Definition and classification
Heart failure with mildly reduced ejection fraction (HFmrEF) is a clinical syndrome defined by the combination of symptoms and/or signs of heart failure and a left ventricular ejection fraction (LVEF) of 41–49%. It occupies an intermediate position between heart failure with reduced ejection fraction (HFrEF), defined by an LVEF ≤40%, and heart failure with preserved ejection fraction (HFpEF), defined by an LVEF ≥50%.
The ejection-fraction classification is clinically useful but should not be regarded as a series of completely discrete diseases. Heart failure extends across the full range of LVEF, and echocardiographic measurement is subject to meaningful variability. HFmrEF may therefore represent several clinically distinct trajectories:
A patient whose LVEF has improved from a previous value below 40%.
A patient whose LVEF has declined from a previous value of at least 50%.
A patient with persistently mildly reduced systolic function.
This dynamic nature makes prior imaging particularly important when interpreting a current LVEF of 41–49%.
Diagnostic phenotype
| Criterion | HFmrEF |
|---|---|
| Symptoms and/or signs of heart failure | Required |
| LVEF | 41–49% |
| Natriuretic peptides | BNP ≥35 pg/mL or NT-proBNP ≥125 pg/mL supports the diagnosis |
| Structural or functional cardiac abnormality | Evidence such as increased left atrial size, left ventricular hypertrophy or abnormal LV filling supports the diagnosis |
Unlike HFpEF, objective evidence of structural or functional cardiac abnormality or raised natriuretic peptides is not mandatory for HFmrEF when the diagnosis of heart failure is clinically secure and the LVEF measurement is reliable. Nevertheless, these findings increase diagnostic confidence.
The presence of symptoms alone is insufficient. Anaemia and pulmonary, renal, thyroid or hepatic disease may produce a similar symptom complex; in the absence of cardiac dysfunction, these conditions do not fulfil the definition of heart failure. They may, however, coexist with heart failure and aggravate the syndrome.
Epidemiology and clinical phenotype
Heart failure with an LVEF greater than 40%—comprising HFmrEF and HFpEF—accounts for approximately half of patients with symptomatic heart failure. These patients experience substantial morbidity and mortality, despite often having a considerable burden of non-cardiac comorbidity.
HFmrEF has clinical characteristics that, on average, resemble HFrEF more closely than HFpEF. Patients are more commonly male and younger than those with HFpEF and have a greater likelihood of coronary artery disease, which is present in approximately 50–60% of patients. Conversely, atrial fibrillation and non-cardiac comorbidities are less frequent than in HFpEF.
The clinical population is heterogeneous because the HFmrEF range includes both patients with recovering systolic function and those with deterioration from a previously preserved LVEF. This heterogeneity is relevant to treatment selection and prognosis.
Pathophysiology
The defining physiological abnormality is heart failure occurring with mildly impaired LV systolic function. The syndrome remains fundamentally one of impaired cardiac performance, in which the heart cannot provide blood flow commensurate with the body’s requirements or can do so only at the cost of elevated filling pressures.
Congestion and elevated filling pressures produce the characteristic clinical syndrome of breathlessness, fatigue and oedema. The underlying mechanisms are not uniform across the HFmrEF population. Some patients have a pathophysiological profile closer to HFrEF, whereas others have features overlapping with HFpEF, including abnormalities of LV relaxation and filling.
Hypertension and diabetes can contribute to the development of heart failure in the preserved and mildly reduced EF ranges, and obesity is increasingly recognised as a potential contributor. Coronary artery disease is particularly relevant in HFmrEF and may provide an important substrate for LV dysfunction.
Because LVEF may improve or deteriorate over time, the phenotype should be understood as a point on a continuum rather than as a permanent biological category. Serial assessment can therefore reveal clinically important change in systolic function.
Clinical presentation and symptoms
HFmrEF presents with the typical manifestations of heart failure:
Breathlessness
Fatigue
Peripheral or systemic oedema
Other symptoms and signs attributable to congestion or reduced cardiac performance
Signs may be absent in early disease and may also be absent in patients receiving effective treatment. Their absence therefore does not exclude HFmrEF.
The clinical presentation can be influenced substantially by associated conditions. Atrial fibrillation, coronary artery disease, hypertension, diabetes, obesity and other comorbidities may contribute to symptoms, complicate assessment and increase overall risk. Non-cardiac disorders—including anaemia and pulmonary, renal, thyroid or hepatic disease—may mimic or worsen heart failure symptoms.
HFmrEF may be encountered in either ambulatory chronic heart failure or during a decompensated presentation. The source material does not provide a detailed symptom-based distinction between these clinical settings or specific acute-care thresholds.
