REVIEW URRENT C OPINION
Impact of anti-inflammatory therapies, xanthine oxidase inhibitors and other urate-lowering therapies on cardiovascular diseases in gout Pascal Richette a,b, Aline Frazier a,b, and Thomas Bardin a,b
Purpose of review The purpose of this study is to give an overview of recently published articles covering the impact of antiinflammatory therapies, xanthine oxidase inhibitors and other urate-lowering therapies on cardiovascular diseases in gout. Recent findings In patients with gout, long-term xanthine oxidase inhibition might reduce some cardiovascular comorbidities because of the dual effect of lowering serum uric acid levels and reducing free-radical production during uric acid formation. Among the anti-inflammatory therapies, colchicine has been shown to reduce some major cardiovascular events. Summary Epidemiological and experimental studies have shown that hyperuricaemia and gout are independent risk factors for cardiovascular diseases. The mechanisms that link high serum uric acid levels and gout with cardiovascular diseases are multifactorial, implicating low-grade systemic inflammation and xanthine oxidase activity as well as the deleterious effect of hyperuricaemia itself. Keywords cardio vascular diseases, colchicines, gout, hypertension, hyperuricaemia, xanthine oxidase
INTRODUCTION Gout is strongly associated with several comorbidities and particularly traditional vascular risk factors. Indeed, among patients with gout, about two-thirds have hypertension, half are obese and half have diabetes [1]. Evidence from prospective and interventional studies [2–4] of various populations suggests that gout and hyperuricemia are independent risk factors for cardiovascular diseases. Hyperuricemia and gout are associated with an increased risk of myocardial infarction, peripheral artery disease and death primarily due to an increased risk of cardiovascular diseases [5]. The mechanisms linking hyperuricemia and gout with cardiovascular events are unclear but may include the oxidative stress generated by xanthine oxidase [6], the enzyme that catalyzes the formation of urate [7]. Other explanations are a direct contribution to endothelial dysfunction [8] and low-grade inflammation associated with increased urate levels and tophi [9,10]. Glut9deficient mice show impaired enterocyte uric acid transport kinetics, hyperuricaemia, spontaneous www.co-rheumatology.com
hypertension and dyslipidaemia, the latter reversed by treatment with allopurinol, a xanthine oxidase inhibitor. These data provide evidence that hyperuricaemia per se could also have deleterious metabolic consequences [11]. In addition to requiring symptomatic treatment of acute gout attacks, nearly all cases of gout require long-term urate-lowering therapy (ULT) [6]. Therefore, knowledge of the effects of both antiinflammatory therapies and ULT on the cardiovascular system is of major interest.
a
Universite´ Paris Diderot, Sorbonne Paris Cite´, UFR de Me´decine and AP-HP, Service de Rhumatologie, Poˆle appareil Locomoteur, Hoˆpital Lariboisie`re, Paris, France b
Correspondence to Pascal Richette, Fe´de´ration de Rhumatologie, Hoˆpital Lariboisie`re, 2 Rue Ambroise Pare´, 75475 Paris cedex 10, France. Tel: +33 1 49 95 62 90; fax: +33 1 49 95 86 31; e-mail: [email protected] Curr Opin Rheumatol 2015, 27:170–174 DOI:10.1097/BOR.0000000000000149 Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Impact of anti-inflammatory therapies and xanthine oxidase inhibitors on cardiovascular diseases in gout Richette et al.
KEY POINTS Hyperuricaemia and gout are independent risk factors for cardiovascular diseases. This association probably involves the direct deleterious effect of hyperuricemia, low-grade inflammation and xanthine oxidase activity. In some patients with coronary heart disease, long-term colchicine may reduce the incidence of major cardiovascular events. Lowering serum uric acid levels might decrease blood pressure in adolescents. Xanthine oxidase inhibition may improve cardiovascular comorbidities by its dual roles in lowering serum uric acid levels and scavenging free radicals during uric acid formation.
