Definition and pathophysiology
Heart failure is a clinical syndrome in which the heart cannot provide blood flow commensurate with the body’s requirements, or can do so only at the expense of abnormally high filling pressures. The resulting haemodynamic congestion produces a characteristic clinical phenotype of breathlessness, fatigue and oedema. This definition does not depend on left ventricular ejection fraction (LVEF).
Heart failure with reduced ejection fraction (HFrEF) is defined by the combination of symptoms, with or without physical signs, and an LVEF below 40%. Signs may be absent in early disease or after effective treatment. HFrEF is commonly associated with structural and functional ventricular abnormalities and progressive neurohormonal activation. The therapeutic rationale for disease-modifying treatment is to reduce mortality, prevent recurrent hospitalization for worsening heart failure, and improve symptoms, functional capacity and quality of life.
The underlying aetiology is heterogeneous. Chronic heart failure evaluation should therefore seek reversible or treatable causes. The source material identifies coronary disease, hypertension, diabetes, obesity, valvular disease, cardiomyopathies, myocarditis, arrhythmias, thyroid disease, iron deficiency and anaemia, kidney dysfunction, sleep-disordered breathing, cancer-related disease and cardiac amyloidosis among the relevant clinical settings or comorbidities.
HFrEF is distinguished from heart failure with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) and heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%). Patients with HFmrEF may represent individuals whose LVEF has improved from below 40% or has declined from at least 50%. This distinction is clinically important because the strongest evidence for the four-pillar disease-modifying strategy applies to symptomatic HFrEF.
Clinical presentation and symptoms
Typical manifestations reflect pulmonary and systemic congestion, reduced forward cardiac output and limited exercise reserve. Symptoms may include:
Breathlessness
Fatigue
Reduced exercise tolerance
Peripheral oedema
Symptoms related to fluid retention and worsening congestion
The clinical course may be chronic and relatively stable or punctuated by episodes of worsening heart failure requiring hospitalization. Progressive sodium and fluid retention is described as a frequent mechanism of clinical deterioration and acute decompensation despite apparently effective chronic treatment.
Functional limitation is commonly described using the New York Heart Association (NYHA) classification. The source material specifically frames many pharmacological recommendations for patients with symptomatic NYHA class II–IV HFrEF.
Advanced or refractory heart failure should be considered when there is recurrent clinical deterioration despite careful follow-up and appropriate therapy. In this setting, the risk of sudden death and end-stage heart failure is high, and assessment for advanced therapies may be required.
Evaluation and physical examination
Assessment begins by establishing that the patient has a clinical heart-failure syndrome and by determining the LVEF. Physical signs may be absent, particularly in early disease and in optimally treated patients; their absence therefore does not exclude HFrEF.
Clinical evaluation should define:
The severity of symptoms and functional limitation.
Evidence of congestion or fluid retention.
The presence of precipitating or aggravating conditions.
The likely underlying aetiology.
Comorbidities that may influence treatment selection and tolerability.
Whether the patient has persistent or progressive disease suggestive of an advanced phenotype.
Particular attention should be paid to potentially reversible causes and associated cardiovascular conditions, including coronary syndromes, valvular disease, atrial fibrillation, ventricular arrhythmias, conduction disease and hypertension. Non-cardiovascular contributors include diabetes, thyroid disease, obesity, iron deficiency, anaemia, renal dysfunction, electrolyte abnormalities, pulmonary disease and sleep-disordered breathing.
A multidisciplinary model of care is recommended in chronic heart failure management. Patient education, self-care, lifestyle advice, exercise rehabilitation, structured follow-up and, where appropriate, telemonitoring form part of comprehensive management.