Evaluation and physical examination
Evaluation begins with confirmation of a heart-failure syndrome rather than simply identifying an LVEF in the 41–49% range. The clinical assessment should establish whether symptoms and/or signs are consistent with congestion or impaired cardiac performance and should consider alternative and coexisting causes of breathlessness, fatigue and oedema.
Physical findings may be absent, particularly in early or optimally treated disease. Consequently, clinical suspicion should not be dismissed because overt congestion is not detected on examination.
The assessment should also seek evidence of structural heart disease and associated conditions. Findings that support HFmrEF include:
Increased left atrial size
LV hypertrophy
Echocardiographic evidence of impaired or abnormal LV filling
Clinical evidence of coronary artery disease or atrial fibrillation
The underlying aetiology should be investigated systematically. The available source material indicates that this investigation is addressed by broader heart-failure diagnostic pathways, but it does not provide the complete aetiological testing protocol.
Diagnostics
Echocardiography
Echocardiography is the usual method for measuring LVEF and is central to establishing HFmrEF. A value of 41–49%, in the presence of symptoms and/or signs of heart failure, fulfils the EF component of the definition.
Echocardiography also helps identify abnormalities that support the diagnosis, including:
LV hypertrophy
Increased left atrial size
Abnormal LV filling or other measures consistent with elevated filling pressures
Structural cardiac disease
The variability inherent in echocardiographic EF measurement should be recognised, particularly when a value is close to a classification boundary. The interpretation is strengthened by reviewing previous studies and considering the direction of change over time.
Cardiac magnetic resonance and nuclear techniques
When echocardiography cannot provide a reliable assessment of EF, cardiac magnetic resonance imaging may be used. Nuclear techniques are described as an alternative, although rarely required.
Other diagnostic approaches
The source material identifies several approaches relevant to the evaluation of patients with HFpEF and HFmrEF, including more detailed echocardiographic assessment, cardiac magnetic resonance, exercise or diastolic stress testing, invasive haemodynamic assessment and cardiopulmonary exercise testing. However, it does not provide sufficient procedural criteria or thresholds to define their routine use specifically in HFmrEF.
Biomarkers and laboratory findings
Natriuretic peptides support the diagnosis of HFmrEF. The guideline thresholds provided are:
BNP ≥35 pg/mL
NT-proBNP ≥125 pg/mL
Raised natriuretic peptide concentrations make HFmrEF more likely, but they are not mandatory when the clinical diagnosis of heart failure is certain and the LVEF has been reliably measured.
Natriuretic peptide interpretation should occur in the context of the entire clinical assessment. The source material specifically notes that non-cardiac diseases may produce symptoms resembling heart failure and may coexist with or exacerbate it. It does not provide a comprehensive account of the effects of individual comorbidities on natriuretic peptide concentrations.
Other laboratory tests, biomarker thresholds and monitoring schedules are not specified in the available material.
Treatment and management
General principles
Management should address both congestion and the cardiovascular conditions contributing to the syndrome. HFmrEF has historically lacked a substantial prospective randomised evidence base dedicated exclusively to this phenotype. Consequently, treatment recommendations are less definitive than for HFrEF and have partly been informed by subgroup analyses and evidence from adjacent EF categories.
The therapeutic approach should take account of:
Current symptoms and congestion
Previous LVEF and trajectory of ventricular function
Coronary artery disease
Atrial fibrillation
Hypertension
Diabetes
Obesity and other comorbidities
The patient’s response and tolerance to treatment
Diuretics
Diuretics remain the principal treatment for controlling congestion in HFmrEF. They are used to relieve fluid overload and associated symptoms. The source material does not specify individual diuretic agents, dosing regimens, titration schedules or laboratory monitoring requirements.
Diuretic therapy is primarily directed at symptomatic decongestion and should be integrated with management of the underlying cardiac disease and comorbidities.
Disease-modifying treatment
Evidence suggests that some therapies established in HFrEF may also benefit patients with HFmrEF, particularly those closer to the reduced-EF range. The therapies identified include:
Angiotensin-converting enzyme inhibitors
Angiotensin-receptor blockers
Beta-blockers
Mineralocorticoid receptor antagonists
Sacubitril/valsartan
The evidence base is not described as sufficiently robust to support strong, phenotype-specific recommendations for every treatment in all patients with HFmrEF. Treatment decisions should therefore be individualised, with particular attention to the patient’s clinical phenotype and prior or current LVEF.
Sodium-glucose co-transporter 2 inhibitors
Sodium-glucose co-transporter 2 inhibitors have demonstrated benefit across the spectrum of ejection fraction. The available material states that their benefit does not decline as EF rises and that they should currently be considered standard therapy in heart failure, including HFpEF and HFmrEF.
