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CVS Pathology - Part 2: Complete Summary Notes

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1. SUDDEN CARDIAC DEATH (SCD)

SCD Substrates:

• Typical finding: chronic multi-vessel CAD with fixed, critical atherosclerotic stenoses
• Acute plaque disruption found in only 10-20% of cases
• 80-90% of resuscitated SCD patients show NO troponin or ECG evidence of fresh necrosis
• Healed/silent remote MIs found in ~40% of hearts
• Microscopy shows subendocardial myocyte vacuolization (sign of chronic ischemia)

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2. HYPERTENSIVE HEART DISEASE (HHD)

A. Systemic (Left-Sided) HHD

1. Isolated LV hypertrophy (no other cause e.g., aortic stenosis, coarctation)
2. Documented hypertension history or evidence in other organs (e.g., hypertensive nephrosclerosis)

• Framingham Study: even borderline HTN (>140/90) causes severe LVH; affects ~30% of US population
• Modern threshold: >120/90 mmHg systolic/diastolic; ~50% of population qualifies

• Concentric LV hypertrophy (thickening WITHOUT initial dilation; lumen compressed)
• Heart weight can exceed 500g (normal ~300-350g)
• LV free wall can exceed 2.0 cm (normal 1.1-1.2 cm)
• Diastolic stiffening → LA dilation (to force blood into stiff LV)

• Cardiomyocyte bizarre enlargement: dark, hyperchromatic, square-shaped "boxcar" nuclei
• Reactive fibrosis: perivascular fibrosis + interstitial fibrosis → wall stiffening

• Silent for years; detected by ECG voltage criteria or echo
• Atrial fibrillation from LA dilation/stretching
• Four terminal pathways if uncontrolled: (1) Progressive CHF, (2) Accelerated CAD, (3) Vascular stroke/renal failure, (4) Sudden Cardiac Death
• With treatment: hypertrophy is reversible with BP control

B. Pulmonary (Right-Sided) HHD - Cor Pulmonale

• Cause: massive pulmonary embolism
• RV has no time to hypertrophy
• RV undergoes marked acute dilation: normal crescentic shape → large failing ovoid

• Cause: emphysema/COPD, primary pulmonary HTN
• RV free wall thickens to >1.0 cm (normal 0.3-0.5 cm)
• Subtle early markers: thickening at pulmonary valve outflow tract + moderator band thickening
• Complications: (1) Tricuspid regurgitation from annular stretch; (2) LV compression from septal shift

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3. VALVULAR HEART DISEASE

• Intrinsic leaflet disease (e.g., infective endocarditis)
• Supporting structure disruption: mitral annulus dilation, chordae rupture, papillary muscle dysfunction, chamber/aortic dilation

1. Aortic stenosis - dystrophic calcification (aging normal tricuspid OR congenital bicuspid valve)
2. Aortic insufficiency - ascending aortic dilation (HTN, aging, connective tissue disease)
3. Mitral stenosis - Rheumatic Heart Disease (post-Group A Strep pharyngitis)
4. Mitral insufficiency - Myxomatous degeneration (MVP) or LV chamber dilation

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4. CALCIFIC AORTIC STENOSIS

• Chronic injury + hyperlipidemia + inflammation
• Valvular interstitial cells transdifferentiate into osteoblast-like cells
• Synthesize bone matrix proteins + deposit hydroxyapatite (calcium phosphate)
• NOTE: Statins do NOT slow progression once osteoblastic mechanism is active (unlike atherosclerosis)

• Gross hallmark: dense, mounded calcified masses on the OUTFLOW surface (facing aorta)
• Free edges of cusps are SPARED
• NO commissural fusion (differs from rheumatic AS)
• Microscopy: calcification starts in the fibrosa layer at the outflow surface

• Normal orifice: ~4 cm² → severe stenosis: 0.5-1 cm²
• LV pressure climbs to >200 mmHg → massive concentric hypertrophy
• Even with clear coronary arteries: ischemia occurs from (1) compressed microvessels + (2) spiked O2 demand

