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Cardiomyopathies: DCM, HCM (HOCM), and RCM

Overview Comparison

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1. Dilated Cardiomyopathy (DCM)

Definition & Epidemiology

Pathogenesis & Genetics

• Genetic causes (20–50% of cases): Autosomal dominant is the predominant pattern. Over 50 genes implicated — mostly loss-of-function mutations in cytoskeletal or sarcomere-linking proteins.
  • TTN (titin) mutations: most common — ~25% of familial cases, 18% of sporadic cases
  • Others: β-myosin heavy chain, α-myosin, cardiac troponin T
  • Lamin A/C mutations: cause arrhythmogenic DCM with AV conduction disease preceding heart failure
  • X-linked (2–5%): dystrophin gene mutations (Duchenne, Becker, Emery-Dreifuss muscular dystrophies account for 90% of X-linked forms)
• Acquired causes: Viral myocarditis (parvovirus B19, HHV-6, coxsackievirus B, adenovirus), alcohol (>6 drinks/day for 5–10 years; contributes to >10% of US heart failure cases), anthracyclines (overt HF in 5–10% at doses ≥450 mg/m²), peripartum state, hemochromatosis, cocaine, radiation therapy, nutritional deficiencies, sarcoidosis, tachycardiomyopathy

Morphology (Robbins)

• Four-chamber dilation and hypertrophy; heart is flabby and poorly contractile
• Small mural thrombi may form at the LV apex (embolic risk)
• Histology: myocyte hypertrophy + interstitial fibrosis (non-specific); no specific pathologic features at end-stage

Clinical Features

• Most present with symptoms of high pulmonary venous pressure or low cardiac output: exertional dyspnea, orthopnea, PND, fatigue, peripheral edema
• First presentation may be sudden cardiac death or thromboembolic event (AF, LV thrombus → stroke)
• Increasingly diagnosed incidentally on imaging

Diagnosis

• Echo: dilated LV with EF <40%, global hypokinesis
• CMR: dilated chambers, no focal LGE in idiopathic form (vs. ischemic cardiomyopathy which shows subendocardial/transmural scar)
• BNP/NT-proBNP elevated
• Genetic testing for familial cases

Management

• HFrEF guideline-directed therapy: ACE inhibitor/ARB/ARNI + β-blocker + MRA + SGLT2 inhibitor
• ICD for EF <35% after 3 months of GDMT
• CRT (biventricular pacing) if LBBB + QRS ≥150 ms + EF ≤35%
• Anticoagulation for AF or LV thrombus
• Abstinence from alcohol in alcoholic cardiomyopathy (≥50% improve)
• Heart transplantation for refractory cases

Prognosis

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2. Hypertrophic Cardiomyopathy (HCM) / HOCM

Definition

Pathogenesis & Genetics

• Caused by gain-of-function missense mutations in sarcomeric proteins → myocyte hypercontractility → increased energy use → net negative energy balance
• Autosomal dominant with variable expression; >400 causative mutations identified
• β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) together with troponin T (TNNT2) account for 70–80% of all HCM cases
• Note: The same genes can cause either HCM (gain-of-function) or DCM (loss-of-function)

Morphology (Robbins)

• Massive myocardial hypertrophy without ventricular dilation
• Asymmetric septal hypertrophy (ASH) in 90% of cases (disproportionate thickening of interventricular septum > LV free wall)
• Concentric hypertrophy in 10%
• LV cavity compressed into a "banana-like" shape on longitudinal section
• Systolic anterior motion (SAM) of the mitral valve: anterior mitral leaflet contacts the septum during systole → LVOT obstruction → subaortic plaque on septal endocardium + mitral leaflet thickening
• Histology: myocyte disarray (hallmark) — haphazardly arranged myocytes with interstitial fibrosis

Outflow Obstruction (HOCM)

• LVOT gradient present at rest or provoked in ~33% of patients
• Worsened by: decreased preload (dehydration, Valsalva, standing), decreased afterload, increased contractility (exercise, digoxin, sympathomimetics)
• Improved by: increased preload (squatting, leg raise), increased afterload (hand grip), decreased contractility (β-blockers, verapamil)
• Classic murmur: harsh crescendo-decrescendo systolic ejection murmur at LLSB, increases with Valsalva and standing, decreases with squatting

