Diminished Global Arginine Bioavailability as a Metabolic Defect in Chronic Systolic Heart Failure

Abstract Background Systemic alterations in arginine bioavailability occur in heart failure (HF) patients with more advanced myocardial dysfunction and poorer clinical outcomes, and they improve with beta-blocker therapy. Methods and Results We measured fasting plasma levels of L-arginine and related biogenic amine metabolites in 138 stable symptomatic HF patients with left ventricular ejection fraction ≤35% and comprehensive echocardiographic evaluation. Long-term adverse clinical outcomes (death and cardiac transplantation) were followed for 5 years. Lower global arginine bioavailability ratio (GABR; ratio of L-arginine to L-ornithine + L-citrulline) was associated with higher plasma natriuretic peptide levels, more advanced left ventricular diastolic dysfunction, and more severe right ventricular systolic dysfunction (all P < .001). Patients taking beta-blockers had significantly higher GABR than those not taking beta-blockers (0.86 [interquartile range (IQR) 0.68–1.17] vs 0.61 [0.44–0.89]; P < .001). Subjects with higher GABR experienced fewer long-term adverse clinical events (hazard ratio 0.61 [95% confidence interval 0.43–0.84]; P = .002). In an independent beta-blocker naïve patient cohort, GABR increased following long-term (6 month) beta-blocker therapy (0.89 [IQR 0.52–1.07] to 0.97 [0.81–1.20]; P = .019). Conclusions In patients with chronic systolic heart failure, diminished global L-arginine bioavailability is associated with more advanced myocardial dysfunction and poorer long-term adverse clinical outcomes. GABR levels improved with beta-blocker therapy.