Heart failure
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Heart Failure - Comprehensive Exam-Level Review
1. Definition
Heart failure (HF) is a clinical syndrome in which the heart cannot pump sufficient blood to meet the metabolic demands of the body, or can only do so at elevated filling pressures. It is a syndrome, not a single disease - cardiac output is typically below the normal ~5 L/min/70 kg, though "high-output" failure is a rare exception (see below).
- Braunwald's Heart Disease defines HF as a complex clinical syndrome resulting from any structural or functional impairment of ventricular filling or ejection of blood.
2. Classification
2a. By Ejection Fraction (EF)
| Type | EF | Key Feature |
|---|---|---|
| HFrEF (HF with reduced EF) | < 40% | Systolic dysfunction; impaired contraction |
| HFmrEF (mildly reduced EF) | 40-49% | Intermediate; often ischemic etiology |
| HFpEF (preserved EF) | ≥ 50% | Diastolic dysfunction; stiff ventricle |
HFpEF accounts for ~50% of all HF and does not respond well to positive inotropic drugs. Cardiac output may be reduced despite a normal EF due to impaired diastolic filling.
2b. ACC/AHA Stages vs. NYHA Functional Classification
(from Braunwald's Heart Disease, ACC/AHA table)
| ACC/AHA Stage | Description | NYHA Class |
|---|---|---|
| A | High risk, no structural disease, no symptoms | None |
| B | Structural heart disease, no symptoms | I |
| C | Structural disease + current or prior symptoms | I, II, III |
| D | Refractory HF requiring specialized intervention | IV |
NYHA Classes:
- I - No limitation; ordinary activity does not cause symptoms
- II - Slight limitation; ordinary activity causes dyspnea/fatigue
- III - Marked limitation; less-than-ordinary activity causes symptoms
- IV - Symptoms at rest; unable to carry on any activity without symptoms
Both systems are used together: ACC/AHA stages emphasize disease progression and prevention; NYHA class guides therapy eligibility (e.g., mineralocorticoid receptor antagonists require NYHA class II-IV; CRT requires class III-IV).
2c. High-Output Failure (rare)
Occurs when body demands exceed even a supranormal cardiac output. Causes: hyperthyroidism, beriberi (vitamin B1 deficiency), severe anemia, arteriovenous shunts. Treatment targets the underlying cause, not standard HF drugs. - Katzung's Basic and Clinical Pharmacology, 16th Edition
3. Pathophysiology
3a. Initiating Injury and Hypertrophy
Any sustained increase in mechanical work - pressure overload (e.g., hypertension, aortic stenosis) or volume overload (e.g., mitral/aortic regurgitation) - causes myocyte hypertrophy via increased protein synthesis and sarcomere assembly.
- Concentric hypertrophy (pressure overload): new sarcomeres assembled in parallel → increased wall thickness, normal/reduced cavity size
- Eccentric hypertrophy (volume overload): new sarcomeres assembled in series → ventricular dilation; wall thickness may be normal or reduced
Importantly, myocyte hypertrophy is NOT accompanied by a proportional increase in capillary density, creating a supply-demand mismatch, especially under pressure overload. - Robbins, Cotran & Kumar Pathologic Basis of Disease
3b. Cellular/Molecular Changes
With progressive failure, the following occur:
- Calcium handling abnormalities: Phosphorylation of RyR channels in SR enhances Ca²⁺ leak; SERCA activity is impaired (reduced Ca²⁺ reuptake) → reduced contractility + arrhythmias
- Beta-receptor downregulation: Prolonged sympathetic drive causes β1-receptor downregulation, reducing inotropic response; β3 receptors (not downregulated) may mediate negative inotropy
- Remodeling: Dilation beyond passive stretch, connective tissue proliferation, abnormal fetal-phenotype myocytes. Myocytes die by accelerated apoptosis (caspase activation by excessive β-stimulation), increasing stress on remaining cells
- Potassium channel changes: Facilitate arrhythmogenesis - a primary cause of death in HF
- Katzung's Basic and Clinical Pharmacology, 16th Edition
3c. Neurohumoral Compensation - The Vicious Cycle
This is the central mechanism driving HF progression:
Key pathway:
- ↓ CO → ↓ carotid sinus firing → baroreceptor reflex reset → ↑ sympathetic outflow + ↓ parasympathetic outflow
- ↓ CO → ↓ renal blood flow → ↑ renin → ↑ angiotensin II → vasoconstriction + aldosterone secretion + NE release
- Angiotensin II causes: vasoconstriction (↑ afterload), myocyte + ECM hypertrophy (maladaptive remodeling), sodium/water retention (↑ preload), prothrombotic effects
- ↑ Afterload → ↓ EF → ↓ CO → cycle repeats (downward spiral)
- Endothelin, vasopressin, aldosterone further worsen congestion and remodeling
Counterregulatory hormones: Natriuretic peptides (BNP, NT-proBNP) released from overstretched ventricles attempt to promote natriuresis/vasodilation - and serve as important diagnostic biomarkers.
