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Myocardial Infarction - Comprehensive Review

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Definition

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Etiology & Risk Factors

• Hyperlipidemia (elevated LDL, low HDL)
• Hypertension
• Cigarette smoking
• Diabetes mellitus
• Obesity / sedentary lifestyle
• Stress / type A personality
• Oral contraceptives (increased thrombotic risk)
• Hyperhomocysteinemia

• Advancing age (frequency rises progressively)
• Male sex (females protected during reproductive years; postmenopausal estrogen decline worsens risk)
• Family history of premature CAD
• Prior MI

• Coronary vasospasm (cocaine, ephedrine, Prinzmetal)
• Embolism (mural thrombus in AF, endocarditis vegetations, prosthetic material, patent foramen ovale)
• Vasculitis of coronary arteries
• Hematologic disorders (sickle cell disease, polycythemia)
• Amyloid deposition in vascular walls
• Microembolization / multifocal microinfarction

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Pathogenesis

• Only severe ischemia (blood flow ≤10% of normal) lasting 20-30+ minutes leads to irreversible necrosis.
• Progressive loss of viability becomes complete by 6-12 hours.
• Necrosis begins in the subendocardial zone (last to receive blood, highest intramural pressure) and progresses outward as a "wavefront."

• LAD (40-50%): Anterior LV wall, anterior 2/3 of ventricular septum, apex
• RCA (30-40%): Inferior/posterior LV wall, posterior 1/3 of septum, posterior RV
• LCX (15-20%): Lateral LV wall

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Gross Morphology (Table 12.5)

• A narrow rim (~0.1 mm) of viable subendocardial myocardium is preserved by diffusion from the ventricular lumen, even in transmural infarcts.
• STEMI (transmural): Full-thickness necrosis; associated with epicardial vessel occlusion
• NSTEMI (subendocardial): Necrosis confined to inner 1/3 to 1/2 of wall; associated with partial or transient occlusion, or global hypotension

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Microscopic Examination

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Diagnosis

• Prolonged (>30 minutes) crushing, squeezing, or stabbing substernal chest pain
• Radiation to left arm, jaw, or back
• Diaphoresis, nausea, vomiting
• Dyspnea (impaired contractility → pulmonary congestion)
• Rapid, weak pulse
• In ~25% of patients, onset is entirely asymptomatic (especially in diabetics due to neuropathy and in the elderly)

• STEMI: ST segment elevation in leads overlying the infarct (caused by rapid repolarization, decreased resting membrane potential, and delayed depolarization of infarcted fibers - all generating current flowing outward from the infarct); reciprocal ST depression in opposite leads; Q wave development after days-weeks
• NSTEMI: ST depression or T-wave inversions; no Q waves
• Non-Q-wave infarcts tend to be less severe but have high risk of reinfarction

• Cardiac Troponin I & T (cTnI, cTnT): Most clinically useful; begin rising at 2-4 hours, peak at 24-48 hours, remain elevated for 7-10 days; with reperfusion, peak higher and earlier (washout effect)
• CK-MB: Rises by 4-6 hours, peaks 18-24 hours, normalizes by 72 hours - useful for detecting reinfarction
• Myoglobin: Earliest marker (within 1-2 hours) but not cardiac-specific
• LDH (LDH1 > LDH2): Historical; rises late, peaks at 3-6 days, not preferred today

• Echocardiography: regional wall motion abnormalities
• Coronary angiography: gold standard for identifying culprit lesion
• Radionuclide imaging, CT coronary angiography, MRI (late gadolinium enhancement for scar)

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Treatment

1. Oxygen - supplementation for hypoxic patients (SaO2 <90%)
2. Nitrates - vasodilation, reversal of vasospasm; sublingual NTG initially
3. Aspirin + P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) - antiplatelet
4. GPIIb/IIIa inhibitors - in selected high-risk PCI patients
5. Anticoagulants - unfractionated heparin, LMWH, direct thrombin inhibitors, or factor Xa inhibitors (to prevent thrombus propagation)
6. Beta-blockers - reduce myocardial O2 demand, reduce arrhythmia risk; give early unless contraindicated (heart failure, bradycardia, bronchospasm)
7. Morphine - analgesia, reduces sympathetic activation
8. Prompt reperfusion - the single most effective intervention (see below)

• ACE inhibitors / ARBs - reduce ventricular remodeling, especially post-STEMI
• Beta-blockers - ongoing cardioprotection
• Statins - stabilize plaques, reduce LDL
• Dual antiplatelet therapy for 12 months post-PCI
• Aldosterone antagonists (eplerenone/spironolactone) in EF <40%

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Reperfusion & Reperfusion Injury

