Heart Failure with Reduced Ejection Fraction (HFrEF)

Risk factors

• Coronary artery disease (most common cause, ~50%)
• Long-standing hypertension
• Valvular disease (severe AR, MR, AS)
• Non-ischemic dilated cardiomyopathy: viral myocarditis, peripartum, alcohol, cocaine, chemotherapy (anthracyclines, trastuzumab), genetic, idiopathic
• Tachycardia-induced cardiomyopathy (sustained AFib with RVR)

Pathophysiology

Reduced myocardial contractility lowers cardiac output, triggering compensatory activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. Chronic neurohormonal activation drives maladaptive remodeling (chamber dilation, fibrosis, apoptosis), creating a self-perpetuating cycle. GDMT (guideline-directed medical therapy) blocks each arm of this cascade.

Clinical presentation

Differential diagnosis

• HFpEF — Preserved EF ≥50%; same symptoms; differentiated by echocardiography — both can coexist over time
• COPD exacerbation — Smoking history, wheezing, hyperresonant chest, prolonged expiration, hyperinflation on CXR; BNP normal or mildly elevated
• Pulmonary embolism — Sudden dyspnea, pleuritic pain, hypoxia, hemodynamic instability; D-dimer, CTPA; RV strain on echo
• Constrictive pericarditis — Right HF features (JVD, ascites, edema) dominate, Kussmaul sign, pericardial knock; thickened or calcified pericardium on CT/MRI
• Restrictive cardiomyopathy — Biventricular failure with preserved EF; consider amyloid (especially elderly), hemochromatosis, sarcoid; specialized imaging
• High-output failure (anemia, thyrotoxicosis, AV fistula, beriberi) — Warm extremities, bounding pulses, wide pulse pressure; treat the underlying cause
• Cirrhosis / nephrotic syndrome — Peripheral edema and dyspnea from volume overload but without elevated BNP; LFTs and urinalysis discriminate
• Obesity hypoventilation / OSA — BMI >30, daytime somnolence, witnessed apneas; polysomnography; can coexist with HF

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[LVEF ≤40%<br/>HFrEF diagnosis] --> B[Pillar 1<br/>ARNI/ACEi/ARB]
  A --> C[Pillar 2<br/>Beta-blocker<br/>carvedilol, metop succ, bisop]
  A --> D[Pillar 3<br/>MRA<br/>spironolactone/eplerenone]
  A --> E[Pillar 4<br/>SGLT2i<br/>dapa or empagliflozin]
  B --> F[Loop diuretic<br/>for congestion<br/>symptom-directed]
  C --> F
  D --> F
  E --> F
  F --> G{LVEF ≤35%<br/>after ≥3 mo GDMT?}
  G -->|Yes| H[ICD<br/>± CRT if QRS ≥150 LBBB]
  G -->|No| I[Continue GDMT<br/>reassess]

Treatment

Complications

• Acute decompensation requiring hospitalization (frequent driver of mortality and cost)
• Ventricular arrhythmias, sudden cardiac death
• Cardiorenal syndrome (worsening renal function with diuresis)
• Atrial fibrillation
• LV thrombus → embolic stroke
• Cardiac cachexia (advanced disease)

PANCE pearls

• BNP <100 has high negative predictive value to exclude HF in acute dyspnea workup.
• NYHA functional classification (I-IV) is symptom-based; ACC/AHA stages (A-D) are structural — both used clinically.
• Start all 4 GDMT pillars early at low doses, then titrate. Don't withhold ARNI to perfect ACEi titration first.
• Acute decompensated HF: IV loop diuretic, consider IV nitrates if SBP >110 and pulmonary edema. Avoid beta-blocker initiation in acute decompensation; continue if already taking unless cardiogenic shock.
• Iron deficiency is common in HFrEF (with or without anemia); IV ferric carboxymaltose improves symptoms and reduces hospitalization.

References

• AHA/ACC/HFSA 2022 — 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (Heidenreich et al., Circulation 2022)
• PARADIGM-HF — Angiotensin-Neprilysin Inhibition vs Enalapril in Heart Failure (McMurray et al., NEJM 2014)
• DAPA-HF — Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (McMurray et al., NEJM 2019)
• EMPEROR-Reduced — Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (Packer et al., NEJM 2020)
• RALES Trial — Effect of Spironolactone on Morbidity and Mortality in Severe Heart Failure (Pitt et al., NEJM 1999)