Cardiomyopathy Pathology — Dilated, Hypertrophic, Restrictive

DILATED CARDIOMYOPATHY (DCM)

Primary Pathophysiological Mechanisms

• Sarcomeric protein dysfunction and loss of force transmission: Mutations in genes encoding sarcomeric proteins (titin, beta-myosin heavy chain, cardiac troponin T, alpha-tropomyosin) and cytoskeletal proteins (dystrophin, sarcoglycan, lamin A/C) disrupt the mechanical linkage between myofilaments and the Z-disc. This leads to progressive loss of contractile force generation, impaired force transmission to the extracellular matrix, and eventual myocyte death. Non-sarcomeric mutations in lamin A/C (LMNA gene) cause nuclear envelope destabilization, accelerated cellular senescence, and predisposition to conduction abnormalities and arrhythmias.

• Neurohumoral activation and adverse remodeling: Initial myocardial injury triggers compensatory activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. Chronic elevation of angiotensin II and catecholamines causes concentric hypertrophy initially; however, sustained pathological signaling leads to eccentric hypertrophy with progressive chamber dilation, increased wall stress (via Laplace's law), myocyte slippage, and deposition of replacement fibrosis. Myocyte apoptosis and necrosis occur secondary to oxidative stress and mitochondrial dysfunction.

• Myocardial inflammation and immune-mediated injury: Viral infections (enterovirus, adenovirus, parvovirus B19, human herpesvirus 6, COVID-19) trigger acute myocarditis with CD8+ T-cell infiltration and inflammatory cytokine release (TNF-α, IL-1β, IL-6). Persistent viral replication, molecular mimicry, and autoimmune responses against cardiac myosin and other contractile proteins perpetuate chronic inflammation, leading to progressive myocyte loss and fibrosis. Autoantibodies against β1-adrenergic receptors are present in 20-30% of DCM patients.

• Metabolic dysfunction and mitochondrial failure: Cardiomyocytes exhibit impaired fatty acid oxidation, glucose metabolism, and ATP production. Mitochondrial DNA mutations, reduced complex I and III function, and increased reactive oxygen species (ROS) generation cause oxidative stress, calcium handling dysfunction, and myocyte apoptosis. Myocardial lipid accumulation and reduced AMPK signaling perpetuate the metabolic crisis.

• Calcium handling abnormalities: Dysfunction of the sarcoplasmic reticulum calcium ATPase (SERCA2a), ryanodine receptor (RyR2), and phospholamban dysregulation impair calcium cycling. Diastolic calcium overload promotes mitochondrial calcium accumulation, energy depletion, and myocyte death. Increased diastolic wall stress further impairs calcium reuptake and contractility.

HYPERTROPHIC CARDIOMYOPATHY (HCM)

Primary Pathophysiological Mechanisms

• Gain-of-function sarcomeric mutations with hypercontractility: Mutations in thick filament proteins (beta-myosin heavy chain [MYH7], myosin-binding protein C [MYBPC3]) and thin filament proteins (cardiac troponins, alpha-tropomyosin, actin) typically cause increased contractility and hyperresponsiveness to calcium. The mutant proteins create an imbalance in myofilament calcium sensitivity: even at physiological calcium levels, the sarcomere generates excessive force. This hypercontractility leads to myocyte degeneration, disarray, and compensatory hypertrophy of remaining viable myocytes.

• Myocyte disarray and architectural chaos: The hallmark histological finding is myocyte disarray—chaotic, non-parallel arrangement of myocytes at oblique and perpendicular angles to the ventricular long axis. This occurs predominantly in the interventricular septum but can be diffuse. Disarray comprises >5-10% of myocardial tissue in HCM versus <5% in normal hearts. The disorganized architecture creates zones of electrical heterogeneity and mechanical inefficiency, predisposing to re-entrant arrhythmias. Myocyte disarray is thought to result from aberrant embryonic cardiomyogenesis and abnormal myocyte proliferation during development driven by sarcomeric mutations.

• Progressive replacement fibrosis and left ventricular outflow tract obstruction (LVOTO): Hypertrophy is accompanied by extensive interstitial and replacement fibrosis, creating an electrically unstable substrate. Fibrotic scar alternates with islands of viable myocardium, promoting micro-re-entry. Asymmetric septal hypertrophy can obstruct the left ventricular outflow tract (LVOT). The systolic anterior motion (SAM) of the mitral valve occurs when the enlarged septum narrows the LVOT, causing the mitral leaflet to move anteriorly and occlude flow. This creates a dynamic left ventricular outflow tract gradient (pressure drop across the LVOT during systole) that worsens with decreased preload, increased contractility (Valsalva maneuver), or positive inotropic stimulation.

