Definition

Types / Classification

By Ejection Fraction

ACC/AHA Staging (complements NYHA)

NYHA Functional Classes

• I — No limitation of ordinary activity
• II — Slight limitation; comfortable at rest
• III — Marked limitation; comfortable only at rest
• IV — Symptoms at rest; any activity causes discomfort

Epidemiology

• 650,000 new cases/year in the USA

• ~50% mortality within 5 years of diagnosis
• 1-month rehospitalization rate ~25%
• Estimated cost >$39 billion annually

Pathophysiology

The Core Problem: LV Remodeling

Neurohormonal Activation (the vicious cycle)

Katzung's Basic & Clinical Pharmacology, 16th ed.

1. Sympathetic Nervous System (SNS)
   • Baroreceptor resetting → ↑ sympathetic outflow, ↓ parasympathetic
   • → Tachycardia, ↑ contractility, vasoconstriction (↑ afterload)
   • Chronic: β₁-receptor downregulation, Ca²⁺ overload via RyR channels, apoptosis via caspases
2. RAAS
   • ↓ Renal perfusion → ↑ renin → ↑ Angiotensin II → ↑ aldosterone
   • Angiotensin II causes myocyte apoptosis, hypertrophy, ventricular fibrosis, and ↑ afterload
   • Aldosterone "escapes" ACE inhibitor suppression → selective aldosterone blockade needed
3. Other mediators: Endothelin-1 (potent vasoconstrictor), inflammatory cytokines (TNF-α, IL-6), natriuretic peptides (BNP/NT-proBNP — counter-regulatory, used as biomarker)

Cellular Changes

• ↑ MMPs → cardiac fibrosis and collagen deposition
• Impaired SERCA Ca²⁺ reuptake into SR → diastolic dysfunction
• Altered β-adrenergic signaling: β₁ ↓, β₂ and α₁ ↑ (important for drug choice)
• Metabolic switch: fatty acid oxidation → glycolysis
• Myocardial hypertrophy → initially compensatory, then ischemia, diastolic impairment, geometric distortion

Four Determinants of Cardiac Performance

1. Preload — Frank-Starling curve; filling pressure >20–25 mmHg → pulmonary congestion; target of diuretics/venodilators
2. Afterload — vascular resistance; increased in HF by Ang II, endothelin; target of vasodilators, ACE inhibitors, ARBs
3. Contractility — reduced in HFrEF; target of inotropes (digoxin, dobutamine)
4. Heart rate — tachycardia increases O₂ demand; target of β-blockers

Clinical Features

Symptoms

• Left-sided failure: dyspnea on exertion → orthopnea → PND, fatigue, exercise intolerance, non-productive cough
• Right-sided failure: peripheral edema, ascites, RUQ pain (hepatic congestion), anorexia, nausea
• Both: reduced urine output (↓ renal perfusion), confusion (↓ cerebral perfusion in severe HF)

Signs

Diagnosis

Initial workup (all patients with suspected HF)

• 12-lead ECG — LVH, Q waves (previous MI), LBBB, arrhythmias
• Chest X-ray — cardiomegaly (CTR >0.5), upper lobe diversion, Kerley B lines, bat-wing pulmonary edema, pleural effusions
• Echocardiography (key) — quantifies EF, assesses wall motion, valve function, filling pressures. Essential for distinguishing HFrEF vs HFpEF
• Natriuretic peptides — BNP or NT-proBNP: elevated in HF; helps distinguish cardiac vs non-cardiac dyspnea
• Labs: CBC, electrolytes, BUN/Cr, LFTs, glucose, TFTs, iron studies (ferritin + TSAT), ESR/ANA, urinalysis
• Coronary angiography — if ischemic etiology suspected and EF significantly reduced

When to biopsy

1. New-onset HF (<2 weeks) with dilated LV + hemodynamic compromise
2. New-onset HF (2 weeks–3 months) with dilated LV + new ventricular arrhythmias/heart block/failure to respond to therapy

Management

Non-Pharmacological

• Sodium restriction: ≤2 g/day
• Free water restriction: 1 L/day (in fluid-overloaded patients)
• Daily weight monitoring; report ≥3 lb/week gain
• Regular aerobic exercise (improves functional capacity in stable HF)
• Smoking cessation, alcohol avoidance
• Supplemental O₂ if SpO₂ <92%
• Screen and treat sleep apnea (associated with HF and arrhythmias)
• Aggressive BP, lipid, and diabetes control
• Referral to specialist HF clinic (reduces hospitalizations)

Pharmacological Therapy — HFrEF (Mortality-Modifying)

