Heart Failure: Basic to Clinical

1. Definition

• Robbins & Cotran Pathologic Basis of Disease, p. 498
• Katzung's Basic and Clinical Pharmacology, 16e, p. 334

2. Etiology and Classification

By Ejection Fraction

By Output

• Low-output failure (most common): IHD, cardiomyopathy, hypertension, valvular disease
• High-output failure (rare): Hyperthyroidism, beriberi, severe anemia, arteriovenous shunts - responds poorly to standard HF drugs; treat the underlying cause

By Side

• Left-sided HF: IHD, hypertension, aortic/mitral valve disease, primary cardiomyopathy
• Right-sided HF: Most often caused by left-sided HF; also pulmonary disease (cor pulmonale), pulmonary hypertension

3. Basic Pathophysiology

3a. Cardiac Hypertrophy - the Initial Response

• Pressure overload (hypertension, aortic stenosis): new sarcomeres assemble in parallel → concentric hypertrophy (increased wall thickness, normal cavity size)
• Volume overload (valvular regurgitation): new sarcomeres assemble in series → eccentric hypertrophy/dilation

Fig. 12.2 - Robbins & Cotran: Causes and consequences of cardiac hypertrophy

3b. The Four Determinants of Cardiac Performance (Frank-Starling Framework)

1. Preload: End-diastolic fiber length/filling pressure. The ascending limb of the Frank-Starling curve (<15 mmHg) shows increasing stroke work with filling; beyond ~20-25 mmHg, pulmonary congestion occurs. Preload is increased in HF due to volume/sodium retention.
2. Afterload: Ventricular wall stress at the onset of ejection (largely arterial resistance). Increased in HF via sympathetic/RAAS-driven vasoconstriction - this further reduces ejection fraction.
3. Contractility (inotropy): Intrinsic myocardial strength at a given preload/afterload. Force of contraction is directly proportional to free cytosolic Ca²⁺.
4. Heart rate: Sympathetic-driven tachycardia initially compensates, but long-term chronic elevation is harmful.

3c. Neurohumoral Compensatory Mechanisms

Fig. 10.3 - Lippincott Pharmacology: Cardiovascular consequences and compensatory responses in HF

3d. Calcium Handling Abnormalities

• SERCA (SR Ca²⁺-ATPase) activity is impaired → Ca²⁺ reuptake into SR is reduced
• RyR channels are hyperphosphorylated (CaMKII, PKA) → SR Ca²⁺ leaks during diastole
• Phospholamban regulation is disrupted
• Net result: cytosolic Ca²⁺ overload during diastole (stiffness) and reduced Ca²⁺ transient during systole (reduced contractility)

4. Morphology and Organ Effects

Left-Sided HF

• Exertional dyspnea → orthopnea → paroxysmal nocturnal dyspnea (PND) → acute pulmonary edema

Right-Sided HF

• Robbins & Cotran Pathologic Basis of Disease, pp. 498-502

5. Clinical Features and Diagnosis

Symptoms

• LHF: Dyspnea on exertion, orthopnea, PND, cough, fatigue, decreased exercise tolerance
• RHF: Peripheral edema, abdominal distension (ascites), anorexia, RUQ discomfort (liver congestion)
• Both: Fatigue, weakness, tachycardia, cardiomegaly

Signs

• S3 gallop (ventricular filling sound - hallmark of systolic HF)
• S4 gallop (atrial contraction against stiff ventricle - diastolic dysfunction)
• Displaced apical impulse (cardiomegaly)
• Elevated JVP, hepatojugular reflux
• Bilateral basal crackles (pulmonary edema)
• Peripheral pitting edema

Key Investigations

6. Pharmacological Treatment

6a. ACE Inhibitors / ARBs

• Block RAAS at ACE or AT1 receptor
• Reduce afterload, preload, prevent remodeling and myocyte hypertrophy
• ACE inhibitors: first-line; ARBs: used when ACEi not tolerated (dry cough, angioedema)

6b. ARNI - Sacubitril/Valsartan

• Sacubitril inhibits neprilysin (which degrades BNP, ANP, bradykinin) → ↑natriuretic peptides → natriuresis, vasodilation, anti-fibrosis
• Valsartan blocks AT1 receptor (offsets RAAS activation; prevents angioedema from dual bradykinin buildup)
• Shown superior to ACEi in the PARADIGM-HF trial
• Indication: Replace ACEi/ARB in symptomatic HFrEF on optimized β-blocker + ACEi/ARB
• Key caution: Must washout ACEi ≥36 hours before starting to avoid angioedema

6c. β-Blockers (bisoprolol, carvedilol, metoprolol succinate)

• Counterintuitive but proven: reduce chronic sympathetic overdrive, prevent β1 downregulation, reverse cardiac remodeling, decrease apoptosis, reduce arrhythmias
• Carvedilol is non-selective (β1, β2, α1 blockade); bisoprolol and metoprolol are β1-selective
• Start low, titrate gradually; avoid in acute decompensation until stable

6d. Mineralocorticoid Receptor Antagonists (Spironolactone, Eplerenone)

• Block aldosterone → prevent Na⁺ retention, myocardial hypertrophy, hypokalemia
• Spironolactone has off-target effects (gynecomastia, dysmenorrhea); eplerenone is MR-selective
• Indicated in symptomatic HFrEF; also for HFrEF post-MI; reduces hospitalizations in HFpEF

6e. SGLT2 Inhibitors (Dapagliflozin, Empagliflozin)

