Journal of Cardiology and Heart Failure

ABSTRACT

Background

Heart failure (HF) remains among the most consequential syndromes in cardiovascular medicine, affecting an estimated 64 million individuals worldwide and accounting, in developed health systems, for more hospital admissions than any other single diagnosis. The 2021 European Society of Cardiology (ESC) guidelines formalised the tripartite classification of HF by left ventricular ejection fraction (LVEF): HF with reduced EF (HFrEF, LVEF < 40%), HF with mildly reduced EF (HFmrEF, LVEF 40-49%), and HF with preserved EF (HFpEF, LVEF ≥ 50%). This classification has brought conceptual clarity while also revealing that phenotypic categories are not immutable, and that a patient's position within the EF spectrum may shift substantially over months to years depending on the adequacy of therapy, the underlying aetiology, and the systemic comorbidity burden.

Objectives

This narrative review synthesises current evidence on the natural history, pathophysiological mechanisms, prognostic biomarkers, phenotypic transition dynamics, and pharmacological management of HFrEF, HFmrEF, and HFpEF, with particular emphasis on the cross-phenotype therapeutic activity of sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Data Sources

A structured search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials was conducted for the period 2015-2024 using standardised MeSH terms. Landmark randomised controlled trials (RCTs), pre-specified sub-group analyses, registry-based cohort studies, and consensus guidelines from the ESC, AHA/ACC, and HFA were included.

Results

HFrEF carries the highest short-term mortality risk, with sudden cardiac death accounting for 42% of total deaths; however, reverse cardiac remodelling is achievable in 35-40% of patients under full optimal medical therapy (OMT). HFmrEF demonstrates marked trajectory instability: at two-year follow-up, 35-40% of patients transition toward HFpEF and 25-35% deteriorate toward HFrEF without prompt pharmacological optimisation. HFpEF, now representing up to 52% of all incident HF cases, is driven by systemic microvascular inflammation; its mortality profile now approaches that of HFrEF when adjusted for age and multimorbidity. Across all three phenotypes, SGLT2 inhibitors yield consistent reductions in the composite of cardiovascular death and HF hospitalisation (pooled HR 0.77; 95% CI 0.72-0.83; n = 20,725).

Conclusions

LVEF-based phenotyping provides an indispensable but inherently dynamic framework for clinical decision-making in HF. Therapeutic strategies should be informed by serial echocardiographic reassessment and biomarker monitoring. SGLT2 inhibitors represent the most significant therapeutic advance in HF pharmacotherapy since neurohumoral blockade and warrant early, universal implementation in the eligible HF population.

Keywords: Heart Failure; Ejection Fraction; Hfref; Hfmref; Hfpef; SGLT2 Inhibitors; Cardiac Remodelling; Phenotypic Transition; Biomarkers; Prognosis; Reverse Remodelling