Plasma amino acid profiling improves predictive accuracy of adverse events in patients with heart failure

AIMS: The clinical outcome of heart failure (HF) is complicated by the presence of multiple comorbidities including malnutrition and cachexia, and prediction of the outcome is still difficult in each patient. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiling improves prediction of clinical outcomes in patients with HF. METHODS AND RESULTS: We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male). Blood samples for measurements of amino acid concentrations were collected in a fasting state after stabilization of HF. Plasma amino acid concentrations were measured using ultraperformance liquid chromatography. Clinical endpoint of this study was adverse event defined as all‐cause death and unscheduled readmission due to worsening HF or lethal arrhythmia. During a mean follow‐up period of 380 ± 214 days, 40 patients (13%) had adverse events. Results of analyses of variable importance in projection score, a measure of a variable's importance in partial least squares–discriminant analysis (PLS‐DA) showed that the top five amino acids being associated with adverse events were 3‐methylhistidine (3‐Me‐His), β‐alanine, valine, hydroxyproline, and tryptophan. Multivariate Cox‐proportional hazard analyses indicated that a high 3‐Me‐His concentration and low β‐alanine and valine concentrations were independently associated with adverse events. When HF patients were divided according to the cut‐off values of amino acids calculated from receiver operating characteristic curves, Kaplan–Meier survival curves showed that event‐free survival rates were lower in HF patients with high 3‐Me‐His than in HF patients with low 3‐Me‐His (68% vs. 91%, P < 0.01). In a subgroup with high 3‐Me‐His, HF patients with low β‐alanine and those with low valine had significantly lower event‐free survival rates than did HF patients with high β‐alanine and those with high valine, respectively. On the other hand, Kaplan–Meier curves of event‐free survival rates did not differ between HF patients with and those without low β‐alanine and low valine in subgroups of patients with low 3‐Me‐His. Inclusion of both high 3‐Me‐His and low β‐alanine or low valine into the adjustment model including N‐terminal pro‐brain natriuretic peptide improved the accuracy of prediction of adverse events after discharge. 3‐Me‐His concentration was associated with muscle mass and nutritional status. CONCLUSIONS: Simple measurement of 3‐Me‐His with either β‐alanine or valine improved the predictive ability for adverse events, indicating the utility of plasma amino acid profiling in risk stratification of hospitalized HF patients.