• Ischemia of 20-30 minutes → reversible injury → full recovery with reperfusion
• Longer ischemia → irreversible necrosis in affected zone
• But reperfusion can also salvage non-necrotic at-risk tissue

1. Fibrinolysis (thrombolysis) - tPA, streptokinase
2. Percutaneous coronary intervention (PCI) - preferred when available
3. CABG (in selected cases)

1. Mitochondrial dysfunction - ischemia alters mitochondrial membrane permeability; reperfusion causes swelling and outer membrane rupture, releasing pro-apoptotic contents
2. Myocyte hypercontracture - intracellular Ca2+ accumulates during ischemia; reperfusion augments uncontrolled myofibril contraction → cytoskeletal damage and cell death (contraction band necrosis on microscopy)
3. Oxidative stress (free radicals) - increased generation of reactive oxygen species (O2•-, H2O2, •OH, peroxynitrite) from reperfused endothelial cells, damaged parenchymal cells, and infiltrating leukocytes; compromised antioxidant defenses sensitize cells to further damage
4. Calcium overload - influx through damaged sarcolemma and ROS-injured sarcoplasmic reticulum → mitochondrial permeability transition pore (mPTP) opens → ATP depletion → further injury
5. Inflammation - "danger signals" from dead cells + cytokines from resident macrophages + increased adhesion molecule expression on hypoxic endothelium → neutrophil recruitment → additional tissue destruction

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Intervention (PCI)

• The preferred reperfusion strategy for STEMI when available within 90 minutes of first medical contact (vs. 120 minutes of symptom onset)
• Balloon angioplasty + drug-eluting stent (DES) placement at culprit lesion
• Superior to fibrinolysis in reducing death, reinfarction, and stroke

• Indicated for multivessel disease, left main disease, or failed PCI
• Saphenous vein grafts or internal mammary artery grafts

• Invasive strategy (early angiography + PCI/CABG) vs. conservative strategy based on risk score (TIMI, GRACE)
• High-risk features (elevated troponins, hemodynamic instability, recurrent ischemia) favor early invasive approach

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Complications of MI

Early Complications (hours to days)

Late Complications (weeks to months)

• Larger, transmural infarcts → higher probability of cardiogenic shock, arrhythmias, late CHF
• Anterior transmural: Higher risk of free-wall rupture, dilation, mural thrombi, aneurysm
• Posterior transmural: Higher risk of conduction blocks, RV involvement
• Subendocardial infarcts: Pericarditis, rupture, and aneurysm rarely occur
• Poor prognostic factors in STEMI: female sex, age >70, diabetes, previous MI

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Dressler Syndrome (Post-MI Syndrome)

• Friction rub
• Typical ECG changes (saddle-shaped ST elevation, PR depression)
• Pleuritic chest pain, fever
• May develop pericardial effusion and even cardiac tamponade

• NSAIDs (first-line) for 2-3 weeks
• Colchicine - reduces recurrence
• Steroids - reserved for refractory cases; note: steroids should be avoided early post-MI as they can impair conversion of infarcted myocardium to scar (leading to greater wall thinning and rupture risk)
• Usually self-limited

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Summary of Key Points

• Robbins, Cotran & Kumar Pathologic Basis of Disease, 10th ed., Chapter 12 (pp. 510-519)
• Robbins & Kumar Basic Pathology, Chapter 4 (Ischemic Heart Disease)
• Mulholland & Greenfield's Surgery, 7th ed., Chapter on Pericardial Disease

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Rheumatic Fever - Comprehensive Review

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Definition

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Epidemiology

• Age: Most common in children 5-15 years; rare before age 3, uncommon after 15. Carditis is more severe in younger children; arthritis predominates in adults (20% of first attacks).
• Global burden: ~34 million people worldwide live with RHD. In developing nations, ARF remains a leading cause of childhood mortality.
• Incidence: ARF incidence of 2-14 cases/100,000 children per year in endemic areas; rare in high-income countries due to antibiotic use and improved living conditions.
• RHD peaks in adults aged 25-34 years.
• Latent period: Symptoms begin approximately 2-3 weeks after streptococcal pharyngitis (average 18.6 days); Sydenham chorea follows a longer latency of 4-8 weeks.
• Attack rate: ARF develops in only ~1.6-2.5% of patients with untreated streptococcal pharyngitis, confirming host genetic susceptibility.
• Sex: Chorea is more common in females. Genetic susceptibility shows 44% concordance in monozygotic twins vs. 12% in dizygotic twins.

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Pathogenesis

Organism Factors

Host Factors

• Only ~3-6% of any population is susceptible - genetic factors are key.
• HLA class II alleles, polymorphisms in TNF, mannose-binding lectin, IGHV4-61*02 allele, complement factor H, and multiple HLA-DQ loci are implicated.

