BACKGROUND: Oxidative stress due to purine degradation is associated with the development of chronic heart failure (CHF). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine degradation that plays a key role in uric acid (UA) production with a resultant increase in reactive oxygen species. However, the relationship between plasma XOR activity and CHF severity and clinical outcome remains unclear. METHODS AND RESULTS: We measured XOR activity in 440 patients with CHF and 44 control subjects. Abnormally high and low XOR activities were identified based on the results for 95% of the control subjects (high and low XOR activities ≥120 and <33pmol/100μL/h, respectively). The prevalence rates of high and low XOR activities increased with advancing New York Heart Association functional class. There were 158 cardiac events during a median follow-up period of 1034days. Multivariate Cox proportional hazard regression analysis showed that both high and low XOR activities were significantly associated with cardiac events in patients with CHF after adjustment for confounding risk factors including serum UA and loop diuretic use. Kaplan-Meier analysis revealed that the cardiac event rate was significantly higher in patients with either high or low XOR activity. The net reclassification index was significantly improved by adding XOR activity to the basic risk factors. CONCLUSIONS: We provide the first evidence of an association of plasma XOR activity with CHF severity and clinical outcome. Plasma XOR activity could be used to identify high-risk CHF patients and could be a therapeutic target for XOR inhibitors.
BACKGROUND: Oxidative stress due to purine degradation is associated with the development of chronic heart failure (CHF). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine degradation that plays a key role in uric acid (UA) production with a resultant increase in reactive oxygen species. However, the relationship between plasma XOR activity and CHF severity and clinical outcome remains unclear. METHODS AND RESULTS: We measured XOR activity in 440 patients with CHF and 44 control subjects. Abnormally high and low XOR activities were identified based on the results for 95% of the control subjects (high and low XOR activities ≥120 and <33pmol/100μL/h, respectively). The prevalence rates of high and low XOR activities increased with advancing New York Heart Association functional class. There were 158 cardiac events during a median follow-up period of 1034days. Multivariate Cox proportional hazard regression analysis showed that both high and low XOR activities were significantly associated with cardiac events in patients with CHF after adjustment for confounding risk factors including serum UA and loop diuretic use. Kaplan-Meier analysis revealed that the cardiac event rate was significantly higher in patients with either high or low XOR activity. The net reclassification index was significantly improved by adding XOR activity to the basic risk factors. CONCLUSIONS: We provide the first evidence of an association of plasma XOR activity with CHF severity and clinical outcome. Plasma XOR activity could be used to identify high-risk CHFpatients and could be a therapeutic target for XOR inhibitors.