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Cardiomyopathies: DCM, HOCM (HCM), and RCM

Overview & Classification

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Echocardiographic Comparison

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I. Dilated Cardiomyopathy (DCM)

Definition

Etiology & Classification

Genetic (20–50% of cases)

• Predominantly autosomal dominant inheritance; >50 causative genes identified
• Titin (TTN) mutations: most common — ~25% of familial DCM, ~18% of sporadic cases
• Other genes: β-myosin heavy chain (MYH7), cardiac troponin T, α-myosin heavy chain
• X-linked DCM: mutations in dystrophin (also causes Duchenne/Becker muscular dystrophy); accounts for 2–5% of familial DCM
• Lamin A/C (LMNA) mutations: cause arrhythmogenic DCM with progressive AV conduction disease and ventricular arrhythmias
• Filamin C (FLNC) mutations: mixed arrhythmogenic/dilated phenotype with lethal ventricular arrhythmias in adolescents
• Desmin mutations: may cause DCM with skeletal myopathy and conduction disease

Acquired Causes

Key pathogenetic distinction: in DCM, mutations cause loss of function in sarcomeric proteins; in HCM, similar mutations cause gain of function — Robbins Pathology

Morphology

• Four-chamber dilation and hypertrophy
• Small mural thrombi may form at the LV apex (risk of systemic embolism)
• Histology: myocyte hypertrophy + interstitial fibrosis (nonspecific); no myocyte disarray (unlike HCM)

Clinical Symptoms

• Heart failure symptoms: dyspnea on exertion → orthopnea, PND, dyspnea at rest
• Fatigue, exercise intolerance
• Palpitations, syncope (arrhythmias: AF, VT/VF, conduction disease in genetic forms)
• Systemic thromboembolism (LV thrombus, AF)
• Physical exam: S3 gallop, displaced PMI, MR/TR murmurs (annular dilation), elevated JVP, peripheral edema, hepatomegaly, pulmonary crackles

Diagnosis

• ECG: sinus tachycardia, LBBB, ST/T-wave changes, AF, conduction abnormalities
• Echocardiogram: dilated LV/BiV, EF <40%, wall motion abnormalities, functional MR/TR, LV thrombus
• CXR: cardiomegaly, pulmonary venous congestion, pleural effusions
• Labs: BNP/NT-proBNP elevated, troponin may be mildly elevated, metabolic panel, TFTs, iron studies, CBC
• Cardiac MRI: late gadolinium enhancement (LGE) to characterize fibrosis; absence of subendocardial LGE helps distinguish from ischemic disease
• Coronary angiography: mandatory to exclude ischemic etiology
• Endomyocardial biopsy: in selected cases (rapidly deteriorating HF, suspected giant cell myocarditis, eosinophilic myocarditis)
• Genetic testing: recommended when DCM has a diagnostic phenotype; cascade screening of first-degree relatives

Differential Diagnosis

• Ischemic cardiomyopathy: CAD on angiography; subendocardial LGE pattern on CMR
• Hypertensive heart disease: hypertension history, concentric hypertrophy
• Valvular cardiomyopathy: significant valvular lesion precedes LV dysfunction
• Myocarditis: acute presentation, viral prodrome, biopsy confirmation
• Alcoholic cardiomyopathy: heavy alcohol history; reversible with abstinence
• Peripartum cardiomyopathy: timing of presentation (peripartum period)
• Takotsubo cardiomyopathy: apical ballooning, emotional trigger, usually reversible

Treatment

Pharmacological (HFrEF guideline-directed therapy)

Non-pharmacological / Device Therapy

• ICD: primary prevention of SCD if EF ≤35% on optimal therapy ≥3 months
• CRT (cardiac resynchronization therapy): if EF ≤35%, LBBB, QRS ≥150 ms
• Anticoagulation: for AF or documented LV thrombus (DOAC preferred)
• Exercise rehabilitation: improves functional capacity and QoL
• Alcohol abstinence: can lead to partial or complete recovery in alcoholic CMP
• Advanced HF: inotropes, LVAD (left ventricular assist device), cardiac transplantation