Molecular Mimicry (Core Mechanism)

1. GAS M protein antigens are presented by innate immune antigen-presenting cells to T cells.
2. This activates both humoral (antibody) and cellular (T cell) immunity.
3. Cross-reactive antibodies (targeting M protein epitopes) also bind to endothelial cells on heart valves, activating adhesion molecule VCAM-1.
4. Activated lymphocytes are recruited and lyse endothelial cells (via complement).
5. Damaged endothelium releases peptides (laminin, keratin, tropomyosin) that activate cross-reactive T cells.
6. These T cells invade the heart, amplifying damage and causing "epitope spreading."
7. Cytokine production by stimulated T cells leads to macrophage activation → Aschoff bodies form.

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Acute Rheumatic Fever - Clinical Features

• Fever - high grade (≥39°C) in most cases; may be absent in pure chorea
• Migratory polyarthritis (most common and earliest major symptom)
• Carditis (pancarditis)
• Sydenham chorea
• Erythema marginatum
• Subcutaneous nodules
• Elevated acute-phase reactants (ESR, CRP)

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Jones Criteria (2015 AHA Revision)

Essential Criterion (for ALL populations)

• Pure Sydenham chorea (may occur months after infection)
• Low-grade/subclinical carditis presenting late

• Positive throat culture for GAS or positive rapid streptococcal antigen test
• Elevated or rising streptococcal antibody titers - most commonly Anti-Streptolysin O (ASO) and Anti-DNase B (ADB)

Diagnosis Rules

Major and Minor Criteria by Population Risk

Note: Arthralgia cannot be used as a minor criterion if arthritis is being used as a major criterion. Similarly, prolonged PR interval cannot be used as a minor criterion if carditis is a major criterion.

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Rheumatic Carditis

Acute Rheumatic Carditis

1. Pericarditis

• Fibrinous pericarditis (fibrinohemorrhagic exudate)
• Manifests clinically in ~10% of patients as pleuritic chest pain and pericardial friction rub
• Pericardial effusion may be present; cardiac tamponade is rare
• Generally resolves without sequelae

2. Myocarditis

• Scattered Aschoff bodies in the interstitial connective tissue
• May cause cardiac dilation and functional mitral insufficiency
• Conduction system involvement → P-R interval prolongation (1st degree AV block); rarely higher-degree block
• Softening of the first heart sound

3. Endocarditis (Valvulitis) - Most Important

• Fibrinoid necrosis and fibrin deposition along the lines of closure of valve leaflets
• Forms 1-2 mm warty vegetations (verrucae) - see below
• Mitral valve involved in almost ALL cases of carditis
• Tricuspid valve frequently affected but rarely in a meaningful manner
• Aortic valve involved in 20-30% of cases
• Mitral regurgitation is the most common acute valvular lesion (from valvular inflammation, deformity, annular dilation, chordal elongation)
• Carey-Coombs murmur = low-pitched, apical, mid-diastolic flow murmur (due to acute mitral valvulitis)
• Heart failure occurs in 5-10% of first ARF episodes; more frequent with recurrences

Aschoff Bodies (Pathognomonic)

• Central zone of fibrinoid necrosis
• Surrounding lymphocytes (primarily T cells)
• Scattered plasma cells
• Anitschkow cells (pathognomonic macrophages)

• Plump, activated macrophages
• Abundant cytoplasm
• Nuclei with chromatin centrally condensed into a slender, wavy ribbon (the "caterpillar" appearance in longitudinal section; "owl-eye" in cross-section)
• Found in any layer of the heart during acute RF → evidence of pancarditis

Types of Vegetation in Valvular Disease (Comparison)

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Chronic Rheumatic Heart Disease

• Aschoff bodies are replaced by fibrous scar (rarely seen in chronic disease)
• Valve cusps and leaflets become permanently thickened and retracted
• Commissural fusion - fibrous bridging across valvular commissures
• Shortening and thickening of chordae tendineae, with fusion
• Calcification → "fishmouth" or "buttonhole" stenoses (classic mitral stenosis appearance)
• Microscopy: neovascularization and diffuse fibrosis obliterating normal leaflet architecture

• Mitral valve alone: 70% of cases (most common acquired cause of mitral stenosis worldwide)
• Combined mitral + aortic: 25% of cases
• Tricuspid: less frequently and less severely involved
• Pulmonic valve: almost always spared

• Left atrial dilation (pressure overload from mitral stenosis) → atrial fibrillation
• AF + dilation → mural thrombus → systemic embolism (stroke)
• Pulmonary hypertension → right ventricular hypertrophy and failure
• Infective endocarditis (scarred, deformed valves are predisposed)
• Cardiac hypertrophy and dilation, CHF

People with RHD are often asymptomatic for years. In low-incidence countries, 20-40 years pass before surgery is required; in high-incidence countries, mitral stenosis can develop much more rapidly.