• Diastolic dysfunction and impaired relaxation: Despite preserved ejection fraction, HCM hearts exhibit profound diastolic dysfunction. The hypertrophied, fibrotic myocardium has increased stiffness and impaired active relaxation (lusitropy). Delayed early diastolic filling increases left atrial pressure, promoting atrial fibrillation. The combination of increased afterload (due to LVOT obstruction in HCM-obstructive) and impaired relaxation worsens hemodynamics.

• Microvascular ischemia and sudden cardiac death substrate: HCM hearts show abnormal intramural coronary arteries with medial hypertrophy and intimal proliferation, reducing luminal diameter and coronary vasodilatory reserve. This leads to chronic myocardial ischemia despite normal epicardial coronary arteries. Ischemia and fibrosis create a substrate for ventricular arrhythmias. HCM is the leading cause of sudden cardiac death (SCD) in young athletes; arrhythmogenic mechanisms include electrical heterogeneity, re-entry through fibrotic regions, and triggered activity (early and delayed afterdepolarizations).

RESTRICTIVE CARDIOMYOPATHY (RCM)

Primary Pathophysiological Mechanisms

• Infiltration or deposition of extracellular material: In infiltrative RCM (amyloidosis, hemochromatosis, fabry disease, glycogen storage diseases), extracellular material accumulates within the myocardial interstitium and between myocytes. Amyloid fibrils (composed of misfolded proteins—transthyretin, immunoglobulin light chains, apolipoprotein A-I) deposit in a beta-pleated sheet configuration, forming rigid structures that physically restrict myocardial compliance. In secondary restrictive patterns (e.g., endomyocardial fibrosis, sarcoidosis), transmural or subendocardial fibrosis obliterates the ventricular cavity and impairs systolic and diastolic function.

• Severe diastolic dysfunction with preserved or mildly reduced ejection fraction: The primary pathophysiological abnormality is severely reduced ventricular compliance (increased stiffness). During diastole, the ventricles fail to relax properly, and any increase in chamber volume requires disproportionately large increases in diastolic pressure. This causes restrictive diastolic filling pattern on cardiac catheterization ("square root sign"—rapid rise in diastolic pressure followed by a plateau). Ventricular volumes remain small or normal while diastolic pressures are markedly elevated. Ejection fraction is initially preserved but may decline late in disease.

• Atrial dilation and atrial fibrillation: The elevated diastolic pressures are transmitted retrograde to the atria, causing marked atrial enlargement and atrial fibrillation. Atrial fibrillation is present in 50-80% of RCM patients and contributes to hemodynamic deterioration.

• Biventricular involvement and pulmonary/systemic venous congestion: Both right and left ventricles are restrictive, causing both pulmonary venous congestion (dyspnea, pulmonary edema) and systemic venous congestion (hepatomegaly, peripheral edema, elevated JVP with prominent S wave). Coronary sinus pressure elevation may be more pronounced than in other cardiomyopathies.

DILATED CARDIOMYOPATHY (DCM)

Genetic/Inherited Causes (30% of DCM)

• Sarcomeric gene mutations: TTN (titin, most common), MYH7 (beta-myosin heavy chain), LMNA (lamin A/C), TNNT2 (cardiac troponin T), TPM1 (alpha-tropomyosin)
• Cytoskeletal and Z-disc proteins: DMD (dystrophin; X-linked, Duchenne muscular dystrophy), SGCB/SGCG/SGCA/SGCD (sarcoglycans), DES (desmin), LDB3 (Z-disc protein)
• Autosomal dominant inheritance (most common), autosomal recessive, or X-linked inheritance patterns

Acquired Causes (70% of DCM)

• Myocarditis: Viral (enterovirus, adenovirus, parvovirus B19, HHV-6, SARS-CoV-2), bacterial, fungal, parasitic (Chagas disease—trypanosomiasis causing chronic chagasic cardiomyopathy), autoimmune (giant cell myocarditis)
• Chronic valvular disease: Aortic or mitral regurgitation with volume overload
• Hypertension: Chronic uncontrolled hypertension leading to LV dilatation
• Coronary artery disease: Extensive myocardial infarction and ischemic cardiomyopathy with scar tissue
• Peripartum cardiomyopathy: DCM occurring in the third trimester through 5 months postpartum, etiology incompletely understood but may involve immune activation, oxidative stress, and prolactin cleavage products
• Alcohol abuse: Alcoholic cardiomyopathy from chronic ethanol-induced myocyte toxicity, thiamine deficiency, and oxidative stress
• Chemotherapy: Anthracyclines (doxorubicin, daunorubicin), trastuzumab (anti-HER2), tyrosine kinase inhibitors
• Infiltrative/Storage diseases: Hemochromatosis, glycogen storage diseases, lipid storage disorders
• Endocrine disorders: Thyroid dysfunction (hypothyroidism), diabetes mellitus, pheochromocytoma
• Metabolic/Nutritional: Selenium deficiency (Keshan disease), carnitine deficiency, thiamine deficiency
• Other: Cocaine abuse, radiation therapy, acute decompensation of hypertension

