Cardiomyopathies

Introduction and Classification

Intrinsic myocardial disease without associated structural heart deformity. Heterogeneous group characterized by mechanical and/or electrical dysfunction, exhibiting inappropriate ventricular hypertrophy or dilation.

• Classified clinically into Dilated (DCM), Hypertrophic (HCM), Restrictive (RCM), Left Ventricular Non-compaction (LVNC), and Arrhythmogenic Cardiomyopathy (ACM).
• MOGE(s) classification system integrates Morphofunctional phenotype, Organ involvement, Genetic/familial inheritance, and Etiology.

Cardiomyopathy Type	Incidence (per 100,000)	Proportion of Pediatric Cases	Hallmark Feature
Dilated (DCM)	0.57	~50-60%	Enlarged left ventricle, decreased systolic function.
Hypertrophic (HCM)	0.47	~40%	Ventricular hypertrophy, non-dilated cavity.
Restrictive (RCM)	0.03 - 0.04	2.5 - 5%	Restrictive filling, biatrial enlargement, normal ventricles.
LV Non-compaction (LVNC)	0.12	~9.5%	Hypertrabeculation, deep intertrabecular recesses.
Arrhythmogenic (ACM)	Rare	Rare	Fibrofatty myocardial infiltration, ventricular arrhythmias.

Dilated Cardiomyopathy (DCM)

Definition & Epidemiology

• Myocardial systolic insufficiency with left ventricular (LV) dilation.
• Most common pediatric cardiomyopathy.
• Bimodal age distribution: highest frequency in infancy and adolescence.
• Incidence higher in males, infants <1 year, and black children.

Etiology & Genetics

• 50-66% cases classified idiopathic/undetermined.
• 25-30% cases feature identifiable familial component.
• Identifiable secondary causes: Viral myocarditis (14-22%), Kawasaki disease, anomalous left coronary artery from pulmonary artery (ALCAPA), arrhythmias (tachycardia-induced).

Genetic/Molecular Category	Genes/Pathways Implicated in DCM
Force Generation (Sarcomere)	MYH7, TNNT2, TNNI3, TTN (diminished mechanical myocyte function).
Force Transmission	Dystrophin (Duchenne/Becker), Laminin, Alpha-dystroglycan.
Gene Expression	GATA4, RBM20 (alternative splicing), GATAD1.
Metabolic / Mitochondrial	TAZ (Barth syndrome), Fatty acid oxidation defects, Carnitine deficiency.
Protein Processing	BAG3, LAMP2, CRYAB.

Pathophysiology & Morphology

• Decreased contractility is primary defect.
• Compensatory dilation maintains cardiac output (Frank-Starling mechanism).
• Ventricular septum and posterior wall appear thinned; posterior wall thinning predicts worse prognosis.
• Secondary mitral regurgitation occurs due to annular dilation.
• Myocardial fibrosis uncommon in pediatric idiopathic DCM (primarily endocardial when present).

Clinical Presentation

• Insidious onset possible; prolonged compensated heart failure phase.
• Infants: Feeding intolerance, irritability, failure to thrive, tachypnea, diaphoresis.
• Older children: Shortness of breath (50%), exercise intolerance, gastrointestinal upset (33%), fatigue.
• Severe cases: Cardiogenic shock, arrhythmias (3-10%), sudden cardiac arrest (8-15%).
• Physical signs: Tachycardia, ventricular gallop (S3), mitral regurgitation murmur, hepatomegaly, abdominal ascites, tachypnea.

Diagnostic Evaluation

• Echocardiography (Gold Standard): LV end-diastolic volume (LVEDV) >2 standard deviations (SD) above normal for body surface area (BSA). Fractional shortening (FS) or ejection fraction (EF) >2 SD below normal.
• Electrocardiogram (ECG): Sinus tachycardia, biatrial abnormalities, right axis deviation, ventricular hypertrophy. Prolonged QTc or conduction delays possible.
• Chest X-Ray (CXR): Severe cardiomegaly, pulmonary venous congestion, asymmetric pulmonary edema.
• Laboratory Studies: BNP/NT-proBNP (elevated), troponin, lactate. Metabolic screening for inborn errors (carnitine, acylcarnitine profile). Viral PCR for myocarditis.
• Cardiac MRI (CMR): Differentiates idiopathic DCM from myocarditis (edema, late gadolinium enhancement).

Risk Stratification & Prognosis

• 20-40% cases normalize cardiac size and function.
• 40% require heart transplant within 2 years of diagnosis.
• Predictors of adverse outcome (death/transplant): Older age at diagnosis, severe LV dilation, worse systolic function, inotropic support requirement, familial history, ischemic etiology.
• Sudden Cardiac Death (SCD) Risk: Low incidence (1-1.3%), higher risk with extreme posterior wall thinning, prolonged anti-arrhythmic use, or ischemic origin.