Clinical Features

• Wide spectrum: many asymptomatic (incidental echo/ECG finding)
• Symptomatic triad: dyspnea on exertion, angina, syncope
• Sudden cardiac death (SCD): most common cause of SCD in young athletes; arrhythmia-mediated
• Atrial fibrillation common; anti-arrhythmics of choice are disopyramide + β-blocker, or amiodarone

Management

• β-blockers (first-line for symptomatic relief)
• Verapamil or diltiazem (if β-blocker not tolerated)
• Disopyramide (added to β-blocker for refractory obstruction)
• Mavacamten (cardiac myosin inhibitor, FDA-approved 2022): reduces LVOT obstruction by decreasing excessive myosin–actin cross-bridge formation
• Avoid: vasodilators, nitrates, diuretics (reduce preload → worsen obstruction), digoxin, sympathomimetics

• Septal myectomy (Morrow procedure): gold standard; surgical resection of proximal septum
• Alcohol septal ablation: catheter-based, injects ethanol into first septal perforator → controlled infarction → reduces septal thickness

• ICD implantation for: prior SCA/sustained VT, family history of SCD, massive hypertrophy (wall ≥30 mm), unexplained syncope, NSVT on Holter, abnormal BP response to exercise

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3. Restrictive Cardiomyopathy (RCM)

Definition & Epidemiology

Causes

Key Subtypes

• Wild-type transthyretin (ATTR) amyloidosis is most prevalent in older patients
• Mutant ATTR: specific V122I mutation in TTR carried by 4% of African Americans → fourfold increased RCM risk
• AL amyloidosis (plasma cell dyscrasia): immunoglobulin light chains directly cardiotoxic
• "Sparkling" myocardium on echo; thick walls with small LV cavity; CMR shows diffuse subendocardial LGE

• Most common RCM worldwide (tropical Africa, South America, Asia)
• Diffuse fibrosis of ventricular endocardium/subendocardium + tricuspid/mitral valve involvement
• Linked to helminthic infections and nutritional deficiencies

• Associated with peripheral hypereosinophilia + eosinophilic infiltrates
• Eosinophil major basic protein → endocardial/myocardial necrosis → mural thrombus formation → organization/scarring
• No geographic predilection

Morphology (Robbins)

• Ventricles normal size or only slightly enlarged, cavities not dilated
• Myocardium is firm
• Both atria markedly dilated (hallmark) — consequence of restricted ventricular filling
• Microscopy: variable interstitial fibrosis; endomyocardial biopsy often reveals specific etiology

Clinical Features

• Symptoms of heart failure + supraventricular arrhythmias including AF
• Signs of elevated venous pressure: JVP raised, peripheral edema, ascites, hepatomegaly
• Kussmaul's sign (JVP rises on inspiration) — shared with constrictive pericarditis
• Differentiation from constrictive pericarditis is critical (similar hemodynamic profile) but management differs; key tests: CMR (pericardial thickening in CP), endomyocardial biopsy, cardiac catheterization (simultaneous RV/LV pressures)

Diagnosis

• Echo: biatrial dilation with normal ventricular size; restrictive filling pattern (E/A >2, short DT, short IVRT)
• Doppler tissue imaging: annular velocities reduced
• CMR: tissue characterization for amyloid, sarcoid, fibrosis
• Endomyocardial biopsy: often reveals specific etiology

Management

• Treat underlying cause: tafamidis (stabilizes TTR tetramer) for ATTR amyloidosis; phlebotomy for hemochromatosis; steroids for sarcoidosis
• Symptomatic HF: cautious diuresis (small, stiff ventricles are preload-dependent; over-diuresis reduces CO)
• Rate control for AF: prevents tachycardia-mediated filling impairment
• Anticoagulation for AF or intracardiac thrombus
• Transplantation: definitive therapy for refractory primary RCM; contraindicated in systemic amyloidosis (recurs in graft)

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Key Differentiating Features at a Glance

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1. Dilated Cardiomyopathy (DCM)

Definition & Epidemiology

• Prevalence: 1 in 250 adults
• Most common cardiomyopathy in children (58% of pediatric cases)
• Males = Females overall (except X-linked forms: male predominance)

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Pathogenesis

Genetic (20–50% of cases)

