European Journal of Heart Failure (2009) 11, 444–452 doi:10.



Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure
Corinna Bergamini, Mariantonietta Cicoira*, Andrea Rossi, and Corrado Vassanelli
Department of Biomedical and Surgical Sciences, Division of Cardiology, Ospedale Civile Maggiore, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy Received 11 September 2008; revised 5 January 2009; accepted 2 March 2009; online publish-ahead-of-print 4 April 2009

Downloaded from by guest on December 16, 2012

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant-producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up-regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up-to-date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.

Oxidative stress † Ventricular function † Treatment

Heart failure (HF) is the pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of metabolizing tissues, or can do so only from an elevated filling pressure. A complex series of neurohormonal changes takes place as a result of the two principal haemodynamic alterations occurring in this condition: reduction of cardiac output and atrial hypertension. In the early stages of acute systolic failure, these changes—heightened adrenergic drive, activation of the renin– angiotensin –aldosterone axis, and augmented release of vasopressin and endothelin—are truly compensatory, maintaining perfusion to vital organs and increasing the inadequate arterial blood volume. As HF becomes chronic, several of these compensatory mechanisms can cause undesirable effects such as excessive vasoconstriction, increased afterload, excessive retention of salt and water, electrolyte abnormalities, and arrhythmias.1 HF is also a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular

alterations. Oxidative stress can be defined as the condition in which excessive production of reactive oxygen species (ROS)— a family of molecules including molecular oxygen and its derivatives which are produced in all aerobic cells, outstripping endogenous antioxidant defence mechanisms—has been implicated in processes in which they oxidize biological macromolecules. The pathophysiological effects of ROS depend on the type, concentration, and specific site of production and involve three broad types of action. When the local levels of ROS are high, they tend to react with numerous protein centres, DNA, cell membranes, and other molecules, causing considerable cellular damage as well as generating other more reactive radicals. At lower concentrations, however, local targeted production of ROS serves as a secondmessenger system that transmits biological information through the highly specific modulation of intracellular signalling molecules, enzymes, and proteins (redox signalling function). The third general ROS-related pathophysiological mechanism involves the reaction of O2 with the signalling molecule nitric oxide (NO), 2

* Corresponding author. Tel: þ39 0458123706, Fax: þ39 045914727, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email:

ROS have been implicated in most processes thought to have a significant effect on cardiac function. NO reacts to produce peroxinitrite (ONOO2). This regulatory control mechanism is effective as long as XO does not generate superoxide anion. Xanthine oxidase is a variant of XDH. norepinephrine. These effects would induce a decrease in cardiac contractility and in the rate of relaxation of cardiac muscle. which contributes to systemic vasoconstriction and increased cardiac loading. sex.3 2 Although their role in the pathogenesis of clinical HF remains unclear. Whereas XDH uses NADþ as a cofactor (reducing it to NADH). reducing its control over vascular oxidase. Uric acid is primarily excreted through the kidney.10 Hess et al. implying a role for ROS. XO utilizes molecular oxygen (reducing it to O2/H2O2). 2 which inhibits XO function primarily by oxidative disruption of the molybdenum catalytic site. including increased expression of pro-fibrotic growth factors and genes. Growing evidence also suggests an important role for increased oxidative stress in adverse left ventricular remodelling after myocardial infarction (MI). increasing permeability.21 A significant factor for the detrimental effect of ROS in this setting is the activation of matrix metalloproteinases.5 Excess interstitial fibrosis is an important detrimental aspect of chronic LVH and chronic heart failure (CHF). apocynin.18. tumour necrosis factor a.6. A similar inhibition of interstitial fibrosis was found in a model of aldosterone infusion.oxfordjournals. Normal serum UA levels are generally . and either the quantity or spatial localization of NO-producing enzymes (NOSs and XO) is altered. reducing left ventricular dilatation. leading to peroxidation of membrane phospholipids.11 reported that oxygen free radicals generated by XO depressed Ca2þ accumulation by sarcoplasmatic reticulum (SR) Downloaded from http://eurjhf. completely reabsorbed in the proximal tubule. Oxidative stress is well known to be pro-fibrotic in many organs. or pulsatile mechanical stretch has been shown to involve intracellular ROS production and to be inhibited by antioxidants. hypertrophy induced by angiotensin II. is expressed as a 150 kDa homodimer that produces superoxide or hydrogen peroxide as by-products of the terminal steps of purine metabolism. endothelin I.2 The major cardiovascular sources of ROS include the enzymes xanthine oxidoreductase (XOS). Xanthine oxidoreductase. NAD(P)H oxidase. NO activity would be expected to be sufficient to put a brake on XO activity. reducing its activity and production of oxygen free radicals. and finally reabsorbed. activation of matrix metalloproteinases. which in health has a central role in vascular homeostasis as well as in modulating cardiac function.7 mg/dL for men and . the development of experimental pressure overload left ventricular hypertrophy (LVH) in mice or guinea pigs is attenuated by antioxidants. Another mechanism causing a decrease in myocardial contractility might be the cell damage produced by oxygen free radicals. which suggests that NO may be a global modulator of oxygen free radicals. Hyperuricaemia is a very common metabolic disorder.6 In Nox2deficient mice subjected to angiotensin II infusion. Oxidative stress may be critical in the activation of apoptosis. the production of ROS by XO has potential pathophysiological relevance: their production by this enzyme leads to a worsening of cardiac function and of indices of myocardial contractility that might be due to oxygen free radicals depressing the excitation–contraction coupling mechanism in cardiac muscle. Contractile impairment is a central feature of CHF and has a multifactorial basis. increases in superoxide may inactivate NO. either in Nox2 knockout mice or in animals treated with NADPH oxidase inhibitor. In vitro studies have shown that myocyte contractile function may be impaired by increased ROS through several mechanisms.Oxidative stress and hyperuricaemia 445 and Ca2þ ATPase of SR. varying in relation to age. and loss of membrane integrity. The mechanism is related to ROSmediated activation of various mitogen-activated protein kinases and the transcription factor nuclear factor-kB. .org/ by guest on December 16. High serum UA levels have been observed in hypoxic states. 2012 Hyperuricaemia: mechanisms and clinical consequences in heart failure Uric acid (UA) is the end-product of purine metabolism catalysed by XO from hypoxanthine or xanthine (Figure 1). In particular. where it is completely filtered at the glomerulus. and NOS. This process may occur in the presence of hypoxia when the enzyme transfers electrons to molecular oxygen rather than to NADþ during the different stages of purine metabolism.4 In vivo. and many other factors. It is mainly due to reduced excretion of UA. but in many cases the exact mechanism is not fully understood. In cultured cardiomyocytes. resulting from either irreversible proteolytic cleavage or reversible oxidation of sulfydril residues of XDH. interstitial fibrosis was virtually abolished compared with wild-type mice. which drive matrix turnover and promote left ventricular dilatation.7. involving changes in cardiomyocytes function as well as altered chamber structure and properties. and lowering mortality. Growing evidence implicates redox-sensitive pathways in the development of cardiac hypertrophy in response to either neurohumoral stimuli or chronic pressure overload. then secreted (50% of the filtered load).17 Under these conditions.15 In the presence of O2. as well as mitochondrial cytochromes and haemoglobin.19 and in experimental models it has been shown that various antioxidant approaches can ameliorate this reverse remodelling.8 Interstitial cardiac fibrosis was also inhibited in Nox2 knockout mice subjected to aortic banding. which is thought to be an important contributor to the progression of CHF especially in its advanced stages. and recent work suggests that Nox2 oxidase-derived ROS are centrally involved in the development of interstitial cardiac fibrosis.9 Multiple underlying mechanisms are likely to be involved in these Nox2-dependent pro-fibrotic effects.16 If endothelial function is preserved and oxidative stress is low. which can result in an increase in membrane fluidity.12 – 14 Oxidant-producing enzymes are up-regulated in congestive HF. improving contractile function.12 suggesting an important underlying mechanism in the development of vascular endothelial dysfunction in CHF. increased activation of NF-kB. The enzyme has two isoforms: xanthine oxidase (XO) and xanthine dehydrogenase (XDH).5 mg/dL for women. and inflammatory cell infiltration.20. A relative NO deficiency may further promote oxidase activities. a molybdenum-containing enzyme. Elevated serum UA levels occur in 2–18% of the population.