3d. Frank-Starling Mechanics
- In the normal heart, increasing preload (LVEDP <15 mmHg) increases stroke work (ascending limb of Starling curve)
- In HF, the curve is shifted downward and rightward - the same preload produces less stroke work
- At filling pressures >20-25 mmHg, pulmonary congestion occurs
- Increased preload in HF comes from increased blood volume and venous tone
3e. Four Determinants of Cardiac Performance
- Preload - ventricular filling pressure / end-diastolic fiber length
- Afterload - systemic vascular resistance opposing ejection
- Contractility (inotropy) - intrinsic myocardial contractile state (independent of load)
- Heart rate
In HF: contractility ↓ → compensatory ↑ preload (Starling) and ↑ HR and ↑ SVR (neurohumoral), but these compensations become maladaptive over time.
4. Etiology
Common causes:
- Ischemic heart disease (most common in developed world) - myocardial infarction, ischemic cardiomyopathy
- Hypertension - pressure overload → concentric LVH → diastolic HF or eventual systolic dysfunction
- Dilated cardiomyopathy - idiopathic, viral, alcoholic, peripartum, familial
- Valvular disease - aortic stenosis (pressure overload), mitral/aortic regurgitation (volume overload)
- Hypertrophic cardiomyopathy
- Other: diabetes, obesity, thyroid disease, amyloidosis, tachycardia-mediated, cardiotoxins (doxorubicin)
5. Clinical Features
Symptoms
| Left HF (pulmonary congestion) | Right HF (systemic venous congestion) |
|---|---|
| Dyspnea on exertion | Peripheral edema (dependent) |
| Orthopnea (dyspnea lying flat) | Ascites |
| Paroxysmal nocturnal dyspnea (PND) | Hepatomegaly / hepatojugular reflux |
| Fatigue, reduced exercise tolerance | Jugular venous distension (JVD) |
| Cough (cardiac asthma) | Anorexia, nausea (bowel edema) |
| Tachycardia |
Signs
- S3 gallop - best sign of elevated LVEDP; high specificity for systolic HF
- S4 gallop - stiff, non-compliant ventricle (diastolic dysfunction)
- Displaced apex (cardiomegaly)
- Bi-basal crackles (pulmonary edema)
- Pleural effusion (more common on right)
- Cheyne-Stokes respiration (in severe HF with low CO)
- Pulsus alternans (alternating strong/weak beats - severe LV dysfunction)
6. Diagnosis
Per Braunwald's Heart Disease, the goals of clinical assessment are to:
- Confirm HF is present
- Define the type (HFrEF vs HFpEF)
- Identify the underlying cause
- Assess severity
- Identify comorbidities
No single sign or symptom defines HF - a multi-modal approach is required.