1. ACE Inhibitors (first-line)

• ↓ Absolute mortality ~4%; ↓ combined morbidity/mortality 30–35%
• Block Ang II → ↓ vasoconstriction, ↓ aldosterone, ↓ remodeling
• Examples: Enalapril 2.5–20 mg BID; Lisinopril 5–40 mg QD; Ramipril 5 mg BID; Captopril 6.25–50 mg TID
• If ACE inhibitor intolerant (cough/angioedema) → use ARB (Candesartan, Valsartan, Losartan)

2. Beta-Blockers (first-line)

• Reverse β-receptor downregulation; reduce catecholamine-mediated toxicity and arrhythmias
• Titrate slowly (every 2 weeks) to maximum tolerated dose; start only in stable (not decompensated) HF
• Approved agents (USA): Carvedilol (non-selective β₁/β₂/α₁), Metoprolol succinate XL (β₁-selective), Bisoprolol (β₁-selective)
• COMET trial: carvedilol (non-selective) → 17% further reduction in mortality vs metoprolol tartrate
• Carvedilol preferred in diabetics (no adverse glycemic effect; improves insulin sensitivity)

3. Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)

• Spironolactone / Eplerenone — add when aldosterone "escapes" ACE inhibitor suppression
• Reduce mortality in symptomatic HFrEF (RALES, EPHESUS trials)

4. ARNi (Sacubitril/Valsartan — Entresto)

• Replaces ACE inhibitor; neprilysin inhibitor + ARB combination
• Reduces mortality and hospitalization in HFrEF vs ACE inhibitor alone (PARADIGM-HF)
• Now a Class I recommendation in ACC/AHA guidelines for HFrEF

5. SGLT2 Inhibitors (Dapagliflozin, Empagliflozin)

• Mortality and hospitalization reduction in both HFrEF and HFpEF
• The DAPA-HF and EMPEROR-Reduced trials established Class I indication for HFrEF
• Recent 2025 meta-analysis (PMID: 40884036) — dapagliflozin in hospitalized HF reduces subsequent events

6. SGLT2 + ARNi = "Fantastic Four" of HFrEF

• ACE-I/ARB/ARNi + Beta-blocker + MRA + SGLT2 inhibitor

Drug Dosage Summary (Selected)

Pharmacological Therapy — HFpEF

• Less evidence-based than HFrEF
• SGLT2 inhibitors (empagliflozin/dapagliflozin) — now recommended (EMPEROR-Preserved, DELIVER trials)
• Aggressive BP control (target <130/80)
• Diuretics for congestion
• Non-dihydropyridine CCBs (diltiazem, verapamil) for rate control
• ACE-I/ARBs may reduce LVH over time

Diuretics (symptom relief only — no mortality benefit)

• Loop diuretics (furosemide) for fluid overload
• No proven survival benefit; monitor electrolytes closely
• Avoid simultaneous initiation with ACE inhibitor (risk of hypotension, ↑Cr)

Digoxin

• Improves symptoms in symptomatic systolic HF with severely reduced EF; also useful for rate control in AF
• No mortality benefit; narrow therapeutic window (target 0.5–0.8 ng/mL)

Device Therapy

• ICD: for HFrEF (EF <35%) despite GDMT — sudden cardiac death prevention
• CRT (Cardiac Resynchronization Therapy): for HFrEF with LBBB (QRS ≥150 ms) — improves EF, symptoms, mortality
• CRT-D: combined ICD + CRT
• LVAD (Left Ventricular Assist Device): bridge to transplant or destination therapy in Stage D HF (INTERMACS 1–3)
• Heart transplantation: definitive therapy in end-stage HF

Key Points to Remember for Exams

1. Definition & Types — HFrEF vs HFpEF vs high-output; ACC/AHA Stages A–D; NYHA Classes I–IV
2. Pathophysiology — LV remodeling as the core process; the SNS + RAAS vicious cycle (with diagram); cellular changes in calcium handling, β-receptor remodeling, apoptosis; the four determinants of cardiac performance (preload, afterload, contractility, HR)
3. Clinical Features — left-sided vs right-sided symptoms and signs; S₃ gallop as hallmark
4. Diagnosis — ECG, CXR, echo (key test), BNP/NT-proBNP, targeted labs, indications for biopsy
5. Management:
   • Non-pharmacological (salt/fluid restriction, exercise, monitoring)
   • "Fantastic Four" GDMT for HFrEF: ACE-I/ARNi + β-blocker + MRA + SGLT2 inhibitor — all with mortality benefit
   • HFpEF management (SGLT2i now evidence-based as of 2022–2025)
   • Devices: ICD, CRT, LVAD, transplant
   • What doesn't improve mortality: diuretics, digoxin (symptom relief only)