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Major Manifestations - Detailed

1. Arthritis in Rheumatic Fever

• Most common (and often earliest) major manifestation of ARF
• Incidence increases with age: almost 100% in young adults, 82% in teenagers, 66% in children
• Classic pattern: migratory (flitting) polyarthritis - one large joint after another becomes painful and swollen for a few days, then spontaneously resolves, affecting the next joint
• Also seen: additive pattern (especially in adults)
• Joints affected most: knees (76%), ankles (50%), elbows and wrists (12-15%); less commonly shoulders, phalangeal, lumbosacral, cervical
• Pain is disproportionate to physical findings - exquisitely tender joints
• Sterile synovial fluid (inflammatory)
• No radiographic destruction - fully resolves without residual disability
• Responds dramatically to NSAIDs/salicylates ("aspirin test")
• Jaccoud's arthropathy (chronic post-RF arthropathy with reversible deformities) can occur after recurrent articular episodes

Arthritis typically lasts only a few days per joint and rarely more than 1 week per joint per ARF attack. In untreated patients, 6-16 joints are affected.

2. Sydenham Chorea (St. Vitus Dance)

• Involuntary, purposeless, non-repetitive choreiform movements
• Long latent period (4-8 weeks after GAS infection; sometimes months)
• More common in females and younger children
• Affects particularly the head (darting tongue movements) and upper limbs
• May be generalized or restricted to one side (hemichorea)
• Associated emotional lability and obsessive-compulsive traits
• Chorea usually resolves in 6 weeks but may take up to 6 months
• May occur in absence of other ARF manifestations (does not require positive streptococcal serology for diagnosis)
• >50% of patients presenting with pure chorea will have carditis - echocardiography is mandatory
• In severe cases: unable to perform activities of daily living

3. Subcutaneous Nodules

• Painless, small (0.5-2 cm), firm, mobile lumps
• Located beneath the skin overlying bony prominences
• Sites: hands, feet, elbows, occiput, occasionally vertebrae
• Delayed manifestation - appear 2-3 weeks after onset of disease
• Last only a few days to 3 weeks
• Strongly associated with carditis (rarely occur without carditis)
• Histologically resemble Aschoff bodies (fibrinoid necrosis with mononuclear infiltrate)

4. Erythema Marginatum

• Classic skin rash of ARF (but quite rare/evanescent)
• Pink macules that clear centrally, leaving a serpiginous, spreading, advancing edge
• Rash is evanescent - appears and disappears before the examiner's eyes
• Location: trunk, sometimes limbs; almost never on the face
• Non-pruritic
• May come and go with fever
• More common in children

5. Carditis (summarized above)

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Fibrinous Pericarditis in Rheumatic Fever

• A fibrinohemorrhagic exudate coats the epicardial surface
• Grossly: rough, shaggy "bread-and-butter" appearance of epicardium (exudate on both surfaces sticking together)
• Microscopically: fibrin strands on pericardial surface with underlying inflammatory infiltrate
• Generally resolves without sequelae in RF (unlike other causes of pericarditis)
• Clinically: anterior chest pain, pericardial friction rub; effusion possible; tamponade rare
• Does NOT usually progress to constrictive pericarditis (unlike bacterial or tuberculous pericarditis)

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Diagnosis

Clinical Diagnosis

1. Evidence of preceding GAS infection (essential, except for pure chorea)
2. Jones criteria (2015 revision, as above)
3. Exclusion of other diagnoses

Investigations

• ECG - look for prolonged PR interval, ST/T changes
• Echocardiogram - to detect subclinical carditis, assess valves, determine severity
• CBC - neutrophilia, elevated WBC
• CRP (elevated)
• ESR (elevated)
• Streptococcal serology: ASO titer (Anti-streptolysin O) and Anti-DNase B (ADB) titers - one or both elevated in >95% of ARF; age-specific reference ranges apply; rising titer is more significant than single elevated value

• Throat swab culture for GAS
• Rapid streptococcal antigen test
• Synovial fluid analysis (sterile inflammatory fluid)
• Blood cultures
• Autoantibodies (ANA, ds-DNA, anti-CCP) to exclude other diagnoses

• Rises 1-3 weeks after GAS pharyngitis
• Peaks at 3-5 weeks
• Falls to pre-infection levels by 6-12 months
• May be falsely negative in chorea (occurs late) and skin infections
• If ASO negative but ARF suspected, check Anti-DNase B (remains elevated longer)

