Heart Failure with Reduced Ejection Fraction (HFrEF)
Summary
Heart Failure with Reduced Ejection Fraction (HFrEF) is a clinical syndrome characterised by the heart's inability to pump blood effectively due to impaired left ventricular contraction. Defined as a left ventricular ejection fraction (LVEF) of 40% or less, HFrEF represents approximately 50% of all heart failure cases. The condition results from structural or functional cardiac abnormalities, leading to characteristic symptoms of dyspnoea, fatigue, and fluid retention. Modern pharmacotherapy with guideline-directed medical therapy (GDMT) has transformed outcomes, with the "four pillars" of therapy—ARNI/ACE-I/ARB, beta-blockers, MRAs, and SGLT2 inhibitors—demonstrating significant mortality reduction.
Key Facts
- Definition: LVEF ≤40% with symptoms of heart failure
- Prevalence: Affects 1-2% of the adult population in developed countries
- Mortality: 5-year mortality approximately 50% without optimal treatment
- Aetiology: Ischaemic heart disease accounts for 60-70% of cases
- Treatment Revolution: Optimal GDMT reduces mortality by up to 60-70%
- Biomarkers: Elevated BNP/NT-proBNP supports diagnosis
- Device Therapy: ICD and CRT improve outcomes in selected patients
Clinical Pearls
High-Yield Points for Clinical Practice:
- Always initiate all four pillars of GDMT unless contraindicated
- Titrate medications to target doses, not just until symptoms improve
- SGLT2 inhibitors show benefit regardless of diabetes status
- Iron deficiency is common and should be treated with IV iron
- Consider referral for advanced therapies when EF remains under 35% despite optimal therapy
Why This Matters Clinically
HFrEF is a leading cause of hospital admissions and healthcare expenditure worldwide. Early diagnosis and prompt initiation of GDMT dramatically improves survival and quality of life. The condition requires lifelong management with regular monitoring and medication optimisation. Understanding the pathophysiology and treatment principles is essential for all healthcare providers, as heart failure presentations are common across all medical specialties.
Incidence and Prevalence
| Metric | Value | Notes |
|---|---|---|
| Global Prevalence | 64 million | Approximately 50% are HFrEF |
| Developed Countries | 1-2% of adults | Increases with age |
| Age over 70 | 10-15% | Peak prevalence |
| Annual Incidence | 1-9 per 1000 | Varies by population |
Demographics
- Age: Mean age at diagnosis is 70-75 years
- Sex: Slightly more common in males (55-60%)
- Ethnicity: Higher rates in African Americans with worse outcomes
- Geography: Higher prevalence in regions with high IHD burden
Risk Factors
Non-Modifiable:
- Age over 65 years
- Male sex
- Family history of cardiomyopathy
- Genetic mutations (TTN, LMNA, MYH7)
Modifiable:
- Coronary artery disease (60-70% of cases)
- Hypertension (long-standing)
- Diabetes mellitus
- Obesity
- Smoking
- Excessive alcohol consumption
- Cardiotoxic chemotherapy
- Valvular heart disease
Geographic Variation
- High-income countries: Predominantly ischaemic aetiology
- Low/middle-income countries: Higher rates of rheumatic and infectious causes
- Sub-Saharan Africa: Increased hypertensive and peripartum cardiomyopathy
Mechanism Overview
HFrEF develops through a cascade of events following initial myocardial injury:
Stage 1: Initial Cardiac Injury
- Myocardial infarction (loss of functional myocardium)
- Cardiomyopathy (genetic or acquired)
- Chronic pressure/volume overload (hypertension, valvular disease)
Stage 2: Compensatory Mechanisms
- Frank-Starling mechanism (increased preload leads to increased stroke volume)
- Neurohormonal activation:
- RAAS activation leads to fluid retention and vasoconstriction
- Sympathetic nervous system activation leads to tachycardia and inotropy
- Cardiac hypertrophy (initially compensatory)
Stage 3: Maladaptive Remodeling
- Chronic neurohormonal activation becomes harmful
- Left ventricular dilation and spherical remodeling
- Myocyte apoptosis and fibrosis
- Functional mitral regurgitation develops
- Further reduction in cardiac output
Stage 4: Clinical Heart Failure
- Symptoms of congestion and low output
- Progressive deterioration without intervention
- Risk of arrhythmias and sudden death
Key Molecular Events
| Pathway | Effect | Clinical Consequence |
|---|---|---|
| RAAS Activation | Angiotensin II leads to vasoconstriction and aldosterone release | Salt/water retention, afterload increase |
| Sympathetic Activation | Norepinephrine leads to chronotropy and inotropy | Tachycardia, increased oxygen demand |
| Natriuretic Peptides | BNP/ANP counter-regulatory | Natriuresis, vasodilation (overwhelmed) |
| Inflammation | IL-6, TNF-alpha elevated | Cardiac remodeling, cachexia |
| Oxidative Stress | ROS production | Myocyte dysfunction, apoptosis |
Typical Presentation
Symptoms:
Signs:
NYHA Functional Classification
| Class | Description | Activity Level |
|---|---|---|
| I | No limitation | Ordinary activity causes no symptoms |
| II | Slight limitation | Comfortable at rest; ordinary activity causes symptoms |
| III | Marked limitation | Comfortable at rest; less than ordinary activity causes symptoms |
| IV | Severe limitation | Symptoms at rest; any physical activity increases discomfort |
Atypical Presentations
Elderly:
Young Adults:
Red Flags and Emergencies
URGENT ASSESSMENT REQUIRED:
- Cardiogenic shock: Hypotension (SBP under 90 mmHg), cold extremities, altered consciousness
- Acute pulmonary oedema: Severe dyspnoea, pink frothy sputum, SpO2 under 90%
- Ventricular arrhythmias: Palpitations, syncope, sustained VT/VF
- New chest pain: Exclude acute coronary syndrome
- Syncope: Risk of sudden cardiac death
Structured Examination Approach
1. General Inspection
- Level of distress, breathlessness at rest
- Body habitus (cachexia in advanced HF)
- Pallor, cyanosis, jaundice
2. Vital Signs
- BP: Hypotension may indicate advanced disease or over-diuresis
- Heart rate: Tachycardia is common
- Respiratory rate: Elevated in decompensation
- SpO2: Low in pulmonary congestion
3. Cardiovascular Examination
- JVP: Elevated (over 8 cm) indicates fluid overload
- Apex beat: Displaced laterally and inferiorly
- Heart sounds: S3 gallop, murmurs (MR common)
- Carotid pulse: Small volume, slow rising
4. Respiratory Examination
- Tracheal position: Midline unless effusion
- Percussion: Dull at bases with effusions
- Auscultation: Bilateral basal crackles, wheeze
5. Abdominal Examination
- Hepatomegaly: Tender in acute congestion
- Ascites: Advanced cases
- Hepatojugular reflux: Positive
6. Peripheral Examination
- Peripheral oedema: Ankles, sacrum
- Peripheral perfusion: Cold extremities suggest low output
- Capillary refill: Prolonged over 2 seconds
Special Tests
| Test | Technique | Positive Finding | Sensitivity/Specificity |
|---|---|---|---|
| Hepatojugular Reflux | Press on liver for 15 seconds | JVP rises and stays elevated | 70%/85% for elevated filling pressures |
| Valsalva Maneuver | Sustained expiration against closed glottis | Square wave response | Specific for elevated LVEDP |
| Bendopnea | Breathlessness when bending forward | Symptom within 30 seconds | Correlates with elevated filling pressures |
First-Line Investigations
| Investigation | Expected Findings | Clinical Use |
|---|---|---|