Management

• Medical (Heart Failure Therapy):
  • Afterload reduction: ACE inhibitors (enalapril, captopril), Angiotensin receptor blockers (ARBs).
  • Beta-blockade: Carvedilol, metoprolol (reverses remodeling).
  • Angiotensin receptor-neprilysin inhibitors (ARNI): Sacubitril/valsartan.
  • Diuretics: Furosemide (volume overload reduction), Aldosterone antagonists (spironolactone).
  • Inotropes (Acute): Milrinone (inodilator, improves lusitropy/inotropy, decreases SVR).
• Device Therapy: Implantable cardioverter-defibrillator (ICD) for aborted sudden death or severe LV dysfunction with syncope.
• Surgical: Ventricular Assist Device (VAD) bridge to transplant. Orthotopic heart transplantation (OHT) for end-stage medically refractory failure.

Hypertrophic Cardiomyopathy (HCM)

Definition & Epidemiology

• Hypertrophied, non-dilated LV in absence of hemodynamic stimulus (excludes physiologic hypertrophy/athlete’s heart, systemic hypertension, aortic stenosis).
• Incidence 0.47/100,000 children. Constitutes ~40% of pediatric cardiomyopathies.

Etiology & Genetics

• Genetic disorder affecting heart isolated (Primary) or multi-system (Secondary/Syndromic).
• Primary HCM: Autosomal dominant. Sarcomere protein mutations (MYH7, MYBPC3, TNNT2, TNNI3).
• Secondary HCM:
  • RASopathies: Noonan syndrome, Costello syndrome (PTPN11, BRAF mutations).
  • Infiltrative/Metabolic: Pompe disease (alpha-glucosidase absence), Danon disease (LAMP2), Fabry disease, PRKAG2 deficiency.
  • Maternal Diabetes: Transient hyperinsulinemic hypertrophy.
  • Neuromuscular: Friedreich ataxia (frataxin deficiency).

Pathophysiology & Morphology

• Myocardial disarray, subendocardial/interstitial fibrosis, myocyte hypertrophy.
• Asymmetric septal hypertrophy most common.
• Dynamic Left Ventricular Outflow Tract (LVOT) obstruction (25% of patients).
• Systolic Anterior Motion (SAM) of anterior mitral leaflet, causing mid-systolic aortic valve closure and mitral regurgitation.
• Impaired relaxation/diastolic dysfunction due to cellular disarray and fibrosis.

Clinical Presentation

• Frequently asymptomatic; identified via murmur or family screening.
• Symptoms: Exertional dyspnea, anginal chest pain, palpitations, syncope, dizziness.
• First major symptom may be sudden cardiac death (SCD), especially during physical exertion.
• Physical signs: Sharp pulse upstroke (bisferiens), forcible apex beat, systolic ejection murmur (aortic region), apical blowing murmur (mitral insufficiency).

Diagnostic Evaluation

• Echocardiography: Maximum LV wall thickness Z-score >5-7 standard deviations represents definitive hypertrophy equivalent to adult 15mm cutoff. Identifies SAM, LVOT gradient, asymmetric septal hypertrophy.
• Electrocardiogram (ECG): Increased voltages (LVH), repolarization abnormalities (T-wave inversion in left precordial leads). Giant inverted lateral T-waves in apical HCM. Short PR, massive QRS in Pompe disease. WPW pattern in PRKAG2/Danon.
• Cardiac MRI (CMR): Late gadolinium enhancement (LGE) confirms fibrosis. Refines SCD risk stratification.
• Exercise Testing: Abnormal blood pressure response (failure to increase systolic BP >20 mmHg or drop >20 mmHg) implies risk.

SCD Risk Stratification

• Personal/family history of cardiac arrest or SCD.
• Unexplained syncope.
• Massive ventricular wall thickness (>30 mm in adults; extreme Z-scores in children).
• Non-sustained ventricular tachycardia (NSVT).
• Blunted/hypotensive BP response to exercise.
• Inborn errors of metabolism exhibit worst survival outcomes.

Management

• Restriction from competitive sports/strenuous activity.
• Medical Therapy: Non-vasodilating beta-blockers (propranolol, atenolol, metoprolol) or calcium channel blockers (verapamil) to diminish LVOT obstruction, modify hypertrophy, improve diastolic filling, and control arrhythmias.
• Avoid: Diuretics, ACE inhibitors, dihydropyridine calcium channel blockers (exacerbate LVOT obstruction by reducing preload/afterload).
• Device Therapy: Implantable cardioverter-defibrillator (ICD) for high-risk patients (primary/secondary SCD prevention).
• Surgical: Septal myectomy for refractory LVOT obstruction. Heart transplant for “burned-out” end-stage HCM with systolic failure.

Restrictive Cardiomyopathy (RCM)

Definition & Epidemiology

• Characterized by restrictive filling, reduced diastolic volume, normal/near-normal systolic function, and normal wall thickness.
• Rarest pediatric cardiomyopathy (2.5-5% of cases). Incidence 0.03-0.04/100,000.
• Mean age at diagnosis ~6 years.

Etiology & Genetics

• Most pediatric cases are idiopathic. Secondary infiltrative causes (amyloidosis, sarcoidosis, hemochromatosis) are exceptionally rare in children.
• 25-30% exhibit positive family history.
• Sarcomeric Mutations: TNNI3, TNNT2, MYH7, ACTC1, TTN, FLNC.
• Non-sarcomeric Mutations: BAG3, DES (Desmin - associated with AV block), LMNA.
• Mixed RCM/HCM phenotype exists, confusing classification but generally portends better survival than “pure” RCM.

