Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Adverse long-term prognosis is associated with clinically relevant metabolomic profile in acute heart failure
M. Behnes1, T. Bertsch2, J. Müller3, J. Volke1, A. Schmid1, R. Klingbeil1, T. Schupp1, G. Poschet4, J. Januzzi5, B. Karaca1, I. Akin1
1I. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim; 2Institut für klinische Chemie und Laboratoriumsmedizin und Transfusionsmedizin, Klinikum Nürnberg Nord, Nürnberg; 3Herz- und Gefäß-Klinik Campus Bad Neustadt, Bad Neustadt a. d. Saale; 4Centre of Organismal Studies, Heidelberg; 5Massachusetts General Hospital, Boston, US;

Purpose: Patients suffering from acute heart failure (AHF) are endangered by an adverse clinical outcome. The patho-biochemical alterations on the level of metabolomics predisposing AHF patients to increasing rates of recurrent rehospitalization and all-cause mortality have not been investigated.


Methods: Consecutive AHF patients presenting to the emergency department as well as healthy subjects serving as controls, were included prospectively in the MEMORIA study. All patients were followed up to 12 months regarding the composite endpoint of AHF related rehospitalization and all-cause mortality at 12 months of follow-up. Blood samples including EDTA plasma were drawn and stored. EDTA plasma from healthy subjects served as the control group. 630 different metabolites were measured by the MxP® Quant 500 kit (Biocrates life sciences ag) based on a targeted mass spectrometry approach. Statistical analysis was performed by metaboanalyst (5.0) and R statistics (The R Foundation ©, including fold change analyses, univariable t-test and false discovery rating (FDR), multivariate principal component analysis (PCA), partial least squares regression with discriminant analysis (PLS-DA), permutation testing, heatmaps and C-statistics with calculation of area under the receiver operating characteristic curves (AUC). Differences of metabolomic profiles of both AHF patients with adverse prognosis (AHF-AP) and without AP (AHF-nonAP) were compared to healthy controls.


Results: Within a total of 150 consecutive 150 AHF patients, the composite endpoint of AHF related rehospitalization and all-cause mortality at 12 months occurred in 45% compared to 55%. Mean age of AHF patients was 75 years (range 51-93 years), 57% males and 43% females. Coronary artery disease was present in 64%, valvular heart disease in 96%, median left ventricular function (LVEF) was 40% (interquartile range (IQR) 31-49%), E/E´ 14 (IQR 11-20), and tricuspid annular systolic excursion (TAPSE) was 17 mm (IQR 14-21 mm). Significantly altered metabolites were detected more frequently in AHF-AP (n=40) compared to AHF-nonAP (n=18) patients by univariable t-tests. Even after applying FDR, multivariable PCA and PLS-DA including permutation testing still 10 compared to 3 metabolites remained significantly altered. AHF-AP group: Phosphatidylcholine (PC aa 24:0) (p= 3.4564e-13), triglycerides (TG) (18:3 36:4) (p=0.000002), medium-chain acylcarnitines (C3-DC (C4-OH) (p=0.000004), TG(18:3 36:3) (p=0.000005), xanthine (p= 0.0000004), TG (18:3 36:2) (p=0.00002), TG (18:1 36:5) (p=0.00007), TG (18:2 36:4) (p=0.0006), TG (18:1 36:6) (p=0.0008), TG (18:2 36:5) (p=0.0008).


Multivariable C-statistics revealed better discrimination of AHF-AP patients than of AHF-nonAP patients by their metabolomic profile compared to healthy controls (AHF-AP, AUC = 0.908 (95% confidence interval (CI) 0.829-0.963; AHF-nonAP, AUC = 0.891 (95% CI 0.822-0.953).


Conclusion: Adverse long-term prognosis in AHF is associated with clinically relevant differences of metabolomic profiles.