| BNP | Over 100 pg/mL | Diagnosis, prognosis |
| NT-proBNP | Over 300 pg/mL | Diagnosis, prognosis |
| ECG | LBBB, Q waves, LVH, AF | Identify aetiology, CRT eligibility |
| Troponin | May be mildly elevated | Exclude ACS, prognostic |
| FBC | Anaemia common (30-50%) | Identifies treatable cause |
| U and E | Renal impairment, electrolytes | Monitor diuretics, ACE-I/ARB |
| LFTs | Elevated in congestion | Hepatic congestion marker |
| TFTs | Hypo/hyperthyroidism | Treatable causes |
| HbA1c | Diabetes screening | Comorbidity identification |
| Iron Studies | Ferritin under 100 or TSAT under 20% | IV iron indication |
Imaging
Echocardiography (Essential)
- LVEF quantification (over 40% is HFrEF definition)
- Wall motion abnormalities
- Chamber dimensions
- Valvular assessment
- Diastolic function
- Pulmonary pressures
Chest X-ray
- Cardiomegaly (CTR over 0.5)
- Pulmonary venous congestion
- Pleural effusions
- Kerley B lines
Cardiac MRI (Selected Cases)
- Precise EF measurement
- Fibrosis assessment (LGE)
- Aetiology determination
- Viability assessment pre-revascularisation
Coronary Angiography
- Indicated for suspected ischaemic aetiology
- Assess revascularisation candidacy
- May perform FFR/iFR if needed
Diagnostic Criteria (ESC 2021)
Diagnosis requires ALL of:
- Symptoms and/or signs of heart failure
- LVEF ≤40%
- Elevated natriuretic peptides (BNP over 35 pg/mL or NT-proBNP over 125 pg/mL)
EF-Based Classification (ESC/AHA)
| Category | LVEF | Description |
|---|---|---|
| HFrEF | ≤40% | Reduced ejection fraction |
| HFmrEF | 41-49% | Mildly reduced ejection fraction |
| HFpEF | ≥50% | Preserved ejection fraction |
| HFimpEF | Was ≤40%, now over 40% | Improved ejection fraction |
ACC/AHA Stages
| Stage | Description | Management Focus |
|---|---|---|
| A | At risk, no structural disease | Risk factor modification |
| B | Structural disease, no symptoms | GDMT initiation |
| C | Structural disease with current/prior symptoms | Optimal GDMT, devices |
| D | Advanced HF requiring specialized interventions | LVAD, transplant, palliative care |
INTERMACS Profiles (Advanced HF)
| Profile | Description | Urgency |
|---|---|---|
| 1 | Cardiogenic shock | Critical |
| 2 | Progressive decline on inotropes | High |
| 3 | Stable but inotrope-dependent | Moderate |
| 4 | Resting symptoms | Elective |
| 5-7 | Exertion limited to housebound | Less urgent |
Guideline-Directed Medical Therapy: The Four Pillars
CRITICAL: Initiate all four classes simultaneously or in rapid succession unless contraindicated. Titrate to maximum tolerated doses.
Pillar 1: RAAS Inhibition
| Drug Class | First Choice | Target Dose | Key Monitoring |
|---|---|---|---|
| ARNI (Preferred) | Sacubitril/Valsartan | 97/103 mg BD | BP, K+, renal function |
| ACE-I (Alternative) | Ramipril, Lisinopril | Ramipril 10 mg OD | Cough, K+, renal function |
| ARB (If ACE-I intolerant) | Candesartan, Losartan | Candesartan 32 mg OD | K+, renal function |
Note: Allow 36-hour washout between ACE-I and ARNI
Pillar 2: Beta-Blockers
| Drug | Starting Dose | Target Dose | Notes |
|---|---|---|---|
| Bisoprolol | 1.25 mg OD | 10 mg OD | Cardioselective |
| Carvedilol | 3.125 mg BD | 25-50 mg BD | Alpha and beta blockade |
| Metoprolol Succinate | 12.5-25 mg OD | 200 mg OD | Extended release |
| Nebivolol | 1.25 mg OD | 10 mg OD | For elderly over 70 |
Pillar 3: Mineralocorticoid Receptor Antagonists (MRA)
| Drug | Dose | Contraindications |
|---|---|---|
| Spironolactone | 25-50 mg OD | K+ over 5.0, eGFR under 30 |
| Eplerenone | 25-50 mg OD | Less gynaecomastia |
Pillar 4: SGLT2 Inhibitors
| Drug | Dose | Evidence |
|---|---|---|
| Dapagliflozin | 10 mg OD | DAPA-HF trial |
