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C hronic heart failure (CHF) is the terminal stage of heart disease caused by myocardial infarction (MI), hypertension, cardiomyopathy, and valvular heart disease. Despite guideline-recommended therapy (pharmacological treatment, implantable devices, mechanical circulating support, and heart transplantation), the prognosis of patients with CHF remains very poor 1,2) and another strategy is necessary. Improper functioning of various signaling pathways, including the sympathetic nervous system and renin-angiotensinaldosterone system leads to progression of heart failure (HF). In addition, several studies have reported that oxidative stress 4) and change of myocardium metabolism 5) also play important roles in the pathophysiology of cardiac remodeling and HF. Thus, intervention of oxidative stress and myocardial metabolism is expected to pave the way for new treatments for CHF. Reactive oxygen species (ROS) directly influence or activate several downstream signaling pathways, which stimulate myocardial growth, matrix remodeling, and cellular dysfunction. ROS directly influence contractile function by modifying proteins involved in excitation-contraction coupling. ROS interfere with the Ca transport system through impaired activation of the sarcoplasmic reticulum Ca ATPase (adenosine triphosphatase) (SERCA) and they might play an important role in Ca overload of the heart, causing cardiac systolic and diastolic dysfunction. Excessive ROS generation leads to mitochondrial injury, including loss of mitochondrial membrane potential, resulting in cellular apoptosis through released cytochrome C from mitochondria and decreased ATP production. Both of these factors are now believed to be major mechanisms for the development of HF. The cellular sources of ROS generation in HF include cardiac myocytes, endothelial cells, and neutrophils. Regarding cardiac myocytes, ROS are derived from several intracellular sources, including xanthine oxidase (XO), mitochondrial electron transporters, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nitric oxide (NO) synthase, and cyclooxygenase. XO catalyzes a critical and terminal reaction in ATP and purine degradation and acts as an important source of ROS during ischemia and HF. In an ischemic event, cellular hypoxanthine, a substrate of XO, accumulates via degradation of ATP. Several clinical reports have demonstrated activation of myocardial XO and ROS increases in patients with CHF, and that they reflect the severity of HF. From the viewpoint of myocardium metabolism, Decherd, et al observed that in the setting of CHF, cardiomyocytes exist in a state of “energy starvation”. Their findings are supported by recent evidence that impaired activity of respiratorychain enzymes and altered glycolipid metabolism could cause the decreased myocardial ATP production in CHF. Energy derived from free fatty acid (FFA) metabolism accounts for 70% of the myocardial supply of ATP in the healthy heart. However, myocardium metabolism transits from a fatty acid metabolismdependent pathway to a glucose metabolism-dependent pathway in CHF. The amount of energy that may be derived from glucose is much less than the amount that may be derived from FFA. In addition, in heart failure, p-53-dependent chronic inflammation leads to insulin-resistance; which in turn leads to decreased glucose metabolism in the myocardium and reduced generation of energy in CHF. Patients with CHF frequently present hyperuricemia. Several reports have indicated that a high level of uric acid (UA) is an independent prognostic factor or independent marker of CHF. Hyperuricemia in CHF is attributed to impaired renal urate excretion, while, on the other hand, overproduction of urates via activation of XO also could contribute to hyperuricemia in CHF. Allopurinol, a specific XO inhibitor, is approved for the clinical treatment of hyperuricemia. Studies in animals and humans with HF have shown that allopurinol can improve myocardial energy efficiency and reduce oxygen consumption. Notably, usage of allopurinol was a marker of improved survival in the Seattle Heart Failure Model. Several clinical trials addressed the question whether allopurinol might restore cardiac function in hyperuricemic patients with CHF. The OPT-CHF study (Oxypurinol compared with placebo for class with placebo with CHF. the Seattle) showed that a subgroup of patients with hyperuricemia (UA ≧ 9.5 mg/dL) responded favorably with improved clinical status and trends toward decreased all-cause and cardiovascular death. However, the EXACT-HF study (Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients) failed to show improved clinical status, exercise capacity, quality of life, or ventricular ejection fraction in patients treated with allopurinol. These results suggest there is still controversy with respect to the actions of allopurinol on cardiac function in hyper-

Can Xanthine Oxidase Inhibitors Improve Cardiac Function in Patients With Chronic Heart Failure?