Altered Plasma Urea Cycle Metabolites Are Independently Associated With Frailty in Patients With Heart Failure

BACKGROUND: Frailty is common in patients with heart failure and is associated with adverse outcomes. Although metabolic dysregulation has been implicated in frailty, the relationship between plasma amino acid profiles and frailty remains incompletely defined. METHODS AND RESULTS: We conducted a single-center ambispective cross-sectional study of 413 patients hospitalized for heart failure (median age 78 years). Plasma concentrations of 31 amino acids were measured. Frailty status was assessed using the Japanese version of the Cardiovascular Health Study criteria. An unbiased analytical framework integrating multivariate analyses and multivariable logistic regression was applied with adjustment for heart failure severity, renal function, nutritional status, and body composition. Associations with all-cause mortality were evaluated using Cox models. Frailty was present in 228 (55%) patients. Unbiased analyses identified urea cycle-related metabolites as key features associated with frailty. In fully adjusted models, higher plasma citrulline and ornithine concentrations were independently associated with frailty, whereas arginine concentrations were not. These associations were independent of nutritional indices, skeletal muscle mass, and established prognostic factors. Neither citrulline nor ornithine was independently associated with mortality. Pathway analysis demonstrated enrichment of arginine biosynthesis and arginine-proline metabolism. CONCLUSIONS: Elevated citrulline and ornithine were independently associated with frailty in patients with heart failure, suggesting that dysregulated arginine-related metabolism may represent a metabolic signature of the frailty phenotype distinct from mortality risk.