CARDIOVASCULAR IMPACT OF ANTIINFLAMMATORY THERAPIES FOR GOUT Low-grade inflammation has a major role in coronary heart disease, and elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with an increased cardiovascular risk [12]. Monosodium urate (MSU) crystals can activate the NACHT, LRR and PYD domains-containing protein 3 inflammasome, which leads to the production of high levels of interleukin (IL)-1b and IL-18 [13], characterizing acute attacks of gout. Asymptomatic hyperuricaemia might also induce a pro-inflammatory state associated with an increase in several inflammatory markers, such as white blood cell count and levels of CRP, IL-6, IL-1, IL-18 and tumour necrosis factor [14,15]. For instance, uric acid can regulate critical inflammatory pathways in vascular smooth muscle cells (VSMCs) by activating nuclear factor kappa B and mitogen-activated protein kinase pathways [16]. In addition, serum uric acid (SUA) has direct immunomodulating effects [17] independently of the formation of MSU crystals. SUA may be directly involved in the inflammatory cascade associated with atherosclerosis and, consequently, cardiovascular disease [15]. Whether targeting inflammation might have a cardiovascular benefit in gout is unclear. However, recent studies have suggested that among the available therapeutic options for treatment or prevention of flares, colchicine might have a potential to reduce major cardiovascular events.
Colchicine Colchicine destabilizes microtubules and thereby disrupts inflammasome activation. Therefore, it
limits both the initiation and amplification of joint inflammation by modulating cytokine production and by inhibiting neutrophil and endothelial-cell adhesion-molecule activity [7,18]. We have indirect support for a beneficial effect of colchicine on cardiovascular diseases from retrospective observations of an association of continuous use of colchicine and a lower-than-expected risk of myocardial infarction in patients with familial Mediterranean fever [19] and gout [20]. Also, low-dose colchicine can reduce levels of high-sensitivity CRP in patients with stable coronary disease [21] or heart failure [22]. A randomized trial found that colchicine, 0.5 mg/day, for 3 years appeared effective in preventing cardiovascular events in patients with stable coronary disease [23 ]. These results suggest that long-term colchicine may have a role in preventing cardiovascular events caused by instability of native atherosclerotic plaque, a condition often encountered with gout. Another trial found that low-dose colchicine is associated with less neointimal hyperplasia and a decrease in in-stent restenosis rate when administered to diabetic patients [24 ]. In addition, a recent prospective randomized study [25] found that perioperative use of colchicine reduced the incidence of postpericardiotomy syndrome in patients undergoing cardiac surgery, although it had no clinical benefit in patients with heart failure [22]. &&
&
NSAIDs, corticosteroids and interleukin-1 blockers NSAIDs given for several weeks can cause serious cardiovascular events. A recent meta-analysis found that the vascular risks of high-dose diclofenac, and possibly ibuprofen, were comparable with that with inhibitors of Cyclo-oxygenase 2, whereas high-dose naproxen was associated with less vascular risk than other NSAIDs [26 ]. The impact of a short course of NSAIDs (i.e. 3–5 days) on the heart is less known. A recent systematic review of NSAIDs for acute gout did not report any significant cardiovascular side effects [27]. In addition, a short course of oral corticosteroids to treat flares did not seem to have any cardiovascular side effects according to two randomized trials [28–30]. However, given their mineralocorticoid activity, prednisolone and prednisone may be contraindicated in patients with uncontrolled hypertension or uncompensated heart failure. Some, but not all, IL-1 inhibitors, known to be effective for auto-inflammatory diseases, have demonstrated efficacy in both treating and preventing acute gout flares [31]. No particular cardiovascular safety issues have been reported with this class of
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Crystal deposition diseases
drug [32]. Because IL-1 is also involved in heart failure, several phase II trials with IL-1 blockers are under way to assess its potential for heart failure and myocardial infarction [33].
CARDIOVASCULAR BENEFIT OF XANTHINE OXIDASE INHIBITORS SUA levels can be reduced with drugs that inhibit uric acid production (such as the xanthine oxidase inhibitors allopurinol and febuxostat); uricosuric agents (including lesinurad, benzbromarone and probenecid), which increase excretion of uric acid; or other drugs with urate-lowering effects (such as atorvastatin or the angiotensin receptor blocker losartan) [7,34]. Interestingly, data from epidemiological and interventional studies have suggested that lowering SUA levels below its saturation point not only cures gout but might also translate into cardiovascular benefits.
Role of xanthine oxidase and urate in vascular oxidative stress Intracellular uric acid could induce oxidative stress by activating nicotinamide adenine dinucleotide phosphate oxidase [35]. In blood vessels, uric acid decreases nitric oxide production while increasing the production of reactive oxygen species (ROS), vascular inflammation and proliferation of VSMCs with inhibition of endothelial-cell growth [3,36,37].
