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Cardiomyopathy

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Classification Overview

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1. Dilated Cardiomyopathy (DCM)

Pathogenesis & Etiology

• Genetic (20-50% of cases): Over 50 causal genes identified, predominantly autosomal dominant. Most commonly involves loss-of-function mutations in cytoskeletal or sarcomere-linking proteins:
  • Titin (TTN) - the most common genetic cause; titin is key for sarcomeric force generation; truncating variants account for up to 20% of all DCM
  • β-myosin heavy chain, α-myosin heavy chain, troponin T - also implicated
  • Dystrophin (DMD gene, X-linked) - Duchenne and Becker muscular dystrophy
  • Desmin - connects nuclear/plasma membranes, Z-lines, and intercalated disks; impairs both cardiac and skeletal muscle
  • Nuclear lamins A and C - associated with conduction defects
• Viral infection: Coxsackievirus B, adenovirus, enteroviruses; increasingly parvovirus B19 and human herpesvirus 6. Viral nucleic acid footprints can persist into the late-stage DCM heart
• Alcohol/toxins: Ethanol and acetaldehyde have direct cardiotoxic effects; chronic alcohol use disorder is strongly associated with DCM
• Peripartum: DCM developing in the last trimester or within months of delivery
• Anthracyclines (e.g., doxorubicin): Dose-dependent cardiotoxicity
• Hemochromatosis, sarcoidosis, chronic anemia
• Idiopathic: A substantial proportion

Gross & Histologic Pathology

• Gross: Four-chamber dilation and hypertrophy; flabby, poorly contractile walls; mural thrombi (especially at LV apex). Heart weight often exceeds 800 g (upper limit of normal ~360 g). The LV wall appears thinned despite significant overall hypertrophy.
• Histology: Myocyte hypertrophy with interstitial fibrosis (nonspecific pattern); no diagnostic features on light microscopy at end-stage.

Clinical Features

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2. Hypertrophic Cardiomyopathy (HCM)

Definition

Pathogenesis

• Virtually always genetic: autosomal dominant gain-of-function mutations in sarcomeric contractile proteins

• 1,400 mutations identified in >9 genes; the three most common - MYH7 (β-myosin heavy chain), MYBPC3 (myosin-binding protein C), TNNT2 (troponin T) - account for 70-80% of all HCM cases

• The gain-of-function mutations cause myocyte hypercontractility, increased energy demand, and net negative energy balance, ultimately leading to pathological hypertrophy and fibrosis
• Contrast with DCM: the same gene (e.g., β-myosin) can cause either disorder depending on whether the mutation is gain-of-function (HCM) or loss-of-function (DCM)

Gross & Histologic Pathology

• Gross: Massive myocardial hypertrophy without ventricular dilation
  • 90% of cases: asymmetric septal hypertrophy - disproportionate thickening of the interventricular septum relative to the LV free wall
  • 10% of cases: concentric hypertrophy
  • On longitudinal section, LV cavity takes a "banana-shaped" configuration
  • Fibrous endocardial plaque in the LV outflow tract (from contact of anterior mitral leaflet with septum during systole)
  • Systolic anterior motion (SAM) of the mitral valve causes variable LV outflow tract obstruction in ~one-third of cases
• Histology: Extreme myocyte hypertrophy, haphazard myocyte (and myofiber) disarray (the hallmark), and interstitial fibrosis

Clinical Features

• Typically manifests during the postpubertal growth spurt, but can present at any age
• Diastolic dysfunction is the fundamental problem: the stiff, poorly relaxing LV limits filling, reducing stroke volume
• Symptoms: exertional dyspnea, harsh systolic ejection murmur, angina (even without CAD - caused by massive hypertrophy + high LV pressure + compromised intramural arterial flow)
• Complications:
  • Atrial fibrillation with mural thrombus formation
  • Sudden cardiac death from ventricular fibrillation - HCM is the most common cause of sudden cardiac death in athletes under 35 (accounting for ~1/3 of all such deaths)
  • Infective endocarditis of the mitral valve
  • Progressive CHF
• Treatment:
  • Beta-blockers, calcium channel blockers (promote ventricular relaxation)
  • Partial surgical septal myectomy
  • Alcohol septal ablation (controlled therapeutic infarction of septal muscle via intracoronary alcohol injection)
  • ICD for high-risk patients