XO is localized solely in the capillary endothelium. 2012 Figure 1 Purine metabolism. immediately fully reabsorbed from the proximal tubule. A decrease in renal perfusion can also lead to increasing UA levels. Bergamini et al.oxfordjournals.446 C. including increased abundance and activity of XO. renal UA excretion can be further impaired as lactate competes with urate via an organic anion exchanger in the proximal tubule38 (Figure 2). rather than from the myocardium.28 – 35 and several potential mechanisms have been identified to explain this association.26 and activation of XDH and XO. Serum UA may increase in patients with failing circulation because of increased generation.36 increased conversion of XDH to XO. 40% of the filtered load is reabsorbed. such as in obstructive pulmonary disease. . Purines arise from metabolism of dietary and endogenous nucleic acids and are degraded ultimately to uric acid through the action of the enzyme xanthine oxidase.27. and finally. Uric acid has long been linked with cardiovascular disease.40 and hyperuricaemia in HF may reflect the metabolic effects of hypoxia on the microvasculature. decreased excretion. the endothelium also contributes to its production. Figure 2 Diagram showing renal excretion of uric acid. In the heart. Downloaded from http://eurjhf.24 and acute25 or CHF.22 neonatal hypoxia. There are several possible contributors to increased UA production in by guest on December 16. This leaves 10% of the filtered load excreted in the urine.37 or an increase in XO substrate resulting from enhanced ATP breakdown to adenosine and hypoxanthine. Uric acid is completely filtered at the glomerulus. the UA generated in hypoxic states originates from capillary endothelial cells. Hypoxia and impaired oxidative metabolism contribute to enhanced UA levels. or a combination of the two. Although the liver is the principal source of UA. then secreted back into the proximal tubule (50% of the filtered load).23 cyanotic heart disease. hypoxanthine and xanthine. As advancing HF leads to tissue ischaemia and a rise in serum lactate.39 Therefore. Hypoxia leads to accumulation of its precursors.

