Heart Failure: Pathophysiology and Diagnosis¶

Chapter 264 | Part 6: Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders · Chapter 264

Key Clinical Points¶

Heart failure (HF) is a complex clinical syndrome resulting from structural or functional impairment of ventricular filling or ejection of blood.
The Universal Definition of HF requires symptoms/signs of volume overload corroborated by either elevated natriuretic peptide levels or objective evidence of cardiogenic congestion.
HF phenotypes are classified by ejection fraction: HFrEF (≤40%), HFmrEF (41–49%), and HFpEF (≥50%).
Ventricular remodeling involves both concentric hypertrophy (pressure overload) and eccentric hypertrophy (volume overload), involving myocyte growth, interstitial fibrosis, and fetal gene expression (e.g., β-myosin heavy chain).
Neurohormonal activation (SNS, RAAS, Vasopressin) provides initial compensation but leads to long-term maladaptation, including vasoconstriction, sodium retention, and myocyte toxicity.
SGLT-2 inhibitors have demonstrated beneficial effects on morbidity and mortality in HF with or without diabetes mellitus.
High-output heart failure can be caused by conditions such as thyrotoxicosis, anemia, or arteriovenous shunts.
Predictors of poor outcomes include advanced NYHA class, reduced ejection fraction, tachycardia, and presence of a third heart sound or elevated JVP.
Diagnosis of HFpEF is often challenging due to the need to rule out noncardiac causes of dyspnea or fluid retention.
HFrecEF (recovered EF) has a superior prognosis but may still present with symptoms due to persistent diastolic dysfunction.

DEFINITION & OVERVIEW¶

• General Definition: A complex clinical syndrome with symptoms and signs resulting from any structural or functional impairment of ventricular filling or ejection of blood. • Terminology Note: The term 'heart failure' is preferred over 'congestive heart failure' because some patients present without signs of volume overload. • Related Terms: ◦ Cardiomyopathy: Disorders of myocardial structure and/or function, which may lead to HF. ◦ Left ventricular dysfunction: A more general term for structural/functional issues leading to HF. • Universal Definition of HF: ◦ Requirement 1: Symptoms/signs of heart failure caused by a structural and/or functional cardiac abnormality. ◦ Requirement 2: Corroborated by at least one of the following: ◦ Elevated natriuretic peptide levels. ◦ Objective evidence of cardiogenic pulmonary or systemic congestion. • Clinical Phenotypes: ◦ HFrEF: Heart Failure with Reduced Ejection Fraction (≤40%). ◦ HFmrEF: Heart Failure with mildly Reduced Ejection Fraction (41–49%). ◦ HFpEF: Heart Failure with Preserved Ejection Fraction (≥50%). • HFrecEF (Recovered EF): ◦ Definition: Patients with HFrEF who show rapid or gradual improvement in EF to the normal range. ◦ Predictors of HFrecEF: Younger age, shorter duration of HF, nonischemic etiology, smaller ventricular volumes, and absence of myocardial fibrosis. ◦ Note: These patients may remain symptomatic due to persistent diastolic dysfunction, exercise-induced pulmonary hypertension, or other comorbidities (e.g., obesity).