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3. Restrictive Cardiomyopathy (RCM)

Causes

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4. Arrhythmogenic Cardiomyopathy (ACM / ARVC)

• Progressive replacement of the RV myocardium by fibro-fatty tissue
• The RV is markedly dilated; the LV may also be involved to a lesser extent
• Results in ventricular arrhythmias and sudden cardiac death, particularly in young athletes

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Key Comparison Table

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CARDIOMYOPATHY - Complete Medical Student Guide

Updated with 2023 ESC, 2024 ACC/AHA, and 2025-2026 Guidance

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PART 1: DEFINITION & CLASSIFICATION

2023 ESC Classification (NEW - Replaces Older Systems)

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PART 2: DILATED CARDIOMYOPATHY (DCM)

Definition & Epidemiology

• LV (or biventricular) dilation + impaired systolic function in absence of CAD, valvular disease, or pericardial disease
• LVEF <40% (or severely reduced)
• Prevalence: ~1 in 250 adults; most common cardiomyopathy in children (58% of pediatric cases; peak age 18 months)
• Males and females approximately equally affected, except X-linked forms (male predominance)

Etiology & Genetics

• Autosomal dominant most common pattern
• TTN (titin) truncating mutations = single most common cause (~25% familial, ~18% sporadic)
• Also: MYH7, TNNT2, TPM1, ACTC1 (sarcomeric proteins - note: SAME genes cause HCM when gain-of-function; cause DCM when loss-of-function)
• Lamin A/C (LMNA): arrhythmogenic form - AF, conduction disease, VT/VF often PRECEDE heart failure; high SCD risk - ICD recommended even with LVEF >35%
• Filamin C (FLNC): mixed arrhythmogenic + dilated phenotype; lethal VAs in adolescents/young adults
• Dystrophin (DMD gene, X-linked): Duchenne and Becker muscular dystrophy
• Desmin: combined cardiac + skeletal myopathy; intermediate filament protein

Clinical Presentation

• Symptoms of biventricular heart failure: exertional dyspnea, orthopnea, PND, peripheral edema
• First presentation may be sudden death or thromboembolic event (LV thrombus, especially at apex)
• Family history is important (30-40% familial clustering)
• May also present with arrhythmias (AF, VT, conduction disease) - especially with LMNA, FLNC mutations

Pathology

• Gross: Four-chamber dilation and hypertrophy; flabby, poorly contractile walls; mural thrombus (LV apex). Heart weight often >800 g (normal upper limit ~360 g)
• Histology: Nonspecific - myocyte hypertrophy + interstitial fibrosis (Masson trichrome shows blue collagen). No diagnostic features at end-stage

Diagnosis

• TTE (transthoracic echo): first line; LV dilation, reduced LVEF, wall motion abnormalities
• CMR: gold standard for tissue characterization; mid-wall late gadolinium enhancement (LGE) is a key prognostic marker and predicts VT; 2023 ESC endorses CMR as primary diagnostic modality
• Biomarkers: BNP/NT-proBNP elevated; high-sensitivity troponin (consensus across all guidelines)
• ECG: LBBB, conduction defects, arrhythmias; LBBB + DCM = indication for CRT evaluation
• Genetic testing: Recommended when diagnostic phenotype established; essential for cascade family screening

Management: DCM

• CRT (cardiac resynchronization therapy): LVEF ≤35% + LBBB + QRS ≥150 ms (Class I) or QRS 120-149 ms (Class IIa)
• ICD for primary prevention: Standard threshold LVEF ≤35% despite 3+ months of GDMT
• Genotype-driven ICD (earlier implantation): LMNA or FLNC variants - ICD before LVEF <35% if ≥2 risk factors (male sex, NSVT, >10% fibrosis on CMR, non-missense mutations). 2023 ESC recommends SCD risk stratification by genotype even when LVEF >35% (Class IIa B)

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PART 3: HYPERTROPHIC CARDIOMYOPATHY (HCM)

Definition & Epidemiology

• Unexplained LV hypertrophy in absence of abnormal loading conditions (valve disease, HTN, congenital defects)
• Prevalence: 0.2-0.5% worldwide; all racial groups
• Most common inherited cardiac disease

