Low Valine Serum Levels Predict Increased 1-Year Mortality in Acute Heart Failure Patients

Abstract

Considering the relationship between disease severity and the extent of metabolic derangement in heart failure, we hypothesized that the serum levels of metabolites may have prognostic value for 1-year mortality in acute heart failure (AHF). The AHF study was a prospective, observational study enrolling consecutive patients hospitalized due to AHF. Metabolites were measured in serum collected at admission using NMR spectroscopy. Out of 315 AHF patients, 118 (37.5%) died within 1 year after hospitalization for AHF. The serum levels of 8 out of 49 identified metabolites were significantly different between patients who were alive and those who died within 1 year after hospitalization for AHF. Of these, only valine was significantly associated with 1-year mortality (hazard ratio 0.73 per 1 standard deviation increase, 95% confidence interval: 0.59-0.90, p = 0.003) in the multivariable Cox regression analyses. Kaplan-Maier analysis showed significantly higher survival rates in AHF patients with valine levels above the median (>279.2 µmol/L) compared to those with valine levels ≤ 279.2 µmol/L. In a receiver operating characteristics curve analysis, valine was able to discriminate between the two groups with an area under the curve of 0.65 (95% CI 0.59-0.72). We conclude that valine serum levels might be of prognostic value in AHF.

Keywords: NMR spectroscopy; acute heart failure; metabolomics; mortality; prognostic biomarkers; risk; valine.

Figure 1

Volcano plot showing metabolites whose serum levels are significantly decreased, increased or not significantly different in patients who died compared to those who were alive within 1 year after hospitalization for AHF. Differences between the groups were tested with the Mann-Whitney U test. A p-value of <0.001 was considered significant after a Bonferroni correction for multiple testing.

Figure 2

Cox regression analyses of metabolites as predictors of 1-year mortality in AHF patients. Metabolites (µmol/L) were log-transformed before Cox regression analysis. Results are presented as hazard ratios (HR) and the respective 95% confidence intervals (CI) per 1-SD increase. p-values < 0.05 were considered significant and are depicted in bold. In the adjusted model, age, sex, BMI, MAP, eGFR, BUN, CRP, NT-proBNP, hemoglobin, ALT, albumin, and total cholesterol were used as covariates. The total numbers of patients and events were 315 and 118, respectively, in the univariable analyses and 303 and 112, respectively, in the adjusted analyses. ALT, alanine aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; C, cholesterol; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MAP, mean arterial pressure; N, number of observations; NT-proBNP, N-terminal pro-brain natriuretic peptide; SD, standard deviation.

Figure 3

Kaplan-Meier survival curves for valine predicting 1-year mortality of AHF patients. The number of patients at risk at each time point is presented below the graph.

Figure 4

Receiver operating characteristics curve for prediction of death within 1 year of valine.

Figure 5

Heatmap of correlations of valine serum levels with laboratory and clinical parameters. Values presented are the Spearman correlation coefficients. p-values < 0.05 were considered significant and are depicted in bold. SPAP was measured in 259 patients; other analyses were based on 315 samples. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; hsTnI, high-sensitivity troponin I; IL-6, interleukine-6; LDH, lactate dehydrogenase; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; SPAP, systolic pulmonary artery pressure; TC, total cholesterol.