Diagnostics
Echocardiography and LVEF
LVEF is central to classification. HFrEF requires an LVEF below 40% in the presence of symptoms, with or without signs. Echocardiography is therefore essential for:
Measurement of LVEF
Assessment of ventricular structure and function
Evaluation of valvular disease
Identification of structural abnormalities
Assessment of findings that may suggest a specific aetiology
The diagnostic work-up should be directed toward identifying reversible or treatable causes of heart failure. The source material lists dedicated investigations for underlying aetiologies, but does not provide a complete test-by-test diagnostic protocol.
Electrocardiography
The source material identifies ECG assessment as relevant to cardiovascular comorbidities and device therapy, particularly in relation to conduction disturbances, atrial fibrillation, ventricular arrhythmias, atrioventricular block and left bundle branch block. It does not provide a complete ECG diagnostic pattern for HFrEF or a full set of device eligibility thresholds.
Imaging and aetiological assessment
Further investigation is determined by the suspected cause. Relevant disease-specific areas include:
Coronary disease and myocardial revascularization
Valvular heart disease
Cardiomyopathies
Myocarditis
Cardiac amyloidosis
Pulmonary hypertension associated with left-heart disease
Cancer-related cardiac disease
The source material indicates that cardiovascular magnetic resonance, genetic testing and other specialized investigations may have roles in selected cardiomyopathies and in the evaluation of HFpEF, but does not provide a comprehensive HFrEF imaging algorithm.
Electrophysiology and device assessment
Rhythm and conduction assessment is important because HFrEF may coexist with atrial fibrillation, ventricular arrhythmias, symptomatic bradycardia, pauses or atrioventricular block. Device-based treatment is considered after, and alongside, guideline-directed pharmacological therapy.
The principal devices discussed are:
Implantable cardioverter-defibrillator (ICD)
Cardiac resynchronization therapy (CRT)
Subcutaneous and wearable ICD systems
Mechanical circulatory support in advanced disease
The source material states that pharmacotherapy should be implemented before device therapy, while also emphasizing that pharmacological and non-pharmacological interventions should be used together. It does not provide the complete numerical criteria for ICD or CRT implantation.
Biomarkers and laboratory findings
Natriuretic peptides are important in the diagnostic assessment of heart failure, particularly in the non-acute setting. Raised natriuretic peptide concentrations support the diagnosis, although the source material does not provide a general diagnostic threshold for HFrEF.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) was used as an inclusion criterion in trials of patients with LVEF above 40%:
More than 300 pg/mL in sinus rhythm
More than 900 pg/mL in atrial fibrillation in the EMPEROR-Preserved population
At least 300 pg/mL in sinus rhythm
At least 600 pg/mL in atrial fibrillation in the DELIVER population
These thresholds belong to the cited trial populations and are not presented as universal treatment thresholds. The guideline discussion specifically states that NT-proBNP thresholds were not specified for treatment recommendations.
Laboratory assessment should also address comorbidities and treatment safety, particularly:
Renal dysfunction
Potassium and other electrolyte disorders
Diabetes and glycaemic status
Iron deficiency and anaemia
Thyroid disease
The source material does not provide a complete laboratory monitoring schedule or drug-specific biochemical stopping rules.
Treatment and management
Therapeutic objectives
Pharmacological treatment is the cornerstone of HFrEF management and should precede consideration of device therapy while being delivered alongside non-pharmacological care. The major objectives are:
Reduction in mortality
Prevention of recurrent hospitalization from worsening heart failure
Improvement in symptoms and clinical status
Improvement in functional capacity
Improvement in quality of life
The guideline approach is based on simultaneous use of four foundational treatment classes rather than prolonged sequential reliance on a single neurohormonal pathway.
The four pillars of HFrEF therapy
The four foundational classes are:
An angiotensin receptor-neprilysin inhibitor (ARNI), or an angiotensin-converting enzyme inhibitor (ACE-I) when an ARNI is not used.
A beta-blocker.
A mineralocorticoid receptor antagonist (MRA).
A sodium-glucose co-transporter 2 (SGLT2) inhibitor.
These treatments complement one another through distinct mechanisms and are intended for patients with symptomatic HFrEF. The source material identifies the relevant guideline population as NYHA class II–IV with LVEF ≤40%.