• Angina → 5-year survival limit
• Syncope → 3-year survival limit
• Heart failure/CHF → 2-year survival limit
• Medical therapy is INEFFECTIVE; requires surgical valve replacement or TAVR

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5. CONGENITAL BICUSPID AORTIC VALVE (BAV)

• Incomplete commissural separation during embryogenesis → only two functional cusps
• Familial clustering; associated with coarctation of aorta and LVOT malformations
• Linked to loss-of-function mutations in NOTCH1 gene (chromosome 9q34.3)

• Two unequal cusps; larger cusp has a midline raphe (developmental vestige of unfused cusps)
• Raphe is the primary site of early dystrophic calcification

1. Valvular insufficiency (aortic regurgitation)
2. Infectious endocarditis (turbulent jets damage endothelium)
3. Aortic dissection/aneurysm - BAV is a systemic aortopathy; concomitant cystic medial degeneration of ascending aorta persists even when valve is hemodynamically normal

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6. MITRAL ANNULAR CALCIFICATION (MAC)

• Irregular, stony-hard nodules: 2-5 mm thick
• Semi-circular ring at base of leaflets (especially posterior mitral leaflet)
• Can ulcerate, exposing surfaces to blood

1. Mitral regurgitation (rigid ring cannot contract during systole)
2. Mitral stenosis (bulky nodules encroach on orifice)
3. Conduction block (calcium burrows into AV node or Bundle of His → arrhythmias/SCD)
4. Embolic stroke (rough surfaces → platelet adhesion → thrombus)
5. Infective endocarditis (irregular surfaces → bacterial seeding)

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7. MITRAL VALVE PROLAPSE (MVP) - Myxomatous Degeneration

• Most cases: unknown trigger (sporadic)
• In Marfan Syndrome: autosomal dominant FBN1 mutations → altered TGF-β signaling
• FBN1 mutations → pathological hyperactivation of TGF-β → ECM disruption
• Animal model proof: TGF-β inhibitors completely prevent myxomatous changes

• Inter-chordal ballooning ("hooding") - leaflets enlarged, redundant, thick, rubbery
• Chordae: elongated and thinned (prone to snapping)
• Mitral annulus: dilated
• Can affect tricuspid, aortic, or pulmonary valves concurrently

• Spongiosa expansion: massive proliferation with deposition of sulfated hydrophilic glycosaminoglycans
• Fibrosa attenuation: dense collagen core thinned, frayed, weakened

1. Frictional leaflet thickening (fibrous scabbing at rubbing edges)
2. Linear friction calluses on LV endocardium (chordae snapping against wall)
3. Mural endocardial thickening (LA wall - constant friction)
4. Thrombogenic crevices on atrial surface of leaflets
5. Focal calcification at base of posterior mitral leaflet

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8. RHEUMATIC FEVER (RF) & RHEUMATIC HEART DISEASE (RHD)

1. Group A β-hemolytic Strep pharyngitis (Weeks 0-1)
2. Latent immune window: 2-3 week delay for antibody/T-cell development
3. Antibodies + CD4+ T-cells against strep M proteins cross-react with cardiac self-antigens (e.g., myosin)
4. Complement activation + macrophage recruitment → granulomatous inflammation
5. Chronic healing → fibrosis → permanent valvular scarring

• Sterile lesion rule: Live strep CANNOT be cultured from cardiac lesions
• Only ~3% of untreated Strep-A infections develop RF
• Genetic susceptibility: HLA class II molecule variations

Acute Pancarditis - Pathological Triad:

1. Myocarditis - Aschoff Bodies (pathognomonic): Focal interstitial inflammatory granulomas with:
   • Infiltrating T-lymphocytes + plasma cells
   • Anitschkow cells ("caterpillar cells"): large activated macrophages with slender, wavy ribbon-shaped chromatin
2. Endocarditis - Verrucae: Small (1-2 mm) gritty inflammatory vegetations along lines of valve closure; overlying focal fibrinoid necrosis
3. MacCallum Plaques: Rough, map-like endocardial thickenings in posterior LA wall from high-velocity regurgitant streams