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Treatment

1. Antibiotics (Eradication of GAS)

• Drug of choice: Penicillin
  • Oral: Phenoxymethyl penicillin (penicillin V) 500 mg (250 mg for children ≤27 kg) PO twice daily × 10 days
  • OR Amoxicillin 50 mg/kg (max 1 g) daily × 10 days
  • OR single IM dose: Benzathine penicillin G 1.2 million units (600,000 units for children ≤27 kg)
• Penicillin allergy: Erythromycin or a narrow-spectrum cephalosporin

2. Anti-inflammatory Therapy

• Aspirin (salicylates) - first-line; 50-60 mg/kg/day up to 80-100 mg/kg/day (divided doses); typically given for 4-8 weeks, tapered as inflammation resolves
• NSAIDs (naproxen) - alternative

• Corticosteroids (prednisone 1-2 mg/kg/day, max 80 mg/day) - may be used for severe carditis with HF; taper over 2-4 weeks with overlapping aspirin to prevent rebound; no proven benefit on preventing long-term valvular damage
• No proven therapy alters the likelihood or severity of developing RHD

• Mild: symptomatic; aspirin/NSAIDs are of no value for chorea
• Moderate-severe: carbamazepine or valproic acid (anticonvulsants that reduce choreiform movements)
• Severe/refractory: IVIG (may lead to more rapid resolution; no benefit on carditis without chorea; not routinely recommended)
• Haloperidol or other antidopaminergic agents (second-line)

3. Heart Failure Management

• Bed rest
• Diuretics, ACE inhibitors/ARBs
• Digoxin (with caution in myocarditis)
• Temporary pacemaker if high-degree heart block with hemodynamic compromise

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Secondary Prophylaxis (Prevention of Recurrence)

• Dose: 1.2 million units IM (600,000 units for children <27 kg) every 3-4 weeks

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Complications

Acute Complications

• Severe carditis with acute heart failure (5-10% of first attacks; more with recurrences)
• High-degree heart block (rare, usually reversible)
• Pericardial tamponade (rare)
• Chordae tendineae rupture → acute HF requiring emergency surgery
• Chorea-related disability (self-limited but prolonged)

Chronic Complications

• Rheumatic heart disease - most significant long-term consequence
  • Mitral stenosis (most common form; only acquired cause - "mitral stenosis is always rheumatic until proven otherwise")
  • Mitral regurgitation (acute and chronic)
  • Aortic stenosis/regurgitation
  • Combined mitral + aortic disease (25%)
  • Tricuspid involvement (less common)
• Atrial fibrillation (from left atrial dilation due to mitral stenosis)
• Systemic embolism/stroke (from mural thrombi in dilated left atrium + AF)
• Pulmonary hypertension → right heart failure
• Infective endocarditis (damaged valves are predisposed)
• Heart failure (long-term)
• Surgery/valve replacement requirement

Surgical repair or replacement (mitral valvuloplasty, valve replacement) has greatly improved long-term prognosis for patients with chronic RHD.

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Summary Table

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Comparison of the Four Major Forms of Vegetative Endocarditis

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Mnemonic: "RINS" - Remember It's Not Simple

• Row = RHD verrucae line up in a row along closure line
• Bulky = IE has bulky, destructive, irregular masses
• Flat/sterile = NBTE is flat, sterile, loosely attached
• Both sides = LSE on both sides of valve (unique!)

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Full Comparison Table

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Memory Hook for Each Type

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Quick Reference: The "4 S's" of Vegetation Character

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Cardiomyopathy - Comprehensive Review

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Definition

• Primary: Principally confined to the myocardium
• Secondary: Cardiac manifestation of a systemic disorder

Important exclusions: myocardial dysfunction secondary to coronary artery disease, hypertension, valvular disease, and congenital heart disease are NOT classified as cardiomyopathies.

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Types (Three Major Patterns)

1. Dilated Cardiomyopathy (DCM) - most common (90% of cases)
2. Hypertrophic Cardiomyopathy (HCM)
3. Restrictive Cardiomyopathy (RCM) - least common
4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) - sometimes listed as a 4th type

Mnemonic: "D-H-R = Dilates, Hypertrophies, Restricts"

• DCM = heart gets Doughy and Dilated (can't squeeze)
• HCM = heart gets Huge and Hard (can't relax)
• RCM = heart gets Rigid and Restricted (can't fill)

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1. Dilated Cardiomyopathy (DCM)

Definition

Causes / Etiology

• Idiopathic (most common, ~50%)
• Alcohol / toxic (alcohol + acetaldehyde direct toxicity; also cocaine, doxorubicin/anthracyclines, heavy metals)
• Myocarditis → viral (coxsackievirus B, parvovirus B19, HHV-6, enteroviruses, adenovirus, HIV)
• Anemia (chronic severe)
• Beritberi (thiamine/nutritional deficiency)
• Chaga's disease (Trypanosoma cruzi); also Hemochromatosis
• DNA mutations - Genetic (20-50% hereditary)

• Loss-of-function mutations in sarcomeric proteins or cytoskeletal linker proteins
• Titin (TTN) mutations - most common genetic cause
• β-myosin heavy chain, α-myosin heavy chain, cardiac troponin T
• Dystrophin mutations (X-linked DCM; also seen in Duchenne/Becker muscular dystrophy)
• Desmin (intermediate filament protein) and nuclear lamins A/C

• Peripartum cardiomyopathy (last trimester / first 6 months post-delivery)
• Sarcoidosis
• Thyroid disease (hypo- or hyperthyroid)

Pathogenesis

1. Myocyte damage (via genetic, toxic, or infectious mechanisms)
2. Loss of contractile function → compensatory ventricular dilation and hypertrophy
3. Progressive pump failure (systolic dysfunction)
4. Secondary mitral/tricuspid regurgitation (from annular dilation)
5. Low cardiac output → neurohormonal activation (RAA, sympathetic) → fluid retention, more dilation → vicious cycle

Gross Morphology

• Enlarged, heavy, flabby heart ("globoid" shape)
• 4-chamber dilation (especially left-sided)
• Ventricular wall: may be thickened, thinned, or normal
• Mural thrombi often present in dilated chambers (especially LV apex) → embolic risk
• Mitral and tricuspid valves may show functional regurgitation secondary to dilation
• Coronary arteries normal (no primary coronary disease)

Microscopy

• Myocyte hypertrophy (large, irregular nuclei - "boxcar nuclei")
• Interstitial fibrosis (variable, patchy or diffuse)
• Myocyte loss (dropouts replaced by fibrosis)
• No specific diagnostic finding - the picture is non-specific
• May see scattered inflammatory cells (if post-myocarditis)

Diagnosis

• Echo: Dilated LV/all chambers; reduced EF (<40%); regional wall motion abnormalities
• ECG: Non-specific ST/T changes; LBBB common; arrhythmias
• CXR: Cardiomegaly; pulmonary congestion
• BNP/NT-proBNP: Markedly elevated (heart failure marker)
• Troponin: May be mildly elevated in acute decompensation
• Endomyocardial biopsy: Rarely reveals specific diagnosis; useful if myocarditis or infiltrative disease suspected
• Cardiac MRI: Late gadolinium enhancement (fibrosis pattern); useful for etiology
• Genetic testing: For familial/young-onset DCM

Special Points

• Most common cardiomyopathy (90% of all cardiomyopathies)
• Peripartum DCM: develops in previously healthy women; may partially or fully recover post-partum
• Alcohol-related: partial/full recovery with abstinence
• Doxorubicin toxicity: dose-dependent; related to total cumulative dose; free radical mechanism
• Dystrophin mutations: X-linked; associated with Duchenne/Becker muscular dystrophy

Treatment

• Treat underlying cause (abstain from alcohol, antiviral, treat thyroid disease)
• Heart failure medications: ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists (spironolactone/eplerenone), SGLT2 inhibitors (dapagliflozin)
• Diuretics: For fluid overload
• Anticoagulation: For mural thrombi or AF
• Antiarrhythmics / ICD: For ventricular arrhythmias; ICD if EF <35%
• CRT (cardiac resynchronization therapy): For LBBB + EF <35%
• Heart transplantation: End-stage refractory DCM

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2. Hypertrophic Cardiomyopathy (HCM)

Definition

Causes / Etiology

• Genetic (primary/most common): Autosomal dominant; >400 causative missense mutations in sarcomeric protein genes
  • β-myosin heavy chain (MYH7) - most common (35-40%)
  • Myosin-binding protein C (MYBPC3) - second most common (20-25%)
  • Cardiac troponin T (TNNT2), troponin I (TNNI3)
  • α-tropomyosin, actin, titin, etc.
  • All are GAIN-OF-FUNCTION mutations enhancing myofilament function → myocyte hypercontractility

Contrast with DCM: same genes (e.g., β-myosin) but loss-of-function in DCM vs. gain-of-function in HCM

• Secondary/Other causes:
  • Friedreich's ataxia
  • Glycogen storage diseases (Pompe, Fabry)
  • Infants of diabetic mothers (transient neonatal HCM)
  • Noonan syndrome

Pathogenesis

1. Gain-of-function sarcomere mutations → myocyte hypercontractility and energy inefficiency
2. Myocyte hypercontractility → cell death → replacement fibrosis
3. Fibrosis + hypertrophy → diastolic stiffness (cannot relax after systole)
4. Asymmetric hypertrophy → interventricular septum bulges into LVOT
5. Systolic anterior motion (SAM) of mitral valve → LVOT obstruction (in ~1/3)
6. LV cavity becomes small, elongated, "banana-shaped"
7. High LV pressure + massive hypertrophy + compressed intramural vessels → subendocardial ischemia (even without CAD)

Gross Morphology

• Massive myocardial hypertrophy WITHOUT ventricular dilation
• Asymmetric septal hypertrophy (ASH) in 90% of cases (septum disproportionately thickened vs. LV free wall; septal:free wall ratio >1.3)
• Concentric hypertrophy in remaining 10%
• LV cavity: "banana-shaped" (compressed into elongated slit)
• Left atrium: dilated (from elevated LA pressure due to diastolic dysfunction)
• Fibrous endocardial plaque on LVOT (where anterior mitral leaflet contacts septum during SAM)
• Small-to-normal LV cavity; small or obliterated at end-systole

Microscopy

1. Myocyte disarray (myofiber disarray): Haphazard, whirling arrangement of myocytes and myofibers (loss of parallel orientation) - pathognomonic of HCM
2. Extreme myocyte hypertrophy with "boxcar" nuclei; exaggerated branching
3. Interstitial fibrosis (replacement and reactive)

Diagnosis

• Echocardiography (gold standard):
  • LV wall thickness ≥15 mm (in adults, unexplained)
  • Asymmetric septal hypertrophy (septum:posterior wall ratio ≥1.3-1.5)
  • Systolic anterior motion (SAM) of anterior mitral leaflet
  • LVOT gradient ≥30 mmHg (obstructive HCM)
  • Preserved/hyperdynamic EF (>50-80%)
  • Diastolic dysfunction
• ECG: LVH, deep narrow Q-waves (from septal depolarization), T-wave inversions, LBBB, AF
• Cardiac MRI: Best for wall thickness quantification, fibrosis (late gadolinium)
• Genetic testing: Confirms diagnosis; guides family screening
• Auscultation: Harsh crescendo-decrescendo systolic ejection murmur at LLSB; increases with Valsalva/standing, decreases with squatting/hand-grip (classic dynamic maneuvers)

Special Points

• Most important cause of sudden cardiac death in young athletes (<35 years): HCM accounts for ~1/3 of SCD in athletes
• Autosomal dominant with variable expression (same mutation → different severity)
• Dynamic outflow obstruction: Valsalva, dehydration, standing all worsen obstruction
• Carey-Coombs murmur not applicable here; the LVOT murmur is the key
• Mitral regurgitation (from SAM) commonly accompanies obstruction
• Atrial fibrillation with mural thrombus is a major complication

Treatment

• Beta-blockers (first-line) - slow heart rate, promote filling, reduce LVOT gradient
• Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) - same mechanism
• Disopyramide (negative inotrope) - reduce gradient
• Mavacamten (myosin inhibitor) - newer drug specifically for obstructive HCM

• Surgical septal myectomy (Morrow procedure) - gold standard for obstructive HCM
• Alcohol septal ablation - catheter-based controlled infarction of septal branches; alternative to surgery

• ICD: High-risk patients for SCD (family history SCD, massive hypertrophy ≥30 mm, unexplained syncope, NSVT, abnormal BP response to exercise)
• Anticoagulation for AF
• Avoid: Vasodilators, nitrates, diuretics (worsen outflow obstruction), digoxin
• Exercise restriction: Competitive sports discouraged

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3. Restrictive Cardiomyopathy (RCM)

Definition

Causes / Etiology

• Radiation-induced fibrosis
• Amyloidosis (most common secondary cause in high-income countries)
• Idiopathic
• Sarcoidosis; Sphincolipidosis/Storage diseases (Gaucher, Fabry, mucopolysaccharidoses)
• Endomyocardial fibrosis (most common worldwide - tropical/Africa)

• Hemochromatosis (iron deposition)
• Loeffler endomyocarditis (hypereosinophilia)
• Metastatic tumors
• Carcinoid heart disease

• Most common cause in high-income countries
• AL amyloid (immunoglobulin light chains, in multiple myeloma/plasma cell dyscrasias)
• ATTR amyloid (transthyretin): Wild-type (senile) or hereditary (mutant transthyretin)
  • 4% of African Americans carry V122I TTR mutation → 4-fold increased risk
  • Cardiac amyloid → sparkling/granular appearance on echo; concentric LV thickening
• Classic cardiac echo: "sparkling" myocardium; low voltage on ECG despite thick walls

• Children and young adults in Africa and other tropical areas
• Worldwide most common form of restrictive cardiomyopathy
• Fibrosis from apex upward, eventually involving AV valves
• Linked to nutritional deficiency and/or parasitic infections (hypereosinophilia)
• Mural thrombi common

