Explain heart failure with reduced ejection fraction (HFREF).

Heart Failure with Reduced Ejection Fraction (HFrEF)

HFrEF is a clinical syndrome characterized by symptoms of heart failure (dyspnea, fatigue, fluid retention) combined with left ventricular ejection fraction (LVEF) ≤40%, representing impaired cardiac pumping function that requires aggressive guideline-directed medical therapy to reduce mortality and hospitalizations. 1

Definition and Diagnostic Criteria

HFrEF requires three components to be present 1:

• Clinical diagnosis of heart failure with typical symptoms (breathlessness, ankle swelling, fatigue) and/or signs (elevated jugular venous pressure, pulmonary crackles, peripheral edema)
• LVEF ≤40% measured by echocardiography, cardiac MRI, or radionuclide imaging
• Objective evidence of either:
  • Elevated natriuretic peptides (BNP or NT-proBNP), OR
  • Objective evidence of cardiogenic pulmonary or systemic congestion

The LVEF cutoff of ≤40% is the current consensus definition across major guidelines 2, 3, 1, 4, though historical trials variably used cutoffs between 30-45%.

Pathophysiology

HFrEF develops through a cascade of maladaptive processes 5, 6:

Initial insult → Myocardial injury (ischemic, toxic, inflammatory, genetic) causes reduced cardiac output → Neurohormonal activation (sympathetic nervous system, renin-angiotensin-aldosterone system) → Short-term compensation maintains blood pressure and perfusion → Chronic activation leads to progressive left ventricular dilatation, adverse cardiac remodeling, and worsening systolic dysfunction → Clinical heart failure syndrome.

The neurohormonal activation, while initially compensatory, becomes the primary driver of disease progression through hemodynamic stress, myocardial fibrosis, and cellular dysfunction 6. This understanding forms the basis for all effective HFrEF therapies, which target these neurohormonal pathways.

Clinical Staging

HFrEF exists within the broader ACC/AHA staging system 1:

• Stage A: At risk (hypertension, diabetes, coronary disease) - no structural disease yet
• Stage B: Pre-HF with structural disease (reduced EF, LV hypertrophy, valvular disease) but asymptomatic
• Stage C: Symptomatic HF with structural heart disease - this is where HFrEF diagnosis applies
• Stage D: Advanced HF with marked symptoms despite optimal guideline-directed therapy

Epidemiology and Prognosis

HFrEF represents approximately 50% of all heart failure cases globally 7, 8. The lifetime risk of developing heart failure is 20% for Americans ≥40 years old, with 75% having antecedent hypertension 9.

Prognosis remains serious despite therapeutic advances: approximately 50% mortality within 5 years of diagnosis, with only 25% 5-year survival after hospitalization for HFrEF 9, 7. However, contemporary guideline-directed medical therapy has substantially improved these outcomes compared to historical data.

Guideline-Directed Medical Therapy (GDMT)

The cornerstone of HFrEF management is quadruple foundational therapy initiated early and uptitrated rapidly 10, 4, 8:

Four Foundational Drug Classes (all patients unless contraindicated):

1. SGLT2 Inhibitors 10, 4

   • Dapagliflozin 10 mg daily OR Empagliflozin 10 mg daily (target 10-25 mg)
   • Reduces cardiovascular death and HF hospitalization regardless of diabetes status
   • Should be initiated early, often as first-line therapy

2. Angiotensin Receptor-Neprilysin Inhibitor (ARNI) or ACE Inhibitor/ARB 10, 4

   • Preferred: Sacubitril-valsartan 24/26 or 49/51 mg twice daily → target 97/103 mg twice daily
   • Alternative: ACE inhibitor (enalapril 2.5 mg BID → 10-20 mg BID, lisinopril 2.5-5 mg daily → 20-40 mg daily)
   • Alternative: ARB if ACE inhibitor intolerant (candesartan 4-8 mg daily → 32 mg daily)

3. Evidence-Based Beta-Blockers 10, 4

   • Carvedilol 3.125 mg BID → 25-50 mg BID (based on weight)
   • Metoprolol succinate 12.5-25 mg daily → 200 mg daily
   • Bisoprolol 1.25 mg daily → 10 mg daily

4. Mineralocorticoid Receptor Antagonists (MRA) 10, 4

   • Spironolactone 12.5-25 mg daily → 25-50 mg daily
   • Eplerenone 25 mg daily → 50 mg daily
   • For persistent symptoms after initiating other therapies

Additional Therapies for Specific Populations:

• Ivabradine (2.5-5 mg BID → 7.5 mg BID): For sinus rhythm with heart rate >70 bpm despite beta-blocker 10
• Hydralazine/Isosorbide dinitrate: For self-identified Black patients or those intolerant to ACE/ARB/ARNI 10
• Vericiguat: For high-risk patients with recent HF hospitalization 7, 11
• Diuretics: For symptom relief of volume overload (not mortality benefit) 4, 8

Critical Implementation Points:

Initiate all four foundational therapies rapidly - do not wait for sequential uptitration of one before starting another 8. The evidence supports early, simultaneous initiation with rapid uptitration to target or maximally tolerated doses. Patients require frequent follow-up during initiation and titration phases to assess tolerability and adjust therapy 10.

Common pitfall: Underutilization of GDMT in real-world practice despite compelling evidence 11. Clinicians must prioritize achieving target doses rather than accepting suboptimal dosing.

Device Therapies

For select HFrEF patients 4, 7:

• Implantable Cardioverter-Defibrillator (ICD): LVEF ≤35% despite optimal medical therapy for ≥3 months (primary prevention)
• Cardiac Resynchronization Therapy (CRT): LVEF ≤35%, sinus rhythm, QRS ≥150 ms with left bundle branch block pattern
• Transcatheter Mitral Valve Repair: Severe secondary mitral regurgitation despite optimal medical therapy

Trajectory and Reclassification

HFrEF with improved EF (HFimpEF) describes patients whose LVEF improves from ≤40% to >40% with treatment 4. This represents a distinct subgroup with better prognosis, but these patients must continue HFrEF therapy as EF can decline with medication withdrawal 4. This is not "recovery" - structural abnormalities and dysfunction typically persist despite improved EF.

Distinguishing from Other HF Types

• HFmrEF (mildly reduced EF): LVEF 41-49% 1, 4
• HFpEF (preserved EF): LVEF ≥50% 1, 4

The distinction is critical because only HFrEF has proven mortality-reducing therapies from randomized controlled trials 3, 9. HFmrEF and HFpEF management differs substantially, with emerging evidence for SGLT2 inhibitors and other agents but without the robust evidence base supporting the quadruple therapy approach in HFrEF.