Genetics & Pathogenesis

• Autosomal dominant, gain-of-function mutations in sarcomeric contractile proteins

• 1,400 mutations in >9 genes identified; 50-60% of cases have identifiable sarcomere variants

• The Big 3 genes (account for 70-80%):
  • MYH7 (beta-myosin heavy chain) - most common
  • MYBPC3 (myosin-binding protein C)
  • TNNT2 (troponin T)
• Mechanism: hypercontractility → increased energy use → net negative energy balance → compensatory hypertrophy + fibrosis
• Same genes (MYH7, etc.) cause DCM when loss-of-function; cause HCM when gain-of-function

Pathology

• Massive hypertrophy WITHOUT ventricular dilation
• 90%: Asymmetric septal hypertrophy - septum disproportionately thicker than LV free wall
• 10%: concentric hypertrophy
• LV cavity: "banana-shaped" on longitudinal section
• Fibrous endocardial plaque in LV outflow tract (from SAM contact with septum)
• Systolic anterior motion (SAM) of the mitral valve → LV outflow tract obstruction (LVOTO) in 1/3 of cases

1. Extreme myocyte hypertrophy
2. Myocyte disarray (haphazard, chaotic architecture) - the pathognomonic feature
3. Interstitial fibrosis

Clinical Features

• Often asymptomatic or mild; presents during postpubertal growth spurt or young adulthood
• Triad of symptoms: exertional dyspnea, chest pain (angina without CAD), syncope
• Harsh systolic ejection murmur at LLSB; increases with Valsalva, standing (decreased preload); decreases with squatting, leg raise
• Sudden cardiac death - most important complication; HCM is responsible for ~1/3 of SCD in athletes under 35

ECG findings in HCM

• LVH pattern
• Deep narrow Q waves in lateral and inferior leads (septal depolarization)
• T-wave abnormalities
• AF is common (20-25%)

2024 AHA/ACC HCM Guidelines - Key Updates (PMID: 38718139)

• TTE: first-line; LV wall thickness ≥15 mm (or ≥13 mm with family history/genetic variant)
• CMR: when TTE inconclusive; superior tissue characterization; LGE ≥15% of LV mass = major SCD risk factor

• Selective, reversible cardiac myosin ATPase inhibitor
• Approved by FDA; EXPLORER-HCM trial showed significant improvement in LVOT gradient, symptoms, and exercise capacity
• Monitoring: Echo every 4 weeks for first 12 weeks (FDA requirement); discontinue if LVEF drops <50%
• Contraindicated with strong CYP3A4 inhibitors; teratogenic

• Surgical septal myectomy (Morrow procedure) - gold standard; preferred for younger patients
• Alcohol septal ablation (ASA): catheter-based; intracoronary ethanol injection causes controlled septal MI; preferred for older/high surgical risk patients
• Indication: LVOT gradient ≥50 mmHg at rest or with provocation + refractory symptoms (NYHA III-IV) despite maximal medical therapy

1. Family history of SCD at young age (≤40 years)
2. Unexplained syncope (especially within 6 months)
3. LVEF <50%
4. Apical aneurysm with transmural scar
5. Extensive LGE on CMR (≥15% of LV mass)
6. NSVT on ambulatory monitoring

• Anticoagulation recommended in ALL HCM patients with AF regardless of CHA2DS2-VASc score
• DOACs (direct oral anticoagulants) = first-line
• Vitamin K antagonists = second-line
• Rate control: beta-blockers, verapamil, diltiazem
• Rhythm control: amiodarone (effective in HCM); catheter ablation (higher relapse rate vs non-HCM)

• HCM patients should engage in mild to moderate recreational exercise for cardiovascular health
• Competitive/vigorous sports: individualized shared decision-making with HCM expert (no longer blanket prohibition)
• 2025 ACC/AHA Sports Participation Guidelines: athletes with confirmed HCM - "Reasonable to consider participation" (vs 2015 guideline: "Should not participate")

• First-degree relatives of HCM proband: ECG + TTE every 12-18 months during adolescence; every 3-5 years in adults
• Genetic testing: recommended when clinical diagnosis established; valuable for cascade screening
• Genotype positive/phenotype negative: annual clinical evaluation

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PART 4: RESTRICTIVE CARDIOMYOPATHY (RCM)

Definition

Pathology

• Ventricles normal or slightly enlarged (NOT dilated)
• Both atria markedly dilated (consequence of chronic elevated filling pressures)
• Myocardium is firm
• Mimics constrictive pericarditis clinically (must distinguish - important exam distinction!)