Pathophysiology & Morphology

• Markedly dilated atria with normal-sized ventricles. Absence of significant ventricular hypertrophy.
• Severe diastolic dysfunction. Increased myocardial rigidity.
• Elevated end-diastolic filling pressures lead to secondary pulmonary venous congestion, pulmonary edema, and reactive pulmonary hypertension.

Clinical Presentation

• Dyspnea, severe exercise intolerance, fatigue. Frequently misdiagnosed as “asthma” or recurrent respiratory infections.
• Syncope (due to ischemia, arrhythmias, thromboembolism).
• Physical signs: Loud P2 (pulmonary hypertension), S3/S4 gallop, hepatomegaly, elevated jugular venous pressure.

Diagnostic Evaluation

• Echocardiography: Pathognomonic biatrial enlargement with normal ventricles. Abnormal mitral inflow (short deceleration time), elevated E/A ratio, elevated E/e’ ratio.
• Electrocardiogram (ECG): Abnormal in >90%. Biatrial enlargement, ST segment depression, T-wave abnormalities. High-grade AV block (seen in DES mutations).
• Chest X-Ray (CXR): Cardiomegaly (due to atrial enlargement), pulmonary venous congestion, possible pleural effusions.
• Cardiac Catheterization: Confirms elevated filling pressures and evaluates pulmonary vascular resistance (PVR). Differentiates RCM from constrictive pericarditis.

Outcomes and Management

• Worst prognosis among pediatric cardiomyopathies. High risk of sudden death, thromboembolism, and irreversible pulmonary hypertension.
• 1- and 5-year transplant-free survival extremely poor (48% and 22% for pure RCM).
• Medical Therapy (Symptom-based only):
  • Judicious diuretics (relieve congestion but maintain necessary preload).
  • Anticoagulation/Antiplatelet agents (aspirin, warfarin, enoxaparin) to prevent atrial thrombus.
  • ACE inhibitors, digoxin, calcium channel blockers generally avoided/contraindicated.
• Surgical Therapy: Early listing for Orthotopic Heart Transplantation (OHT) is definitive treatment. Mechanical circulatory support (VAD) rarely successful due to small ventricular cavities and filling restrictions.

Left Ventricular Non-compaction (LVNC)

Definition & Epidemiology

• Cardiomyopathy characterized by excessive reticulated trabecular wall formation and deep intertrabecular recesses.
• Two-layered myocardium: thin compacted epicardial layer, thick non-compacted endocardial layer.
• Children account for 9.5% of all LVNC cases. Incidence 0.12/100,000 children.

Etiology & Genetics

• Arrest of normal myocardial compaction process during early embryogenesis.
• ~30% of pediatric cases have identified genetic cause.
• Genetics: Heterogeneous. X-linked (Barth syndrome/TAZ mutation), sarcomeric mutations, mitochondrial defects, arrhythmogenic overlap.

Diagnostic Evaluation

• Echocardiography: Non-compacted to compacted layer ratio >2 at end-systole (Jenni criteria). Color Doppler confirms deep intertrabecular recesses supplied by intraventricular blood.
• Cardiac MRI (CMR): Superior contrast-to-noise ratio. Non-compacted to compacted ratio >2.3 at end-diastole (Petersen criteria). Highly reproducible.

Outcomes and Management

• Clinical course mirrors the associated overlapping phenotype. Isolated LVNC portends excellent outcomes.
• LVNC combined with DCM phenotype exhibits outcomes matching pure DCM (40% mortality/transplant within 2 years).
• Management dictated by underlying clinical phenotype (heart failure medications for systolic failure, arrhythmia management, anticoagulation for thromboembolic risk in deep recesses).

Arrhythmogenic Cardiomyopathy (ACM)

Definition and Genetics

• Arrhythmogenic disorder of the myocardium (not secondary to ischemia/valvular disease) featuring fibrofatty pathological infiltration.
• Primarily involves right ventricle (Arrhythmogenic Right Ventricular Cardiomyopathy - ARVC), but left ventricular/biventricular involvement recognized.
• Genetics: Desmosomal gene mutations (DSP, PKP2, DSG2, DSC2). Ion channel gene overlap (RYR2).

Clinical Features & Diagnosis

• Presentation: Ventricular tachyarrhythmias, palpitations, syncope, sudden cardiac arrest. Often triggered/accelerated by exercise or acute myocarditis.
• Diagnosis: Based on revised Padua criteria integrating multiple domains:
  • Global/regional right or left ventricular dysfunction.
  • Fibrofatty infiltration on CMR.
  • Repolarization changes on ECG (T-wave inversion in right precordial leads).
  • Depolarization changes on ECG (epsilon waves).
  • Ventricular arrhythmias (LBBB morphology VT or frequent PVCs).
  • Positive family history/genetics.
• Management: Exercise restriction, beta-blockers, antiarrhythmics, ICD placement for sudden death prevention.