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Heart Failure - Complete Overview

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Universal Definition

• Elevated natriuretic peptide levels (BNP/NT-proBNP)
• Objective evidence of cardiogenic pulmonary or systemic congestion

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Epidemiology

• ~6.7 million American adults are treated for HF; over 600,000 new cases per year
• Globally, an estimated 56.2 million people live with HF
• Prevalence: 1-2% in adults aged 40-49; >10% in those over 80
• Lifetime risk: ~24% (approximately 1 in 4 persons will develop HF)
• Leading cause of hospitalization in adults >65 years old
• HF is a major cause of morbidity and mortality worldwide - Harrison's, p. 2020

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Classification by Ejection Fraction (EF)

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ACC/AHA Staging (A to D)

• Goldman-Cecil Medicine, p. 477-478

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NYHA Functional Classification

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Pathophysiology

Overview Diagram

1. Hemodynamic Alterations

2. Neurohormonal Activation

• Sympathetic nervous system (SNS) - activated early, increases HR, BP, contractility. Chronically causes vasoconstriction, arrhythmias, and direct myocardial toxicity via catecholamines
• RAAS - renin-angiotensin-aldosterone system activation causes sodium and water retention, vasoconstriction, ventricular remodeling, and fibrosis
• ADH (vasopressin) - increased water retention, hyponatremia
• These initially compensatory responses ultimately become maladaptive and cause disease progression - Harrison's, p. 2022-2023

3. Ventricular Remodeling

• Abnormal excitation-contraction coupling
• Fetal gene re-expression (e.g., beta-myosin heavy chain)
• Beta-adrenergic receptor desensitization
• Myocyte hypertrophy and impaired cytoskeletal proteins

• Myocyte necrosis, apoptosis, and autophagy
• Interstitial and perivascular fibrosis
• Matrix metalloproteinase activation with matrix degradation

• Ventricular dilation and wall thinning
• Increased sphericity; displacement of papillary muscles
• Functional atrioventricular valve regurgitation (worsens MR)

4. Counterregulatory Hormones (Vasodilatory)

• Natriuretic peptides (ANP, BNP) - secreted in response to wall stress; promote natriuresis and vasodilation. These are used diagnostically (elevated in HF)
• Prostaglandins and bradykinin also oppose RAAS effects

5. HFpEF-Specific Pathophysiology

• Myocardial fibrosis
• Coronary microvascular dysfunction
• Low-grade inflammation (driven by obesity, DM, hypertension)
• Collagen cross-linking
• This leads to elevated filling pressures at rest or exercise, causing dyspnea despite normal EF

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Common Causes (Etiology)

• Ischemic heart disease / MI (most common in developed world)
• Dilated cardiomyopathy (idiopathic, viral, alcoholic, familial)
• Hypertension (long-standing)
• Valvular heart disease (especially aortic stenosis, mitral regurgitation)
• Myocarditis
• Chemotherapy / cardiotoxic drugs (doxorubicin, trastuzumab)
• Arrhythmia-induced (tachycardia-mediated)

• Hypertension (most common cause)
• Hypertrophic cardiomyopathy
• Restrictive cardiomyopathy (amyloidosis, sarcoidosis, hemochromatosis)
• Constrictive pericarditis

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Precipitating Factors for Decompensation

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Clinical Features

Symptoms

• Dyspnea (exertional > orthopnea > PND - paroxysmal nocturnal dyspnea) - left HF
• Fatigue and reduced exercise tolerance
• Ankle edema / leg swelling - right HF
• Nocturia (recumbency improves renal perfusion, triggering diuresis overnight)
• Abdominal bloating, right upper quadrant discomfort (hepatic congestion)
• Cardiac cachexia in advanced HF (unintentional edema-free weight loss >5% over 12 months)

Signs

• Tachycardia
• Displaced apex beat (cardiomegaly)
• S3 gallop (ventricular gallop) - highly specific for HF; indicates rapid ventricular filling in dilated LV
• S4 gallop - indicates impaired relaxation (HFpEF, LVH)
• Fine bibasal crackles (pulmonary edema)
• Cardiac wheeze ("cardiac asthma")

• Raised JVP (jugular venous pressure)
• Hepatomegaly (tender); may progress to ascites
• Peripheral pitting edema (ankles, sacrum in bedridden)
• Hepatojugular reflux
• Right-sided S3
• Tricuspid regurgitation murmur

• Cheyne-Stokes respirations
• Cool peripheries, cyanosis, pallor
• Low pulse pressure; pulsus alternans (alternating strong/weak pulse)
• Cardiac cachexia, muscle wasting

