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  • Review Article
  • Published:

Heart failure with mid-range or mildly reduced ejection fraction

Nature Reviews Cardiology volume 19, pages 100–116 (2022)Cite this article

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Abstract

Left ventricular ejection fraction (EF) remains the major parameter for diagnosis, phenotyping, prognosis and treatment decisions in heart failure. The 2016 ESC heart failure guidelines introduced a third EF category for an EF of 40–49%, defined as heart failure with mid-range EF (HFmrEF). This category has been largely unexplored compared with heart failure with reduced EF (HFrEF; defined as EF <40% in this Review) and heart failure with preserved EF (HFpEF; defined as EF ≥50%). The prevalence of HFmrEF within the overall population of patients with HF is 10–25%. HFmrEF seems to be an intermediate clinical entity between HFrEF and HFpEF in some respects, but more similar to HFrEF in others, in particular with regard to the high prevalence of ischaemic heart disease in these patients. HFmrEF is milder than HFrEF, and the risk of cardiovascular events is lower in patients with HFmrEF or HFpEF than in those with HFrEF. By contrast, the risk of non-cardiovascular adverse events is similar or greater in patients with HFmrEF or HFpEF than in those with HFrEF. Evidence from post hoc and subgroup analyses of randomized clinical trials and a trial of an SGLT1–SGLT2 inhibitor suggests that drugs that are effective in patients with HFrEF might also be effective in patients with HFmrEF. Although the EF is a continuous measure with considerable variability, in this comprehensive Review we suggest that HFmrEF is a useful categorization of patients with HF and shares the most important clinical features with HFrEF, which supports the renaming of HFmrEF to HF with mildly reduced EF.

Key points

  • Heart failure (HF) with mildly reduced ejection fraction (EF) (HFmrEF) has been extensively studied, generally using an EF of 40–49%, and accounts for up to 25% of patients with HF.

  • On the basis of contemporary trials and definitions, HFmrEF might be defined as an EF of 41–49%.

  • HFmrEF is an intermediate HF type between HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF) for some characteristics but is more similar to HFrEF for others, especially for the high prevalence of ischaemic heart disease.

  • HFmrEF and HFpEF are milder forms of HF than HFrEF and are associated with a lower risk of cardiovascular and HF events but with a similar or greater risk of non-cardiovascular adverse events.

  • Clinical trials on therapies for HFpEF enrolled patients with an ejection fraction of >40% or ≥45% and did not demonstrate a clear treatment effect; however, subgroup and post hoc analyses suggest that some therapies for HFrEF might also be effective in HFmrEF.

  • These arguments support the current redefinition of HFmrEF as HF with mildly reduced EF instead of HF with mid-range EF.

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Fig. 1: Phenotype, risk of cause-specific outcomes and effect of therapies in HFrEF, HFmrEF and HFpEF.
Fig. 2: HFmrEF clinical characteristics and similarities to HFrEF and HFpEF in major HF registries.
Fig. 3: HFmrEF clinical characteristics and similarities to HFrEF and HFpEF in major RCTs of HF.
Fig. 4: Outcomes according to EF in patients with HF in major registries and RCTs.
Fig. 5: Trajectories and changes in EF and outcomes over time in patients with HF.
Fig. 6: Outcomes in patients with HF according to EF.

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Acknowledgements

L.H.L. is supported by the Karolinska Institutet, the Swedish Research Council (grant 523-2014-2336), the Swedish Heart Lung Foundation (grants 20150557, 20190310) and Stockholm County Council (grants 20170112, 20190525).

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  1. These authors contributed equally: Gianluigi Savarese, Davide Stolfo.

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Gianluigi Savarese, Davide Stolfo & Lars H. Lund

  2. Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden

    Gianluigi Savarese & Lars H. Lund

  3. Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and University Hospital of Trieste, Trieste, Italy

    Davide Stolfo & Gianfranco Sinagra

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  1. Gianluigi Savarese
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G. Savarese, D.S. and L.H.L. researched data for the article, contributed substantially to discussion of the content and wrote the manuscript. All the authors reviewed and/or edited the manuscript before submission.

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Correspondence to Lars H. Lund.

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Competing interests

G. Savarese reports grants and personal fees from AstraZeneca and Vifor; grants and non-financial support from Boehringer Ingelheim; personal fees from Cytokinetics, GENESIS, Medtronic, Radcliffe, Roche, Servier and Società Prodotti Antibiotici; and grants from Boston Scientific, Novartis and Pharmacosmos, unrelated to this Review. D.S. reports personal fees from GlaxoSmithKline, MSD and Novartis. L.H.L. reports personal fees from Abbott, Bayer, Lexicon, Medscape, Merck, Myokardia, Pharmacosmos, Radcliffe Cardiology and Sanofi; grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis and Vifor–Fresenius; and grants from Boston Scientific, unrelated to this Review. G. Sinagra declares no competing interests.

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Savarese, G., Stolfo, D., Sinagra, G. et al. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol 19, 100–116 (2022). https://doi.org/10.1038/s41569-021-00605-5

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