plasma creatinine.005). a powerful antioxidant) becomes pro-oxidant in the atherosclerotic milieu of free radical generation from Fe2þ and Cu2þ ions leaked from atherosclerotic plaques and vasa vasorum rupture through the Fenton and Haber –Weiss reactions.001). peak VO2. 0. respectively. independent of age. body mass index. Maximal oxygen uptake (MVO2) and regression slope relating minute ventilation to carbon dioxide output (VE-VCO2) were measured during a maximal treadmill exercise test. 0. and insulin sensitivity index. pro-oxidant urate redox shuttle by which urate (under normal circumstances. All patients underwent metabolic assessment.9). insulin sensitivity. 0. especially in cachectic patients. serum UA emerged as the strongest predictor of peak leg vascular resistance (standardized coefficient 0. as well as a 60. 0. R 2 ¼ 0. 0. functional capacity. exercise time (r ¼ 20.5% lower insulin sensitivity (P .001)].86. serum UA concentration emerged as a significant predictor of MVO2 (r ¼ 20. VE-VCO2 slope (r ¼ 0. both P . independently of diuretic dose. In stepwise regression analysis.04. alcohol intake. and New York Heart Association class (r ¼ 0. Twenty-two patients with CHF were included in their study.54 – 56 Anker and Coats55 initially proposed a metabolic. serum creatinine. Chronic heart failure is associated with chronic inflammation. and metabolic factors. both P . 51 and acute urate infusions in healthy volunteers have not been shown to worsen endothelial function. 2012 Oxidative metabolism and prognosis in heart failure Several factors are predictive of impaired survival in CHF. The three main areas of prognostic importance are haemodynamics. Compared with healthy controls. This correlation was not found in the healthy control subjects (r ¼ 20. P ¼ 0.1) mL/100 mL/ min. Doehner et al. 0. Hyperuricaemia. and insulin sensitivity. post-ischaemic vascular resistance correlated significantly and independently of age with UA (r ¼ 0. both P .47 a prerequisite for leucocyte adhesion to vascular intima.001). correlates with increased postischaemic vascular resistance.6 (2. urate switches from being an antioxidant to a pro-oxidant is intriguing but further data must be collected in order to confirm it.61.01). This inverse correlation between serum UA and lower limb blood flow can be explained by the deleterious effects of XO-derived free radicals on vascular function.001). independent of diuretic dose. 0. P .48 and XO-derived free radical release has been implicated in the increased expression of adhesion molecules by leucocytes. However. Serum UA levels also parallel the chronic inflammatory response which appears to occur with increasing severity of CHF. These free radicals. creatinine.0001). UA emerged as the only predictor of maximum blood flow [standardized coefficient 20.83 (P .46 Serum UA is strongly related to circulating markers of inflammation in patients with CHF. So it is possible that the association between circulating UA and markers of chronic inflammation reflects the relationship between XO activity and leucocyte activation close to the vascular endothelium.33.34). fasting lipids. 56.43 of their soluble receptors. P .oxfordjournals. creatinine (r ¼ 0. and alcohol intake. Serum UA correlated with maximum blood flow (r ¼ 20. 0. including neuroendocrine and immunological processes. plasma insulin levels. Various studies have suggested that metabolic factors may be of greater importance than more conventional assessments of haemodynamic status and clinical features. Many proposals have been put forward to explain this paradox. In multivariate regression analysis.44. but not with resting blood flow.68 (P . compared with the non-cachectic patients and controls (612 + 36 vs. which included measurements of serum UA. P ¼ 0.53) (both P .org/ by guest on December 16.53 A clinical study41 revealed that there is an inverse relationship between serum UA concentration and measures of functional capacity in patients with HF.8% higher serum UA concentrations (P .42 as suggested by findings of elevated levels of circulating cytokines.Oxidative stress and hyperuricaemia 447 control in cardiovascular disorders. in whom protein degradation and muscle wasting influence UA production. Lower limb blood flow was measured at rest and after maximum exercise followed by a 5 min period of ischaemia (maximum blood flow) using strain gauge venous occlusion plethysmography. 0. 0.61). and the reduction in relative leg vascular resistance after ischaemia was lowest in cachectic patients (283% + 2%) compared with both non-cachectic patients (288% + 1%) and healthy control subjects (290% + 1%. Hayden and Tyagi52 proposed the antioxidant.001). The idea that in a fluid biological system at a particular concentration.0001). peak VO2 (r ¼ 20. Many of these have not been proved. 0. So the question then remains as to whether high UA levels represent a compensatory response of the body towards increased free radical production by XO or are merely a marker of XO activity. Patients in the upper tertile of serum UA had lower maximum blood flow than those in the lowest tertile [15. fasting and IVGTT glucose and insulin. and diuretic dose. maximum oxygen uptake and exercise time during the treadmill exercise test. and NYHA functional class (r ¼ 0.02).45 and of soluble adhesion molecules.49 demonstrated that there is also a strong inverse relation between serum UA concentrations and maximum leg blood flow in patients with CHF. age. In multivariate and stepwise regression analyses. age. 31. In all patients. 0.47. hydroxyl (OH2) and O2 in particular.50). uncouple 2 endothelial NO synthase and produce ONOO2. . assessed leg resting and post-ischaemic vascular resistance (calculated from mean blood pressure and leg blood flow by venous occlusion plethysmography) in 23 cachectic and 44 non-cachectic patients with CHF and 10 healthy control subjects. This correlation between hyperuricaemia and post-ischaemic leg vascular resistance in cachectic patients with CHF indicates that the XO metabolic pathway may contribute to impaired vasodilator capacity in CHF.0 (2.50 The cachectic patients had the highest UA levels. 0.45). This strong correlation between serum UA and MVO2—the latter indicating an impairment in functional capacity following a reduction in cardiac output—suggests that impaired oxidative metabolism plays an important role in the pathophysiology and generation of symptoms in HF. both P . Oxygen free radicals seem to play an important role in the impairment of vasomotor Downloaded from http://eurjhf.003].001). 459 + 18 and 346 + 21 mmol/L. body mass index.001). UA itself has potent antioxidant properties per se. The metabolic assessment consisted of measuring serum UA.2) vs. New York Heart Association class. Fifty-nine patients with CHF due to coronary heart disease or dilated cardiomyopathy and 16 healthy control subjects made up the study population.36) (both P . patients with CHF had a 52% lower MVO2 (P .0001).48 Anker et al.

org/ by guest on December 16. In the validation study. 3.56 subsequently proposed that the metabolic marker could be serum UA levels. diuretic dose. 12 month survival was lowest (31%) compared with patients with two risk factors (64%).0001). DtE (r ¼ 0. one (77%). 0. P . 2012 Figure 3 Kaplan– Meier survival plot for patients in the three HFSS subgroups. the best mortality-predicting UA cut-off (at 12 months) was 565 mmol/L (9. P . LVEF. which is known to regulate myocardial diastolic function: it has been reported that endogenous NO facilitates the . UA predicted DtE independently of renal function.08 mmol/L. Anker et al. P . 0.22. 0.48 + 0.58 functional impairment. and haemodynamic (MFH) staging system for the assessment of prognosis in CHF.26. In a multivariate model. Bergamini et al. E/A ratio. P . In an independent study. Patients underwent a complete echo-Doppler examination. high-risk group (reprinted from Anker et al.38 + 0. 0. and RMFP (P ¼ 0.63 Our group64 evaluated the effects of elevated UA levels on cardiac function in 150 patients with CHF resulting from dilated cardiomyopathy of diverse aetiology.140 ms. stratified by serum uric acid (cut-off 565 mmol/L). An RMFP was defined as either E/A ratio .50 mg/dL) (independent of age. P . 0. Such a system would depend on a straightforward metabolic marker.0001) (Figure 4).oxfordjournals. so they graded the relation between serum UA and survival. UA 565 mmol/L predicted mortality (hazard ratio 7.21.05).1 and DtE . 0. diuretic dose.448 C. P . ejection fraction. In separate studies. In the derivation study.001). Relation between uric acid levels and diastolic dysfunction Markers of diastolic dysfunction are frequently observed in patients with HF. left ventricular volumes. These findings might partly result from free radical-mediated endothelial injury with consequent reduction of NO production.14. 0.57 Severe diastolic dysfunction is characterized by a restrictive mitral filling pattern (RMFP) and is associated with the severity of symptoms. E/A ratio (r ¼ 0. these patients had significantly higher UA levels compared with patients without RMFP (0. We found a significant relationship between serum UA and parameters of diastolic function. a marker of low functional capacity (peak VO2 14 mL/kg/min) (F).59 and adverse prognosis in patients with CHF. and left ventricular volumes. Downloaded from http://eurjhf. Twenty-four patients (16%) had an RFMP.0001). 0. with measurement of mitral E-wave and mitral A-wave velocities. Uric acid levels correlated significantly with mitral E-wave velocity (r ¼ 0. urate levels did not correlate with markers of systolic function or with left ventricular volumes.56) functional. HFSS 1 indicates low-risk group. they validated the prognostic value of UA (n ¼ 182) and investigated the relationship between the decision to list a patient for heart transplantation (n ¼ 120) and the MHF score. or none (98%.14 mmol/L vs. P . LVEF 25%.2 or E/A . 51% of patients with an MFH score of 2 and 81% of patients with an MHF score of 3 were listed for transplantation. respectively. In 16 patients (from both studies) with UA 565 mmol/L. The positive predictive value of not being listed for heart transplantation with an MHF score of 0 or 1 was 100% (Figure 3).01). peak VO2.0001).01. sodium. creatinine. On the other hand. 2. E-wave deceleration time (DtE). medium-risk group. and stroke volume. and a marker of poor cardiac function [left ventricular ejection fraction (LVEF) 25%] (H). a three-risk-factor model based on three parameters: a high UA level as marker of metabolic status (M). and peak VO2 114 mL/kg per min (MFH score 3).60 The diastolic abnormalities relate to elevated left ventricular filling pressures resulting from increased left ventricular chamber stiffness with consequent upward shift of the left ventricular pressure–volume loop. and urea.61 Myocardial diastolic properties are in part linked with histological myocardial changes resulting from increased collagen deposition62 and with the active process of isovolumetric relaxation of the myocardium.