Inhibition of xanthine oxidase The inhibition of xanthine oxidase per se might have an additional benefit in cardiovascular diseases by
NAD+
reducing ROS production, known to cause cellular damage and tissue injury, particularly in the myocardium and endothelial cells [36]. The enzyme xanthine oxidoreductase exists in two interconvertible forms: a dehydrogenase (XDH, the constitutive reduced form), which preferably utilizes NADþ as an electron acceptor, and an oxidase (xanthine oxidase, the oxidized form represented in oxidative stress conditions), which uses oxygen as the terminal electron acceptor, thus producing ROS (Fig. 1). XOR is present mainly in the liver and also in blood vessels. The vascular endothelium also contains XDH [38]. Xanthine oxidoreductase acts as a ‘housekeeping’ enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid. Importantly, during this conversion, xanthine oxidase generates two superoxide anions. The superoxide anions then form hydrogen peroxide and hydroxyl radicals by interacting with hydrogen ions. The newly created free radicals also interact with nitric oxide to form the oxidant peroxynitrite, which generates more free radicals [38]. Thus, increased xanthine oxidase activity, by leading to ROS formation, might cause cellular damage and tissue injury, in particular in the myocardium and endothelial cells. Oxypurinol, the metabolite of the purine analogue allopurinol, inhibits only the reduced form of xanthine oxidoreductase, whereas the nonpurine xanthine oxidase inhibitor febuxostat is able to inhibit both isoforms (xanthine oxidase and XDH), resulting in a more effective blockade of ROS production [39,40]. It has been recently shown that febuxostat suppressed atherosclerotic plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(–/–) mice without affecting plasma cholesterol levels [37].
NADH
NAD+
XDH ATP
Hypoxanthine
XDH Xanthine
XO O2
NADH
URIC ACID
XO O2
H2O2
•
O2
O2 •
H2O2
FIGURE 1. Xanthine oxidoreductase exists in two interconvertible forms: XDH, the constitutive form of the enzyme and XO, the oxidized form of the enzyme that utilizes oxygen as the terminal electron acceptor. 172
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Impact of anti-inflammatory therapies and xanthine oxidase inhibitors on cardiovascular diseases in gout Richette et al.
Cardiovascular impact of xanthine oxidase inhibition Treatment with xanthine oxidase inhibitors improved endothelial dysfunction and oxidative stress in patients with stable coronary artery disease [41,42], exercise capacity in patients with chronic stable angina [43] and morbidity and mortality in patients with congestive heart failure and a history of gout [35]. In an observational study [44], allopurinol prescription was associated with an approximately 30% reduction in risk of readmission for heart failure or death in patients with a history of gout. More recently, a pharmaco-epidemiological study [45 ] found allopurinol use associated with a 20% reduction in risk of myocardial infarction. Therefore, apart from its urate-lowering properties, allopurinol might have a cardioprotective effect. Whether these beneficial effects resulted from reduced free radicals production, inhibition of xanthine oxidase or lowering of SUA level is uncertain. Posthoc analyses of clinical trials suggest that reduced cardiovascular risk associated with atorvastatin or losartan use is attributable, in part, to their urate-lowering properties [46,47]. Conversely, two randomized trials showed that the uricosuric agents probenecid and benzbromarone had no effect on endothelial function and haemodynamic impairment, respectively [48,49]. Thus, the improved endothelial function with xanthine oxidase inhibition might rely more on reduced oxidative stress (by reducing free radicals production) than lowering SUA levels [50]. Therefore, highly effective and well tolerated xanthine oxidase inhibiting compounds may be beneficial. &
Urate, xanthine oxidase inhibitors and hypertension ULTs seem to have a beneficial effect on blood pressure, in particular in adolescents [51,52 ]. Several animal model experiments showed that increased urate levels led to hypertension and vascular injury. In these experiments, uric acid causes hypertension by a two-step process. Initially, uric acid uptake into vascular endothelial cells causes acute activation of the renin angiotensin system and decreased vascular nitric oxide production, which result in vasoconstriction and increased blood pressure. At this stage, if hyperuricaemia resolves or if treated, vascular tone and blood pressure return to normal. However, longstanding hyperuricaemia induces vascular smooth proliferation and reduced vascular compliance that result in sodium-sensitive hypertension that is irreversible [53]. One trial of adolescents with hyperuricaemia and newly diagnosed hypertension demonstrated &&
that treatment with allopurinol (400 mg per day) normalized blood pressure in 66% of patients [3]. In another placebo-controlled study [54] of adolescents with obesity and prehypertension, allopurinol (400 mg per day) or probenecid (1 g per day) markedly reduced ambulatory SBP and DBP, which suggests that the blood pressure lowering resulted from SUA reduction.
