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Abstract   Aims  Chronic heart failure with reduced ejection fraction remains a major health issue. To date, no reliable biomarker is available to predict reduced left ventricular ejection fraction (LV‐EF). We aimed to identify novel circulating biomarkers for reduced left ventricular function using untargeted serum metabolomics in two independent patient cohorts.    Methods and results  Echocardiography and non‐targeted serum metabolomics were conducted in two patient cohorts with varying left ventricular function: (1) 25 patients with type 2 diabetes with established cardiovascular disease or high cardiovascular risk (LV‐EF range 20–66%) (discovery cohort) and (2) 37 patients hospitalized for myocardial infarction (LV‐EF range 25–60%) (validation cohort). In the discovery cohort, untargeted metabolomics revealed seven metabolites performing better than N‐terminal pro‐B‐type natriuretic peptide in the prediction of impaired left ventricular function shown by LV‐EF. For only one of the metabolites, acisoga, the predictive value for LV‐EF could be confirmed in the validation cohort ( r  = −0.37,  P  = 0.02). In the discovery cohort, acisoga did not only correlate with LV‐EF ( r  = −60,  P  = 0.0016), but also with global circumferential strain ( r  = 0.67,  P  = 0.0003) and global longitudinal strain ( r  = 0.68,  P  = 0.0002). Similar results could be detected in the discovery cohort in a 6 month follow‐up proofing stability of these results over time. With an area under the curve of 0.86 in the receiver operating characteristic analysis, acisoga discriminated between patients with normal EF and LV‐EF &lt; 40%. Multivariate analysis exposed acisoga as independent marker for impairment of LV‐EF (Beta = −0.71,  P  = 0.004).    Conclusions  We found the polyamine metabolite acisoga to be elevated in patients with impaired LV‐EF in two independent cohorts. Our analyses suggest that acisoga may be a valuable biomarker to detect patients with heart failure with reduced ejection fraction.

Non‐targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function