Causes

• "Sparkling" myocardium on echo (granular appearance)
• Low-voltage ECG despite LV hypertrophy on echo (pseudo-LVH)
• Bilateral carpal tunnel syndrome + HF
• Spinal stenosis + HF
• Macroglossia (AL type)
• "Cherry blossoms" (HCC-like) on CMR with specific LGE pattern

• Pyrophosphate (PYP/DPD) bone scintigraphy - can diagnose ATTR noninvasively (Perugini Grade 2-3) if monoclonal protein screen is negative (SPEP, UPEP, serum FLC)
• If monoclonal protein present → biopsy needed to exclude AL

• Tafamidis (Vyndaqel) - TTR stabilizer; FDA-approved; reduces mortality (ATTR-ACT trial); first-line
• Acoramidis - TTR stabilizer; newer, approved 2023-2024
• Vutrisiran (siRNA) - TTR silencer; reduces TTR production; alternative approach
• SGLT2 inhibitors and MRAs: now endorsed as broadly effective HF therapies in ATTR
• Standard HF therapy: diuretics (symptom relief); digoxin relatively contraindicated (binds amyloid fibrils); calcium channel blockers generally avoided

• Most common RCM worldwide (children/young adults, sub-Saharan Africa, tropical regions)
• Diffuse fibrosis of ventricular endocardium and subendocardium
• Often involves tricuspid and mitral valves
• Linked to nutritional deficiencies and helminthic infections

• No geographic predilection
• Peripheral hypereosinophilia + eosinophilic tissue infiltrates
• Eosinophil major basic protein → endocardial necrosis → mural thrombus → organization → fibrosis
• Stages: necrotic → thrombotic → fibrotic

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PART 5: ARRHYTHMOGENIC CARDIOMYOPATHY (ACM/ARVC)

Definition

• Responsible for up to 22% of SCD in athletes
• Prevalence: ~1 in 5,000

Genetics

• Desmosomal protein mutations (cell-cell adhesion):
  • PKP2 (plakophilin-2) - most common
  • DSP (desmoplakin)
  • DSG2 (desmoglein-2)
  • DSC2 (desmocollin-2)
  • JUP (junction plakoglobin)
• Non-desmosomal: LMNA, desmin, others
• Naxos disease: autosomal recessive; PKP2 mutation; clinical triad = ARVC + woolly hair + palmoplantar keratoses (first described on Greek island of Naxos)
• Carvajal syndrome: DSP mutation; ARVC + woolly hair + palmoplantar keratosis + DILATED (not just RV) cardiomyopathy

Pathology

• RV markedly dilated; fibro-fatty replacement of RV free wall (almost transmural)
• LV may be involved to lesser extent
• "Triangle of dysplasia": RV inflow, outflow, and apex

Diagnosis: Task Force Criteria (Major and Minor)

• Epsilon wave (classic) - small high-frequency deflection after QRS in V1-V3
• T-wave inversions V1-V3 (most sensitive)
• Terminal QRS prolongation >55 ms in V1-V3 (distinct from RBBB)
• VT with LBBB morphology + superior or inferior axis = arises from RV

Management

• Lifestyle: Avoid strenuous exercise/competitive sports (especially endurance); exercise accelerates disease progression by increasing RV wall stress
• Beta-blockers: first-line for arrhythmia prevention
• Antiarrhythmics: sotalol (160-240 mg/day), amiodarone (200 mg/day maintenance); flecainide (endorsed by 2023 ESC for atrial and ventricular arrhythmias in ARVC)
• ICD indications:
  • Definite: prior SCA, sustained VT, LVEF ≤35%
  • Primary prevention (Class IIa): LVEF ≤50% + ≥1 major risk factor (NSVT, inducible VT, RV dysfunction, male sex, proband, >1 desmosomal mutation)
• Catheter ablation: for drug-refractory VT or frequent ICD shocks
• Heart failure therapy (ACEi, beta-blocker, diuretics) if progresses to severe HF
• Anticoagulation: if AF, marked ventricular dilation, or ventricular aneurysms
• Cardiac transplantation: for refractory end-stage disease