CONCLUSION High SUA levels and gout seem to be independent risk factors for the development of cardiovascular diseases. The mechanisms that link elevated SUA levels, gout and these comorbidities are presumably multifactorial, implicating low-grade inflammation, xanthine oxidase activity and the deleterious impact of hyperuricemia itself. In patients with gout, long-term pharmacological xanthine oxidase inhibition might ameliorate cardiovascular comorbidities because of the dual effects of lowering SUA and scavenging free radicals during uric acid formation. In the same way, colchicine might have a cardiovascular benefit, particularly in patients with coronary heart disease. Large randomized trials are warranted to demonstrate that a long-term decrease in SUA level improves cardiovascular outcomes and to determine whether xanthine oxidase inhibition is a better approach than use of uricosuric agents. Acknowledgements We thank Laura Smales for editing this manuscript. Financial support and sponsorship This work was funded by the Association Rhumatisme et Travail (Department of Rheumatology, Lariboisie`re Hospital, Paris, France). Conflicts of interest P.R. has received consultancy and/or speaker fees from Me´narini, Ipsen, Savient, Novartis and Astra Zeneca. T.B. has received consultancy and/or speaker fees from Ardea Biosciences, Biocryst, Ipsen, Menarini, Novartis and Savient. A.F. declared no conflict of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med 2011; 125:679– 687; e1. 2. Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Ther 2010; 12:223. 3. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359:1811–1821. 4. Kanbay M, Segal M, Afsar B, et al. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013; 99:759–766.
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29. Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev 2008; CD005521. 30. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007; 49:670–677. 31. Latourte A, Bardin T, Richette P. Prophylaxis for acute gout flares after initiation of urate-lowering therapy. Rheumatology (Oxford) 2014; 53:1920–1926. 32. Tran TH, Pham JT, Shafeeq H, et al. Role of interleukin-1 inhibitors in the management of gout. Pharmacotherapy 2013; 33:744–753. 33. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11:633–652. 34. Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol 2010; 6:30–38. 35. Kelkar A, Kuo A, Frishman WH. Allopurinol as a cardiovascular drug. Cardiol Rev 2011; 19:265–271. 36. Neogi T, George J, Rekhraj S, et al. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum 2012; 64:327–338. 37. Nomura J, Busso N, Ives A, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep 2014; 4:4554. 38. Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58:87–114. 39. Love BL, Barrons R, Veverka A, Snider KM. Urate-lowering therapy for gout: focus on febuxostat. Pharmacotherapy 2010; 30:594–608. 40. Malik UZ, Hundley NJ, Romero G, et al. Febuxostat inhibition of endothelialbound XO: implications for targeting vascular ROS production. Free Radic Biol Med 2011; 51:179–184. 41. Higgins P, Dawson J, Lees KR, et al. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther 2012; 30:217–226. 42. Rajendra NS, Ireland S, George J, et al. Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris. J Am Coll Cardiol 2011; 58:820–828. 43. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010; 375:2161–2167. 44. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010; 170:1358–1364. 45. Grimaldi-Bensouda L, Alperovitch A, Aubrun E, et al. Impact of allopurinol on & risk of myocardial infarction. Ann Rheum Dis 2014. [Epub ahead of print] This is a pharmaco-epidemiological study suggesting that allopurinol could decrease the risk of myocardial infarction. 46. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronaryheart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004; 43:589– 599. 47. Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65:1041– 1049. 48. George J, Carr E, Davies J, et al. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006; 114:2508–2516. 49. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010; 3:73–81. 50. Harzand A, Tamariz L, Hare JM. Uric Acid, heart failure survival, and the impact of xanthine oxidase inhibition. Congest Heart Fail 2012; 18:179– 182. 51. Gois PH, Souza ER. Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev 2012; 1:CD008652. 52. Agarwal V, Hans N, Messerli FH. Effect of allopurinol on blood pressure: a && systematic review and meta-analysis. J Clin Hypertens (Greenwich) 2013; 15:435–442. A comprehensive review on the link between urate and hypertension. 53. Feig DI. Serum uric acid and the risk of hypertension and chronic kidney disease. Curr Opin Rheumatol 2014; 26:176–185. 54. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 2012; 60:1148–1156.
Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Impact of anti-inflammatory therapies, xanthine oxidase inhibitors and other urate-lowering therapies on cardiovascular diseases in gout Pascal Richette a,b, Aline Frazier a,b, and Thomas Bardin a,b
Purpose of review The purpose of this study is to give an overview of recently published articles covering the impact of antiinflammatory therapies, xanthine oxidase inhibitors and other urate-lowering therapies on cardiovascular diseases in gout. Recent findings In patients with gout, long-term xanthine oxidase inhibition might reduce some cardiovascular comorbidities because of the dual effect of lowering serum uric acid levels and reducing free-radical production during uric acid formation. Among the anti-inflammatory therapies, colchicine has been shown to reduce some major cardiovascular events. Summary Epidemiological and experimental studies have shown that hyperuricaemia and gout are independent risk factors for cardiovascular diseases. The mechanisms that link high serum uric acid levels and gout with cardiovascular diseases are multifactorial, implicating low-grade systemic inflammation and xanthine oxidase activity as well as the deleterious effect of hyperuricaemia itself. Keywords cardio vascular diseases, colchicines, gout, hypertension, hyperuricaemia, xanthine oxidase
INTRODUCTION Gout is strongly associated with several comorbidities and particularly traditional vascular risk factors. Indeed, among patients with gout, about two-thirds have hypertension, half are obese and half have diabetes [1]. Evidence from prospective and interventional studies [2–4] of various populations suggests that gout and hyperuricemia are independent risk factors for cardiovascular diseases. Hyperuricemia and gout are associated with an increased risk of myocardial infarction, peripheral artery disease and death primarily due to an increased risk of cardiovascular diseases [5]. The mechanisms linking hyperuricemia and gout with cardiovascular events are unclear but may include the oxidative stress generated by xanthine oxidase [6], the enzyme that catalyzes the formation of urate [7]. Other explanations are a direct contribution to endothelial dysfunction [8] and low-grade inflammation associated with increased urate levels and tophi [9,10]. Glut9deficient mice show impaired enterocyte uric acid transport kinetics, hyperuricaemia, spontaneous www.co-rheumatology.com
hypertension and dyslipidaemia, the latter reversed by treatment with allopurinol, a xanthine oxidase inhibitor. These data provide evidence that hyperuricaemia per se could also have deleterious metabolic consequences [11]. In addition to requiring symptomatic treatment of acute gout attacks, nearly all cases of gout require long-term urate-lowering therapy (ULT) [6]. Therefore, knowledge of the effects of both antiinflammatory therapies and ULT on the cardiovascular system is of major interest.
a
Universite´ Paris Diderot, Sorbonne Paris Cite´, UFR de Me´decine and AP-HP, Service de Rhumatologie, Poˆle appareil Locomoteur, Hoˆpital Lariboisie`re, Paris, France b
Correspondence to Pascal Richette, Fe´de´ration de Rhumatologie, Hoˆpital Lariboisie`re, 2 Rue Ambroise Pare´, 75475 Paris cedex 10, France. Tel: +33 1 49 95 62 90; fax: +33 1 49 95 86 31; e-mail: [email protected] Curr Opin Rheumatol 2015, 27:170–174 DOI:10.1097/BOR.0000000000000149 Volume 27 Number 2 March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Impact of anti-inflammatory therapies and xanthine oxidase inhibitors on cardiovascular diseases in gout Richette et al.
KEY POINTS Hyperuricaemia and gout are independent risk factors for cardiovascular diseases. This association probably involves the direct deleterious effect of hyperuricemia, low-grade inflammation and xanthine oxidase activity. In some patients with coronary heart disease, long-term colchicine may reduce the incidence of major cardiovascular events. Lowering serum uric acid levels might decrease blood pressure in adolescents. Xanthine oxidase inhibition may improve cardiovascular comorbidities by its dual roles in lowering serum uric acid levels and scavenging free radicals during uric acid formation.