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Investigations

Biomarkers

• BNP >100 pg/mL or NT-proBNP >300 pg/mL - highly sensitive for HF
• BNP <35 pg/mL / NT-proBNP <125 pg/mL essentially rules out HF in outpatients
• Troponin - elevated in acute decompensation or myocarditis
• Newer markers: Galectin-3, soluble ST2 (for prognosis, less used clinically) - Harrison's, p. 2449

ECG

• May show LVH, Q waves (ischemia), LBBB (common in HFrEF), AF, prolonged QRS
• No finding is specific; normal ECG makes HF less likely

Chest X-Ray

• Cardiomegaly (cardiothoracic ratio >0.5)
• Pulmonary venous congestion: upper lobe diversion, Kerley B lines
• Interstitial or alveolar edema (bat-wing perihilar opacities)
• Pleural effusions (usually bilateral or right-sided)

Echocardiography

• EF measurement (HFrEF vs HFpEF vs HFmrEF)
• LV size, wall thickness, regional wall motion
• Diastolic function assessment (E/A ratio, tissue Doppler e')
• Valvular lesions
• Right heart assessment (RVSP, RV size)
• Pericardial disease

Additional Tests

• Cardiac MRI - gold standard for myocardial structure, function, fibrosis, infiltrative disease
• Coronary angiography - to exclude ischemic etiology
• Cardiopulmonary exercise test (CPET) - VO2 max; gold standard for HF severity and transplant listing (VO2 max <14 mL/kg/min indicates high-risk)
• Pulmonary artery catheter (Swan-Ganz) - in ICU for hemodynamic guidance; measures PCWP (elevated in left HF), CO
• Endomyocardial biopsy - for myocarditis, amyloidosis, rejection post-transplant

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Management

Overview of the "Four Pillars" in HFrEF

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1. RAAS Inhibition

• Reduce mortality, hospitalizations, and improve NYHA class in all grades of symptomatic HF
• Also delay or prevent symptomatic HF in asymptomatic LV dysfunction (Stage B)
• Start low, titrate up; monitor K+ and creatinine
• Contraindications: History of angioedema, bilateral renal artery stenosis, K+ >5.0, creatinine ≥2.5 mg/dL
• Side effect: Dry cough in ~5% - switch to ARB

• Used when ACEi not tolerated (cough, angioedema)
• Similar efficacy; Candesartan reduces CV death + HF hospitalization
• Do NOT combine ACEi + ARB (increased toxicity without benefit) - Goldman-Cecil, p. 478

• Combines ARB (valsartan) + neprilysin inhibitor (sacubitril)
• Neprilysin degrades natriuretic peptides; inhibiting it augments BNP, vasodilation, natriuresis, and anti-fibrotic effects
• Now preferred as first-line over ACEi/ARB
• PARADIGM-HF trial: Sacubitril/valsartan reduced CV death and HF hospitalization vs enalapril by 20%
• Must wait 36 hours after last ACEi dose before starting (risk of angioedema)
• Target dose: 97/103 mg twice daily - Goldman-Cecil, p. 3247-3249

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2. Beta-Blockers

• Reduce mortality, hospitalizations, and improve symptoms when added to standard therapy
• Carvedilol is substantially more effective than short-acting metoprolol
• Start only in euvolemic (compensated) patients; do NOT initiate during acute decompensation
• Contraindications: asthma, 2nd/3rd degree AV block - Goldman-Cecil, p. 3140-3170

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3. Mineralocorticoid Receptor Antagonists (MRA)

• Spironolactone and Eplerenone
• Block aldosterone-mediated sodium retention and fibrosis
• RALES trial: Spironolactone reduced mortality by 30% in class III-IV HFrEF
• Used in NYHA class II-IV; EF ≤35%
• Monitor K+ closely (risk of hyperkalemia, especially with ACEi/ARB)
• Eplerenone: more selective, less gynecomastia

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4. SGLT2 Inhibitors

• Dapagliflozin (DAPA-HF) and Empagliflozin (EMPEROR-Reduced)
• Fourth pillar of HFrEF therapy; also benefit HFpEF (EMPEROR-Preserved, DELIVER trials)
• Reduce hospitalization for HF, CV death, and all-cause death when added to standard therapy
• Mechanisms in HF: osmotic diuresis, reduce cardiac preload/afterload, improve ketone metabolism, anti-fibrotic effects, weight loss
• Also reduce serum uric acid (beneficial in gout comorbidity)
• Preferred antidiabetic agents in HF patients with type 2 DM - Goldman-Cecil, p. 3460