The source material does not state drug-specific doses, renal thresholds or practical instructions for initiation and monitoring.
Sacubitril/valsartan and renin–angiotensin system blockade
Patients with HFmrEF may benefit from therapies used in HFrEF, including renin–angiotensin system blockade and sacubitril/valsartan. The evidence is particularly relevant to the overlap between HFmrEF and HFrEF, although the material does not provide drug doses, target doses or comparative treatment algorithms.
Beta-blockers and mineralocorticoid receptor antagonists
Beta-blockers and mineralocorticoid receptor antagonists are included among treatments that may be considered in HFmrEF based on evidence extrapolated from other EF categories. The available material does not specify selection criteria, dosing or monitoring requirements.
Treatment of associated disease
The high prevalence of coronary artery disease and the frequent presence of hypertension, diabetes, obesity and atrial fibrillation make treatment of associated disease an essential component of care. These conditions may contribute to the development and progression of HFmrEF and increase the patient’s overall risk.
Specific recommendations for revascularisation, rhythm management, anticoagulation, blood-pressure targets, weight management or diabetes therapy are not provided in the source material and cannot be detailed here.
Guideline-oriented treatment summary
The guideline-based therapeutic position can be summarised as follows:
| Therapeutic objective | Management principle |
|---|---|
| Relieve congestion | Use diuretics |
| Provide disease modification | Consider therapies established in HFrEF, including ACE inhibitors, ARBs, beta-blockers, MRAs and sacubitril/valsartan |
| Treat heart failure across the EF spectrum | Consider SGLT2 inhibitors as standard therapy |
| Address the individual phenotype | Incorporate prior LVEF, coronary disease, atrial fibrillation and comorbidities |
| Manage uncertainty | Recognise that evidence for HFmrEF-specific treatment remains less extensive than for HFrEF |
No specific drug doses, treatment sequence or class and level-of-recommendation grades are supplied in the source material.
Prognosis
HFmrEF is associated with substantial morbidity and mortality. In ambulatory populations, mortality is lower on average than in HFrEF and is more similar to that observed in HFpEF. Nevertheless, HFmrEF should not be considered a benign or low-risk condition.
Among patients hospitalised with decompensated heart failure, long-term outcomes are poor across EF categories. The available material indicates that post-discharge rehospitalisation and long-term mortality are similarly high in HFpEF and HFrEF, and provides outcome data showing comparable five-year mortality and readmission burden across reduced, borderline/mildly reduced and preserved EF groups. Patients with preserved or mildly reduced EF may have a greater burden of non-cardiovascular comorbidity, which contributes to non-cardiovascular rehospitalisation and death.
Prognosis is influenced by the patient’s clinical trajectory. HFmrEF caused by recovery from a previously reduced EF is clinically different from HFmrEF caused by deterioration from preserved function, although the source material does not provide separate outcome estimates for these groups.
Follow-up
Follow-up should include reassessment of symptoms, congestion, treatment response and ventricular function. Because HFmrEF may reflect improvement or deterioration from another EF category, serial echocardiography and review of prior LVEF are clinically important when there is a change in symptoms or when treatment decisions depend on the phenotype.
Ongoing care should also monitor the conditions that contribute to HFmrEF and its prognosis, particularly coronary artery disease, hypertension, diabetes, obesity, atrial fibrillation and other comorbidities. The source material identifies multidisciplinary management, chronic-heart-failure follow-up and biomarker monitoring as components of guideline-based care, but does not provide a detailed follow-up schedule or specific monitoring intervals.
Key points
HFmrEF is defined by symptoms and/or signs of heart failure with an LVEF of 41–49%.
Natriuretic peptide elevation, increased left atrial size, LV hypertrophy and abnormal LV filling support the diagnosis but are not mandatory when the clinical diagnosis and LVEF measurement are certain.
HFmrEF is a heterogeneous and dynamic phenotype that may represent improvement from HFrEF or deterioration from HFpEF.
Coronary artery disease is common, whereas atrial fibrillation and non-cardiac comorbidity are less frequent than in HFpEF.
Diuretics are used to control congestion.
Therapies used in HFrEF—including renin–angiotensin system blockade, beta-blockers, mineralocorticoid receptor antagonists and sacubitril/valsartan—may benefit selected patients.
SGLT2 inhibitors should be considered standard therapy across the heart-failure EF spectrum.
Despite a generally lower mortality than HFrEF in ambulatory cohorts, HFmrEF carries substantial morbidity, mortality and rehospitalisation risk.