CARDIOVASCULAR IMPACT OF ANTIINFLAMMATORY THERAPIES FOR GOUT Low-grade inflammation has a major role in coronary heart disease, and elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with an increased cardiovascular risk [12]. Monosodium urate (MSU) crystals can activate the NACHT, LRR and PYD domains-containing protein 3 inflammasome, which leads to the production of high levels of interleukin (IL)-1b and IL-18 [13], characterizing acute attacks of gout. Asymptomatic hyperuricaemia might also induce a pro-inflammatory state associated with an increase in several inflammatory markers, such as white blood cell count and levels of CRP, IL-6, IL-1, IL-18 and tumour necrosis factor [14,15]. For instance, uric acid can regulate critical inflammatory pathways in vascular smooth muscle cells (VSMCs) by activating nuclear factor kappa B and mitogen-activated protein kinase pathways [16]. In addition, serum uric acid (SUA) has direct immunomodulating effects [17] independently of the formation of MSU crystals. SUA may be directly involved in the inflammatory cascade associated with atherosclerosis and, consequently, cardiovascular disease [15]. Whether targeting inflammation might have a cardiovascular benefit in gout is unclear. However, recent studies have suggested that among the available therapeutic options for treatment or prevention of flares, colchicine might have a potential to reduce major cardiovascular events.
Colchicine Colchicine destabilizes microtubules and thereby disrupts inflammasome activation. Therefore, it
limits both the initiation and amplification of joint inflammation by modulating cytokine production and by inhibiting neutrophil and endothelial-cell adhesion-molecule activity [7,18]. We have indirect support for a beneficial effect of colchicine on cardiovascular diseases from retrospective observations of an association of continuous use of colchicine and a lower-than-expected risk of myocardial infarction in patients with familial Mediterranean fever [19] and gout [20]. Also, low-dose colchicine can reduce levels of high-sensitivity CRP in patients with stable coronary disease [21] or heart failure [22]. A randomized trial found that colchicine, 0.5 mg/day, for 3 years appeared effective in preventing cardiovascular events in patients with stable coronary disease [23 ]. These results suggest that long-term colchicine may have a role in preventing cardiovascular events caused by instability of native atherosclerotic plaque, a condition often encountered with gout. Another trial found that low-dose colchicine is associated with less neointimal hyperplasia and a decrease in in-stent restenosis rate when administered to diabetic patients [24 ]. In addition, a recent prospective randomized study [25] found that perioperative use of colchicine reduced the incidence of postpericardiotomy syndrome in patients undergoing cardiac surgery, although it had no clinical benefit in patients with heart failure [22]. &&
&
NSAIDs, corticosteroids and interleukin-1 blockers NSAIDs given for several weeks can cause serious cardiovascular events. A recent meta-analysis found that the vascular risks of high-dose diclofenac, and possibly ibuprofen, were comparable with that with inhibitors of Cyclo-oxygenase 2, whereas high-dose naproxen was associated with less vascular risk than other NSAIDs [26 ]. The impact of a short course of NSAIDs (i.e. 3–5 days) on the heart is less known. A recent systematic review of NSAIDs for acute gout did not report any significant cardiovascular side effects [27]. In addition, a short course of oral corticosteroids to treat flares did not seem to have any cardiovascular side effects according to two randomized trials [28–30]. However, given their mineralocorticoid activity, prednisolone and prednisone may be contraindicated in patients with uncontrolled hypertension or uncompensated heart failure. Some, but not all, IL-1 inhibitors, known to be effective for auto-inflammatory diseases, have demonstrated efficacy in both treating and preventing acute gout flares [31]. No particular cardiovascular safety issues have been reported with this class of
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Crystal deposition diseases
drug [32]. Because IL-1 is also involved in heart failure, several phase II trials with IL-1 blockers are under way to assess its potential for heart failure and myocardial infarction [33].
CARDIOVASCULAR BENEFIT OF XANTHINE OXIDASE INHIBITORS SUA levels can be reduced with drugs that inhibit uric acid production (such as the xanthine oxidase inhibitors allopurinol and febuxostat); uricosuric agents (including lesinurad, benzbromarone and probenecid), which increase excretion of uric acid; or other drugs with urate-lowering effects (such as atorvastatin or the angiotensin receptor blocker losartan) [7,34]. Interestingly, data from epidemiological and interventional studies have suggested that lowering SUA levels below its saturation point not only cures gout but might also translate into cardiovascular benefits.
Role of xanthine oxidase and urate in vascular oxidative stress Intracellular uric acid could induce oxidative stress by activating nicotinamide adenine dinucleotide phosphate oxidase [35]. In blood vessels, uric acid decreases nitric oxide production while increasing the production of reactive oxygen species (ROS), vascular inflammation and proliferation of VSMCs with inhibition of endothelial-cell growth [3,36,37].
