Vascular Oxidative Stress and Endothelial Dysfunction in Patients With Chronic Heart Failure: Role of Xanthine-Oxidase and Extracellular Superoxide Dismutase

Abstract

Background— Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in patients with chronic heart failure (CHF) results, at least in part, from accelerated degradation of nitric oxide by oxygen radicals. The mechanisms leading to increased vascular radical formation, however, remain unclear. Therefore, we determined endothelium-bound activities of extracellular superoxide dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a potent radical producing enzyme, and their relation to FDD in patients with CHF. Methods and Results— ecSOD and xanthine-oxidase activities, released from endothelium into plasma by heparin bolus injection, were determined in 14 patients with CHF and 10 control subjects. FDD of the radial artery was measured using high-resolution ultrasound and was assessed before and after administration of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium-bound ecSOD activity was substantially reduced (5.0±0.7 versus 14.4±2.6 U · mL −1 · min −1 ; P <0.01) and closely related to FDD ( r =0.61). Endothelium-bound xanthine-oxidase activity was increased by >200% (38±10 versus 12±4 nmol O 2 ·− · μL −1 ; P <0.05) and inversely related to FDD ( r =−0.35) in patients with CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by radicals correlated negatively with ecSOD ( r =−0.71) but positively with xanthine-oxidase ( r =0.75). Conclusions— These results demonstrate that both increased xanthine-oxidase and reduced ecSOD activity are closely associated with increased vascular oxidative stress in patients with CHF. This loss of vascular oxidative balance likely represents a novel mechanism contributing to endothelial dysfunction in CHF.