| Empagliflozin | 10 mg OD | EMPEROR-Reduced trial |
Benefit independent of diabetes status
Additional Medical Therapy
Diuretics (Symptom Control)
- Loop diuretics for congestion: Furosemide 40-80 mg, titrate to euvolaemia
- Not mortality-reducing but essential for symptoms
Ivabradine
- Indication: Sinus rhythm, HR over 70 bpm despite maximised beta-blocker
- Dose: 5-7.5 mg BD
- Trial: SHIFT
Hydralazine + Isosorbide Dinitrate
- Indication: RAAS inhibitor intolerant (especially African Americans)
- Evidence: A-HeFT
Vericiguat
- Indication: Recent HF hospitalisation despite GDMT
- Trial: VICTORIA
Device Therapy
Implantable Cardioverter-Defibrillator (ICD)
- Indication: LVEF ≤35% despite over 3 months of optimal GDMT
- Purpose: Primary prevention of sudden cardiac death
- Benefit: 30% relative risk reduction in mortality
Cardiac Resynchronisation Therapy (CRT)
- Indication: LVEF ≤35%, QRS ≥150 ms with LBBB, NYHA II-IV ambulatory
- Purpose: Improve contractility via biventricular pacing
- Benefit: Improves symptoms, reduces hospitalisations, reduces mortality
Advanced Therapies
Left Ventricular Assist Device (LVAD)
- Bridge to transplant or destination therapy
- For INTERMACS profiles 1-4
Heart Transplantation
- Gold standard for end-stage HF
- Limited by donor availability
- 1-year survival over 85%
Palliative Care
- Integrate early in disease course
- Focus on symptom control and quality of life
- Consider when advanced therapies not suitable
Acute Complications
| Complication | Risk Factors | Prevention | Management |
|---|---|---|---|
| Cardiogenic Shock | Acute decompensation, MI | Optimal GDMT | Inotropes, MCS, urgent assessment |
| Acute Pulmonary Oedema | Fluid overload, non-adherence | Diuretic education | IV diuretics, NIV, positioning |
| Arrhythmias | Low EF, electrolyte disturbance | ICD, K+/Mg2+ balance | DCCV, antiarrhythmics, ablation |
| Acute Kidney Injury | Over-diuresis, low output | Careful diuretic titration | Hold nephrotoxins, volume assessment |
| Thromboembolism | Low EF, AF, immobility | Anticoagulation if indicated | Therapeutic anticoagulation |
Chronic Complications
- Cardiac cachexia: Muscle wasting, weight loss, poor prognosis
- Anaemia: Present in 30-50%, treat with IV iron
- Depression: Screen and treat
- Cognitive impairment: Due to low output, emboli
- Hepatic congestion: Congestive hepatopathy, cardiac cirrhosis
- Renal dysfunction: Cardiorenal syndrome
Long-term Sequelae
- Progressive deterioration without treatment
- Reduced quality of life
- Frequent hospitalisations (30-day readmission 20-25%)
- Sudden cardiac death (50% of deaths)
- Pump failure death
Natural History (Untreated)
Without treatment, HFrEF has a poor prognosis:
- 1-year mortality: 30-40%
- 5-year mortality: 50-60%
- Progressive symptoms and functional decline
With Optimal Treatment
Modern GDMT dramatically improves outcomes:
- Mortality reduction with each therapy: 20-30%
- Combined effect: 60-70% relative risk reduction
- Many patients stabilise or improve EF (HFimpEF)
Prognostic Factors
Poor Prognosis:
- Lower EF (under 25%)
- NYHA Class IV
- Elevated BNP/NT-proBNP
- Hyponatraemia
- Renal dysfunction
- Anaemia
- Diabetes
- Ischaemic aetiology
- Wide QRS
Better Prognosis:
- Response to GDMT with EF improvement
- Non-ischaemic aetiology
- Younger age
- Absence of comorbidities
- Good nutritional status
Quality of Life Considerations
- Regular NYHA and symptom assessment
- Patient goals of care discussions
- Advance care planning early
- Integration of palliative care
- Exercise rehabilitation improves QoL
Key Clinical Trials
PARADIGM-HF (2014)
- Sacubitril/Valsartan vs Enalapril
- 20% reduction in CV death and HF hospitalisation