Key Investigations
| Test | Finding/Use |
|---|---|
| Echocardiography | Gold standard - EF, wall motion, valve function, diastolic indices |
| BNP / NT-proBNP | ↑ in HF; useful for diagnosis and prognosis monitoring |
| Chest X-ray | Cardiomegaly, pulmonary vascular congestion, Kerley B lines, pleural effusion |
| ECG | LVH, prior MI (Q waves), arrhythmias, LBBB (indicates CRT candidacy) |
| Serum electrolytes + renal function | Baseline + monitoring (K⁺, Na⁺, creatinine) |
| CBC | Anemia as a precipitant/comorbidity |
| Thyroid function | Hypothyroidism or thyrotoxicosis as cause |
| Coronary angiography / stress testing | If ischemic etiology suspected |
| Cardiac MRI | Myocarditis, infiltrative disease, viability |
7. Management
7a. Non-Pharmacological
- Sodium restriction (<2 g/day in symptomatic HF)
- Fluid restriction in severe hyponatremia or refractory congestion
- Daily weight monitoring
- Smoking cessation, alcohol avoidance
- Cardiac rehabilitation (approved for HF)
- Vaccinations (influenza, pneumococcus)
- Patient and family education on symptoms and discharge instructions
7b. Pharmacological - Chronic HFrEF (EF <40%)
The "four pillars" of guideline-directed medical therapy (GDMT) reduce mortality:
1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)
- Sacubitril/valsartan (Entresto) - preferred over ACE inhibitor or ARB alone
- Mechanism: sacubitril inhibits neprilysin (↑ natriuretic peptides) + valsartan blocks AT1R
- Must wait 36 hours after stopping ACE inhibitor before starting (angioedema risk)
- Starting dose: 49/51 mg twice daily; target dose: 97/103 mg twice daily
- Do NOT combine ACE inhibitor + ARNI (high angioedema risk)
2. ACE Inhibitors / ARBs (if ARNI not tolerated)
- Mechanism: block renin-angiotensin-aldosterone cascade
- ↓ angiotensin II → vasodilation + ↓ remodeling + ↓ aldosterone + ↓ sympathetic activation
- ACE inhibitors also accumulate bradykinin → cough (10-15%) and rare angioedema
- ARBs block AT1R selectively - no bradykinin accumulation → no cough
- Benefits: reduce LV size, improve EF, reduce symptoms and hospitalizations, prolong survival
- Indicated for all patients with LVSD regardless of symptoms or etiology
- Contraindications: angioedema (ACE-I), symptomatic hypotension, bilateral renal artery stenosis, K⁺ >5.5 mmol/L
- Goldman-Cecil Medicine
3. Beta-Blockers
- Counteract the maladaptive chronic sympathetic activation that worsens remodeling
- Only carvedilol, metoprolol succinate (CR/XL), and bisoprolol have proven mortality benefit
- Start low, titrate up slowly; do not start during acute decompensation
- Add to ARNI (or ACE-I/ARB) as cornerstone of treatment
4. Mineralocorticoid Receptor Antagonists (MRAs)
- Spironolactone or eplerenone
- Block aldosterone → ↓ sodium retention, ↓ hypokalemia, ↓ myocardial fibrosis
- Spironolactone: RALES trial - reduces mortality in severe HF (NYHA class III-IV) added to ACE-I
- Eplerenone: EMPHASIS-HF - reduces mortality in mild HF (NYHA class II) added to ACE-I + β-blocker
- Recommended for NYHA class II-IV with EF ≤35%
- Contraindications: K⁺ >5.0 mmol/L, creatinine >2.5 mg/dL
- Goldman-Cecil Medicine
5. SGLT2 Inhibitors (recent addition to all 4 pillars)
- Empagliflozin (EMPEROR-Reduced) and dapagliflozin (DAPA-HF) reduce cardiovascular death and HF hospitalizations in HFrEF
- Now part of "4 pillars" alongside ARNI, β-blocker, and MRA per the 2024 ACC Expert Consensus on HFrEF treatment
- Mechanism in HF: osmotic diuresis, reduced cardiac preload/afterload, possible direct myocardial effects; benefits are independent of diabetic status
6. Diuretics (symptom relief, not mortality benefit)
- Loop diuretics (furosemide, bumetanide, torsemide) - mainstay of decongestion
- Reduce preload → relieve pulmonary and peripheral congestion
- Monitor electrolytes (K⁺, Mg²⁺), renal function, volume status
- Alone they are not sufficient - must be combined with disease-modifying therapy
- In resistant congestion: IV diuretics, combination diuretics, or ultrafiltration
7. Digoxin (adjunctive)
- Mechanism: inhibits Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → ↓ NCX activity → ↑ intracellular Ca²⁺ → positive inotropy
- Also has vagotonic effects → slows AV conduction (useful if AF coexists)
- Does NOT reduce mortality; reduces hospitalizations (DIG trial)
- Narrow therapeutic index; toxicity risk especially with hypokalemia
- Now used mainly for symptom control or rate control in concomitant AF
7c. Pharmacological - Acute Decompensated HF
| Drug | Role |
|---|---|
| IV loop diuretics | First-line decongestion |
| IV vasodilators (nitrates, nitroprusside) | ↓ preload/afterload if adequate BP |
| Dobutamine | Selective β1-agonist; ↑ CO, ↓ filling pressure; risk of arrhythmia/ischemia |
| Dopamine | Useful if BP support needed |
| Milrinone | PDE3 inhibitor; ↑ cAMP → ↑ contractility + vasodilation; IV only; risk of arrhythmias |
| Levosimendan | Ca²⁺ sensitizer; approved in some countries; not in USA |
Positive inotropes (dobutamine, milrinone) are used only for acute HF or severe exacerbation. They are NOT first-line for chronic HF.