Figure 4 Linear relationship between serum uric acid levels and mitral E-wave velocity (reprinted from Cicoira et al. P ¼ 0. Various studies73. Myocardial ROS production was increased after MI but markedly reduced after allopurinol treatment.120 mmol/L in all patients (mean reduction 217 + 15 mmol/L.74 have evaluated the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow—all have shown an improvement in peripheral vasodilator capacity and blood flow. Analogous results occurred in a very recent study70 in a TO-2 hamster model of dilated cardiomyopathy. Infarct size was similar in the two groups.29%.0001).10 + 18. 455–743 mmol/L) CHF patients were randomly allocated to allopurinol 300 mg/day or placebo for 1 week. confirming the potential role of allopurinol as a beneficial treatment for HF.01.75 determined endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery in 10 CHF patients with normal serum UA levels (315 + 42 mmol/L) and 9 patients with elevated UA (535 + 54 mmol/L). only acute allopurinol treatment reduced left ventricular ROS determined using spin resonance spectroscopy. They found that long-term allopurinol treatment improved left ventricular haemodynamics and function and prevented left ventricular remodelling. 0. by a transient reduction of myocardial ROS shortly after initiation of allopurinol treatment. Treatment reduced UA levels by .31 + 38. This suggested a potential therapeutic strategy for the treatment of this disease. as determined by electron spin resonance spectroscopy. P ¼ 0. 152. 0. Assuming that dilated cardiomyopathy is characterized by an imbalance between left ventricular performance and myocardial energy consumption. allopurinol improved peak blood flow (venous occlusion plethysmography) in the arms (24%. with no parallel decrease in dP/dtmax or SW and no change in ventricular load.69 mice with extensive anterior MI induced by permanent ligation of the left anterior descending coronary artery were randomized to treatment with either vehicle or the XO inhibitor allopurinol for 4 weeks. Cappola et by guest on December 16. 0. Compared with placebo.63.05). stroke work (SW). Downloaded from http://eurjhf. The patients were instrumented to assess myocardial oxygen consumption (MVO2). Mellin et al. at least in part. In a double-blind crossover study. Allopurinol caused a significant decrease in MVO2 (peak effect 216 + 5%. Flow-dependent flow improved by 58% in the arms (P ¼ 0. Xanthine oxidase expression and activity. licence number 2012441095848). 22 + 9%.05). each for 15 min). probably by increasing diastolic distensibility.66 – 68 In Engberding’s study. such as reduced inflammation. Co-infusion of allopurinol (600 mg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricaemic patients (P . 14 hyperuricaemic (558 + 21. 1.21 vs. both P .64 with the permission of Elsevier. 2012 Frank –Starling response in the heart.. 73. P . Doehner et al.0. The net result was a substantial improvement in myocardial efficiency (peak effect: dP/dtmax/ MVO2. were found to be markedly increased in the remote myocardium of mice after MI. n ¼ 9). So these long-term effects were caused.71 compared the effects of a 5 day and 10 day treatment with allopurinol on haemodynamics and left ventricular function and structure in rats with established CHF induced by left coronary ligation. SW/MVO2. Despite XO inhibition .19 vs. involving reversal of the energy inefficiency of the failing heart through pharmacological XO inhibition. as assessed by echocardiography. P . 0. starting 1 day after the acute ischaemic event. peak rate of rise in left ventricular pressure (dP/dtmax). A recent study76 showed that a steep dose–response relationship exists between allopurinol and its effect on endothelial function as assessed by standard forearm venous occlusion plethysmography.96 + 10.72 used intracoronary allopurinol to analyse the effects of XO inhibition on left ventricular function in nine patients with this disease.65 Xanthine oxidase inhibition studies All of these data suggest a role for the XO metabolic pathway in the pathophysiology of CHF and other cardiovascular diseases. indicating that XO activity may contribute to abnormal energy metabolism in human cardiomyopathy.5. by reduced myocardial XO activity and ROS production. n ¼ 9. were involved. P . 0. An increasing number of experimental and clinical studies have begun to test whether this therapeutic approach translates into meaningful beneficial pathophysiological changes.5 mg/min. Allopurinol treatment substantially attenuated left ventricular cavity dilatation and dysfunction after MI. 0. P . Blocking XO-generated oxygen radical accumulation has emerged as an intriguing new treatment option for preventing oxygen radical accumulation and its adverse effects.027) and legs (23%. Allopurinol 600 mg/day significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/day and placebo [%change in forearm blood flow (mean + SEM): 240.oxfordjournals.011). Similarly. both locally and systemically. since both treatments reduce UA plasma levels. and there was a direct relation between change in UA levels and improvement of flowdependent flow after treatment (r ¼ 0.05).029). n ¼ 6.001). and markedly reduced myocardial hypertrophy and interstitial fibrosis. and 1. demonstrating its novel beneficial effect on left ventricular remodelling processes and left ventricular function which was probably mediated. 40 + 17%. but it remains to be confirmed whether other mechanisms independent of myocardial redox status. and efficiency (dP/dtmax/MVO2 and SW/MVO2) at baseline and after sequential infusions of intracoronary allopurinol (0.Oxidative stress and hyperuricaemia 449 after acute and chronic allopurinol therapy. at least in part.