- Established ARNI as first-line therapy
DAPA-HF (2019)
- Dapagliflozin vs placebo in HFrEF
- 26% reduction in CV death and worsening HF
- Benefit independent of diabetes
EMPEROR-Reduced (2020)
- Empagliflozin vs placebo in HFrEF
- 25% reduction in CV death and HF hospitalisation
- Confirmed SGLT2 inhibitor benefit
MERIT-HF (1999)
- Metoprolol succinate in HFrEF
- 34% reduction in mortality
- Established beta-blocker mortality benefit
RALES (1999)
- Spironolactone in severe HFrEF
- 30% reduction in mortality
- Established MRA in GDMT
Current Guidelines
| Guideline | Organisation | Year | Key Recommendations |
|---|---|---|---|
| ESC Heart Failure Guidelines | European Society of Cardiology | 2021 | Four pillars of GDMT, simultaneous initiation |
| AHA/ACC/HFSA HF Guidelines | American Heart Association | 2022 | Similar four-pillar approach, emphasis on SGLT2i |
| NICE NG106 | UK NICE | 2018 (updated 2023) | ARNI, MRA, beta-blockers, specialist referral |
What is Heart Failure with Reduced Ejection Fraction?
Heart failure means your heart muscle has become weak and cannot pump blood as well as it should. "Reduced ejection fraction" means we can measure how much blood your heart pumps out with each beat, and in your case, it is lower than normal (under 40%, when normal is 55-70%).
What causes it?
The most common cause is damage from a heart attack, which kills some of the heart muscle. Other causes include:
- Long-term high blood pressure
- Heart muscle disease (cardiomyopathy)
- Heart valve problems
- Infections or inflammation of the heart
- Genetic conditions
What are the symptoms?
- Feeling breathless, especially when lying flat or during activity
- Swelling in your ankles, legs, or tummy
- Feeling very tired
- Waking up at night gasping for breath
- Needing to urinate more at night
How is it treated?
The good news is that modern medications can dramatically improve your heart function and help you live longer. You will likely be prescribed:
- ACE inhibitors or ARNI: To take pressure off your heart
- Beta-blockers: To slow your heart and help it pump more efficiently
- MRAs: To remove excess fluid and protect your heart
- SGLT2 inhibitors: Originally for diabetes, but proven to help all heart failure patients
Some patients may also need a pacemaker-like device (ICD or CRT) to protect against dangerous heart rhythms or help the heart pump better.
What should I expect?
Many patients feel significantly better within weeks to months of starting treatment. Your heart function may even improve over time. You will need regular check-ups with blood tests and echocardiograms.
When to seek urgent help
Go to A&E or call 999 if you experience:
- Severe breathlessness that does not improve with rest
- Chest pain
- Fainting or feeling very faint
- Confusion or drowsiness
- Very fast or irregular heartbeat
Primary Sources
-
McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. PMID: 34447992
-
Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895-e1032. PMID: 35363499
-
McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med. 2014;371(11):993-1004. PMID: 25176015
-
McMurray JJV, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF). N Engl J Med. 2019;381(21):1995-2008. PMID: 31535829
-
Packer M, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced). N Engl J Med. 2020;383(15):1413-1424. PMID: 32865377
Guidelines
- NICE NG106: Chronic heart failure in adults
- ESC Heart Failure Guidelines 2021
- AHA/ACC Heart Failure Guidelines 2022
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. It does not replace professional medical judgement. Always verify critical information and consider individual patient factors.