Editorial
Allopurinol and risk of myocardial infarction Pascal Richette1,2 Gout is a common arthritis caused by deposition of monosodium urate (MSU) crystals in joints after long-standing hyperuricaemia. Patients with gout often have comorbidities such as cardiovascular (CV) disease, renal failure and metabolic syndrome components. About two-thirds have hypertension, half are obese and half have diabetes. Prospective and interventional studies have demonstrated that hyperuricaemia and gout are associated with increased risk of myocardial infarction (MI) and death primarily because of increased risk of CV events.1 Thus, knowledge of the effects of allopurinol, the most frequently used urate-lowering therapy, on risk of MI is of prime importance. In this context, the report from de Abajo and colleagues2 is of interest: this population-based case-control study found that allopurinol was associated with significantly reduced risk of non-fatal acute MI (OR=0.52 (95% CI 0.33 to 0.83)), mainly in men, with >180 days’ allopurinol exposure and with >300 mg dose. These exciting findings raise several issues: how does allopurinol decrease the risk of MI? Is it through xanthine oxidase (XO) inhibition and/or through a decrease in urate levels?
HYPERURICAEMIA, GOUT AND CV EVENTS The mechanisms linking hyperuricaemia and gout with CV events are not yet completely revealed but may include oxidative stress generated by XO, the enzyme that catalyses the formation of urate (figure 1). Other mechanisms are a direct contribution to endothelial dysfunction and low-grade inflammation associated with increased urate levels and tophi. In cells, uric acid could generate oxidative stress by activating nicotinamide adenine dinucleotide phosphate oxidase. By inhibiting endothelial cell growth in blood vessels, uric acid decreases the production of nitric oxide and increases
reactive oxygen species (ROS) production, vascular inflammation and vascular smooth muscle cell proliferation.3 When the uric acid levels exceed its saturation point, that is, about 400 mM, it can precipitate and form MSU crystals. Under some circumstances, these crystals can activate in monocytes the NLRP3 inflammasome, a protein complex that produces the active forms of interleukin (IL) 1β, which causes the characteristic inflammation encountered in acute gout. Asymptomatic hyperuricaemia can also induce a low grade inflammatory state, with increased levels of some proinflammatory proteins such as IL-6, C-reactive protein level and tumour necrosis factor.1 In vascular smooth muscle cells, uric acid can regulate major signalling pathways such as the NFκB and mitogenactivated protein kinase pathways. Finally, uric acid is considered as a danger signal that may activate the innate immune system to cell injury apart from the presence of MSU crystals. It may be directly involved in different inflammatory processes associated with atherosclerosis and, therefore, CV disease.1
URATE-LOWERING THERAPIES We can reduce SUA levels with drugs that decrease uric acid synthesis (eg, XO inhibitors allopurinol and febuxostat); uricosurics (eg, benzbromarone, probenecid and lesinurad), which decrease the renal reabsorption of uric acid; or molecules with urate-lowering properties such as atorvastatin or the angiotensin receptor blocker losartan.
Inhibition of XO The inhibition of XO per se might benefit CV diseases by reducing ROS production, known to cause cellular damage in endothelial cells and tissue injury, particularly in the myocardium.3 The enzyme xanthine oxidoreductase (XOR) is present in two distinct and interconvertible forms. The first is xanthine dehydrogenase (the constitutive reduced form), preferably using NAD+ as an electron acceptor; the second is an oxidase (XO, the oxidised form found in oxidative stress conditions), using oxygen as the terminal electron acceptor, thereby increasing ROS production (figure 1). XOR is expressed mainly in the liver and in blood vessels. The vascular endothelium also contains xanthine dehydrogenase. XOR catalyses the conversion of hypoxanthine to xanthine and xanthine to uric acid and is considered as a housekeeping enzyme. During this enzymatic step, XO generates two superoxide anions, which then form H2O2 and hydroxyl radicals by interacting with hydrogen ions. In addition, the newly created free radicals interact with nitric oxide to form the oxidant peroxynitrite, which generates more free radicals. Thus, an increase in XO activity, by increasing ROS production, might cause cell and tissue damage, for instance in the vessels and the myocardium.
