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Pathology of Cardiomyopathy — Study Notes

Sources: Robbins & Kumar Basic Pathology (Robbins Pathology), Robbins Cotran & Kumar Pathologic Basis of Disease, Goldman-Cecil Medicine, Braunwald's Heart Disease

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Overview

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1. Dilated Cardiomyopathy (DCM)

Definition & Epidemiology

Pathogenesis

• 50 causative genes identified; autosomal dominant predominant

• Loss-of-function mutations in cytoskeletal/sarcomeric proteins
• Most common gene: TTN (titin) — truncating mutations in ~20–25% of familial DCM and 18% of sporadic cases
• Other genes: β-myosin heavy chain, α-myosin heavy chain, cardiac troponin T, desmin (intermediate filament), nuclear lamins A/C
• Lamin A/C mutations → arrhythmia + progressive AV conduction disease preceding DCM
• X-linked DCM: dystrophin gene mutations (also causes Duchenne/Becker MD); accounts for 2–5% of familial cases

⚡ Key contrast: Gain-of-function mutations in sarcomere genes (β-MHC) → HCM; Loss-of-function mutations in same genes → DCM

• Viral myocarditis → coxsackievirus B, parvovirus B19, HHV-6, adenovirus; often leaves viral "footprints" in end-stage DCM
• Alcohol/toxins: Alcohol + acetaldehyde direct cardiotoxicity → myocyte vacuolisation, mitochondrial abnormalities, fibrosis. Estimated threshold: ~6 drinks/day for 5–10 years. Abstinence improves >50%
• Chemotherapy: Anthracyclines (doxorubicin, daunorubicin) — dose-dependent; risk at >450 mg/m²
• Pregnancy (peripartum cardiomyopathy)
• Iron overload, radiation, nutritional deficiency, cocaine, sarcoidosis, tachycardia-mediated

Morphology (Gross & Microscopic)

Clinical Features

• Symptoms of high pulmonary venous pressure (dyspnoea, orthopnoea, PND) or low cardiac output
• Palpitations, presyncope, syncope (arrhythmias)
• Advanced: sinus tachycardia, weak pulses, hypotension, elevated JVP, displaced apex
• Complications: CHF, systemic/pulmonary emboli from mural thrombi, sudden cardiac death, AF

Management Principles

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2. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Definition

Epidemiology

• Prevalence: 1 in 2000–5000 adults
• Accounts for ~10% of sudden cardiac deaths in athletes

Pathogenesis

• Mutations in desmosomal proteins at the intercalated disk — most commonly plakoglobin, plakophilin-2, desmoplakin, desmoglein-2, desmocollin-2
• Also mutations in desmin (intermediate filament interacting with desmosome)
• Mechanism: Desmosomal detachment → myocyte death (especially during strenuous exercise) → progressive replacement by fat and fibrosis

Morphology

Clinical Features

• Palpitations, syncope, sudden cardiac death (often first presentation)
• Ventricular tachycardia with LBBB morphology (origin in RV)
• ECG: epsilon waves, T-wave inversions in V1–V3
• Diagnosis: Task Force Criteria (imaging, ECG, histology, genetics, family history)

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3. Hypertrophic Cardiomyopathy (HCM)

Definition

Pathogenesis

• Gain-of-function mutations in sarcomeric proteins → hypercontractility → increased energy consumption → net negative energy balance
• Autosomal dominant; >400 causative mutations in 9 genes
• Top 3 genes (account for 70–80% of HCM):
  1. β-myosin heavy chain (MYH7) — most frequently involved
  2. Myosin-binding protein C (MYBPC3)
  3. Cardiac troponin T (TNNT2)
• Same genes as DCM but mutations cause gain vs loss of function

Morphology

• Massive myocardial hypertrophy without ventricular dilation
• 90%: Asymmetric septal hypertrophy (ASH) — septum thicker than LV free wall
• Ventricular cavity → "banana-shaped" configuration on longitudinal section
• Anterior mitral leaflet contacts the hypertrophied septum during systole → fibrous endocardial plaque in LVOT + SAM (systolic anterior motion)
• Both atria dilated

• Marked myocyte hypertrophy
• Myocyte/myofiber disarray — haphazard arrangement (pathognomonic)
• Interstitial fibrosis
• Characteristic branching of myocytes

Clinical Features

• Typically manifests at postpubertal growth spurt
• Exertional dyspnoea + harsh systolic ejection murmur (outflow obstruction)
• Angina — due to massive hypertrophy + increased O₂ demand + compromised intramural coronary flow (even without CAD)
• Murmur increases with Valsalva/standing (↓ preload → more obstruction)
• Murmur decreases with squatting/leg raise (↑ preload)

Major Complications

Management

• Beta-blockers or calcium channel blockers (promote ventricular relaxation)
• Avoid vasodilators, dehydration, intense exercise
• ICD for high-risk SCD
• Septal reduction: surgical myectomy or alcohol septal ablation
• Mavacamten (myosin inhibitor) — reduces hypercontractility

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4. Restrictive Cardiomyopathy (RCM)

Definition

Pathogenesis & Causes

• Idiopathic (interstitial fibrosis)

• Endomyocardial fibrosis: Most common worldwide (tropical Africa); diffuse fibrosis of ventricular endocardium + sub-endocardium; affects tricuspid and mitral valves; linked to helminthic infections and nutritional deficiency
• Loeffler endomyocarditis: Peripheral hypereosinophilia + eosinophilic tissue infiltrates; eosinophil granule products (major basic protein) → endocardial/myocardial necrosis → scarring → mural thrombus

Morphology

• Gross: Ventricles of approximately normal size, cavities not dilated, myocardium firm; both atria typically dilated (due to restricted ventricular filling and pressure overload)
• Microscopic: Variable interstitial fibrosis; endomyocardial biopsy reveals specific cause (amyloid deposits, granulomas, iron, eosinophilic infiltrates)

Clinical Features

• Dyspnoea, fatigue, signs of right-sided failure (elevated JVP, peripheral oedema, ascites)
• Heart sounds may be normal; S3/S4 gallop
• ECG: Low voltage (especially in amyloid), conduction abnormalities
• Echo: Normal or mildly reduced systolic function, biatrial enlargement, diastolic dysfunction
• Key distinction from constrictive pericarditis (can be clinically identical — requires cardiac catheterisation or CMR)

Congo Red Staining in Amyloidosis

• Amyloid deposits stain orange-red with Congo red; show apple-green birefringence under polarised light

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5. Stress (Takotsubo) Cardiomyopathy

Definition

Epidemiology

• Accounts for ~4% of patients presenting with presumed ACS
• ~90% female, predominantly postmenopausal (prevalence 5.9–7.5% in women presenting with ACS)

Pathogenesis

• Trigger: Acute emotional/physical stress → massive catecholamine surge
• Catecholamines cause direct myocardial toxicity (catecholamine-mediated microvascular spasm) or bind β-receptors in the apex (which has higher β-receptor density) → apical stunning
• The 4th Universal Definition of MI does not classify Takotsubo as AMI — it is recognised as a separate syndrome, not MINOCA

Morphology / Findings

• LV apical ballooning (akinesis/dyskinesis of apex + mid-ventricle)
• Hypercontractile LV base
• On CMR: transient wall motion abnormality; can show mid-wall fibrosis in some cases
• Gross pathology: Non-specific; no permanent structural damage in typical cases

Clinical Features

• Presents identically to STEMI: chest pain, ST elevation/T-wave changes, mild troponin rise
• Precipitated by sudden emotional shock (grief, fear, anger) or physical stressor (surgery, stroke, sepsis)
• Coronary angiography: No obstructive CAD (key distinguishing feature)
• Usually reversible — LV function recovers within weeks

Prognosis & Complications

• Not purely benign: in-hospital mortality 4.1%, long-term (1-year) mortality 5.6% (InterTAK Registry)
• Recurrence in 5–10%
• Complications: Acute heart failure, LV outflow obstruction (due to basal hypercontractility), cardiogenic shock, ventricular arrhythmias, LV thrombus, mitral regurgitation

Management

• Supportive care; treat precipitant
• ACE-I — observational benefit; improved 1-year survival
• Beta-blockers — no proven benefit for index event or prevention of recurrence
• No randomised controlled trials guide therapy

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Quick Comparison Table

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Key Pathology Pearls for Exams

1. DCM vs HCM genetics: Both can involve β-MHC and troponin T mutations — but DCM = loss of function; HCM = gain of function
2. HCM hallmark histo: Myocyte disarray — random, haphazard orientation of myofibers with bizarre branching
3. ARVC hallmark histo: Fibrofatty replacement of RV wall (Masson trichrome: blue fibrosis + white fat replacing red myocardium)
4. RCM with Congo red stain → apple-green birefringence = amyloid
5. Endomyocardial fibrosis = most common RCM worldwide (tropical areas); Loeffler = eosinophilia-associated
6. Takotsubo = no obstructive CAD on angiography + stress trigger + women 90% + reversible
7. Titin (TTN) = most common single gene mutated in DCM
8. MYH7 (β-myosin heavy chain) = most common gene mutated in HCM
9. ARVC = desmosomal protein mutations — avoid strenuous exercise; SCD risk in athletes
10. "Banana-shaped" LV lumen = HCM with ASH
11. Atrial dilation without ventricular dilation = hallmark gross finding in RCM
12. Mural thrombus at LV apex = DCM (due to stasis in dilated poorly contractile ventricle)

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