• Autosomal dominant is predominant; X-linked accounts for 2–5%
• All genetic DCM mutations are loss-of-function (contrast with HCM's gain-of-function)
• Because contractile myocytes and conduction fibers share a developmental pathway, conduction abnormalities (LBBB, AV block) are common in inherited DCM

Acquired Causes

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Morphology

• Four-chamber dilation with hypertrophy — heart is flabby, poorly contractile
• Mural thrombi at LV apex (→ systemic emboli/stroke risk)
• Valvular annuli dilated → functional MR/TR

• Myocyte hypertrophy with enlarged nuclei
• Interstitial and replacement fibrosis
• No specific diagnostic histologic pattern at end-stage

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Clinical Manifestations

• Exertional dyspnea → orthopnea → PND (rising pulmonary venous pressure)
• Fatigue, exercise intolerance (low cardiac output)
• Palpitations, presyncope, syncope (arrhythmias — AF, VT/VF)
• First presentation may be sudden cardiac death or thromboembolic stroke
• Increasingly found incidentally on imaging (asymptomatic LV dysfunction)

• Displaced, diffuse apex beat (cardiomegaly)
• S3 gallop (ventricular filling sound)
• Soft S1, functional MR/TR murmurs (pansystolic)
• Elevated JVP, peripheral oedema, hepatomegaly (right HF)
• Pulmonary crackles (pulmonary oedema)

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Investigations

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Management

Guideline-Directed Medical Therapy (GDMT) for HFrEF

1. ACEi/ARB → replace with ARNI (sacubitril/valsartan) if tolerated — reduces mortality
2. β-blocker (carvedilol, metoprolol succinate, bisoprolol) — reduces mortality
3. MRA (spironolactone/eplerenone) — reduces mortality
4. SGLT2 inhibitor (dapagliflozin/empagliflozin) — reduces HF hospitalization + CV death

Device Therapy

• ICD: EF ≤35% after ≥3 months optimal GDMT (for SCD prevention)
• CRT (cardiac resynchronization therapy): EF ≤35% + LBBB + QRS ≥150 ms → improves EF, symptoms, mortality

Anticoagulation

• AF → anticoagulate (stroke risk)
• LV thrombus → anticoagulate (embolism risk)

Specific Causes

• Alcoholic: abstinence → ≥50% improve; some normalize EF
• Tachycardiomyopathy: rate/rhythm control → often reversible
• Peripartum: bromocriptine (inhibits prolactin) may help; avoid β-blockers in breast-feeding
• Hemochromatosis: phlebotomy/chelation
• Myocarditis: immunosuppression in giant cell myocarditis

Advanced HF

• LVAD (left ventricular assist device): bridge to transplant or destination therapy
• Heart transplantation: definitive; 1-year survival ~85%, 5-year ~75%

Prognosis

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3. Restrictive Cardiomyopathy (RCM)

Definition & Epidemiology

• Least common of the primary cardiomyopathies
• Primary (idiopathic) forms are very uncommon; most are secondary to systemic disease
• ~30% of idiopathic RCM is familial (TNNI3, MYH7, DES mutations)

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Causes

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Key Subtypes

A. Cardiac Amyloidosis (most prevalent RCM in adults)

• Wild-type ATTR (transthyretin): most common; age-related accumulation; older males predominate
• Mutant ATTR: V122I variant carried by 4% of African Americans → >4× increased risk
• AL amyloidosis: immunoglobulin light chains deposit + directly cardiotoxic; associated with multiple myeloma/MGUS
• Echo: "sparkling" granular myocardium, biatrial dilation, thick walls, small LV cavity, diastolic dysfunction; pericardial effusion
• CMR: diffuse subendocardial LGE — highly specific for amyloid
• Serum free light chains, SPEP, bone marrow biopsy (AL); nuclear scintigraphy with technetium pyrophosphate (ATTR)

B. Endomyocardial Fibrosis (EMF)

• Most common RCM worldwide (tropical: sub-Saharan Africa, India, South America)
• Diffuse fibrosis of ventricular endocardium + subendocardium, often involving tricuspid and mitral valves
• Apical obliteration → reduces chamber volume and compliance
• Linked to helminthic infections (Toxocara?) and nutritional deficiencies

