Novel Biomarkers of Oxidative Stress are Associated with Risk of Death and Hospitalization in Patients with Heart Failure

Abstract

Background Non-free radical species of oxidative stress (OS) may be clinically important. Our prior work has shown emerging aminothiol markers of non-free radical OS are associated with mortality in patients with coronary artery disease. We sought to examine the association of aminothiol markers of OS with clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Methods Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 200 controls and 138 HFrEF patients. Cox proportional hazards regression was used to examine the association of aminothiols with the composite risk of death and hospitalization in HFrEF patients. Results The level of cystine (oxidized) was higher (102.4 ± 29.7 vs. 69.4 ± 12.4 μM, P Figure ). After adjustment for covariates including age, sex, race, history of diabetes and hypertension, serum creatinine, and ejection fraction, glutathione (HR 0.4, 95% CI 0.2 - 0.9; P=0.02) and a high ratio of cystine:glutathione (HR 2.2, 95% CI 1.1 - 4.4; P=0.03) remained associated with the composite risk of death and hospitalization. Conclusions A high burden of OS, quantified by the plasma aminothiols cystine, glutathione, and their ratio, is associated with clinical outcomes in HFrEF patients. Importantly, this data supports the emerging role of non-free radical biology in driving clinically important OS.