Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients Design and Rationale of the EXACT-HF Study

According to the most recent National Health and Nutrition Examination Survey, an estimated 5.1 million adult Americans have heart failure (HF), and projections show that by the year 2030 the prevalence of HF in the United States will increase by 25%.1 Despite guideline-recommended therapy for patients with HF and reduced ejection fraction,2 the overall 5-year mortality remains ≈50%, and the 1-year mortality in patients with New York Heart Association functional class III to IV HF on maximal medical therapy is 35% to 40%. Given the public health burden of HF, there is a clear need for improved medical therapies. Reduced myocardial antioxidant activity and increased oxidant damage have been demonstrated in animal models of HF, and markers of oxidative stress are increased in HF patients.3 These data support the thesis that reactive oxygen species may contribute to the progression of myocardial failure. Xanthine oxidase (XO) is among the potential stimuli of formation of reactive oxygen species in HF and may be an important target for therapy.4 Current evidence supports the hypothesis that HF is associated with an increase in the activity of XO, which, in turn, increases production of superoxide and uric acid (UA) during purine metabolism. The resulting nitroso-redox imbalance5 may be exacerbated by decreased activity of nitric oxide synthase (Figure 1). Significant hyperuricemia (ie, serum UA ≥9.5 mg/dL) is present in ≈25% of patients with HF and reduced ejection fraction.6,7 In addition to nitroso-redox imbalance, other contributors to hyperuricemia in HF include activation of proinflammatory cytokines, impaired vascular function, and renal insufficiency, as well as loop diuretic therapy.8 In patients with HF, there is a strong relationship between elevated UA levels and worsening symptoms,9 impaired exercise tolerance,10 and increased mortality.6 On the basis of these findings, …