Prognosis

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II. Hypertrophic Cardiomyopathy (HCM / HOCM)

Definition

Etiology & Genetics

• Usually familial, autosomal dominant with variable penetrance
• Mutations in sarcomeric contractile protein genes account for ~50–60% of cases; >1400 distinct mutations identified
• Key genes:
  • MYH7 (β-myosin heavy chain): most common
  • MYBPC3 (myosin-binding protein C): second most common
  • TNNT2 (troponin T)
  • These three account for 70–80% of all HCM cases
• All are gain-of-function mutations → myocyte hypercontractility, increased energy expenditure, net negative energy balance
• Non-sarcomeric causes: Friedreich's ataxia, Noonan/LEOPARD syndrome, Anderson-Fabry disease, glycogen storage diseases, infants of diabetic mothers

Morphology

• Massive myocardial hypertrophy without ventricular dilation
• Asymmetric septal hypertrophy (ASH) in 90% of cases — interventricular septum disproportionately thicker than LV free wall
• In 10%: concentric hypertrophy
• Ventricular cavity compressed into a "banana-like" configuration
• In HOCM: systolic anterior motion (SAM) of the anterior mitral leaflet contacts the septum → LVOTO + mitral regurgitation; contact produces an endocardial plaque in the LVOT
• Histology (pathognomonic): myocyte disarray (chaotic, haphazard arrangement of hypertrophied myocytes), interstitial fibrosis, replacement fibrosis

Clinical Symptoms

• Many patients are asymptomatic and identified incidentally or via family screening
• Classic triad:
  1. Dyspnea (most common) — due to diastolic dysfunction + LVOTO
  2. Angina — supply-demand mismatch, small vessel disease, diastolic dysfunction
  3. Syncope / presyncope — LVOTO, arrhythmia
• Sudden cardiac death (SCD): may be the first manifestation, especially in young athletes (most common cause of SCD in athletes <35 years)
• Palpitations (AF, VT)
• Heart failure (late stage — can develop end-stage dilated phenotype with EF drop)

Physical Examination

• Harsh crescendo-decrescendo systolic murmur at LLSB, not radiating to neck
• Murmur increases with: Valsalva maneuver, standing (↓ preload/afterload), exercise
• Murmur decreases with: squatting, leg raise, handgrip (↑ preload/afterload)
• Double or triple apical impulse (palpable S4)
• Pulsus bisferiens (bifid carotid pulse)
• S4 gallop

Diagnosis

• ECG: LV hypertrophy, deep septal Q-waves in lateral leads (I, aVL, V4–V6), ST/T-wave changes; may show AF or ventricular arrhythmias
• Echocardiogram (key test): septal thickness ≥15 mm (≥13 mm with positive family history), SAM of mitral leaflet, LVOT gradient ≥30 mmHg at rest (significant ≥50 mmHg), diastolic dysfunction, EF often >65%
• Cardiac MRI: gold standard for morphology, myocardial fibrosis (LGE), apical HCM (missed by echo)
• Exercise stress testing: assess functional capacity, provokable LVOT gradient, SCD risk
• 24-hour Holter monitor: detect nonsustained VT (SCD risk stratification)
• Genetic testing: recommended in confirmed HCM (and cascade family screening)
• Coronary angiography: if angina in appropriate-aged patients

SCD Risk Factors (for ICD consideration)

• Prior cardiac arrest or sustained VT
• Family history of HCM-related SCD
• Unexplained syncope
• Massive hypertrophy (wall thickness ≥30 mm)
• Nonsustained VT on Holter
• Abnormal BP response to exercise
• Extensive LGE on CMR (>15% of LV mass)

Differential Diagnosis

• Hypertensive heart disease: concentric LVH, history of HTN, no myocyte disarray
• Aortic stenosis: systolic murmur radiating to neck, calcified valve on echo, murmur decreases with Valsalva
• Athlete's heart: symmetric hypertrophy ≤13 mm, normal diastolic function, regresses with deconditioning
• Fabry disease: symmetric LVH in male with angiokeratoma, renal failure, neuropathy
• Amyloid cardiomyopathy: sparkling myocardium on echo, low voltage on ECG, systemic signs
• Noonan syndrome: facial dysmorphism, pulmonary stenosis