HYPERTROPHIC CARDIOMYOPATHY (HCM)

Genetic/Inherited Causes (70% of HCM)

• Thick filament mutations (most common): MYH7 (beta-myosin heavy chain, ~35% of HCM), MYBPC3 (cardiac myosin-binding protein C, ~25% of HCM)
• Thin filament mutations: TNNT2 (cardiac troponin T), TNNI3 (cardiac troponin I), TPM1 (alpha-tropomyosin), ACTC1 (cardiac actin)
• Z-disc and regulatory proteins: MYL2 (regulatory light chain), MYL3 (essential light chain)
• Autosomal dominant inheritance with variable penetrance and expressivity; 10-15% are de novo mutations
• Genetic heterogeneity: >1,400 mutations identified; genotype-phenotype correlation is poor

Acquired/Secondary HCM (30% of cases)

• Hypertension: Hypertensive heart disease with asymmetric septal hypertrophy can mimic HCM
• Infiltrative/Storage diseases: Cardiac amyloidosis (transthyretin amyloidosis, light chain amyloidosis), Fabry disease (alpha-galactosidase A deficiency causing cardiac glycosphingolipid deposition), Danon disease (LAMP2 mutation), glycogen storage disease type II (Pompe disease)
• Metabolic diseases: Noonan syndrome (PTPN11 mutations causing RAS/MAPK pathway dysregulation with HCM phenotype)
• Endocrine: Acromegaly, hyperthyroidism, pheochromocytoma

RESTRICTIVE CARDIOMYOPATHY (RCM)

Primary/Idiopathic RCM

• Genetic mutations in TNNI3 (cardiac troponin I), TNNT2 (cardiac troponin T), and other sarcomeric proteins can cause restrictive phenotype
• Mutations in TTR (transthyretin) in non-amyloid familial RCM

Infiltrative RCM

• Cardiac amyloidosis:
• AL amyloidosis (light chain—immunoglobulin light chain deposition)
• ATTR amyloidosis (transthyretin; hereditary/mutant TTR and wild-type/senile transthyretin amyloidosis)
• Other types (serum amyloid A, apolipoprotein A-I)
• Hemochromatosis: Iron deposition in myocardium causing oxidative damage and fibrosis
• Fabry disease: Lysosomal storage disease; alpha-galactosidase A deficiency causes accumulation of globotriaosylceramide
• Glycogen storage diseases: Glycogen deposition in myocytes (Pompe disease, other types)
• Sarcoidosis: Granulomatous infiltration of myocardium; can cause restrictive physiology with fibrosis

Endomyocardial RCM

• Endomyocardial fibrosis (EMF): Idiopathic fibrosis of endocardium and subendocardial layer, predominantly in tropical/subtropical regions (Africa, South America); etiology unknown but may involve eosinophilic myocarditis or autoimmune mechanisms
• Hypereosinophilic syndrome: Prolonged peripheral eosinophilia causing acute myocarditis, then fibrotic phase with endocardial thickening (similar to Loeffler endocarditis)

Secondary/Associated RCM

• Post-radiation: Mediastinal radiation therapy causing myocardial fibrosis
• Connective tissue diseases: Systemic lupus erythematosus, systemic sclerosis (scleroderma)
• Pericardial disease: Constrictive pericarditis (must be distinguished from restrictive cardiomyopathy)

DILATED CARDIOMYOPATHY (DCM)

Cardinal Symptoms

• Progressive dyspnea on exertion (DOE) and orthopnea: Reflect pulmonary edema from elevated left ventricular end-diastolic pressure (LVEDP) and pulmonary venous congestion. Morphologically correlates to pulmonary interstitial

Initial evaluation (all phenotypes)

