Despite widespread implementation of effective preventative therapy, stroke-related morbidity and mortality remains high and cerebrovascular disease is the leading cause of disability in the adult population. Beyond these human costs, a significant financial burden is incurred for health services through both in-patient and the subsequent care of stroke patients. Novel therapeutic strategies are needed to reduce this burden. In this article we highlight the growing case for xanthine oxidase inhibition (XOI) as a potential therapeutic approach for the prevention and management of cerebrovascular disease.
Treatment options for patients with acute stroke are limited, and preventative strategies hold the greatest promise for reducing the burden of stroke. Antihypertensive, lipid lowering and anti-thrombotic therapy are effective in this regard Citation[1], but offer incomplete protection and are poorly tolerated by some patients. Accordingly, the development of novel therapeutic interventions is crucial.
The role of uric acid metabolism in the pathophysiology of cardiovascular disease has been the subject of debate for several decades. Numerous epidemiological studies have identified an association between elevated serum uric acid (UA) level and increased incidence of vascular disease, including stroke. Many have reported an independent association, indicating a potentially causal relationship Citation[2]. The predisposing effect on stroke is similar to that for ischemic heart disease. As such, hyperuricemia appears to represent an unaddressed risk factor for both cardio- and cerebro-vascular disease, as well as a target for therapeutic manipulation.
Certainly, there are plausible mechanistic explanations to explain an etiological role for hyperuricemia in relation to atherosclerotic disease. Increased levels of smooth-muscle cell proliferation, low-density lipoprotein oxidation and platelet activation have been reported in association with elevated UA, as well as a putative role in the pathogenesis of hypertension Citation[3].
An alternative hypothesis to explain the association between hyperuricemia and increased vascular risk has been proposed: vascular injury occurs in response to reactive oxygen species that are a byproduct of XO enzymatic activity during production of uric acid. Thus, hyperuricemia may simply represent a surrogate marker for high levels of damaging oxidative stress associated with increased xanthine oxidase (XO) activity, rather than being directly responsible for vascular injury and the subsequent increase in risk.
Uric acid reduction may be achieved through several therapeutic approaches. However, XOI, with drugs such as allopurinol, oxypurinol and febuxostat, represents a therapeutic approach with a potentially dual mechanism of benefit: reduction of both vascular oxidative stress and circulating UA level. Used routinely in clinical practice for prophylaxis against gout, allopurinol is an agent with an acceptable tolerability and safety record that appears to hold potential for vascular protection.
Despite several decades of interest within the medical literature regarding the XOI hypothesis, the potential effects of treatment remained largely untested in clinical trials. However, the last decade has witnessed something of a renaissance in this area, with a series of interventional studies being conducted across a variety of vascular disease populations. Several studies have reported positive results across a range of surrogate markers of vascular health.
Most recently, promising data from a study of patients with ischemic heart disease have re-emphasized the potential applicability of XOI. Following 6 weeks of treatment with high-dose allopurinol (600 mg daily), patients with angiographically documented coronary artery disease and stable chronic angina pectoris exhibited improved exercise capacity, with prolonged time to chest pain and ST segment depression on exercise tolerance testing Citation[4]. This was in the context of robust antecedent antianginal therapy. Hemodynamic effects were not observed and proposed mechanistic explanations include reduced myocardial demand for metabolic substrate and improved endothelial function. Treatment was well tolerated in the study population and the authors concluded that the agent represents an effective antianginal agent.
This novel finding follows the recent publication of several studies that have reported improvement in endothelial dysfunction, a crucial step in atherogenesis, among patients with established vascular disease. Foremost among these, was the finding that among heart failure patients, this improvement occurred in a dose-dependent manner Citation[5]. Moreover, this appeared independent of reduction in UA level – perhaps suggesting reduction in oxidative stress as the principle mechanism of the observed benefit.
In addition, XOI appears to produce antihypertensive effects Citation[6]. Among hypertensive adolescents, 4 weeks of treatment with allopurinol was associated with a significant reduction in blood pressure.
Beyond these improvements in surrogate markers of cardiovascular function, retrospective population-based studies have indicated potential benefits in relation to mortality, with reduced all-cause mortality associated with XOI treatment among hyperuricemic patients Citation[7]. The largest prospective study to date examined a composite end point of heart failure-related morbidity and mortality in a chronic heart failure population Citation[8]. Disappointingly, no significant treatment effect was identified overall, although retrospective analysis identified a strong trend towards benefit among patients stratified as hyperuricemic.
We might anticipate that improvement in endothelial function, reduced oxidative stress levels and antihypertensive properties are treatment effects that will be beneficial in reducing progression of atherosclerotic disease processes. Although the predisposing risk of hyperuricemia appears to be similar for both stroke and ischemic heart disease, many of the initial intervention studies have been conducted primarily in cardiac disease populations. However, the focus of trial activity is now shifting to include the stroke population.
Studies in stroke survivors have produced largely positive results. Among patients with recent ischemic stroke, 6 weeks of treatment produced reduction in circulating levels of proinflammatory cytokines implicated in atherogenesis and ‘unstable plaque’ Citation[9]. Again, dose-dependent treatment effects were observed. In a separate study, 8 weeks of therapy was associated with an improvement in noninvasively determined arterial stiffness Citation[10]. Crucially, the previously observed finding that endothelial function may be improved in the coronary and peripheral vasculature has been reproduced in the large artery cerebrovasculature: in a diabetic population, improvement in nitric oxide-mediated carotid artery dilatation was observed following treatment Citation[11]. However, in contrast to these encouraging results, intracranial cerebrovascular reactivity was unaffected by treatment in patients following lacunar stroke Citation[12].
Whilst XOI appears to hold promise for the prevention of adverse vascular events, a role in the acute phase of stroke also merits exploration. In contrast to the increase in vascular risk associated with chronic hyperuricemia, in the setting of acute stroke, increased UA levels have been associated with favorable outcomes Citation[13]. Indeed, some groups propose that therapeutic administration of UA, itself holding potent antioxidant properties when administered therapeutically, may hold potential neuroprotective capacity Citation[14], and clinical trials to evaluate the effects of coadministration of uric acid with recombinant tissue plasminogen activator in acute stroke have been proposed. If XO-mediated oxidative stress contributes significantly to ischemic and reperfusion brain injury, perhaps there may also be potential for the additional coadministration of a XOI agent in this setting, to minimize a significant source of damaging oxidative stress.
The various intervention studies to date appear to confirm the beneficial nature of XOI within the vasculature and confirm the potential of this therapeutic strategy for vascular disease. Results suggest that vascular oxidative stress produced through XO activity may be the key mediator or risk factor in patients with hyperuricemia. In clinical practice, this remains an unaddressed risk factor for cerebrovascular disease. Patients require additional treatment options, and this therapeutic avenue now demands further evaluation in definitive end point studies.
Financial & competing interests disclosure
Matthew R Walters holds an academic research grant to evaluate the effect of allopurinol on cardiovascular risk (funded by The UK Stroke Association). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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