Chronic RHD - Structural Changes:

• Marked, asymmetric leaflet thickening
• Commissural fusion and shortening
• Severe thickening and fusion of chordae tendineae (become rigid fibrous pillars)

• Mitral valve: virtually always; isolated in 65%, paired with aortic valve in 25%
• Tricuspid: infrequent; Pulmonary: exceptionally rare

• Massive LA dilation → large mural thrombi → systemic emboli
• Pulmonary back-pressure → RVH
• LV remains largely normal (obstruction is before LV entry)

Revised Jones Criteria:

• 1% die acutely from fulminant myocarditis
• Recurrent infections create destructive positive feedback loop → cumulative deformity
• Clinical symptoms appear years to decades after initial episode
• Prophylactic penicillin to prevent strep recurrence is critical

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9. INFECTIVE ENDOCARDITIS (IE)

Acute vs. Subacute IE:

• MVP with thick myxomatous leaflets
• Degenerative calcific aortic stenosis
• Congenital bicuspid aortic valve
• Prosthetic valves
• IV drug use

Pathogens:

Morphology of Vegetations:

• Friable, bulky, destructive clusters of fibrin + platelets + inflammatory cells + live bacteria
• Aortic and mitral valves most common (left-sided); tricuspid in IV drug users (right-sided)
• Local destruction: ring abscess (pus collection in fibrous skeleton)

• Left-sided → brain/spleen/kidneys → septic infarcts + mycotic aneurysms
• Right-sided → lungs → septic pulmonary emboli + abscesses

• Acute IE: overwhelming neutrophils, necrosis, massive bacterial colonies
• Subacute IE: granulation tissue at base (healing attempt) → granulation → calcification → organizing fibrosis

Modified Duke Criteria:

1. Persistent bacteremia (positive cultures from multiple sites)
2. Endocardial involvement (echo: oscillating mass, abscess, or prosthetic dehiscence)
3. New regurgitation murmur

• Acute: rapid onset, high fever, shaking chills, profound weakness
• Geriatric: blunted fever; chronic fatigue + weight loss + flu-like syndrome
• Murmurs present in most left-sided IE
• Immune complexes → glomerulonephritis

Peripheral Vascular Signs (rare, in neglected cases):

• S. viridans: 98% cure
• Enterococci/S. aureus: 60-90%
• Fungal/Gram-negative: ~50% die
• Prosthetic valve endocarditis: worse prognosis (biofilm formation)

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10. NONINFECTED (STERILE) VEGETATIONS

A. Nonbacterial Thrombotic Endocarditis (NBTE) - "Marantic Endocarditis"

• Small (1-5 mm) sterile bland thrombi (fibrin + platelets)
• Loosely attached; NO inflammatory reaction; NO tissue destruction
• Form on previously NORMAL valves
• Highly dangerous: loose anchoring → systemic emboli → stroke/organ infarcts

• Mucinous adenocarcinomas (release tumor-derived mucin/tissue factor) → Trousseau Syndrome
• DIC or hyperestrogenic states
• Indwelling central venous or swan-ganz catheters (endocardial trauma)

B. Libman-Sacks Endocarditis (SLE/Antiphospholipid Syndrome)

• Small (1-4 mm) sterile, inflammatory vegetations in SLE
• Pathogenesis: immune complex deposition → complement activation → leukocyte recruitment → fibrinoid necrosis of valve
• Unique distribution: random - can form on closure lines, tips, UNDERSIDES of leaflets, chordae, mural endocardium
• Persistent attacks → leaflet fusion + permanent valvular deformity (mimics RHD)

Vegetation Comparison Summary:

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11. CARCINOID HEART DISEASE

• GI neuroendocrine tumor secretes serotonin → portal vein → liver metabolizes to inactive 5-HIAA → heart protected
• When liver is overwhelmed by metastases → serotonin escapes via hepatic veins into IVC → right heart bathed in raw serotonin
• Right-sided predominance: Tricuspid + pulmonary valves primarily affected
• Left side usually protected: Pulmonary vascular bed degrades serotonin before it reaches LA

1. Interatrial/interventricular septal defect (ASD/PFO) creating right-to-left shunt
2. Primary pulmonary carcinoid tumor

• Carcinoid plaque: glistening white plaque-like fibrous thickenings on endocardial surfaces
• Tricuspid: leaflets held OPEN → severe tricuspid insufficiency (regurgitation)
• Pulmonary: narrowed outflow → pulmonary stenosis
• Microscopically: smooth muscle cells + collagen in acid mucopolysaccharide ground substance; underlying native valve structures intact underneath

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12. PROSTHETIC HEART VALVES

• Materials: rigid carbon flaps (bileaflet tilting discs); older: caged balls or single tilting discs
• Advantage: exceptionally durable (rare material failure)
• Disadvantage: highly thrombogenic → requires lifetime anticoagulation (warfarin)

• Materials: porcine aortic valves OR bovine pericardium (glutaraldehyde preserved); OR cryopreserved human homografts
• TAVR: catheter-based deployment over native calcific valve
• Advantage: smooth laminar flow; no long-term anticoagulation needed
• Disadvantage: nonviable tissue → progressive dystrophic calcification, tearing, fraying → fails within 10-15 years

Prosthetic Complications:

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13. CARDIOMYOPATHIES

Three Dominant Anatomic Patterns:

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14. DILATED CARDIOMYOPATHY (DCM)

• Autosomal dominant (most common); also X-linked, autosomal recessive, mitochondrial
• Titin (TTN) truncations: 10-20% of all DCM; titin is molecular spring of sarcomere
• Lamin A/C (LMNA) mutations: nuclear envelope breakdown → concurrent conduction blocks
• Dystrophin mutations (X-linked): affects young men after puberty; linked to Duchenne/Becker MD
• Mitochondrial deletions: disrupt oxidative phosphorylation → pediatric presentation

• Coxsackie B virus + enteroviruses most common
• Direct evolution: acute myocarditis → chronic DCM
• Un-cleared viral infection → continuous immune destruction of myocytes

• Ethanol/acetaldehyde: direct myocardial toxin; can cause thiamine deficiency (Beriberi heart disease)
• Heavy metals (Cobalt): shut down myocyte energy generation
• Iron overload (hemochromatosis): ROS via Fenton reactions → lipid peroxidation; rusty brown heart discoloration

• Late pregnancy or up to 5 months postpartum
• Prolactin/sFLT1 rise → anti-angiogenic fragments → excessive microvascular loss → functional ischemia
• Exacerbated by volume overload + pregnancy-induced HTN + genetic vulnerability

• Pheochromocytoma, cocaine/meth, vasopressor infusions
• Contraction band necrosis: myocytes freeze mid-contraction → sarcomere snapping → fibrous sheets
• Takotsubo (Broken Heart Syndrome): acute stress → catecholamine surge → apical ballooning deformity resembling a Japanese octopus trap; classically follows extreme emotional shock

• Gross: globally enlarged (2-3x normal weight), heavy, flabby; all 4 chambers dilated; mural thrombi in ventricular apices + atrial appendages
• Valve/vessel exclusion: structural leaflets appear normal (no primary VHD); epicardial coronaries normal or insufficiently diseased to explain damage
• Microscopic: mix of hypertrophied myocytes (large dark nuclei) + attenuated, stretched myocytes; interstitial and endocardial fibrosis; small subendocardial scars
• "Ninja star" nuclei in TTN-truncation DCM: hyperchromatic, stellate nuclei in ≥5% of myocytes

• EF typically <25% (normal 50-65%)
• Age 20-50 years most common; can affect infants
• Classic CHF presentation; systolic failure → retrograde pulmonary congestion → dyspnea + fatigue
• Terminal events: refractory pump failure OR sudden ventricular arrhythmia
• Annual mortality (untreated): 10-50%

