Heart failure with mildly reduced ejection fraction (HFmrEF): where are we now?

Heart failure (HF) with mildly reduced ejection fraction (HFmrEF), recently also termed HF with mid-range EF, describes a patient with a left ventricular ejection fraction of 40-49% (5). This classification was initially introduced to bridge the gap between traditional HF with reduced ejection fraction (HFrEF, EF < 40%) and HF with preserved ejection fraction (HFpEF, EF ≥ 50%), as many trial populations and guidelines had previously classified patients by EF (2). HFmrEF patients often display intermediate characteristics: they share etiologies and risk factors with HFrEF (i.e., ischemic heart disease), while their comorbidity profile and overall prognosis more closely resemble HFpEF (1). HFmrEF displays considerable overlap in pathophysiology with HFpEF and HFrEF. Since EF values in this range can fluctuate over time, this introduces even more complexity to its classification. Many individuals with HFmrEF have either improved from a lower EF or deteriorated from a higher EF, and up to one-third will transition to HFrEF or HFpEF during follow-up (58). In terms of outcomes, patients with HFmrEF have mortality and quality-of-life metrics generally between those of HFrEF and HFpEF (often closer to the latter) (9). Importantly, management of HFmrEF is similar to that of HFrEF. Evidence from subgroup analyses and recent trials suggests that standard neurohormonal therapies are beneficial in this EF range. Agents, including β-blockers, renin-angiotensin system inhibitors, angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs), all demonstrate reduced hospitalizations and/or mortality in HFmrEF patients, which highlights the similarity in treatment profiles with HFrEF (33). Additional therapies have solidified the treatment approach: sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) significantly lowered HF hospitalization risk in patients with EF > 40% (HFmrEF/HFpEF) (42), and the FINEARTS-HF trial showed finerenone (a non-steroidal MRA) meaningfully improved outcomes in this group (53). As a result, guidelines now give Class I recommendations for SGLT2 inhibitors in HFmrEF, and finerenone is emerging as an important add-on therapy (43). Device therapy (ICD/CRT) remains generally reserved for those who have either had EF ≤ 35% or other indications. This review synthesizes current evidence on HFmrEF, reframing it as a clinical spectrum rather than a distinct phenotype, with emphasis on management implications, biological overlap, and directions for future research.