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

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 naive 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. (J Cardiac Fail 2013;19:87-93)