Treatment

Pharmacological

Invasive / Interventional

• Surgical septal myectomy (Morrow procedure): gold standard for symptomatic HOCM with LVOT gradient ≥50 mmHg refractory to medical therapy; mortality <1% at experienced centers
• Alcohol septal ablation: catheter-based; ethanol injected into first septal perforator → controlled infarction of basal septum; alternative when surgery is high risk
• DDD Pacemaker: may reduce LVOT gradient in selected patients; less reliable
• ICD: primary or secondary prevention of SCD (per HCM risk score)
• Cardiac transplantation: end-stage HCM with burned-out dilated phenotype

Lifestyle

• Restriction from competitive sports and high-intensity exercise
• Genetic counseling and family screening
• Avoid dehydration, excessive alcohol

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III. Restrictive Cardiomyopathy (RCM)

Definition

Etiology & Classification

Infiltrative Disorders

• Cardiac amyloidosis (most prevalent form of RCM overall): transthyretin amyloid (ATTR) — wild-type increases in frequency with age; mutant ATTR (Val122Ile) in ~4% of African Americans; AL amyloid in plasma cell dyscrasias (light chains also directly cardiotoxic)
• Sarcoidosis: granulomatous infiltration → fibrosis, conduction disease, arrhythmia

Storage Disorders

• Hemochromatosis: iron deposition → initially diastolic dysfunction, later systolic
• Fabry disease: sphingolipid storage; mimics HCM in early stages, RCM at later stages
• Glycogen storage diseases (Pompe disease, etc.)

Fibrotic / Radiation / Drug-induced

• Radiation therapy: diffuse biventricular fibrosis (cancer survivors)
• Anthracyclines (high-dose doxorubicin): chemotherapy-induced
• Scleroderma, drugs (serotonin, ergotamine)

Endomyocardial Disorders

• Endomyocardial fibrosis: most common RCM worldwide; children/young adults in Africa and tropical regions; diffuse fibrosis of ventricular endocardium and subendocardium, often involving AV valves
• Löffler endocarditis (hypereosinophilic syndrome): peripheral hypereosinophilia, eosinophilic tissue infiltrates → endocardial/myocardial necrosis → scarring → mural thrombus → organization; not geographically restricted

Genetic/Idiopathic

• ~30% of idiopathic RCM is familial: mutations in TNNI3 (cardiac troponin I), MYH7
• Desmin (DES) mutations: RCM + skeletal myopathy + conduction abnormalities
• Some overlap with HCM phenotype

Morphology

• Ventricles approximately normal size, non-dilated, firm myocardium
• Both atria markedly dilated (consequence of restricted ventricular filling/pressure overload) — atria may dwarf ventricles
• Thrombus in atrial appendages, patchy endocardial fibrosis
• Histology: variable interstitial fibrosis; endomyocardial biopsy may reveal specific etiology (amyloid, hemochromatosis, sarcoid)

Clinical Symptoms

• HF symptoms: dyspnea on exertion → dyspnea at rest, orthopnea, PND, abdominal discomfort (hepatic engorgement)
• Fatigue, weakness, recurrent respiratory infections
• Palpitations, chest pain
• Physical exam:
  • Elevated JVP with prominent y descent
  • Kussmaul's sign (JVP fails to fall or rises with inspiration) — shared with constrictive pericarditis
  • Loud P2 if pulmonary HTN
  • S3 and/or S4 gallop
  • Peripheral edema, ascites, hepatomegaly
  • Rarely, SCD as first manifestation

Diagnosis

ECG

• Non-diagnostic but common findings: P mitrale/P pulmonale, nonspecific ST-T changes, ST depression, T-wave inversion (inferolateral leads)
• LVH criteria may be present; low QRS voltage in amyloid
• Conduction abnormalities, abnormal Q waves

