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. Rising LV filling pressure is transmitted back through the left atrium to the pulmonary capillaries, and the raised hydrostatic pressure pushes transudate into the interstitium and alveoli (cardiogenic pulmonary edema), unlike the increased capillary permeability of ARDS.

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: give an IV loop diuretic (bowel-wall edema makes oral absorption unreliable) at an initial dose equal to or greater than the total daily oral dose (DOSE trial high-dose arm: 2.5x). Consider IV nitroglycerin if SBP >110 with pulmonary edema; it venodilates, lowering preload and pulmonary capillary hydrostatic pressure. Reserve inotropes for hypoperfusion or cardiogenic shock. Do not start a beta-blocker during decompensation; continue a chronic beta-blocker unless there is cardiogenic shock or hypoperfusion.
• Iron deficiency is common in HFrEF (with or without anemia); IV ferric carboxymaltose improves symptoms and reduces hospitalization.
• Stevenson profiles classify acute HF by congestion (wet vs dry) and perfusion (warm vs cold): warm-wet is the most common and is treated with diuretics ± vasodilators; cold-wet (congestion with low output) prompts evaluation for cardiogenic shock and possible inotropes.
• HF with improved EF (prior LVEF ≤40%, now >40%): continue full GDMT (2022 AHA/ACC/HFSA class 1) and existing devices; withdrawing therapy leads to relapse in many patients (TRED-HF: 44% within 6 months).

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)
• DOSE — Diuretic Strategies in Patients with Acute Decompensated Heart Failure (Felker et al., NEJM 2011)
• TRED-HF — Withdrawal of Pharmacological Treatment for Heart Failure in Patients with Recovered Dilated Cardiomyopathy (Halliday et al., Lancet 2019)