EPIDEMIOLOGY¶

• Global Impact: ◦ ~6.7 million American adults treated for HF; >600,000 new cases annually. ◦ Global prevalence: ~56.2 million people. ◦ Lifetime risk of HF: 24% (approximately one in four persons). • Age Correlation: ◦ Prevalence is 1–2% in adults aged 40–49 years. ◦ Prevalence is ≥10% in adults >80 years old. • Racial and Ethnic Differences: ◦ Highest risk: Black individuals, followed by Hispanic, white, and Chinese Americans. ◦ Higher age-adjusted rates of HF hospitalization for black men and women compared to white counterparts. • Morbidity & Mortality: ◦ 5-year survival after diagnosis: ~50%. ◦ 1-year mortality in severe HF: up to 40%. ◦ Hospitalization: 83% hospitalized at least once; 67% at least twice; 54% three times; 43% four times. ◦ Readmission: 20–25% at 60 days; nearly 50% at 6 months. • Economic Burden: ◦ US cost (2018): $22.3 billion; projected to reach $70 billion by 2030 for hospitalizations alone.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Primary Drivers: ◦ Coronary artery disease: ~2/3 of cases in developed countries. ◦ Hypertension: Primary contributor in up to 75% of cases. ◦ Diabetes mellitus: Contributes to 10–40% of cases. • Congenital & Inherited: ◦ Congenital Heart Disease (CHD): ~13.3 million globally; includes uncorrected defects, repaired/palliated defects, or failing single-ventricle physiology. ◦ Inherited Cardiomyopathies: Hypertrophic and arrhythmogenic cardiomyopathies; others include lamin/titin mutations, muscular dystrophies, and mitochondrial disease. • Systemic & Other: ◦ Systemic: Amyloidosis, sarcoidosis, Chagas, HIV, Lupus myocarditis. ◦ High-Output States: Anemia, thyrotoxicosis, Beriberi (Vitamin B deficiency), cirrhosis, and arteriovenous shunts. • Ventricular Remodeling: ◦ Concentric Hypertrophy: Result of pressure overload (e.g., hypertension, aortic stenosis). ◦ Eccentric Hypertrophy: Result of volume overload (e.g., aortic regurgitation, mitral regurgitation). ◦ Cellular/Molecular Changes: Myocyte hypertrophy, interstitial fibrosis, fetal gene expression (e.g., β-myosin heavy charge), and altered calcium-handling proteins. ◦ Mechanisms of Remodeling (Table 264-3): ◦ Myocyte Biology: Abnormal excitation-contraction coupling, β-Adrenergic receptor desensitization, impaired cytoskeletal proteins. ◦ Composition: Myocyte necrosis, apoptosis, autophagy; interstitial and perivascular fibrosis; matrix degradation. ◦ Geometry: Ventricular dilation and wall thinning; increased sphericity and displacement of papillary muscles; atrioventricular valve regurgitation. • Neurohormonal Activation: ◦ Mechanism: Decreased cardiac output leads to unloading of high-pressure baroreceptors → reduced parasympathetic tone → increased sympathetic tone and nonosmotic release of vasopressin. ◦ Vasopressin: Potent vasoconstrictor; causes reabsorption of free water by the kidney. ◦ RAAS Activation: Sympathetic stimulation of the kidney leads to renin release → Angiotensin II → Aldosterone secretion. ◦ Consequences: Promotion of salt/water retention, peripheral vasoconstriction, myocyte hypertrophy, cell death, and myocardial fibrosis. • Vasodilatory Hormones: ◦ Natriuretic Peptides (ANP, BNP): Released due to stretch; cause vasodilation, sodium excretion, and inhibition of renin/aldosterone. ◦ Other factors: Prostaglandins (PGE, PGI), Bradykinin, Adrenomedullin, Nitric Oxide.