1. CRT (biventricular pacemaker): resynchronizes contraction
2. LVAD: bridge to transplantation or destination therapy
3. Mechanical unloading can sometimes induce native muscle recovery
4. Orthotopic cardiac transplantation (definitive)

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15. ARRHYTHMOGENIC CARDIOMYOPATHY (ARVD/C)

• Autosomal dominant with highly variable penetrance
• Target: desmosomal junctional proteins at intercalated disks
• Affected proteins: plakoglobin, desmoplakin, plakophilin, desmin

• Gross: RV free wall severely thinned and attenuated
• Fibrofatty substitution: yellow-white adipose + collagen replaces myocardium
• Inflammatory footprint: patches of mononuclear cells (lymphocytes) around degenerating myocytes (secondary; NOT primary inflammatory disease)

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16. HYPERTROPHIC CARDIOMYOPATHY (HCM)

• HCM = thick-walled, hyper-contracting, DIASTOLIC failure
• DCM = thin-walled, hypo-contracting, SYSTOLIC failure

• Autosomal dominant, highly variable penetrance

• 400 distinct missense mutations across 9 genes

• Myosin-Binding Protein C (MYBP-C): high prevalence
• β-Myosin Heavy Chain (β-MHC/MYH7): high prevalence
• Combined with TnI, TnT, α-tropomyosin: 70-80% of all HCM cases
• Core defect: impaired energy transfer from mitochondria to sarcomere → impaired diastolic relaxation
• Note: same gene can cause either HCM or DCM depending on exact mutation

• Massive hypertrophy WITHOUT dilation
• Asymmetric Septal Hypertrophy (ASH): in 90% - septum > LV free wall; 10%: symmetric concentric
• "Banana cavity": bulging septum compresses LV lumen into narrow crescentic shape

• Subaortic septal bulge → high-velocity narrow flow → Venturi effect → anterior mitral leaflet sucked forward → slaps against septum
• Result: dynamic LVOT obstruction + fibrous endocardial plaque where leaflet hits wall

1. Extreme myocyte giantism (>40 μm diameter; normal ~15 μm)
2. Myofiber disarray (definitive hallmark): chaotic, tangled, haphazard orientation
3. Intramural arterial narrowing (fibrotic + medial thickening)
4. Replacement fibrosis (interstitial collagen between disorganized myocytes)

• Diastolic filling halt → reduced stroke volume
• Harsh systolic ejection murmur
• Non-atherosclerotic angina (narrow intramural arteries + massive O2 demand)
• #1 or among the most common cause of SCD in young athletes (intense exertion → catecholamines → worse obstruction → VFib)

• Beta-blockers/calcium channel blockers (negative inotropy → slow rate → improve filling + reduce SAM)
• ICD (prevent SCD)
• Surgical septal myectomy (direct excision of bulging subaortic septum)
• Alcohol septal ablation (ethanol through catheter → controlled septal infarction → scar + shrinkage)

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17. RESTRICTIVE CARDIOMYOPATHY (RCM)

• Ventricles: approximately normal size/thickness (NOT dilated)
• Massive bi-atrial dilation (back-pressure from rigid ventricles rejecting blood)
• Microscopy: patchy or diffuse interstitial fibrosis

• Amyloidosis (misfolded β-pleated sheet protein fibrils squeeze between cells)
• Sarcoidosis (non-caseating granulomas disrupt mechanics and pacing)
• Metabolic/radiation (radiation scars matrix; inborn errors store toxic metabolites)

Specific RCM Subtypes:

• Epidemiology: children/young adults in Africa and tropical regions; most common form of RCM worldwide
• Dense thick fibrosis of ventricular endocardium + subendocardium, starting at apex and creeping upward, trapping tricuspid/mitral valves
• Pathogenesis: nutritional deficiencies + eosinophilic inflammation from parasitic infections → mural thrombi organization → scar