• PKP2 ACM: risks may outweigh benefits (sports caution)
• Non-PKP2 ACM: can consider participation with shared decision-making
• Genotype positive/phenotype negative: reasonable to consider participation

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PART 6: PERIPARTUM CARDIOMYOPATHY (PPCM)

Definition & Diagnostic Criteria

• LVEF <45%
• No other identifiable cause of HF

Epidemiology

• US: 1 per ~3,000 live births; Haiti/Africa: 1 per ~300 live births (much higher in Black women)
• Risk factors: older maternal age, hypertension, preeclampsia, African-American race, multifetal pregnancies

Pathogenesis (multifactorial)

1. Genetic: 15% have rare truncating variants (2/3 involve TTN); similar rate to idiopathic DCM → PPCM may be an unmasked familial DCM
2. Prolactin cleavage: Oxidative stress → prolactin cleaved into a pro-inflammatory, vasotoxic 16-kDa fragment → endothelial and cardiomyocyte dysfunction
3. Anti-angiogenic: Placenta releases soluble fms-like tyrosine kinase-1 (sFlt-1) → angiogenic imbalance
4. Overlap with preeclampsia (~25% of PPCM vs 5% population)

Prognosis

• ~40-70% have normalization of LVEF within 5 years (better than idiopathic DCM)
• Patients with persistent LV dysfunction at baseline or African-American race: worse outcomes
• Subsequent pregnancy: Risk of recurrence in all patients, even those who normalize LV function
  • Normalized LV function: HF recurs in 20% of subsequent pregnancies (mortality 0% in this group)
  • Persistent LV dysfunction: HF recurs in 40%; maternal mortality 19%

Treatment

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PART 7: STRESS (TAKOTSUBO) CARDIOMYOPATHY

Overview

• Triggered by acute severe emotional, psychological, or physical stress
• Characterized by transient apical LV ballooning and dysfunction that is usually reversible
• "Takotsubo" = Japanese octopus trap (the shape of the LV during systole)

Epidemiology

• Predominantly postmenopausal women (>90% of cases)
• Accounts for 2-3% of all suspected ACS presentations
• COVID-19 increased incidence: 7.8% of ACS presentations during pandemic vs 1.5-1.8% pre-pandemic

Key Features (how to distinguish from STEMI)

Management

• Supportive care: beta-blockers, ACEi, diuretics for HF
• Avoid catecholamines (worsens condition)
• If cardiogenic shock: IABP or Impella; avoid vasopressors if possible
• Anticoagulation if LV thrombus suspected
• Prognosis: generally excellent with full recovery; mortality ~4-5% in hospitalized patients (usually comorbid conditions)

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PART 8: OTHER / SECONDARY CARDIOMYOPATHIES

Infiltrative/Storage Diseases Mimicking HCM ("Pseudo-hypertrophy")

Chemotherapy-Induced Cardiomyopathy (Cardio-oncology)

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PART 9: MYOCARDITIS (Related Entity)

Overview

• Can cause acute HF
• Can progress to DCM (DCM is considered a potential sequela of viral myocarditis)

Causes

Giant Cell Myocarditis

• Rapidly fatal without treatment
• Diagnosis: endomyocardial biopsy (multinucleated giant cells)
• Treatment: prolonged immunosuppression (cyclosporine + steroids); transplant if refractory

Chagas Cardiomyopathy

• Trypanosoma cruzi - vector: Reduviid (kissing) bug
• Affects 8-10 million in Latin America; leading cause of cardiomyopathy in endemic regions
• Chronic phase: dilated cardiomyopathy + right bundle branch block + left anterior fascicular block (classic ECG pattern) + apical aneurysm + thromboembolic events
• Treatment: Benznidazole/nifurtimox (antiparasitic); standard HFrEF therapy; ICD for VT/VF

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PART 10: SUMMARY COMPARISON TABLE (HIGH-YIELD EXAM REFERENCE)

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PART 11: GUIDELINE SUMMARY REFERENCE

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