CV impact of XO inhibition in humans Several studies have suggested that lowering SUA levels below the saturation point may cure gout and also have CV benefits. Randomised trials found that XO inhibitors improved endothelial dysfunction and decreased the oxidative stress in patients with stable coronary artery disease.4 In addition, large epidemiological studies found that allopurinol decreased morbidity and mortality rates in patients with congestive heart failure and a history of
1
Université Paris 7, UFR médicale, Assistance PubliqueHôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, Paris, Cedex 10, France; 2INSERM UMR1132, Hôpital Lariboisière, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France Correspondance to Professor Pascal Richette, Fédération de Rhumatologie, Hôpital Lariboisière, 2 Rue Ambroise Paré, Paris 75475, Cedex 10, France;
[email protected]
Figure 1 Xanthine oxidoreductase exists in two interconvertible forms: xanthine dehydrogenase (XDH), the constitutive form and xanthine oxidase (XO), the oxidised form, which uses oxygen as the terminal electron acceptor. NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide -hydrogen. Richette P. Heart May 2015 Vol 101 No 9
659
Editorial gout.4 Likewise, in an observational study, allopurinol was associated with approximately 30% reduced risk of readmission for heart failure or death in patients with a history of gout.5 Moreover, two landmark randomised trials also found that high-dose allopurinol (600 mg/day) regressed LV mass in patients with ischaemic heart disease6 and enhanced exercise capacity in patients with chronic stable angina.7 Finally, a recently published pharmacoepidemiological study found results close to those reported by de Abajo and colleagues,2 with allopurinol use associated with 20% reduced risk of MI.8 Therefore, in addition to its uratelowering properties, allopurinol likely has cardioprotective properties. Whether these beneficial effects are from reduced free radical production, inhibiting XO activity or lowering SUA level remains unclear. Interestingly, post hoc analyses of pivotal trials suggested that the uratelowering properties of atorvastatin or losartan were responsible in part for reduced CV risk. Conversely, two randomised trials showed that probenecid and benzbromarone, two uricosurics, had no effect on endothelial function and haemodynamic impairment, respectively.1 Thus, improved endothelial function with XO inhibitors might rely more on reduced oxidative stress (by reducing free radicals production) than on reduced SUA levels.
660
CONCLUSIONS
REFERENCES
Gout and long-lasting, high SUA levels are independent risk factors of the development of coronary heart disease. The mechanisms whereby gout and increased SUA levels can lead to CV events are presumably multifactorial, implicating a lowgrade inflammatory state, XO activity and the deleterious impact of hyperuricaemia itself. According to de Abajo and colleagues,2 long-term pharmacological XO inhibition might decrease the risk of MI, presumably through a dual effect of lowering SUA and scavenging free radicals during uric acid formation.
1
Competing interests PR received fees from Ménarini, Ipsen, Savient and Astra Zeneca.
6
Provenance and peer review Commissioned; internally peer reviewed.
2
3
4
5
7
8
To cite Richette P. Heart 2015;101:659–660.
Richette P, Perez-Ruiz F, Doherty M, et al. Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol 2014;10:654–61. de Abajo F, Gil M, Rodríguez A, et al. Allopurinol use and risk of nonfatal acute myocardial infarction. Heart 2015;101:679–85. 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;64:327–38. 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;30:217–26. Thanassoulis G, Brophy JM, Richard H, et al. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170:1358–64. Rekhraj S, Gandy SJ, Szwejkowski BR, et al. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol 2013;61:926–32. 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;375:2161–7. Grimaldi-Bensouda L, Alperovitch A, Aubrun E, et al. Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis 2015;74:836–42.
Published Online First 13 February 2015
▸ http://dx.doi.org/10.1136/heartjnl-2014-306670 Heart 2015;101:659–660. doi:10.1136/heartjnl-2014-307278
Richette P. Heart May 2015 Vol 101 No 9