Treatment should be individualized according to blood pressure, renal function, potassium concentration, congestion, heart rate, rhythm, comorbidities and tolerability. The supplied material does not specify a titration sequence, target doses or dose-adjustment rules for the four foundational classes.
Angiotensin receptor-neprilysin inhibitor
ARNI therapy is one of the principal disease-modifying treatments for HFrEF. It belongs to the foundational treatment strategy and is used to reduce adverse clinical outcomes while improving the clinical state.
Where an ARNI is not used, an ACE-I forms part of the established foundational approach. Angiotensin II type 1 receptor blockers (ARBs) are additional alternatives or considerations in selected patients, although the source material does not state the precise circumstances or dosing.
No ARNI dose is provided in the source material.
Beta-blockers
Beta-blockers are a foundational treatment for symptomatic HFrEF. They are also relevant to patients with coexisting atrial fibrillation, for whom treatment must be integrated with rhythm and rate management.
The supplied material does not state individual beta-blocker names, starting doses, target doses or titration schedules.
Mineralocorticoid receptor antagonists
MRAs are included among the treatments recommended in symptomatic HFrEF. Their use requires attention to renal function and potassium because kidney dysfunction and electrolyte abnormalities are important comorbid issues in heart failure management.
No specific MRA, dose, biochemical threshold or monitoring interval is supplied.
SGLT2 inhibitors
SGLT2 inhibition is a foundational treatment across the spectrum of heart failure described in the source material. In patients with LVEF above 40%, empagliflozin and dapagliflozin reduced the composite risk of cardiovascular death or heart-failure worsening, with the principal effect driven by fewer heart-failure hospitalizations. These effects were independent of diabetes status.
The doses explicitly provided for the preserved or mildly reduced EF trial populations were:
Empagliflozin: 10 mg once daily
Dapagliflozin: 10 mg once daily
The source material does not separately state HFrEF dosing, but identifies SGLT2 inhibitors as part of the HFrEF four-pillar strategy.
Diuretics
Diuretics are used to control congestion and fluid retention. They are described as the cornerstone of treatment when fluid retention is present, including in pulmonary hypertension associated with left-heart disease.
Diuretic therapy is primarily symptom- and congestion-directed rather than one of the four foundational mortality-modifying pillars. The source material identifies furosemide-based acute-heart-failure algorithms and combination loop-diuretic/thiazide strategies, but does not provide specific chronic outpatient doses.
Other pharmacological options
Selected patients may require additional therapy. The source material lists:
ARBs
Ivabradine, described as a channel inhibitor
Hydralazine combined with isosorbide dinitrate
Digoxin
Recently reported advances in HFrEF pharmacotherapy
Treatments for associated atrial fibrillation and other comorbidities
The provided material does not specify eligibility criteria, doses or detailed outcome indications for these agents.
Management of comorbidities
Comorbidity management is integral to HFrEF care. Relevant domains include:
Coronary disease and myocardial revascularization
Valvular disease
Atrial fibrillation
Ventricular arrhythmias and conduction disorders
Hypertension
Diabetes
Thyroid disorders
Obesity
Iron deficiency and anaemia
Kidney dysfunction
Electrolyte disorders
Lung disease and sleep-disordered breathing
Cancer
Amyloidosis
The primary treatment strategy for pulmonary hypertension due to left-heart disease is optimization of the underlying cardiac disorder. Pulmonary arterial hypertension drugs have limited or conflicting evidence in this setting, and some studies identified fluid retention or other adverse events. Diuresis remains central when fluid retention is present.
Device therapy
Implantable cardioverter-defibrillator
ICD therapy is considered for prevention of sudden cardiac death in selected patients with HFrEF. The source material distinguishes:
Secondary prevention after appropriate clinical events
Primary prevention in selected patients
Patient selection
Programming
Subcutaneous and wearable systems
The complete implantation criteria are not provided.
