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Aims  Differentiation of heart failure with reduced ( HFrEF ) or preserved ( HFpEF ) ejection fraction independent of echocardiography is challenging in the community. Diagnostic strategies based on monitoring circulating  microRNA  ( miRNA ) levels may prove to be of clinical value in the near future. The aim of this study was to identify a novel  miRNA  signature that could be a useful  HF  diagnostic tool and provide valuable clinical information on whether a patient has  HFrEF  or  HFpEF .    Methods and results   MiRNA  biomarker discovery was carried out on three patient cohorts, no heart failure (no‐ HF ),  HFrEF , and  HFpEF , using Taqman  miRNA  arrays. The top five  miRNA  candidates were selected based on differential expression in  HFpEF  and  HFrEF  ( miR ‐30c, −146a, −221, −328, and −375), and their expression levels were also different between  HF  and no‐ HF . These selected  miRNAs  were further verified and validated in an independent cohort consisting of 225 patients. The discriminative value of  BNP  as a  HF  diagnostic could be improved by use in combination with any of the  miRNA  candidates alone or in a panel. Combinations of two or more  miRNA  candidates with  BNP  had the ability to improve significantly predictive models to distinguish  HFpEF  from  HFrEF  compared with using  BNP  alone (area under the receiver operating characteristic curve >0.82).    Conclusion  This study has shown for the first time that various  miRNA  combinations are useful biomarkers for  HF , and also in the differentiation of  HFpEF  from  HFrEF . The utility of these biomarker combinations can be altered by inclusion of natriuretic peptide.  MiRNA  biomarkers may support diagnostic strategies in subpopulations of patients with  HF .

MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure