Cardiomyopathy

Classification Overview

• Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 12.5

1. Dilated Cardiomyopathy (DCM)

Definition & Pathophysiology

Causes / Pathogenesis

• Genetic (20-50% of cases): Over 50 genes implicated, predominantly autosomal dominant inheritance. Loss-of-function mutations in cytoskeletal, sarcolemmal, or nuclear envelope proteins. The most common are titin (TTN) truncation mutations, accounting for 10-20% of all DCM. Other genes: β-myosin heavy chain, cardiac troponin T, desmin, lamin A/C, dystrophin (X-linked; associated with Duchenne/Becker muscular dystrophy).
• Viral myocarditis: Coxsackievirus B, adenovirus, parvovirus B19, HHV-6. Sequential biopsies have documented progression from myocarditis to DCM.
• Alcohol/toxins: Ethanol and its metabolite acetaldehyde are directly cardiotoxic. Chronic alcohol use may also cause thiamine deficiency (beriberi heart disease). Chemotherapy agents (notably doxorubicin/anthracyclines) are important toxic causes.
• Peripartum cardiomyopathy: Occurs in the last trimester or up to 5 months postpartum; likely multifactorial (genetic susceptibility, volume overload, nutritional factors).
• Other: Hemochromatosis, sarcoidosis, chronic anemia, cobalt toxicity, idiopathic.

Morphology

• All four chambers dilated; heart is heavy (up to 900 g)
• Mural thrombi common, especially at the LV apex (risk of systemic embolism)
• Histology: myocyte hypertrophy, nuclear enlargement, interstitial fibrosis - all nonspecific

Clinical Features

• Symptoms of progressive heart failure: dyspnea, fatigue, peripheral edema
• Dilated ventricle promotes dispersion of ventricular depolarization/repolarization - substrate for ventricular tachyarrhythmias and sudden cardiac death
• Mural thrombi - embolic stroke risk
• NYHA class II-III patients: higher risk of sudden cardiac death than pump failure; class IV: more likely to die of pump failure

2. Hypertrophic Cardiomyopathy (HCM)

Definition & Pathophysiology

Pathogenesis

• Almost all cases are autosomal dominant, gain-of-function mutations in sarcomeric proteins
• More than 400 mutations in at least 9 genes identified
• Most commonly affected genes: β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) - together accounting for 70-80% of cases
• These are gain-of-function mutations causing myofilament hypercontractility, increased energy consumption, and net negative energy balance
• Note: some of the same genes (e.g., β-myosin) carry loss-of-function mutations in DCM

Morphology

• Massive myocardial hypertrophy; heart weight often 600-1000 g
• 90% of cases: Disproportionate thickening of the ventricular septum relative to the LV free wall - "asymmetric septal hypertrophy"
• Remaining 10%: concentric hypertrophy
• The thickened septum can bulge into the LV outflow tract
• Histology (pathognomonic): myocyte disarray - haphazardly oriented, interlocking hypertrophic myocytes, with interstitial and replacement fibrosis

Outflow Obstruction (Obstructive HCM)

• The hypertrophied septum narrows the LV outflow tract
• Dynamic obstruction created by systolic anterior motion (SAM) of the anterior mitral leaflet
• SAM causes both outflow obstruction AND mitral regurgitation
• Obstruction is dynamic: worsens with decreased preload (dehydration, Valsalva, standing), decreased afterload, or increased contractility (exercise, inotropes)

Clinical Features

• Dyspnea, angina, syncope (classic triad)
• Harsh systolic ejection murmur along the left sternal border (increases with Valsalva, decreases with squatting)
• Most common cardiovascular cause of sudden cardiac death in young athletes (accounts for ~1/3 of such events)
• Ventricular tachyarrhythmias arise from the substrate of myocyte disarray and fibrosis
• Atrial fibrillation is common; preferred rate/rhythm control: disopyramide + beta-blocker, or verapamil/diltiazem; amiodarone if needed

ICD Indications in HCM

• Prior cardiac arrest or VF
• First-degree relative with sudden cardiac death
• Unexplained syncope
• LV wall thickness ≥ 30 mm
• Abnormal BP response to exercise with other risk factors
• Hemodynamically significant or non-sustained VT
• High-risk children with unexplained syncope, massive LVH, or family history of SCD

3. Restrictive Cardiomyopathy

Definition & Pathophysiology

Morphology

• Ventricles approximately normal in size; cavities not dilated; myocardium is firm
• Both atria markedly dilated (due to high filling pressures)
• Microscopy: variable interstitial fibrosis; etiology-specific features on biopsy

Major Causes

• Extracellular deposition of proteins with β-pleated sheet conformation
• Can occur in systemic amyloidosis (e.g., AL amyloid from multiple myeloma/plasma cell dyscrasias) or isolated cardiac form (ATTR - transthyretin amyloidosis)
• ATTR: deposition of normal or mutant transthyretin in older adults
• A specific TTR mutation (Val122Ile) is found in ~4% of African Americans, increasing cardiac amyloidosis risk >4-fold
• AL amyloid light chains are also directly cardiotoxic beyond just mechanical deposition

• Most common worldwide form of restrictive cardiomyopathy
• Children and young adults in Africa and other tropical regions
• Diffuse fibrosis of ventricular endocardium and subendocardium, involving tricuspid and mitral valves
• Associated with helminthic infections and nutritional deficiencies

• No geographic predilection
• Peripheral hypereosinophilia + eosinophilic tissue infiltrates
• Eosinophil major basic protein causes endocardial/myocardial necrosis, then scarring, mural thrombus formation, and thrombus organization
• Endocardial fibrosis with large mural thrombi

4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

• Right-sided heart failure
• Ventricular arrhythmias of RV origin (VT with left bundle branch block morphology)
• Syncope and sudden cardiac death (especially in young athletes)

Pathogenesis

• Naxos syndrome: ARVC + palmoplantar keratoderma (skin hyperkeratosis) - associated with plakoglobin mutations

Morphology

• Right ventricular wall severely attenuated by myocyte loss
• Near-transmural replacement of RV free wall by fat and fibrosis
• LV involvement possible but less prominent
• Mononuclear inflammation may surround degenerating myocytes

ECG Features

Summary Comparison Table

Key Points for Exams

1. DCM: titin (TTN) is the most common single gene mutated; loss-of-function sarcomere mutations
2. HCM: gain-of-function sarcomere mutations; asymmetric septal hypertrophy in 90%; myocyte disarray is pathognomonic; #1 cause of SCD in young athletes
3. HCM murmur: increases with Valsalva (decreased preload), decreases with squatting (increased preload)
4. Restrictive: both atria dilated; biventricular filling pressures elevated; amyloid is the key cause in the Western world
5. ARVC: desmosomal protein mutations; fatty replacement of RV; epsilon wave; VT with LBBB morphology; Naxos syndrome (+ palmoplantar keratoderma)
6. Peripartum cardiomyopathy: a form of DCM; up to 5 months postpartum; generally reversible in ~50% of cases

Cardiomyopathy

Classification at a Glance

1. Dilated Cardiomyopathy (DCM)

Definition

Pathogenesis

• Autosomal dominant inheritance is predominant, with variable penetrance
• Over 50 genes implicated; all involve loss-of-function mutations in cytoskeletal, sarcolemmal, or nuclear envelope proteins
• Titin (TTN) truncation mutations are the single most common cause, accounting for 10-20% of all DCM
• Other key genes: β-myosin heavy chain, cardiac troponin T, desmin, lamin A/C
• Dystrophin mutations (X-linked DCM): couples cytoskeleton to ECM; also mutated in Duchenne and Becker muscular dystrophies. X-linked DCM typically presents after puberty
• Mitochondrial gene deletions (oxidative phosphorylation defects) affect the pediatric population

• Coxsackievirus B, adenovirus, parvovirus B19, HHV-6
• Sequential endomyocardial biopsies have documented progression from myocarditis to DCM
• Many "idiopathic" DCM cases are attributed to prior unrecognized viral infections

• Ethanol and especially acetaldehyde have direct toxic effects on the myocardium
• Chronic alcohol use causes thiamine deficiency - beriberi heart disease (a form of DCM)
• No morphologic features distinguish alcoholic DCM from other DCM causes
• Chemotherapy agents (doxorubicin/anthracyclines) are important toxic causes
• Cobalt (heavy metal) can cause DCM (historic contamination of beer production)

• Occurs late in pregnancy or up to 5 months postpartum
• Mechanism is multifactorial: genetic susceptibility, volume overload, hypertension, nutritional deficiency
• Recovers spontaneously in approximately 50% of cases

Morphology

• All four chambers dilated; heart weight markedly increased (up to 900 g)
• Mural thrombi common, especially at the LV apex - risk of systemic thromboembolism
• Histology: myocyte hypertrophy, nuclear enlargement, interstitial fibrosis - nonspecific findings

Clinical Features

• Symptoms of progressive heart failure: dyspnea, fatigue, peripheral edema
• Dilated ventricle creates dispersion of depolarization/repolarization - substrate for ventricular tachyarrhythmias and sudden cardiac death
• Mural thrombi - risk of embolic stroke
• NYHA class II-III: higher SCD risk than pump-failure death; class IV: more likely to die of pump failure

2. Hypertrophic Cardiomyopathy (HCM)

Definition

Pathogenesis

• Almost all cases are autosomal dominant with variable penetrance
• Over 400 mutations in 9 different genes; all are gain-of-function mutations in sarcomeric proteins, causing hypercontractility, increased energy consumption, and net negative energy balance
• This insight has led to novel therapeutics targeting myosin inhibition (mavacamten)
• Most commonly mutated genes (accounting for 70-80% of cases):
  • β-myosin heavy chain (MYH7)
  • Myosin-binding protein C (MYBPC3)
  • Cardiac troponin T (TNNT2)
• Key contrast: the same β-myosin gene carries loss-of-function mutations in DCM but gain-of-function mutations in HCM

Morphology

• Massive myocardial hypertrophy; heart weight 600-1000 g
• 90% of cases: asymmetric septal hypertrophy - disproportionate thickening of the ventricular septum vs. LV free wall
• Remaining 10%: concentric hypertrophy
• Histology (pathognomonic): myocyte disarray - haphazardly oriented, bizarrely shaped, interlocking hypertrophic myocytes with interstitial fibrosis

Outflow Obstruction (Obstructive HCM)

• Hypertrophied septum narrows the LV outflow tract
• Dynamic obstruction by systolic anterior motion (SAM) of the anterior mitral leaflet
• SAM produces both outflow obstruction AND mitral regurgitation
• Obstruction worsens with: decreased preload (dehydration, Valsalva, standing), decreased afterload, or increased contractility (exercise, inotropes)
• Obstruction improves with: increased preload (squatting, leg raise), increased afterload

Clinical Features

• Classic triad: dyspnea, angina, syncope
• Harsh systolic ejection murmur along the left sternal border
  • Increases with Valsalva (decreases preload)
  • Decreases with squatting (increases preload)
• #1 cause of sudden cardiac death in young athletes (accounts for ~1/3 of such events)
• VT substrate: myocyte disarray + fibrosis create re-entry circuits
• Atrial fibrillation is common

ICD Indications in HCM

• Prior cardiac arrest or VF
• First-degree relative with sudden cardiac death
• Unexplained syncope
• LV wall thickness ≥ 30 mm
• Non-sustained or hemodynamically significant VT
• Abnormal blood pressure response to exercise (with other risk factors)
• High-risk children with massive LVH, unexplained syncope, or family history of SCD

3. Restrictive Cardiomyopathy

Definition

Morphology

• Ventricles approximately normal in size; cavities not dilated; myocardium is firm
• Both atria markedly dilated - a hallmark finding
• Microscopy shows variable interstitial fibrosis; endomyocardial biopsy often identifies the specific cause

Major Causes

• Extracellular deposition of proteins forming insoluble β-pleated sheets
• AL amyloid: immunoglobulin light chains from multiple myeloma/plasma cell dyscrasias; light chains are also directly cardiotoxic beyond mere deposition
• ATTR amyloid (transthyretin): deposition of normal (wild-type) or mutant transthyretin in older adults - increasingly recognized and treatable (tafamidis)
• ~4% of African Americans carry a TTR Val122Ile mutation, increasing cardiac amyloidosis risk >4-fold

• Most common restrictive cardiomyopathy worldwide
• Children and young adults in Africa and other tropical regions
• Diffuse fibrosis of ventricular endocardium and subendocardium, often involving tricuspid and mitral valves
• Associated with helminthic infections and nutritional deficiencies

• No geographic predilection
• Peripheral hypereosinophilia + eosinophilic tissue infiltrates
• Eosinophil major basic protein causes endocardial/myocardial necrosis → scarring → mural thrombus formation → thrombus organization → fibrosis
• Large mural thrombi are characteristic

4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

• Right-sided heart failure
• Ventricular arrhythmias of RV origin - VT with left bundle branch block morphology
• Syncope and sudden cardiac death, especially in young athletes

Pathogenesis

• Mutations in genes encoding desmosomal junctional proteins at the intercalated disk: plakoglobin, plakophilin-2, desmoplakin, desmoglein-2, or proteins interacting with the desmosome (desmin)
• Disrupted cell-cell adhesion leads to myocyte death and replacement by fat and fibrosis

Morphology

• RV wall severely attenuated by myocyte loss
• Near-transmural replacement of RV free wall by fat and fibrosis (fatty infiltration is the hallmark)
• LV can also be involved but less severely
• Mononuclear inflammation may surround degenerating myocytes (but ARVC is not a primarily inflammatory disorder)

ECG Features

• Epsilon wave - small positive deflection after the QRS in right precordial leads (V1-V3)
• T-wave inversions in V1-V3
• VT with left bundle branch block morphology (arising from RV)

5. Myocarditis (Related Entity)

• Most common cause (USA): Viral - coxsackieviruses A and B, enteroviruses; increasingly parvovirus B19 and HHV-6
• Less common: CMV, HIV, influenza
• Clinical spectrum: asymptomatic → acute heart failure → chronic DCM
• Giant cell myocarditis (autoimmune, rapidly fatal without immunosuppression) must be distinguished from lymphocytic viral myocarditis

Comparison Summary

High-Yield Exam Points

1. DCM = loss-of-function mutations; titin (TTN) most common single gene; all-chamber dilation; flabby heart
2. HCM = gain-of-function mutations; asymmetric septal hypertrophy (90%); myocyte disarray (pathognomonic); #1 SCD cause in young athletes; SAM causes dynamic obstruction
3. HCM murmur increases with Valsalva/standing (reduced preload); decreases with squatting/passive leg raise (increased preload)
4. Restrictive = bilateral atrial dilation; amyloid (#1 in West); endomyocardial fibrosis (#1 worldwide); Congo red + apple-green birefringence for amyloid
5. ARVC = desmosomal mutations; fatty RV replacement; epsilon wave; VT with LBBB morphology; Naxos syndrome (+ palmoplantar keratoderma)
6. Peripartum cardiomyopathy = form of DCM; last trimester to 5 months post-delivery; ~50% recover
7. Same gene, opposite mutation effect: β-myosin loss-of-function → DCM; β-myosin gain-of-function → HCM