Urate-Lowering Drugs and Prevention of Cardiovascular Disease: The Emerging Role of Xanthine Oxidase Inhibition.

The relevance of elevated plasma levels of serum uric acid (SUA) in patients with cardiovascular disease was historically described 2 centuries century ago when Alexander Heig published a paper dealing with the causative role of hyperuricermia in patients with hypertension and several other diseases. More recently, a remarkable number of epidemiological and experimental studies have demonstrated that hyperuricemia and gout are strongly related with hypertension, metabolic syndrome, chronic kidney disease, and cardiovascular disease. The relationship between hyperuricemia and hypertension and metabolic syndrome has been confirmed in both pediatric and adolescent populations and is maintained after an extensive adjustment for almost all of the possible confounding conditions (eg, hypertension, diabetes mellitus, lipid disorders, renal function, etc), thereby supporting the role of elevated SUA as an emerging independent cardiovascular risk factor in patients with and without gout. The mechanisms that link elevated SUA levels and gout with cardiovascular comorbidities seem to be multifactorial, implicating low-grade systemic inflammation and xanthine oxidase (XO) activity, as well as the deleterious effects of hyperuricemia itself. As expected, a decrease in SUA levels has been associated with an improvement in blood pressure control, as well as with some additional benefits in selected populations of patients with cardiovascular diseases (eg, coronary artery disease, heart failure, etc). Most of the these favorable effects have been achieved by treating the patients with allopurinol or its derivative oxipurinol that have have been used in the great majority of studies aimed at evaluating the cardiovascular preventive/therapeutic role of urate-lowering treatment in patients with hyperuricemia. The same treatment has been reported to reduce all-cause and cardiovascular mortality, clearly supporting a possible preventive role of SUA modulation through XO inhibition. In the present issue of Hypertension, MacIsaac et al have reported the results of an important study where the treatment with different doses of allopurinol over a 10-year period significantly improved the cardiovascular outcome in 2032 elderly hypertensive patients (over 65 years) included in the United Kingdom Clinical research Practice Datalink and compared with a propensitymatched, nonexposed population. In particular, the active treatment with allopurinol reduced the risk of stroke (−50%) and cardiac event (−39%), and the reduction was significantly larger in patients treated with the higher allopurinol dose. This article of MacIsaac et al expanded the bulk of observation supporting the possible role of xantino-oxidase inhibitors in the prevention of cardiovascular disease and could open a new frontier in clinical research aimed at developing a solution for the challenging problem of residual cardiovascular risk in patients with hypertension. Indeed, the results of the EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice) study and many others in the same field have provided a clear demonstration that well-controlled hypertension is associated with a considerable amount of residual cardiovascular risk that could be partially reduced by decreasing SUA through XO inhibition. The mechanism involved in the favorable effects of allopurinol in the MacIsaac study would be the prevention of the oxidative stress linearly associated with the biochemical process, leading to uric acid formation that may clearly explain the evidence provided by a recent review of Higgins et al focused on the possible beneficial effects of XO inhibitors in patients with cardiovascular diseases. The plausibility of this interpretation is well supported by the characteristics of this new study that does not include patients with gout or evidence of uric acid deposition and is focused on hypertensive subjects with high cardiovascular risk profile (age >70 years, 23% diabetes mellitus, 28% ischemic heart disease, current treatment with cardiovascular drugs) where the preventive effect of XO inhibition can be magnified. In addition, the dose-dependency of the cardiovascular effects of allopurinol observed in the study further supports the importance of the mechanism of action of allopurinol beyond its propensity of reducing the plasma levels of uric acid that are expected to be probably within the normal range in a large percentage of the studied population. The possible prevailing role of the antioxidant effect of allopurinol over the serum urate decrease is in agreement with the results of 2 recent studies in patients with congestive heart failure where the negative impact of hyperuricemia was restricted to overproducer patients with normal renal function. In the same congestive heart failure population, The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medical and Surgical Sciences, University of Bologna, Bologna Italy (C.B.); and Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy (G.D.). This paper was sent to Takayoshi Ohkubo, Guest Editor, for review by expert referees, editorial decision, and final disposition. Correspondence to Claudio Borghi, Unità Operativa di Medicina Interna, Dipartimento di Scienze Mediche e Chirurgiche, Ospedale Policlinico S.Orsola-Malpighi, Via Albertoni 15, 40138 Bologna, Italy. E-mail [email protected] Urate-Lowering Drugs and Prevention of Cardiovascular Disease The Emerging Role of Xanthine Oxidase Inhibition