Inhibition of xanthine oxidase The inhibition of xanthine oxidase per se might have an additional benefit in cardiovascular diseases by
NAD+
reducing ROS production, known to cause cellular damage and tissue injury, particularly in the myocardium and endothelial cells [36]. The enzyme xanthine oxidoreductase exists in two interconvertible forms: a dehydrogenase (XDH, the constitutive reduced form), which preferably utilizes NADþ as an electron acceptor, and an oxidase (xanthine oxidase, the oxidized form represented in oxidative stress conditions), which uses oxygen as the terminal electron acceptor, thus producing ROS (Fig. 1). XOR is present mainly in the liver and also in blood vessels. The vascular endothelium also contains XDH [38]. Xanthine oxidoreductase acts as a ‘housekeeping’ enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid. Importantly, during this conversion, xanthine oxidase generates two superoxide anions. The superoxide anions then form hydrogen peroxide and hydroxyl radicals by interacting with hydrogen ions. The newly created free radicals also interact with nitric oxide to form the oxidant peroxynitrite, which generates more free radicals [38]. Thus, increased xanthine oxidase activity, by leading to ROS formation, might cause cellular damage and tissue injury, in particular in the myocardium and endothelial cells. Oxypurinol, the metabolite of the purine analogue allopurinol, inhibits only the reduced form of xanthine oxidoreductase, whereas the nonpurine xanthine oxidase inhibitor febuxostat is able to inhibit both isoforms (xanthine oxidase and XDH), resulting in a more effective blockade of ROS production [39,40]. It has been recently shown that febuxostat suppressed atherosclerotic plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE(–/–) mice without affecting plasma cholesterol levels [37].
NADH
NAD+
XDH ATP
Hypoxanthine
XDH Xanthine
XO O2
NADH
URIC ACID
XO O2
H2O2
•
O2
O2 •
H2O2
FIGURE 1. Xanthine oxidoreductase exists in two interconvertible forms: XDH, the constitutive form of the enzyme and XO, the oxidized form of the enzyme that utilizes oxygen as the terminal electron acceptor. 172
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Impact of anti-inflammatory therapies and xanthine oxidase inhibitors on cardiovascular diseases in gout Richette et al.
Cardiovascular impact of xanthine oxidase inhibition Treatment with xanthine oxidase inhibitors improved endothelial dysfunction and oxidative stress in patients with stable coronary artery disease [41,42], exercise capacity in patients with chronic stable angina [43] and morbidity and mortality in patients with congestive heart failure and a history of gout [35]. In an observational study [44], allopurinol prescription was associated with an approximately 30% reduction in risk of readmission for heart failure or death in patients with a history of gout. More recently, a pharmaco-epidemiological study [45 ] found allopurinol use associated with a 20% reduction in risk of myocardial infarction. Therefore, apart from its urate-lowering properties, allopurinol might have a cardioprotective effect. Whether these beneficial effects resulted from reduced free radicals production, inhibition of xanthine oxidase or lowering of SUA level is uncertain. Posthoc analyses of clinical trials suggest that reduced cardiovascular risk associated with atorvastatin or losartan use is attributable, in part, to their urate-lowering properties [46,47]. Conversely, two randomized trials showed that the uricosuric agents probenecid and benzbromarone had no effect on endothelial function and haemodynamic impairment, respectively [48,49]. Thus, the improved endothelial function with xanthine oxidase inhibition might rely more on reduced oxidative stress (by reducing free radicals production) than lowering SUA levels [50]. Therefore, highly effective and well tolerated xanthine oxidase inhibiting compounds may be beneficial. &
Urate, xanthine oxidase inhibitors and hypertension ULTs seem to have a beneficial effect on blood pressure, in particular in adolescents [51,52 ]. Several animal model experiments showed that increased urate levels led to hypertension and vascular injury. In these experiments, uric acid causes hypertension by a two-step process. Initially, uric acid uptake into vascular endothelial cells causes acute activation of the renin angiotensin system and decreased vascular nitric oxide production, which result in vasoconstriction and increased blood pressure. At this stage, if hyperuricaemia resolves or if treated, vascular tone and blood pressure return to normal. However, longstanding hyperuricaemia induces vascular smooth proliferation and reduced vascular compliance that result in sodium-sensitive hypertension that is irreversible [53]. One trial of adolescents with hyperuricaemia and newly diagnosed hypertension demonstrated &&
that treatment with allopurinol (400 mg per day) normalized blood pressure in 66% of patients [3]. In another placebo-controlled study [54] of adolescents with obesity and prehypertension, allopurinol (400 mg per day) or probenecid (1 g per day) markedly reduced ambulatory SBP and DBP, which suggests that the blood pressure lowering resulted from SUA reduction.