CLINICAL FEATURES¶

• NYHA Functional Classification (Table 264-4): ◦ Class I: No limitation; ordinary physical activity does not cause fatigue, dyspnea, palpitations, or angina. ◦ Class II: Mild limitation; comfortable at rest; less than ordinary physical activity leads to symptoms. ◦ Class III: Moderate limitation; comfortable at rest; less than ordinary physical activity (e.g., getting dressed) leads to symptoms. ◦ Class IV: Severe limitation; symptoms even at rest. • Predictors of Adverse Outcomes (Table 264-1): ◦ Clinical: Male sex, older age, DM, CKD, CAD, advanced NYHA class, presence of third heart sound or elevated JVP, decreased exercise capacity, cardiac cachexia, depression. ◦ Biochemical: Worsening renal function, hyponatremia, hyperuricemia, elevated troponin/natriuretic peptides, increased neurohormones (norepinephrine, renin, aldosterone, endothelin-1). ◦ Electrophysiologic: Tachycardia, widened QRS/LBBB, atrial fibrillation, ventricular ectopic activity, VT. ◦ Structural: Reduced LVEF, reduced RVF, increased ventricular volume/mass, pulmonary hypertension, secondary mitral/tricuspid regurgitation. • Precipitating Factors (Table 264-5): ◦ Patient-Related: Excess exertion/stress, excess fluid/sodium, nonadherence, heavy alcohol use. ◦ Provider-Related: NSAIDs (retention), CCBs (negative inotropy), inadequate diuretics. ◦ HF-Related: Uncontrolled HTN, MI, arrhythmias, pulmonary embolism. ◦ Other: Infection, renal/hepatic failure, hyperthyroidism, sleep apnea, anemia. • Cachexia Criteria (Table 264-6): ◦ Definition: Underlying disease and body weight loss ≥5% in ≤12 months (or BMI <20 kg/m²). ◦ Additional Requirements: At least three of the following five criteria: ◦ Decrease in muscle strength. ◦ Fatigue. ◦ Anorexia. ◦ Low fat-free mass index. ◦ Abnormal biochemistry: inflammation, anemia, low serum albumin levels.

DIFFERENTIAL DIAGNOSIS¶

• Symptom-Specific Differentials (Table 264-8): ◦ Dyspnea: Chronic lung disease, Pulmonary arterial hypertension, Neuromuscular disease, Anemia, Iron-deficiency anemia. ◦ Edema: Venous insufficiency, Nephrotic syndrome, Deep vein thrombosis, Lymphedema. ◦ Ascites: Hepatic cirrhosis, Portal vein thrombosis, Malignant carcinomatosis. ◦ Pleural effusion(s): Chronic infection, Lung cancer, Collagen vascular or rheumatologic disease. ◦ Jugular venous distension: Constrictive pericarditis, Pericardial effusion, Superior vena cava syndrome. • High-Output Heart Failure: ◦ Must rule out: Thyrotoxicosis, Arteriovenous shunt, Obesity, Cirrhosis, Anemia, Vitamin B deficiency (beriberi), Myeloproliferative disorder.

DIAGNOSTIC APPROACH¶

Initial Assessment: ◦ Perform thorough history and physical examination. ◦ Identify comorbidities: Hypertension, diabetes, hyperlipidemia. ◦ Screen for specific causes: Valvular disease, vascular disease, radiation history, cardiotoxins (chemo, alcohol, drugs). ◦ Family History: Assess for sudden death, HF, arrhythmias, or cardiomyopathy.
Routine Laboratory & Imaging: ◦ Chest X-ray: Detect cardiomegaly and fluid overload; rule out pulmonary disease. ◦ 12-lead ECG: Detect rhythm abnormalities, conduction issues (LBBB), LVH, and ischemia/infarction.
Echocardiography (Primary Tool): ◦ Perform 2D echocardiography with Doppler imaging to assess structure, function, and valves.
Advanced Investigations (Based on Echo findings): ◦ If specific etiology is unclear: → CMR/CT/PET → Ischemia/viability imaging → Tissue characterization. ◦ To evaluate coronary status: → Coronary angiography → Assess for angina or ischemia. ◦ To rule out systemic causes: → Screen for Hemochromatosis, Amyloidosis, Sarcoidosis. ◦ For definitive tissue diagnosis: → Endomyocardial biopsy.
Risk Stratification (Concurrent with Etiology): ◦ Assess NYHA functional class. ◦ Perform Cardiopulmonary exercise test. ◦ Measure Natriuretic peptide level. ◦ Use Ambulatory rhythm monitor. ◦ Evaluate Hemodynamics. ◦ Review Family history.