Echocardiography

• Markedly dilated atria, small/normal ventricles, normal or mildly reduced EF
• Diastolic dysfunction (Grade III–IV): ↑ E/A ratio, ↓ E deceleration time, ↓ IVRT
• Tissue Doppler: ↓ diastolic annular velocities (e', low e'), ↑ E/e' ratio
• "Sparkling" granular appearance in cardiac amyloidosis
• Hepatic/pulmonary vein Doppler: diastolic-dominant flow

Cardiac MRI

• Diffuse gadolinium enhancement in amyloid (global subendocardial/transmural); patchy LGE in sarcoidosis; hemosiderin signal loss in hemochromatosis

Cardiac Catheterization

• Characteristic "dip-and-plateau" pattern ("square root sign") in ventricular pressure tracings — also seen in constrictive pericarditis
• LVEDP, LAP, PCWP markedly elevated and typically ≥5 mmHg above RVEDP/RAP (helps distinguish from constriction where pressures equalize)

Other

• Endomyocardial biopsy: often definitive — Congo red for amyloid, Prussian blue for hemochromatosis, non-caseating granulomas for sarcoidosis
• Labs: serum protein electrophoresis, free light chains, serum ferritin/iron, ACE level, BNP
• Technetium-99m pyrophosphate (PYP) scintigraphy: highly specific for ATTR amyloid

Differential Diagnosis

Treatment

General Principles

• No specific curative therapy for idiopathic RCM
• Goal: control symptoms of congestion, prevent complications

Pharmacological

Device Therapy

• ICD: for sarcoidosis or other forms with significant VT/VF risk
• Pacemaker: for complete heart block (sarcoidosis, hemochromatosis, desmin mutations)

Advanced / Definitive

• Cardiac transplantation: for end-stage idiopathic RCM; caution in amyloidosis (systemic disease recurs in graft for AL amyloid)
• Pericardiectomy: only if constrictive pericarditis is confirmed

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Summary Comparison Table

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Key Sources

• Robbins & Kumar Basic Pathology, 11e, Chapter 9 (Cardiac Disease)
• Goldman-Cecil Medicine, International Edition, Chapter 47 (Myocardial Disease)
• Goldman-Cecil Medicine, Chapter 62 (Restrictive Cardiomyopathy)
• Tintinalli's Emergency Medicine, 9e, Chapter on CardiomyopathiesThe guide above covers all requested domains comprehensively. Here are a few high-yield clinical pearls to complement the tables:

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High-Yield Pearls

• Titin (TTN) mutations are the single most common genetic cause (~25% familial, ~18% sporadic). Always screen family members.
• Alcohol causes >10% of HF in the US; abstinence can partially or fully reverse the cardiomyopathy.
• Distinguish from ischemic CMP with coronary angiography — this is mandatory before labeling DCM "idiopathic."
• Peripartum DCM: onset in last month of pregnancy or within 5 months postpartum; bromocriptine has shown benefit in some trials.

• The LVOT murmur behaves oppositely to aortic stenosis: it increases with Valsalva/standing (↓ preload) and decreases with squatting/handgrip (↑ preload/afterload).
• Mavacamten (cardiac myosin inhibitor, FDA-approved 2022) is a major therapeutic advance: it directly reduces LV contractility and LVOT gradient without the hemodynamic risks of disopyramide.
• SCD can be the first manifestation — HCM is the leading cause of sudden death in athletes under 35.
• Avoid nitrates, diuretics (excess), vasodilators, and digoxin in HOCM — all worsen LVOTO by reducing preload/afterload or increasing contractility.

• The most critical DDx is constrictive pericarditis — differentiated by pericardial thickness on CT/MRI, hemodynamic equalization vs. discordance, and tissue Doppler (preserved e' in CP, reduced in RCM).
• ATTR amyloidosis is the most prevalent form of RCM overall and is increasingly diagnosed in elderly patients; tafamidis significantly reduces mortality and HF hospitalization.
• Endomyocardial biopsy is often definitive (Congo red stain for amyloid, Prussian blue for hemochromatosis).
• Endomyocardial fibrosis is the most common RCM worldwide (tropical Africa); Löffler endocarditis is the non-tropical eosinophilic counterpart.