Cardiac resynchronization therapy
CRT is another device-based treatment for selected patients with HFrEF, particularly in the setting of ventricular dyssynchrony and relevant conduction disease. Left bundle branch block and QRS assessment are specifically identified in the device-related material.
The source material does not provide the full LVEF, QRS-duration, rhythm, symptom-class or pacing-dependence criteria for CRT.
Advanced therapies
Recurrent hospitalization and progressive deterioration despite optimized treatment may indicate advanced heart failure. Options discussed in the source material include:
Left ventricular assist device implantation
Mechanical circulatory support
Heart transplantation
Symptom control and end-of-life care
In advanced HFrEF, left ventricular assist device implantation may substantially reduce or normalize mean pulmonary artery pressure in some patients, although this response is not universal.
Guideline recommendations
The guideline framework supports the following principles:
Symptomatic HFrEF is defined by symptoms, with or without signs, and LVEF below 40%.
Patients with HFrEF should receive guideline-directed medical therapy.
Pharmacological therapy is the cornerstone of management and should be implemented before device therapy.
Treatment should pursue reductions in mortality and recurrent hospitalization, together with improvement in symptoms, functional capacity and quality of life.
The four foundational treatment classes are ARNI or ACE-I, beta-blocker, MRA and SGLT2 inhibitor.
Diuretics should be used to control congestion and fluid retention.
Device therapy, including ICD and CRT, should be considered in appropriately selected patients after evaluation of the clinical phenotype and response to medical therapy.
Reversible or treatable causes of heart failure should be actively sought.
Multidisciplinary management, patient education, self-care, exercise rehabilitation and structured follow-up are recommended components of chronic care.
Patients with improved LVEF should not be regarded as cured. The source material reports a strong recommendation from ACC/AHA/HFSA guidance to continue the guideline-directed therapy that produced LVEF improvement indefinitely, including in asymptomatic patients, because withdrawal has been associated with early relapse.
Decisions for an individual patient require clinical judgment and discussion with the patient and caregiver where appropriate.
Acute deterioration and transitions of care
Chronic HFrEF may be complicated by acute decompensated heart failure, pulmonary oedema, isolated right-ventricular failure or cardiogenic shock. Acute management is organized around:
Haemodynamic stabilization
Assessment of the clinical presentation and precipitating factors
Oxygen or ventilatory support when indicated
Diuretic treatment for congestion
Vasodilators in appropriate patients
Inotropes and vasopressors in selected severe presentations
Thromboembolism prophylaxis
Short-term mechanical circulatory support in cardiogenic shock when appropriate
Before discharge, patients require clinical assessment and a post-discharge management plan. Early follow-up after hospitalization is specifically recommended, with attention to treatment optimization and recurrence of congestion or worsening symptoms.
Prognosis and follow-up
HFrEF carries substantial risks of death, recurrent hospitalization and progressive functional limitation. Despite treatment, patients remain vulnerable to worsening sodium and fluid retention, acute decompensation, sudden cardiac death and progression to advanced heart failure.
Follow-up should be structured and multidisciplinary. It should reassess:
Symptoms and NYHA functional status
Exercise tolerance and quality of life
Evidence of congestion
Blood pressure and heart rate
Cardiac rhythm and conduction
Renal function and electrolytes
Treatment tolerability and implementation of the four foundational therapies
Comorbidities and potentially reversible causes
Need for ICD, CRT or referral for advanced-heart-failure assessment
Natriuretic peptides may assist in diagnosis and monitoring, although the supplied material does not define a universal biomarker-led follow-up protocol. Telemonitoring is included among recommended chronic-heart-failure care strategies.
LVEF should be interpreted longitudinally. An improved LVEF represents improvement rather than definitive recovery, because residual risk remains and relapse or recurrent events may occur. Accordingly, disease-modifying therapy should be continued indefinitely when it has enabled LVEF improvement, even if symptoms have resolved.
