immune activation [19]. Recognition of CHF as a metabolic illness is increasing, however, no metabolic therapy is available at present. Further studies are needed to establish whether XO inhibition is a useful advance in therapy for CHF patients. References [1] Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart 2004;90-:464–70. [2] Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997;96-:526–34.
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W. Doehner et al. / International Journal of Cardiology 115 (2007) 156–158
[3] Jankowska EA, Ponikowska B, Majda J, et al. Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. Int J Cardiol 2007;115-:151–5. [4] Anker SD, 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-:1991–7. [5] Doehner W, Rauchhaus M, Florea VG, et al. Uric acid in cachectic and non-cachectic CHF patients – relation to leg vascular resistance. Am Heart J 2001;141-:792–9. [6] 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-:3073–8. [7] Doehner W, Tarpey MT, Pavitt DV, et al. Elevated plasma xanthine oxidase activity in chronic heart failure: source of increased oxygen radical load and effect of allopurinol in a placebo controlled, double blinded treatment study. J Am Coll Cardiol 2003;42(Suppl 207A). [8] Doehner W, Schoene N, Rauchhaus M, et al. 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-:2619–24. [9] McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem 1968;243-:5753–60. [10] Jarasch ED, Grund C, Bruder G, Heid HW, Keenan TW, Franke WW. Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium. Cell 1981;25-:67–82.
[11] Sarnesto A, Linder N, Raivio KO. Organ distribution and molecular forms of human xanthine dehydrogenase/xanthine oxidase protein. Lab Invest 1996;74-:48–56. [12] Tubaro E, Lotti B, Cavallo G, Croce C, Borelli G. Liver xanthine oxidase increase in mice in three pathological models. A possible defence mechanism. Biochem Pharmacol 1980;29-:1939–43. [13] Gavin AD, Struthers AD. Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure. Heart 2005;91-:749–53. [14] Doehner W, Anker SD. Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart 2005;91-:707–9. [15] Galbusera C, Orth P, Fedida D, Spector T. Superoxide radical production by allopurinol and xanthine oxidase. Biochem Pharmacol 2006 [Epub ahead of print]. [16] Freudenberger RS, Schwarz Jr RP, Brown J, et al. Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III–IV congestive heart failure. Expert Opin Investig Drugs 2004;13-:1509–16. [17] Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353-:2450–61. [18] Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516–21. [19] Netea MG, Kullberg BJ, Blok WL, et al. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood 1997;89-:577–82.