• ECG: nonspecific but pattern-defining. DCM shows LBBB/poor R-wave progression; HCM shows massive LVH voltage with deep septal Q waves and giant inverted T waves in apical HCM (Yamaguchi); cardiac amyloid shows the paradox of low QRS voltage despite thick walls plus a pseudoinfarct pattern.
• Chest radiograph and natriuretic peptides: cardiomegaly with pulmonary venous congestion in DCM; a near-normal cardiac silhouette with congestion favors RCM. BNP/NT-proBNP is elevated in all and is disproportionately high in amyloidosis.
• Transthoracic echocardiography is the first-line confirmatory test in every suspected cardiomyopathy per the ACC/AHA heart failure and hypertrophic cardiomyopathy guidelines.
• DCM: LV dilation with globally reduced ejection fraction (LVEF ≤40% defines HFrEF by ACC/AHA/HFSA), functional MR, apical mural thrombus.
• HCM: unexplained wall thickness ≥15 mm (≥13 mm in a first-degree relative of an affected patient), systolic anterior motion of the mitral valve, and a dynamic LVOT gradient. A gradient ≥30 mmHg defines obstruction; ≥50 mmHg at rest or with provocation (Valsalva, exercise stress echo) is the threshold for invasive therapy.
• RCM: normal-sized, thick, sparkling ventricles with biatrial enlargement, grade III diastolic dysfunction, and apical sparing ("cherry-on-top") on longitudinal strain in amyloid.

Advanced and etiologic testing

• Cardiac MRI: quantifies mass and defines fibrosis by late gadolinium enhancement — patchy mid-wall in HCM, diffuse subendocardial with abnormal gadolinium kinetics in amyloid, patchy basal septal in sarcoid.
• Amyloid workup: serum and urine immunofixation plus the serum free light-chain ratio come first. 99mTc-pyrophosphate scintigraphy showing grade 2–3 myocardial uptake with a heart-to-contralateral-lung ratio >1.5 establishes ATTR noninvasively only when all monoclonal protein screening is negative (ASNC/AHA consensus); any positive monoclonal screen invalidates the scan regardless of grade and mandates biopsy with typing — Congo red with apple-green birefringence.
• Endomyocardial biopsy remains the gold standard for giant cell myocarditis, sarcoid, hemochromatosis; ischemic evaluation (angiography/CTA), iron studies, TSH, HIV, and genetic testing with cascade family screening complete the DCM/HCM evaluation.
• Constriction vs restriction: constriction shows respirophasic septal shift, ventricular interdependence, annulus reversus, and pericardial thickening; both give a square-root/dip-and-plateau tracing.

• ARNI (sacubitril/valsartan), or ACE inhibitor/ARB if ARNI is unaffordable or not tolerated — blocks maladaptive RAAS remodeling. Requires a 36-hour washout from an ACE inhibitor; angioedema history and pregnancy are absolute contraindications.
• Evidence-based beta blocker (carvedilol, metoprolol succinate, bisoprolol): blunts catecholamine-driven myocyte loss; never start during decompensation.
• MRA (spironolactone): antifibrotic; hold for hyperkalemia or advanced CKD.
• SGLT2 inhibitor (dapagliflozin): mortality benefit independent of diabetes. All four pillars are indicated in HFrEF.
• Escalation: hydralazine/isosorbide dinitrate in self-identified Black patients; ivabradine only in sinus rhythm with resting HR ≥70 bpm despite a maximally tolerated beta blocker; CRT for LVEF ≤35% in sinus rhythm with LBBB and QRS ≥150 ms, NYHA II–IV on GDMT; primary-prevention ICD for LVEF ≤35% after ≥3 months of optimal therapy. Definitive care is LVAD or transplantation. Anticoagulate only for atrial fibrillation or documented LV thrombus.

Hypertrophic cardiomyopathy (ACC/AHA)

• Nonvasodilating beta blocker first-line for obstructive symptoms; nondihydropyridine calcium channel blocker (verapamil) if intolerant — but avoid verapamil/diltiazem in severe resting obstruction, systemic hypotension, or severe dyspnea at rest (Class 3: Harm), since vasodilation plus negative inotropy can precipitate pulmonary edema and shock. Disopyramide as a negative-inotrope add-on.
• Cardiac myosin inhibitor (mavacamten) for symptomatic obstructive HCM, with serial echocardiographic monitoring for systolic dysfunction under a REMS program.
• Septal reduction therapy — surgical myectomy or alcohol septal ablation at experienced centers — for NYHA III–IV symptoms with gradient ≥50 mmHg. ICD per risk stratification (prior arrest, massive hypertrophy, unexplained syncope, NSVT, apical aneurysm, extensive LGE, family history of SCD).
• Contraindicated in obstructive HCM: nitrates, dihydropyridines, digoxin, and aggressive diuresis. Treat hypotension with fluids and phenylephrine — a pure alpha agonist — never with inotropes.