• Produces endomyocardial fibrosis + large layered mural thrombi (morphologically mirrors tropical endomyocardial fibrosis)
• Hallmark: marked peripheral eosinophilia + eosinophilic infiltration of multiple organs
• Mechanism: eosinophils release major basic protein → endomyocardial necrosis → thrombus → organized fibrosis
• Neoplastic link: many patients have myeloproliferative neoplasm with PDGFR-α or PDGFR-β gene fusions (constitutively activated tyrosine kinases)
• Treatment: imatinib (tyrosine kinase inhibitor) → hematologic remission + clears cardiac lesions

• Epidemiology: almost exclusively first 2 years of life; 1/3 have LVOT anomalies
• Diffuse, pearly-white fibroelastic thickening lining the LV endocardium
• Pathogenesis: intrauterine viral infections (mumps) OR mutations in Tafazzin (TAZ) gene (mitochondrial inner membrane integrity)
• Causes rapid progressive cardiac failure and death

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18. CARDIAC AMYLOIDOSIS

1. Systemic amyloidosis (AL/AA): clonal plasma cell dyscrasias or chronic inflammation → aggressive, poor prognosis
2. Transthyretin amyloidosis (ATTR):
   • Wild-type (wtATTR) / "Senile cardiac amyloidosis": elderly (>70 years); slow course, better prognosis
   • Mutant/Hereditary (hATTR): Val122Ile variant in 4% of African Americans; autosomal dominant familial transthyretin amyloidosis targeting the heart

• "Rubbery" heart: wall consistency varies from normal to firm and rigid
• Normal or slightly dilated chambers with marked symmetric wall thickening (mimics concentric hypertrophy)
• "Wax drip" sign: semitranslucent glistening nodules on LA endocardial surface (melted candle wax appearance)

• Amorphous, hyaline, pale eosinophilic extracellular deposits across all layers (interstitium, valves, endocardium, pericardium, conduction tissue)
• Small-vessel disease: amyloid packs walls of intramural arteries → lumen compression → ischemia (independent of epicardial CAD)

• Conduction tissue: AV node/Bundle of His → complex arrhythmias/heart blocks
• Valvular: fibril pooling in leaflet fibrosa → mimics degenerative stenosis/insufficiency
• Microvascular: infiltration of intramural vessels → ischemia + exertional angina

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19. MYOCARDITIS

• Primary pathogens: Coxsackie A and B + other enteroviruses; also CMV, Influenza, HIV
• Dual mechanism: (1) direct cytopathic viral lysis; (2) immune cross-fire (T cells/macrophages killing infected myocytes)
• Cytokine dysregulation can cause cardiac dysfunction wildly disproportionate to actual myocyte death

• Chagas disease (T. cruzi): endemic South America; affects most infected individuals; 10% die acutely; others develop chronic immune-mediated HF over 10-20 years
• Lyme carditis (B. burgdorferi): ~5% of Lyme patients; self-limited conduction block; may require temporary pacemaker
• Diphtheritic toxemia (C. diphtheriae): bacteria remain pharyngeal; diphtheria toxin released into bloodstream → direct myocyte necrosis
• Trichinosis (Trichinella spiralis): most common helminthic disease causing myocarditis
• AIDS-associated: HIV direct infection, opportunistic infections (toxoplasmosis), or idiopathic

• Drug hypersensitivity: sulfonamides, methyldopa
• Immune checkpoint inhibitor (ICI) cardiotoxicity: critical modern oncology complication; T-cell activation against cancer → hyper-acute, often fatal lymphocytic myocarditis
• Systemic autoimmunity: SLE, sarcoidosis
• Giant cell myocarditis: aggressive, idiopathic, lethal; suspected autoimmune

• Normal OR progressive chamber dilation (fulminant: flabby, soft ventricular myocardium)
• Mottled surface: pale necrotic foci + dark red hemorrhagic lesions
• Mural thrombi from stagnant wall kinetics