• Peripheral hypereosinophilia + eosinophilic tissue infiltrates
• Eosinophil major basic protein → endomyocardial necrosis → fibrosis + thrombus formation
• Associated with myeloid neoplasms with eosinophilia (FIP1L1-PDGFRA rearrangement)

Pathogenesis

1. Infiltrative material or fibrosis stiffens the ventricular myocardium
2. Impaired diastolic relaxation → elevated filling pressures
3. Atria dilate (pressure overload from impaired ventricular filling)
4. Systolic function initially preserved
5. Progressive rise in venous pressures → right and left heart failure

Gross Morphology

• Ventricles: approximately normal size or slightly enlarged; cavities not dilated
• Firm myocardium
• Biatrial dilation (characteristic due to restricted ventricular filling)
• In amyloidosis: thick, rubbery ventricular walls with "waxy" texture
• In EMF: fibrous tissue lining of endocardium from apex upward

Microscopy

• Patchy or diffuse interstitial fibrosis (variable)
• Non-specific on routine biopsy; causes determined by special stains:
  • Amyloid: Congo red staining → apple-green birefringence under polarized light
  • Hemochromatosis: Iron stain (Prussian blue)
  • Sarcoidosis: Non-caseating granulomas
• Endomyocardial biopsy often reveals a specific etiology (unlike DCM)

Diagnosis

• Echocardiography:
  • Normal/near-normal LV size and EF
  • Biatrial enlargement (prominent)
  • Increased wall thickness (infiltrative causes)
  • Diastolic dysfunction (abnormal E/e' ratio, restrictive filling pattern)
  • "Sparkling" appearance in amyloidosis
• ECG: Low voltage relative to wall thickness (amyloid); conduction abnormalities
• Cardiac MRI: Late gadolinium enhancement patterns (diffuse subendocardial in amyloid; patchy in sarcoid)
• Nuclear imaging (Tc-99m pyrophosphate scan): Highly specific for ATTR amyloid
• Serum/urine protein electrophoresis + free light chains: For AL amyloid
• Endomyocardial biopsy: Congo red for amyloid, iron stains, granuloma detection - most useful in RCM
• Key clinical challenge: Must distinguish from constrictive pericarditis (similar physiology but different treatment!)

Special Points

• Least common of the three major cardiomyopathies
• Amyloidosis RCM key feature: "paradox of low voltage + thick walls" on ECG
• Must distinguish from constrictive pericarditis (which is treated with pericardiectomy)
  • Constrictive pericarditis: calcified pericardium on imaging; normal myocardium; Kussmaul sign
  • RCM: thick myocardium; normal pericardium; biopsy positive
• Endomyocardial fibrosis is most common worldwide but largely a disease of developing nations

Treatment

• Treat underlying cause:
  • Amyloidosis: Tafamidis (TTR stabilizer) for ATTR amyloid; chemotherapy for AL amyloid
  • Hemochromatosis: Phlebotomy/chelation
  • Sarcoidosis: Corticosteroids
  • Loeffler: Imatinib/tyrosine kinase inhibitors (if associated myeloid neoplasm)
• Diuretics: For fluid overload and elevated filling pressures (use cautiously)
• Rate control: For AF
• Anticoagulation: For AF or mural thrombi
• Heart transplant: End-stage disease
• EMF: Endocardiectomy with AV valve repair

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4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Definition & Key Features

• Autosomal dominant disorder; prevalence 1:2000-1:5000
• Right-sided heart failure + rhythm disturbances → sudden cardiac death
• Mutation in desmosomal junction proteins (plakoglobin, desmoplakin, plakophilin, desmoglein, desmocollin)
• Also mutations in desmin (intermediate filament)
• Mechanism: desmosomal detachment (especially during strenuous exercise) → myocyte death → replacement by fat and fibrosis

Gross Morphology

• Right ventricular wall severely thinned due to myocyte replacement by fatty infiltration + fibrosis
• LV may also be involved to a lesser extent

Microscopy

• RV myocardium replaced by fibro-fatty tissue (fibrous + adipose tissue)
• Residual myocardial strands within fatty tissue

Diagnosis

• ECG: Epsilon waves (post-QRS notch in V1-V3); T-wave inversions in right precordial leads; RBBB morphology VT
• Echo/MRI: RV dilation, wall motion abnormalities, fatty infiltration
• Genetic testing for desmosomal mutations
• Task Force Criteria (major and minor) for diagnosis

Treatment

• ICD (high risk of SCD, especially in athletes)
• Antiarrhythmics (sotalol, amiodarone)
• Beta-blockers
• Exercise restriction (sports strongly discouraged)
• Catheter ablation for refractory VT
• Cardiac transplantation for refractory end-stage disease

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Comparison Table

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Summary Mnemonic: "D Flops, H Pops, R Stops, A Drops"