double-blind study78 of 60 CHF patients (NYHA II–III). Elsevier Saunders. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure.1 vs. Grieve DJ. 360:2327 –2334. 2. improves clinical outcome in CHF patients presenting with high serum UA levels. 8th ed. an intriguing therapeutic possibility which remains to be confirmed by further studies.8 + 2. 9. Pathophysiology of Heart Failure. Braunwald E. Seddon M. Shah AM. Conclusions In patients with CHF. This may mean that high-dose allopurinol can fully negate the adverse effect of urate and improve survival. In a subgroup analysis.56 indicating that UA is a valuable biomarker of morbidity and mortality in C.115:509 – 517. Circulation 2002. Pivotal role of gp91(phox)containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice.9. Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Shah AM.9 mg/dL. Cave A. . Heymes C.95). Cave AC. Heart 2007.450 In a retrospective cohort study. and that HF patients with elevated serum UA may represent a valuable patient population responsive to therapy with XO inhibition. with a four-fold increase in risk of death. Struthers et al. 95% CI 0. benefits occurred in patients with elevated serum UA levels in a manner which correlated with the degree of UA reduction. Johar S. Park JB. J Clin Invest 2005. Shah AM. whereas oxypurinol patients with UA levels . These results suggest that despite the fact that oxypurinol did not improve clinical outcome relative to patients randomized to placebo. Grieve DJ. Johar S. patients with elevated UA levels (. UA has emerged as a strong independent prognostic factor in patients with CHF. oxypurinol 600 mg/day or placebo was administered for 1 month in addition to standard therapy. Zhang M.47:817 –826. 4. In this context. and as recently shown in the OPT-CHF Study. placebo-controlled trial was designed to test whether XO inhibition with oxypurinol (600 mg/day) could produce clinical benefits in patients (n ¼ 405) with systolic dysfunction and symptomatic HF treated with optimal HF therapies. or worsened did not differ between those receiving oxypurinol or placebo. Recent findings also suggest an association between UA levels and parameters of diastolic function. NO/redox disequilibrium in the failing heart and cardiovascular system.105:293–296. double-blind. hyperuricaemia is a common finding and is associated with the impairment of peripheral blood flow and reduced vasodilator capacity. FASEB J 2006.40% at baseline were excluded (increase of 6. 8. Hare JM. Allopurinol improves myocardial energy and endothelial dysfunction and vasodilator reactivity to exercise by reducing markers of oxidative stress responsible for vascular dysfunction. Byrne JA. Gall N. Grieve D. Efficacy was assessed using a composite endpoint compromising HF morbidity. multicentre.93:802 –805. randomized. the OPT-CHF Study79 is the first to evaluate clinical effects in unselected patients with moderate-to-severe HF. and 6 minute walking test were evaluated. 0. Philos Trans R Soc Lond B Biol Sci 2005. Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload. Bergamini et al. 3. Bendall JK. Biochem Biophys Res Commun 2004. J Am Coll Cardiol 2006. n ¼ 108) responded favourably to oxypurinol (P ¼ 0. XO inhibition may represent a novel option in the treatment of CHF subgroups. Conflict of interest: none declared. Park MY. 5. Siva A. 21.8% from baseline to 1 month in the oxypurinol group relative to placebo. Park YM. P . This very recent.20:1546 –1548. The authors suggest that these results may be related to the decrease in oxidative stress. 2012 References 1. It has been proposed that the link between hyperuricaemia and worse clinical status in patients with CHF might be mediated by an increase in oxidative stress. Circ Res 2003. Oxypurinol reduced serum UA by 2 mg/dL (P . Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase.0 + 1. High risk associated with a longstanding high urate concentration is adequately reduced only by long-term high-dose allopurinol. in particular in elevated XO expression and consequent increased production of oxygen free radicals. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. those characterized as either improved or unchanged had significantly greater reductions in serum UA levels compared with patients who worsened (22.93:903–907. Narayanapanicker A. The UA findings are consistent with reports from Anker et al. unchanged. No increase in walking capacity was detected. Shah AM. Byrne JA. Gove C.02 for interaction term).5 mg/dL exhibited a trend towards worsening. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy.300 mg/day) allopurinol was associated with a significantly better survival than longterm low-dose allopurinol (relative risk 0. Downloaded from http://eurjhf. assuming that a high urate concentration is independently associated with mortality. In: Braunwald’s Heart by guest on December 16. myocardial fibrosis. Stamler JS. left ventricular remodelling.oxfordjournals.37–0.313:812 –817. Further to these positive findings for XO inhibition. in particular that after XO inhibition. Shah AM.77 aimed to examine whether allopurinol treatment was associated with any alteration in mortality or hospitalization in patients with CHF. and effects on LVEF. HF. more importantly. 0. They finally speculate that reverse remodelling as a consequence of a decrease in oxidative stress would also increase cardiac performance.59. NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology. Grieve DJ. reduction in serum UA levels by oxypurinol correlated with favourable clinical response. Within the entire oxypurinol patient cohort. A Textbook of cardiovascular medicine.001). and contractility impairment responsible for worsening of cardiac function in CHF. Looi YH. Johar S. 7. Cave AC. P ¼ 0. but this increase was statistically significant only when patients with LVEF .9. Lambeth JD. Cave AC.5 mg/dL. In addition.02).0006). Layland J. Li JM. Cave AC.3 + 2. In a randomized. mortality. Oxypurinol increases LVEF when depressed at baseline. serum UA level. The percentage of patients characterized as improved. Shah AM. which relate closely to clinical status and reduced exercise capacity. and myofilament Ca2þ responsiveness would recover towards normal and therefore improve myocardial contractility. 6. They observed that long-term high-dose (. Colucci WS.. The aforementioned studies outline the potential benefits of XO inhibition in CHF patients. Bendall JK. Suh YL. and quality of life. Left ventricular ejection fraction improved in the active treatment group. less O2 production would lead to more NO availability and 2 a decrease in afterload.