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5. Diuretics (Symptomatic Relief)

• Loop diuretics (furosemide, bumetanide, torsemide) - mainstay for congestion
• No proven mortality benefit, but essential for symptom control
• Thiazides can be combined for diuretic resistance
• Adjust dose based on daily weights, BP, and renal function
• IV furosemide in acute decompensation

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6. Other Pharmacological Agents

• Sinus node If-channel blocker; reduces heart rate without affecting contractility
• Used in sinus rhythm, HR ≥70 bpm, despite maximally tolerated beta-blocker dose, NYHA II-III
• Reduces HF hospitalization

• For patients intolerant of both ACEi and ARB
• Proven mortality benefit specifically in Black patients (A-HeFT trial)
• Reduces afterload (hydralazine) and preload (nitrate)

• Weak positive inotrope; reduces hospitalizations (not mortality)
• Useful in HF + atrial fibrillation for rate control
• Narrow therapeutic window; risk of toxicity

• Soluble guanylate cyclase stimulator; for worsening HFrEF
• Reduces HF hospitalizations in high-risk patients

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Device Therapy

• Indicated: EF ≤35%, NYHA II-III, on optimal medical therapy, life expectancy >1 year
• Prevents sudden cardiac death from ventricular arrhythmias
• Stage B: EF <30% post-MI also benefits

• Biventricular pacing for electro-mechanical dyssynchrony
• Indicated: LBBB + QRS ≥150 ms + EF ≤35% + NYHA II-IV
• Reverses adverse remodeling (improves EF), reduces hospitalizations and mortality

• Mechanical pump for Stage D (refractory) HF
• Used as: Bridge to transplantation, destination therapy, or bridge to recovery
• HeartMate and HVAD devices; modern continuous-flow LVADs have improved survival

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Advanced / Stage D Therapies

• Heart Transplantation - gold standard for end-stage HF
  • Indications: VO2 max <14 mL/kg/min, NYHA IV despite optimal therapy
  • 1-year survival ~85%, 5-year ~70%
  • Limited by donor availability; contraindications include irreversible pulmonary hypertension, malignancy, significant comorbidities
• Chronic IV inotropes (dobutamine, milrinone) - palliative use
• Palliative care / hospice - for those not transplant candidates

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HFpEF Management

• SGLT2 inhibitors (dapagliflozin: DELIVER trial; empagliflozin: EMPEROR-Preserved) - now recommended
• Spironolactone (TOPCAT trial: modest benefit, especially in Americas subgroup)
• Sacubitril/valsartan - PARAGON-HF showed marginal benefit, especially in women
• Main treatment: aggressive risk factor control - hypertension (systolic <130 mmHg), AF rate/rhythm control, weight loss, diuretics for symptom relief

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Comorbidities

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Prognosis

• 1-year mortality after first hospitalization: ~20-30%
• 5-year mortality after diagnosis: ~50%
• Worse prognosis with: lower EF, higher NYHA class, lower Na+ (hyponatremia), elevated BNP/troponin, low VO2 max, renal dysfunction, right ventricular dysfunction, cardiac cachexia

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Acute Heart Failure (Decompensated)

• Wet vs Dry (congestion) - elevated JVP, crackles, edema
• Cold vs Warm (perfusion) - cool peripheries, low BP, oliguria

• IV loop diuretics (furosemide IV) - first-line for congestion
• Oxygen (maintain SpO2 >94%); consider CPAP/BiPAP for pulmonary edema
• IV vasodilators (nitrates, nitroprusside) - reduce preload/afterload in normotensive/hypertensive patients
• Inotropes (dobutamine, dopamine) - for low-output/cardiogenic shock
• Vasopressors (norepinephrine) - in cardiogenic shock with hypotension
• Treat triggering arrhythmias (e.g., cardioversion for AF with rapid ventricular rate)
• Mechanical support: IABP (intra-aortic balloon pump), Impella, or VA-ECMO in cardiogenic shock

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Key Drug Dose Summary (HFrEF)

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Prevention (Stage A)

• Control hypertension (target <130/80 mmHg)
• Treat atherosclerotic risk factors (statins, aspirin)
• Diabetes management (SGLT2 inhibitors protect against HF development)
• Smoking cessation, weight control, Mediterranean diet, regular aerobic exercise
• Avoid cardiotoxic drugs when possible; cardioprotection during chemotherapy (dexrazoxane, SGLT2i)
• Screen with natriuretic peptides in high-risk asymptomatic individuals - Goldman-Cecil, p. 2936

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