CONCLUSION High SUA levels and gout seem to be independent risk factors for the development of cardiovascular diseases. The mechanisms that link elevated SUA levels, gout and these comorbidities are presumably multifactorial, implicating low-grade inflammation, xanthine oxidase activity and the deleterious impact of hyperuricemia itself. In patients with gout, long-term pharmacological xanthine oxidase inhibition might ameliorate cardiovascular comorbidities because of the dual effects of lowering SUA and scavenging free radicals during uric acid formation. In the same way, colchicine might have a cardiovascular benefit, particularly in patients with coronary heart disease. Large randomized trials are warranted to demonstrate that a long-term decrease in SUA level improves cardiovascular outcomes and to determine whether xanthine oxidase inhibition is a better approach than use of uricosuric agents. Acknowledgements We thank Laura Smales for editing this manuscript. Financial support and sponsorship This work was funded by the Association Rhumatisme et Travail (Department of Rheumatology, Lariboisie`re Hospital, Paris, France). Conflicts of interest P.R. has received consultancy and/or speaker fees from Me´narini, Ipsen, Savient, Novartis and Astra Zeneca. T.B. has received consultancy and/or speaker fees from Ardea Biosciences, Biocryst, Ipsen, Menarini, Novartis and Savient. A.F. declared no conflict of interest.
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29. Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev 2008; CD005521. 30. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007; 49:670–677. 31. Latourte A, Bardin T, Richette P. Prophylaxis for acute gout flares after initiation of urate-lowering therapy. Rheumatology (Oxford) 2014; 53:1920–1926. 32. Tran TH, Pham JT, Shafeeq H, et al. Role of interleukin-1 inhibitors in the management of gout. Pharmacotherapy 2013; 33:744–753. 33. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11:633–652. 34. Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol 2010; 6:30–38. 35. Kelkar A, Kuo A, Frishman WH. Allopurinol as a cardiovascular drug. Cardiol Rev 2011; 19:265–271. 36. Neogi T, George J, Rekhraj S, et al. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum 2012; 64:327–338. 37. Nomura J, Busso N, Ives A, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep 2014; 4:4554. 38. Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58:87–114. 39. Love BL, Barrons R, Veverka A, Snider KM. Urate-lowering therapy for gout: focus on febuxostat. Pharmacotherapy 2010; 30:594–608. 40. Malik UZ, Hundley NJ, Romero G, et al. Febuxostat inhibition of endothelialbound XO: implications for targeting vascular ROS production. Free Radic Biol Med 2011; 51:179–184. 41. Higgins P, Dawson J, Lees KR, et al. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther 2012; 30:217–226. 42. Rajendra NS, Ireland S, George J, et al. Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris. J Am Coll Cardiol 2011; 58:820–828. 43. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet 2010; 375:2161–2167. 44. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010; 170:1358–1364. 45. Grimaldi-Bensouda L, Alperovitch A, Aubrun E, et al. Impact of allopurinol on & risk of myocardial infarction. Ann Rheum Dis 2014. [Epub ahead of print] This is a pharmaco-epidemiological study suggesting that allopurinol could decrease the risk of myocardial infarction. 46. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronaryheart-disease Evaluation (GREACE) study. Am J Kidney Dis 2004; 43:589– 599. 47. Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65:1041– 1049. 48. George J, Carr E, Davies J, et al. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006; 114:2508–2516. 49. Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010; 3:73–81. 50. Harzand A, Tamariz L, Hare JM. Uric Acid, heart failure survival, and the impact of xanthine oxidase inhibition. Congest Heart Fail 2012; 18:179– 182. 51. Gois PH, Souza ER. Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev 2012; 1:CD008652. 52. Agarwal V, Hans N, Messerli FH. Effect of allopurinol on blood pressure: a && systematic review and meta-analysis. J Clin Hypertens (Greenwich) 2013; 15:435–442. A comprehensive review on the link between urate and hypertension. 53. Feig DI. Serum uric acid and the risk of hypertension and chronic kidney disease. Curr Opin Rheumatol 2014; 26:176–185. 54. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension 2012; 60:1148–1156.
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