Davos CH. Bengtsson C. Kass DA. The NHANES I Epidemiologic Follow-up Study. Wada A. Eur J Cell Biol 1981. Eiriksdottir G. Cirillo M. 224:549 –555. Williamson DF. 33. George J. Thappa V. Alfthan G. Am J Epidemiol 1995. 43.323: 236 –241. Maeda K. Hare JM. Hassoun PM. Lakka TA. Maeda Y.334:197 –205. Coats AJ. Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury. Lakka HM.302:228 –232. Ye YZ. J Pharmacol Exp Ther 1997. Chan WP. Circ Res 1999. Hisanaga T. Pediatrics 1996. Lapidus L. Curr Heart Fail Rep 2007. 40. Lee K. 22(Suppl. Mancini M. Chaudhary AK. Bruinsma KA. Chua TP. Lab Invest 1982.oxfordjournals.92:1479 –1486. and type 2 diabetes mellitus: the urate redox shuttle. Nakashima JM. Gerbes AL. Bellina LM. Shamim W. J Am Coll Cardiol 1993. Senzaki H. Doehner W. Regulation of xanthine oxidase by nitric oxide and peroxynitrite. 13. Mayer L. Meerson FZ. Rauchhaus M. Urate produced during hypoxia protects heart proteins from peroxynitrite-mediated protein nitration. echocardiographic and hemodynamic correlations and prognostic implications. Shedd AL. Godsland IF. 57. Am J Med Sci 2007. Kuroda Y. metabolic syndrome. Nyyssonen K. Downloaded from http://eurjhf. Benoit R. Am J Cardiol 1989. Tejani AD. Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: clinical. 56. Menotti A. Salonen JT. Wheeler JG. Kox WJ. Arends D. Arch Intern Med 2004. Kannel WB. xanthine and uric acid.1:10. Localization of xanthine oxidase in mammary gland epithelium and capillary endothelium. Poole-Wilson PA. Coats AJ. 283:2404 –2410. Aakvaag A. Gutteridge MC. Uric acid and cardiovascular risk. Temporelli PL. Egerer KR.141:637 – 644. Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts. Confortini R. functional and hemodynamic staging. Nees S. Arch Biochem Biophys 1993. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Ouwerkerk R. Comparison of cord purine metabolites to maternal and neonatal variables of hypoxia. functional. 42:1002 –1016. Marban E. Hellewell PG. The role of urate and xanthine oxidase inhibitors in cardiovascular disease.19:1814 –1822.152:873–876. Obstet Gynecol 1992.47:412–426. Role of reactive oxygen species in myocardial remodeling. Tsutamoto T. Biology of disease: free radicals and tissue injury. Hare JM. Prasad K. Curr Opin Pharmacol 2002. Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. Hamlin RL. Uric acid in chronic heart failure: a marker of chronic inflammation. Khan SA. Zweier JL. Keenan TW. Osterziel KJ.38:1850 –1858. Thakkar RN. 45. Eur Heart J 1998. Larson MG. Knosalla C. Sundsfjord JA. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Rauchhaus M. 17. Stull L. Franke WW. 36. Postlethwait EM. Akita H. Packer M. Evans JD. Hayabuchi Y. Francis D. Kagon VE. Fukai D. Sweden. Hayden MR. J Am Med Assoc 2000. 14. Leyva F. Parish RC. Fox IH. Freeman BA. 26.101:15944 –15948. Niskamen LK. Am J Physiol Heart Circ Physiol 2006. Kinoshita M. Eur J Pediatr 1993. Chacko VP. Kanoupakis EM. Florea VG. Febo O. Anker SD. Shah AM. Hyperuricaemia in cyanotic congenital heart disease. Am Heart J 2000. 41. Teng RJ. Bachetti T. J Mol Cell Cardiol 1981. Colfer H. Coats AJ. Lamers JM. Serum uric acid as an impaired oxidative metabolism in chronic heart failure. Landman MJ. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Culleton BF. Stevenson JC. Metabolic. The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart. Panarelli W. Naumova AV. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.13:767 –772. Omland T.6:617 –624. Gonzales DR. Freedman DS.2:e76. Camerini F. Am J Respir Cell Mol Biol 1992. Anker SD. Shemanski D. Ferrari R. Dickstein K. Segal R. Importance of left ventricular filling pressure on diastolic filling in idiopathic dilated cardiomyopathy. Zhang M. Coats AJ. 16. 1971 –1992.25:67 –82. Raju SV. Uric acid is closely linked to vascular nitric oxide activity. Kox WJ. Zhao L. Corti A. and haemodynamic staging for CHF? Lancet 1996. 11. Pathernakis FI. Ann Intern Med 1999. Lolly JL. Sluiter W. Fang J. Wingrove CS.76:803 –808.93:1963 –1969.82:495–502.141:792–799.24:287 –297. Anker SD. Sun Y. Oxygen radicals and tissue damage. Fanburg BL. Am J Cardiol 1997. Arkkhipenko YV. Circulation 1995. Kemp M. eds. Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population Study. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Sharma R. Left ventricular diastolic filling pattern predicts cardiopulmonary determinants of functional capacity in patients with congestive heart failure. Gunter EW. Cicoira M. Acta Cardiol 2001. Struthers AD. Diezi J.4:26– 30. Am Heart J 2001. Woolliscroft JO. Heart 1997. Isolation. 2012 . Swan JW. Levine B. Acta Med Scand 1988. Coats AJ. Berkowitz DE. Leyva F. Laaksonen DE.Oxidative stress and hyperuricaemia 451 37. Davos CH. 29. identification. Shokek O. Anker SD. Wessale JL. ` Marbaan E. 44. Lavine SJ. Bonarjee VV. Q J Med 2000. Hyperuricaemia and risk of cardiovascular disease and overall death. 15. Halliwell B. Lanti M. Bosimini E. Stendahl C. Simantirakis EN.084 controls: prospective study and meta-analysis.275:9369 –9376. Inhibition of pulmonary artery smooth muscle cell growth by hypoxanthine. 34. 30. Crapo JD. Imparato A. Coats AJ. Staubesand J. Inflammation in chronic heart failure. Saugstad OD. Measurement of uric acid as a marker of oxygen tension in the lung. Evidence for mechanism of association with cardiovascular disease. Kalra J. and continuous culture of coronary endothelial cells from guinea-pig hearts. Beckman JS. Webb DJ. Liu X.93:707 –713. Minhas KM. p403 – 411. Prognostic value of plasma soluble intercellular adhesion molecule-1 and endothelin-1 concentration in patients with chronic congestive heart failure. Heid HW. 12.458 incident cases and 155. Kijtawornrat A. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Poole-Wilson PA. Waring WS.290:H837 –H843. Giannuzzi P. Nutr Metab (Lond) 2004. Sharma R. Gerlach E. 1982. Porter KB. Matsuoka S. Leyva F. Anker SD. Anker S. Levy D. Poole-Wilson PA. Corra U. ` 60. Giordano A. 50. 52. Serum uric acid and cardiovascular mortality. Am J Med 1982. 23. Bologna: Cooperativa Libraria Universitaria Editrice Bologna. Uric acid and survival in chronic heart failure. Opasich C. Silva P. 22. A 12-year follow-up of participants in the Population Study of Women in Gothenburg. 55. Free Radic Biol Med 2002. 59. Life Sci 2008. Proc Natl Acad Sci USA 2004. Di Leonarda A.33:1243 – 1249. Byers T.556: 243 –251. Tunin RS. Alderman MH. Kozlov YP. Heart Muscle Disease Study Group. 38. Fillit HM. Pietersma A. ` 20. Hess ML. Maxwell SR. Hyperuricaemia in acute illness: a poor prognostic sign. Doehner W. 18. Puddu PE. Serum uric acid and coronary heart disease in 9. 4):S37–S44. Lee CI. Waldenstrom J. Validation and application in metabolic. 24. 131:7– 13. Uric acid as a risk factor for cardiovascular disease.79:1426 –1430. Roch-Ramel F. Weiss RG. Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation –contraction coupling. Guisan B.280:839 –845. Angeletti M. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Zanchetti A. 46. Parks DA. Oxidative stress and cardiac repair/remodeling following infarction. Godsland IF. Caidahl K. Ponikowski P. Cardiovasc Ther 2008. by guest on December 16. In: Caldarera CM.26:59 –64. Eur Heart J 1997. PloS Med 2005. Circulation 2003. 35. Kochiadakis GE. Chronic xanthine oxidase inhibition following myocardial infarction in rabbits: effects of early versus delayed treatment. 54. Juzwishin KD. Skalidis EI. Visioli O. Maxwell AJ. Leyva F. Ann Pharmacother 2008. Volk HD. Basic Res Cardiol 1982.72:58 –62.98:103–107.117:1196 –1202.64:61– 65. N Engl J Med 1990. Harrison RW. Li D.77:465 –485. Uric acid in cachectic and noncachectic patients with chronic heart failure: relationship to leg vascular resistance.140:338 –344. 39. 19. Roche BM. 32. Jarasch E. Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles. 58. Cassani G. Am Heart J 1989. Galli M. J Cardiovasc Pharmacol 1993. O’Brien WF.22:808 – 815. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure.85:437–445. Alderman MH. 49. Kox WJ.107:1991 –1997. Sinagra G.78:39 –43. Circulation 1996. 21. Uric acid: a new look at an old risk marker for cardiovascular disease. Advances in Studies on Heart Metabolism.18:858 – 865. 164:1546 –1551. 25. Relation of serum uric acid to mortality and ischemic heart disease. Kontos HA. Lie RT. Kalman J. 27. Stevenson JC. Bruder G. Vardas PE. Teixeira M. Harris P. Okabe E. Koster JF.79:394 –397. Kanakaraki MK.2: 126 –130. 31. J Biol Chem 2000. Bolger AP. Independent and incremental prognostic value of Doppler-derived 10. Elsayed NM.348:1530 –1531. Tyagi SC. Gudnason V. 28. Effect of oxygen free radicals on cardiovascular function at organ and cellular levels. Grund C. Anker SD. 42. Danesh J. Lanzillo JJ. 51. Cell 1981. Mezilis NE. The NHANES I Epidemiologic Follow-up Study. 47. 48. Nilsen DW. Coats AJ. Am J Cardiol 1995. Hetzer R. J Am Coll Cardiol 2001. Proton and free oxygen radical interaction with the calcium transport system of cardiac sarcoplasmatic reticulum. Pinamonti B. Ekelund UE.