MANAGEMENT & TREATMENT¶

Pharmacological Management: ◦ SGLT-2 Inhibitors: Implement for patients with or without diabetes mellitus to improve morbidity and mortality. ◦ Neurohormonal Blockade: Target RAAS and SNS pathways (mitigate vasoconstriction, sodium retention, and myocyte toxicity).
Device & Procedural Interventions: ◦ Address Electrical Dyssynchrony: Targeted treatment of QRS widening/LBBB. ◦ Manage Secondary Mitral Regurgitation: Identify and treat as a contributor to heart failure.
Monitoring & Support: ◦ Fluid Management: Use diuretics for patients with evidence of congestion (JVP, crackles, edema). ◦ Risk Stratification: Continuous assessment of NYHA class and natriuretic peptides to guide intensity of therapy.

COMPLICATIONS & PROGNOSIS¶

• Prognostic Indicators: ◦ Mortality: 8–14% at 30 days; 26–37% at 1 year; up to 75% at 5 years. ◦ Readmission: 20–25% at 60 days; nearly 50% at 6 months. ◦ Risk Escalation: Each subsequent admission increases the risk of death. • Predictors of Poor Outcome (Table 264-1): ◦ Clinical: Advanced NYHA class, presence of third heart sound, cardiac cachexia, depression. ◦ Biochemical: Worsening renal function, hyponatremia, elevated troponin/natriuretic peptides. ◦ Electrophysiologic: Tachycardia, widened QRS, atrial fibrillation.

SPECIAL CONSIDERATIONS¶

• Congenital Heart Disease (CHD): ◦ 13.3 million globally; unique anatomical/physiological challenges. ◦ Categories: Uncorrected defects, repaired/palliated defects with late failure, failing single-ventricle physiology. • Diabetes Mellitus: ◦ Mechanisms of HF in DM (Table 264-7): Altered myocardial substrate, abnormal mitochondrial bioenergetics, oxidative stress, lipotoxicity, ER stress, impaired insulin signaling, G protein–coupled receptor kinase 2 signaling, RAAS activation, advanced glycation end products, Autophagy. • Pediatric Patients: ◦ High costs for acute cases like fulminant myocarditis, stress cardiomyopathy, peripartum cardiomyopathy, and tachycardia-induced cardiomyopathy.

KEY PEARLS & CLINICAL TRAPS¶

• Clinical Pearl: The term 'Heart Failure' is preferred over 'Congestive Heart Failure' because many patients have no signs of volume overload. ◦ Diagnostic Rule: Diagnosis of HFpEF requires ruling out noncardiac causes of dyspnea and fluid retention. ◦ Pathophysiology: Neurohormonal systems (RAAS, SNS) are initially compensatory but become maladaptive over time, leading to tissue damage. ◦ Risk Factor Distinction: In men, both hypertension and prior MI contribute equally to HF risk; in women, hypertension is the dominant contributor.

Reference Tables¶

TABLE 264-1 Independent Predictors of Adverse Outcomes in Heart Failure Clinical¶

Harrison's 22e, p.1977

Clinical	Male sex Older age Diabetes mellitus Chronic kidney disease Coronary artery disease Advanced NYHA classa Presence of third heart sound or elevated JVP Decreased exercise capacity Cardiac cachexia Depression

TABLE 264-2 Selected Causes of Heart Failure

Heart Failure with Reduced Ejection Fraction
Coronary artery disease Myocardial infarction Myocardial ischemia	Nonischemic cardiomyopathy Infiltrative disorders Familial disorders Tachycardia induced
Valvular heart disease Aortic stenosis or regurgitation Mitral or tricuspid regurgitation	Toxic cardiomyopathy Chemotherapy, immunotherapy Drugs such as hydroxychloroquine Alcohol, cocaine
Congenital heart disease Intracardiac shunts Repaired defects Systemic right ventricular failure	Chronic lung/pulmonary vascular disease Cor pulmonale Pulmonary arterial hypertension
Infectious Chagas HIV	Autoimmune disease Giant cell myocarditis Lupus myocarditis
Heart Failure with Preserved Ejection Fraction
Hemodynamic	Elevated pulmonary capillary wedge pressure Reduced cardiac index Reduced peak oxygen consumption Pulmonary hypertension Diastolic dysfunction
Electrophysiologic	Tachycardia Widened QRS interval or LBBB Atrial fibrillation Ventricular ectopic activity Ventricular tachycardia and sudden death
High-Output Heart Failure
Thyrotoxicosis	Arteriovenous shunt
Obesity	Cirrhosis
Anemia	Vitamin B deficiency (beriberi)
Chronic lung disease	Myeloproliferative disorder