Disease-related — emergencies flagged

• Sudden cardiac death (EMERGENCY): re-entry through fibrosis and disarray produces ventricular fibrillation or pulseless VT, the shockable pair — immediate defibrillation. HCM is the classic cause in young athletes; LMNA-DCM and cardiac sarcoid cause SCD at relatively preserved ejection fractions.
• Acute decompensation from atrial fibrillation (EMERGENCY in HCM/RCM): loss of atrial kick in a stiff, noncompliant ventricle abruptly drops stroke volume — hypotension with pulmonary edema signals it; urgent cardioversion is often needed.
• Cardiogenic shock: cool extremities, narrow pulse pressure, rising lactate. In obstructive HCM, shock may be obstruction-driven, worsening with inotropes.
• Cardioembolic stroke: stasis in a dilated ventricle or fibrillating atrium; DCM mural thrombus is the classic source.
• Progressive/"burnout" HCM: wall thinning with falling EF, mimicking DCM.
• High-grade AV block: infiltration or granuloma in amyloid, sarcoid, and LMNA disease — syncope with bradycardia warrants pacing/ICD evaluation.
• Multisystem amyloid: nephrotic proteinuria, autonomic neuropathy with orthostasis, macroglossia and periorbital purpura in AL, bilateral carpal tunnel preceding ATTR by years.

Treatment-related

• Alcohol septal ablation: septal infarction damages the conduction system — complete heart block requiring permanent pacing is the signature complication.
• Surgical myectomy: iatrogenic VSD, aortic regurgitation, LBBB.
• Disopyramide: anticholinergic urinary retention and dry mouth; QT prolongation with torsades.
• Mavacamten: excessive negative inotropy causing LVEF decline — detected on protocol echocardiography.
• RAAS blockade: hyperkalemia and functional AKI; sacubitril/valsartan and ACE inhibitors cause angioedema and are contraindicated in pregnancy.
• SGLT2 inhibitors: euglycemic DKA and genital mycotic infection; MRAs: hyperkalemia, gynecomastia with spironolactone.
• Digoxin in amyloidosis: binds amyloid fibrils, causing toxicity at ordinary levels.
• ICDs: inappropriate shocks, lead fracture, pocket infection.

• Maneuvers separate HCM from aortic stenosis — but only some of them: the HCM murmur increases with Valsalva and abrupt standing (less preload, smaller LVOT) and decreases with squatting and passive leg raise. Aortic stenosis does the opposite for those maneuvers: increases with squatting, decreases with Valsalva. Handgrip decreases BOTH the HCM and AS murmurs (raising afterload/SVR lowers the transvalvular gradient), so handgrip does not distinguish them; handgrip increases the murmurs of mitral regurgitation, VSD, and aortic regurgitation.
• Young athlete with exertional syncope or sudden death: the best next step is transthoracic echocardiography, not stress testing or angiography. HCM is autosomal dominant (MYH7, MYBPC3); screen first-degree relatives with ECG and echo.
• Low-voltage ECG plus thick ventricular walls is amyloid until proven otherwise — the internal contradiction is the buzzword. Confirm with light-chain screening, then 99mTc-PYP; apical sparing on strain is the echo signature.
• Never give digoxin, nitrates, or dihydropyridines in obstructive HCM; treat hypotension with fluids and phenylephrine. The classic distractor is "give dobutamine" — inotropes worsen dynamic obstruction.
• HFrEF from DCM requires all four pillars — ARNI (or ACEI/ARB), beta blocker, MRA, and SGLT2 inhibitor — per ACC/AHA/HFSA; ICD consideration comes only after ≥3 months of optimized therapy with LVEF still ≤35%.
• Restrictive cardiomyopathy versus constrictive pericarditis is the perennial trap: pericardial calcification, a pericardial knock, Kussmaul sign, and respirophasic ventricular interdependence point to constriction (surgically curable by pericardiectomy); markedly elevated natriuretic peptides and abnormal tissue Doppler point to restriction.
• Etiologic one-liners: Loeffler endocarditis with eosinophilia; endomyocardial fibrosis in tropical regions; anthracycline dose-dependent DCM; peripartum DCM in the last month of pregnancy through five months postpartum; alcohol, cocaine, Chagas, and selenium deficiency (Keshan disease).
• Histology: myocyte disarray = HCM; interstitial fibrosis with eccentric hypertrophy = DCM; Congo red apple-green birefringence under polarized light = amyloid.