C. Löffler Endocarditis (Hypereosinophilic Syndrome)

• Peripheral hypereosinophilia (>1500 eosinophils/µL for >6 months) + eosinophilic tissue infiltrates
• Mechanism: Eosinophil major basic protein → endocardial/myocardial necrosis → mural thrombus formation → thrombus organization → fibrosis (scarring of endocardium)
• No geographic predilection (contrast with EMF)
• Three phases: necrotic → thrombotic → fibrotic
• Treatment: corticosteroids + hydroxyurea (reduce eosinophilia); anticoagulation; surgical endocardial resection in fibrotic phase

D. Cardiac Sarcoidosis

• Granulomatous infiltration → patchy fibrosis
• Presents with heart block, VT/VF, HF, or SCD
• Steroid therapy; high SCD risk → ICD

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Morphology

• Ventricles normal size or only slightly enlarged; cavities not dilated
• Myocardium is firm (stiff)
• Both atria markedly dilated — hallmark, due to restricted ventricular filling causing backpressure
• Thrombus in atrial appendages, patchy endocardial fibrosis

• Variable interstitial fibrosis + myocyte disarray (idiopathic/familial)
• Amyloidosis: extracellular amyloid deposits (Congo red stain → apple-green birefringence under polarized light)
• EMF: dense subendocardial fibrous tissue
• Löffler: eosinophilic infiltrates + mural thrombus

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Clinical Manifestations

• Biventricular heart failure: exertional dyspnea, fatigue, peripheral oedema, ascites
• Supraventricular arrhythmias including AF (common, due to massive atrial dilation)
• Chest pain (if associated with infiltrative disease)
• Syncope/sudden death (sarcoid, amyloid with conduction disease)
• Systemic features of underlying disease (e.g., carpal tunnel syndrome in ATTR amyloid; peripheral neuropathy; macroglossia in AL amyloid)

• Raised JVP with Kussmaul's sign (JVP rises on inspiration — failure of RV to accommodate increased venous return)
• S4 gallop (stiff ventricle)
• Hepatomegaly, ascites, peripheral oedema (right HF)
• Pulmonary crackles (left HF)

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Investigations

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RCM vs. Constrictive Pericarditis — Critical Distinction

This distinction is critical because constrictive pericarditis is surgically curable while RCM is not.

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Management

Prognosis

• Highly etiology-dependent
• Idiopathic RCM: poor prognosis; many progress to end-stage HF requiring transplant
• ATTR amyloid: tafamidis improves survival and quality of life
• AL amyloid: poor without treatment; median survival <6 months untreated

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Definition of Cardiomyopathy

Core Definition

Cardiomyopathy describes primary disease of the heart muscle itself, originally excluding myocardial dysfunction resulting from other cardiovascular diseases (e.g., coronary artery disease, valvular disease, hypertensive heart disease, congenital heart disease).

• Ischemic cardiomyopathy (from CAD)
• Valvular cardiomyopathy
• Hypertensive cardiomyopathy

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WHO / Functional Definition

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Key Points from the Definition

1. Primary vs. Secondary: True cardiomyopathy is a primary myocardial disorder — not the result of ischemia, valve disease, or hypertension (though secondary forms do exist)
2. Phenotype vs. Etiology: The traditional morphologic classification (DCM, HCM, RCM) is based on structural phenotype, but etiology (genetic, acquired, inflammatory) is increasingly used to guide management
3. Phenotypes overlap: Over time, HCM can evolve to reduced EF ("HCM-rEF") in ~5% of patients; DCM can "reverse remodel" to near-normal EF with treatment
4. Genetic causes are central: Pathogenic variants are being identified that cause heritable cardiomyopathies, sometimes detectable by imaging before clinical disease appears ("preclinical phase")
5. Two-hit model: Clinical expression of a genetic predisposition may be triggered by an additional environmental or acquired insult (e.g., a person with a TTN mutation who also develops viral myocarditis)

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WHO 1995 Definition (Classic)

"Diseases of the myocardium associated with cardiac dysfunction."

• Primary (idiopathic): No identifiable systemic or cardiac cause
• Secondary (specific): Myocardial disease as part of a known systemic disorder (amyloidosis, hemochromatosis, sarcoidosis, etc.)

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Summary in One Sentence