7d. Device Therapy
| Device | Indication |
|---|---|
| ICD (implantable cardioverter-defibrillator) | EF ≤35%, NYHA class II-III, on GDMT ≥3 months, expected survival >1 year |
| CRT (cardiac resynchronization therapy) | EF ≤35%, LBBB, QRS ≥150 ms, NYHA class II-IV |
| CRT-D | Combines ICD and CRT |
| LVAD (left ventricular assist device) | Bridge to transplant or destination therapy in advanced HF |
7e. HFpEF (EF ≥50%) - Management
HFpEF management is more limited in terms of mortality-reducing drugs:
- SGLT2 inhibitors now show mortality/morbidity benefit in HFpEF (EMPEROR-Preserved, DELIVER trials)
- Treat underlying causes: control hypertension, rate control in AF, manage obesity/diabetes
- Diuretics for symptoms
- ARBs/MRAs: modest benefit
- No proven benefit for ACE inhibitors, β-blockers, or digoxin specifically in HFpEF
- ASE 2025 updated recommendations for evaluating diastolic function and diagnosing HFpEF by echocardiography (PMID 40617625)
8. Prognosis
- Annual mortality of ~10% for stable HF; 50% at 5 years overall
- NYHA class IV: 1-year mortality ~50%
- NT-proBNP and NYHA class are the strongest prognostic markers
- Sudden cardiac death (arrhythmic) accounts for ~50% of deaths in HFrEF - rationale for ICD
- ICD/CRT, ARNI, and SGLT2 inhibitors have substantially improved outcomes in the modern era
9. Key Exam Summary Points
| Point | Detail |
|---|---|
| Gold-standard imaging | Echocardiogram |
| Best biomarker | BNP / NT-proBNP |
| First-line for HFrEF | ARNI + β-blocker + MRA + SGLT2i (4 pillars) |
| ACE-I → ARNI washout | 36-hour gap required |
| β-blockers with mortality benefit | Only carvedilol, metoprolol succinate, bisoprolol |
| MRA contraindication | K⁺ >5.0 mmol/L or creatinine >2.5 mg/dL |
| Digoxin mechanism | Na⁺/K⁺-ATPase inhibition → ↑ Ca²⁺ → positive inotropy |
| Dobutamine use | Acute HF only (β1 agonist, ↑ arrhythmia/ischemia risk) |
| HFpEF drug with mortality benefit | SGLT2 inhibitors |
| CRT indication | EF ≤35% + LBBB + QRS ≥150 ms + NYHA II-IV |
Sources: Braunwald's Heart Disease, 2 Vol Set (A Textbook of Cardiovascular Medicine); Goldman-Cecil Medicine International Edition; Katzung's Basic and Clinical Pharmacology, 16th Edition; Robbins, Cotran & Kumar Pathologic Basis of Disease. Recent guidelines: 2024 ACC Expert Consensus on HFrEF (PMID 38466244); ASE 2025 HFpEF echocardiography recommendations (PMID 40617625).
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