• Block SGLT2 in proximal tubule → glucosuria + natriuresis
• Cardioprotective mechanism: may involve NHE inhibition → prevents Ca²⁺ overload; selectively reduces interstitial fluid (less neurohormonal reflex activation vs. loop diuretics)
• Evidence: DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) showed mortality/hospitalization benefit in HFrEF; also effective in HFpEF
• Indicated: Symptomatic HFrEF on optimized GDMT; also HFpEF

6f. Diuretics (Loop diuretics: furosemide, bumetanide, torsemide)

• Reduce preload and symptoms of volume overload (dyspnea, edema, orthopnea)
• Do NOT improve survival - use only for symptom control
• Thiazides for mild HF; loop diuretics for moderate-severe or renal insufficiency

6g. Vasodilators

• Hydralazine + isosorbide dinitrate: For patients intolerant of ACEi/ARB; fixed-dose combination shown to improve survival in African-American patients with HFrEF on GDMT; hydralazine has antioxidant properties that prevent nitrate tolerance
• Nitrates alone: Venodilators → reduce preload; useful for acute dyspnea/pulmonary edema

6h. HCN Channel Blocker - Ivabradine

• Blocks the If ("funny") current in the SA node → reduces heart rate without affecting contractility or BP
• For patients with HFrEF, EF ≤35%, sinus rhythm, HR ≥70 bpm on maximally tolerated β-blocker

6i. Soluble Guanylate Cyclase Stimulator - Vericiguat

• Stimulates sGC → ↑cGMP → vasodilation and anti-fibrosis
• Corrects the NO deficit in HF (oxidative stress inactivates endogenous NO)
• For high-risk HFrEF patients with recent worsening; less hypotension than traditional NO donors

6j. Inotropes (Acute/Refractory HF)

• Digoxin (cardiac glycoside): Inhibits Na⁺/K⁺-ATPase → ↑intracellular Na⁺ → ↑Ca²⁺ via NCX → ↑contractility; also vagotonic → slows AV conduction (useful in AF with HF). Narrow therapeutic index (0.5-0.9 ng/mL target). Does not improve mortality.
• Dobutamine (β1 agonist): For acute decompensated HF; short-term bridge
• Milrinone (PDE3 inhibitor): Inodilator; ↑cAMP → ↑inotropy + vasodilation

Summary Drug Table for HFrEF (GDMT)

7. Non-Pharmacological and Device Therapy

• Salt/fluid restriction: Reduce preload; 2 g/day sodium restriction is standard
• Cardiac resynchronization therapy (CRT): Biventricular pacing for patients with EF ≤35%, LBBB, QRS ≥150 ms in sinus rhythm; resynchronizes LV wall motion, improves EF and symptoms
• ICD (implantable cardioverter-defibrillator): EF ≤35% despite ≥3 months GDMT; reduces sudden cardiac death
• Ventricular assist devices (VADs): LVAD as bridge to transplant or destination therapy in refractory HF
• Cardiac transplantation: Gold standard for end-stage HF
• Pulmonary artery pressure monitoring (CardioMEMS): Reduces 30-day readmissions by guiding outpatient diuresis
• Exercise rehabilitation: Aerobic exercise promotes physiologic (beneficial) hypertrophy; reduces symptoms and hospitalizations

8. HFpEF - Special Considerations

• EF ≥50%, symptoms and signs of HF, elevated filling pressures
• Mechanism: Diastolic dysfunction (impaired relaxation and filling); myocardial stiffness due to hypertrophy, fibrosis, and inflammation
• Driven by comorbidities: obesity, diabetes, hypertension, CKD, atrial fibrillation
• The Paulus-Tschope paradigm: Systemic inflammation from comorbidities → coronary microvascular endothelial inflammation → reduced NO → reduced cGMP → PKG hypoactivity → titin hypophosphorylation → increased myocardial stiffness
• Treatment: Primarily symptom control with diuretics; SGLT2i (dapagliflozin, empagliflozin) now shown to reduce hospitalizations in HFpEF; MRAs reduce hospitalizations; ARBs may provide modest benefit; ACEi/ARNI/β-blockers not proven to reduce mortality in pure HFpEF

9. Prognosis and Biomarkers

• BNP/NT-proBNP: Primary biomarker; elevated with any increase in wall stress; low BNP has very high negative predictive value to rule out HF
• Hyponatremia: Independent marker of poor prognosis (reflects maximal neurohormonal activation)
• Troponin: Chronic low-level elevation indicates ongoing myocyte death; prognostic
• NYHA Functional Class: I (no symptoms) → IV (symptoms at rest); guides therapy intensity
• 5-year mortality of symptomatic HF remains ~50%, similar to many malignancies, though improving with GDMT

Key Sources

• Robbins, Cotran & Kumar - Pathologic Basis of Disease, pp. 498-502
• Lippincott Illustrated Reviews: Pharmacology, pp. 353-371
• Katzung's Basic and Clinical Pharmacology, 16e, pp. 334-345
• Braunwald's Heart Disease, 2-Vol Set

Recent Evidence

• Pharmacotherapy network meta-analysis (Tang et al., 2025 - PMID 38811344): Confirms the four-pillar GDMT (ARNI + β-blocker + MRA + SGLT2i) provides the greatest mortality benefit in HFrEF
• SGLT2i systematic review (Li et al., 2025 - PMID 40672365): Long-term SGLT2 inhibition also reduces arrhythmia burden in HF