Sen S. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. Circulation 2002. Freudenberger R. Hayashi K.7:291 – 294. Basal release of nitric oxide augments the Frank–Starling response in the isolated heart. by guest on December 16. 62. Cappola TP. 35:746 – 751.19:990 –1003. Brooks WW. Heart 2002. 77. Isabelle M. 65. Colucci WS. Fuchs M. How to diagnose diastolic heart failure. Coats AJ. Xanthine oxidase inhibition improves left ventricular dysfunction in dilated cardiomyopathic hamsters. Lindsay P. Quinones MA. Davies J. Morris AD. Sagach VF. Brighetti G. Brown J. Dautreaux B. Vergely-Vandriesse C. Impact of oxypurinol in patients with symptomatic heart failure. Berger RD. Drexler H.14:238 –244. Zardini P. European Study Group on Diastolic Heart Failure. Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction. J Card Fail 2008. Alexander JK. Plastino JA. Broomhall J. Mangal B. Bergamini et al. Mellin V. Nivorozhkin A. Butler R. Obata K. 66. 63. Circulation 2002.oxfordjournals. Fukata A. Downloaded from http://eurjhf. Engberding N. Cardiovasc Hematol Disord Drug Targets 2007. Monteil C. Kimata H. Doehner W. Schoene N. Eur Heart J 1998. 70. Spiekermann S. Schaefer A. ` Pacher P. J Am Coll Cardiol 1996. Rossi A. Matsushita A. Eur Heart J 2005. Mann DL. Liu P. Belch JJ. Reaveley DA. Golia G. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Struthers AD. Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure. Gaasch WH. Circulation 2006. Hashimoto K. J Am Coll Cardiol 2008.104:2407 – 2411. 61. Shah AM. C. 69. Hajjar RJ. Allopurinol improves endothelial dysfunction in chronic heart failure. Hare JM. Szabo C. Butler R. Mulder P. Koike Y. Zanolla L. Circulation 2001. 68. Carr E. Xanthine oxidase inhibitors the unappreciated treatment for heart failure. Belch JJ. Heineke A. Givertz MM. Struthers AD. Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study.110:2175 –2179. Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy. George J. Nagata K. Iwase M.87:229 –234. 2012 . Hill A. Kass DA. 74. Hilfiker-Kleiner D. Anker SD. 76. Struthers AD. Circulation 1995. Donnan PT. Mangal B.38:645 –653. MacDonald TM. 67. Pharmacol Rev 2006. Escudero EM. McNaughton D. Hornig B. Pavitt DV. Leopold JA. Belch JJ. Marban E.452 mitral deceleration time of early filling in both symptomatic and asymptomatic patients with left ventricular dysfunction. Levine HJ. Robinson KG. Kobeissi ZA. Muller M. Hypertension 2000. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebocontrolled studies. A new action for an old drug? Circulation 2004. Landmesser U. Left ventricular compliance: mechanisms and clinical implications. ` 72. Cicoira M. 64. Fisher C.114:2508 –2516. Hayes JA. Rochette L. J Card Fail 2006.96:1320 –1329.105:2619 –2624.58:87 –114. Perez NG. Brown J. Bing OH. 73. Yokota M. Leyva-Leon F.91:161 – 170. Am Heart J 2002.28:383 –390. Oudot A. Am J Cardiol 1976.51:2301 –2309. Ellestad MH. Thuillez C. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy.26:1544 –1550. Prendergast BD. Hare JM. Conrad CH. Circulation 1997. Di Meglio B. Noda A. 75. Rosas GO. Hambrecht R. Xanthine oxidase inhibition and heart failure: novel therapeutic strategy for ventricular dysfunction? Circ Res 2006. Schuler G. Rauchhaus M. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.143:1107 –1111.12:491 –498. Zeni P. Henry JP. Schwarz RP. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Struthers A.106:221 –226. Farquharson CA. 79. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Hill A. Wiencke A. ´ 78.98:169 –171. Nelson GS. Cingolani HE. Franceschini L.

Sign up to vote on this title
UsefulNot useful