TABLE 264-3 Mechanisms of Ventricular Remodeling Changes in Myocyte Biology¶

Harrison's 22e, p.1980

Changes in Myocyte Biology
Abnormal excitation-contraction coupling and crossbridge interaction
Fetal gene expression (e.g., β-myosin heavy chain)
β-Adrenergic receptor desensitization
Myocyte hypertrophy
Impaired cytoskeletal proteins
Changes in Myocardial Composition
Myocyte necrosis, apoptosis, and autophagy
Interstitial and perivascular fibrosis
Matrix degradation
Changes in Ventricular Geometry
Ventricular dilation and wall thinning
Increased sphericity and displacement of papillary muscles
Atrioventricular valve regurgitation

TABLE 264-4 New York Heart Association Functional Classification¶

Harrison's 22e, p.1982

FUNCTIONAL CLASS	LIMITATION	CLINICAL ASSESSMENT
Class 1	None	Ordinary physical activity does not cause undue fatigue, dyspnea, palpitations, or angina.
	Mild
Class III	Moderate	Comfortable at rest. Less than ordinary physical activity (e.g., getting dressed) leads to symptoms.
	Severe

Harrison's 22e, p.1983

Patient-Related
Excess exertion or emotional stress
Excess fluid and/or sodium intake
Nonadherence with medications
Heavy alcohol use
Provider-Related
Use of medications that cause salt and water retention (e.g., NSAIDs)
Prescribed use of medications with negative inotropic properties (e.g., CCBs)
Unrecognized congestion and inadequate use of diuretics
Heart Failure–Related
Uncontrolled hypertension
Myocardial ischemia or infarction
Atrial or ventricular arrhythmias
Pulmonary embolism
Other Disease States
Systemic infection
Worsening renal or hepatic failure
Hyperthyroidism
Untreated sleep apnea
Anemia or iron deficiency syndrome

TABLE 264-6 Diagnostic Criteria for Cachexia in Adults

• Underlying disease and body weight loss ≥5% in ≤12 months (or BMI <20 kg/m2)
• Plus at least three of the following five criteria
• Decrease in muscle strength
• Fatigue
• Anorexia
• Low fat-free mass index
• Abnormal biochemistry: inflammation, anemia, low serum albumin levels

TABLE 264-7 Mechanisms That Contribute to Development of Heart Failure in Patients with Type 2 Diabetes Mellitus…¶

Harrison's 22e, p.1986

Altered myocardial substrate
Abnormal mitochondrial bioenergetics
Oxidative stress and inflammation
Lipotoxicity
Endoplasmic reticulum stress
Impaired insulin signaling
β-Adrenergic receptor signaling
2
G protein–coupled receptor kinase 2 signaling
RAAS activation
Advanced glycation end products
Autophagy

TABLE 264-8 Differential Diagnosis of Heart Failure

SYMPTOM OR SIGN	DIFFERENTIAL DIAGNOSIS
Dyspnea	Chronic lung disease Pulmonary arterial hypertension Neuromuscular disease Anemia Iron-deficiency anemia
Ascites	Hepatic cirrhosis Portal vein thrombosis Malignant carcinomatosis
Jugular venous distension	Constrictive pericarditis Pericardial effusion Superior vena cava syndrome