What is Heart Failure with reduced Ejection Fraction (HFrEF)?

What is HFrEF (Heart Failure with Reduced Ejection Fraction)?

HFrEF is symptomatic heart failure with a left ventricular ejection fraction (LVEF) of ≤40%. 1

Core Definition

HFrEF represents a clinical syndrome characterized by:

• Typical symptoms: Dyspnea, ankle swelling, fatigue, and exertional intolerance 1
• Structural or functional cardiac abnormality: Impaired ventricular filling or ejection of blood 1
• Reduced pumping capacity: LVEF ≤40% on imaging 1

The LVEF cutoff of ≤40% is the current standard definition used by major cardiology societies including the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). 1, 2

Distinction from Other Heart Failure Types

HFrEF must be differentiated from two other ejection fraction-based categories:

• HFmrEF (Heart Failure with Mildly Reduced EF): LVEF 41-49% 1
• HFpEF (Heart Failure with Preserved EF): LVEF ≥50% 1

This classification is clinically critical because only HFrEF has proven therapies that reduce both morbidity and mortality. 1 Most randomized controlled trials demonstrating survival benefit have enrolled patients with LVEF ≤35% or ≤40%. 1

Clinical Presentation

Patients with HFrEF typically present with:

• Exertional dyspnea and early-onset fatigue 2
• Reduced exercise tolerance and impaired quality of life 2
• Progressive functional limitations assessed by NYHA functional class 2
• Signs of volume overload: Elevated jugular venous pressure, pulmonary crackles, peripheral edema 1

Diagnostic Approach

The diagnosis requires three key elements:

1. Clinical symptoms and signs of heart failure 1
2. Elevated natriuretic peptides (BNP or NT-proBNP) above age-specific thresholds 3
3. Documented LVEF ≤40% on echocardiography or other imaging modality 1, 3

Important caveat: LVEF is a variable measure that can change over time, particularly in the borderline range. 1 A single measurement may not be adequate—consider the trajectory of LVEF and underlying cause when making treatment decisions. 1

Pathophysiology

HFrEF involves progressive left ventricular dilatation and adverse cardiac remodeling driven by:

• Ongoing cardiomyocyte loss and hypertrophy 4
• Mitochondrial dysfunction and impaired calcium cycling 4
• Elevated LV wall stress and reactive interstitial fibrosis 4
• Neurohormonal activation that perpetuates disease progression 4

This explains why HFrEF is a progressive disorder where cardiac structure and function continue to deteriorate even in clinically stable patients. 4

Disease Burden and Prognosis

HFrEF represents approximately 50% of the 23 million heart failure cases worldwide. 3 The condition carries:

• High mortality: 5-year survival rate of only 25% after hospitalization 3
• Frequent readmissions and substantial healthcare costs 5
• Progressive disability impacting physical functioning and independence 2

Treatment Implications

The HFrEF diagnosis triggers specific guideline-directed medical therapy (GDMT) that has proven mortality benefit:

• Foundational therapy: Beta-blockers plus either ACE inhibitor, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI) 3, 5
• Mineralocorticoid receptor antagonists for persistent symptoms 3
• SGLT2 inhibitors which reduce cardiovascular and all-cause mortality regardless of diabetes status 3, 5
• Device therapies: Implantable cardioverter-defibrillators (ICDs) for LVEF ≤35% and cardiac resynchronization therapy for interventricular dyssynchrony 3, 6

Critical point: Unless contraindications exist, all patients with HFrEF should receive this quadruple therapy (ARNI/ACE/ARB + beta-blocker + MRA + SGLT2 inhibitor) with target dose titration within 6-12 weeks. 5, 7