• Asymptomatic + total recovery (most common)
• Great MI mimic: precordial pain + fever + dyspnea + tachycardia
• Late DCM: failure to clear chronic inflammation → progressive fibrosis → DCM
• Fulminant crash: refractory CHF + malignant arrhythmias → SCD

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20. CARDIOTOXIC DRUGS & RADIATION-INDUCED DISEASE

A. Anthracycline Cardiotoxicity:

• Agents: doxorubicin and daunorubicin (most notorious)
• Result: irreversible cardiomyocyte damage → classic DCM phenotype + progressive CHF
• Dose-dependent: exponential risk above cumulative lifetime dose of 250 mg/m²

• Myofiber swelling (excess fluid + sarcomere stretching)
• Cytoplasmic vacuolization (intracellular clear spaces)
• Fatty change (broken lipid metabolism)
• If detected early + drug stopped: changes often reverse without permanent scarring
• If prolonged: extensive myocyte death → irreversible chronic DCM

B. Radiation-Induced Cardiac Disease:

• Context: thoracic radiation (Hodgkin lymphoma, breast cancer, lung malignancies)
• Mechanism: ionizing radiation → burst of toxic free radicals → slice cellular membranes + DNA
• Chronic fibrotic cascade targeting all cardiac structures

1. Coronary artery trunks → accelerated atherosclerosis (direct endothelial radiation injury)
2. Valvular apparatus → severe rigid valvular stenosis
3. Myocardial interstitium → thick collagen scars → restrictive cardiomyopathy (RCM)
4. Pericardium → visceral + parietal layers fuse → pericardial constriction

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21. PERICARDIAL DISEASE

Pericardial Effusion & Hemopericardium

• Chronic slow effusion: can scale up to 500+ mL (pericardium has time to stretch) → globular "water-bottle heart" on X-ray; minimal pump compromise
• Acute rapid effusion: as little as 200-300 mL → cardiac tamponade

1. Ruptured MI (3-7 days post-MI, transmural necrosis → ventricular free wall rupture)
2. Aortic dissection (ascending aorta tear → retrograde blood through aortic root)
3. Penetrating thoracic trauma

Acute Pericarditis - Four Histopathological Patterns:

• Drivers: non-infectious conditions (RF, SLE, scleroderma, uremia, adjacent malignancy)
• Also: viral upper respiratory infections; concurrent myocarditis in young adults
• Histology: mild lymphocytic infiltrate in epipericardial fat
• Rarely organizes into permanent adhesions

• Fibrous exudate + serous fluid
• Causes: Early post-MI (1-3 days; transmural necrosis leaks cytokines), Dressler syndrome (autoimmune, weeks after MI), uremia, post-cardiotomy, blunt trauma, SLE, thoracic radiation
• "Bread and butter" appearance: shaggy fibrin strands on visceral/parietal layers
• Clinical triad: (1) sharp pleuritic chest pain (worsens supine, relieves leaning forward), (2) fever, (3) pericardial friction rub
• Paradox: large fluid volume separates layers → rub disappears

• Frank pus (up to 500 mL) from high-virulence infection
• Vectors: direct extension (empyema, pneumonia, ring abscess), hematogenous seeding, surgical contamination
• Histology: dense neutrophils + bacteria; can track into mediastinum (mediastinopericarditis)
• Course: complete resolution is rare → usually organizes into constrictive fibrous sheets

• Blood + fibrinous/purulent fluid
• Most common cause: metastatic malignancy (pericardiocentesis → cytology reveals malignant cells)
• Other causes: severe bacterial infections, TB, bleeding disorders, post-surgical bleeding
• Risk: rapid blood loss + sudden cardiac tamponade

Chronic/Healed Pericardial Disease:

• Soldiers' Plaque: smooth pearl-white fibrous thickenings; clinically silent
• Adhesive pericarditis: fine mesh-like adhesions obliterating pericardial cavity; rarely impairs function

• After purulent infection, open-heart surgery, or mediastinal radiation
• Pericardial cavity obliterated + parietal pericardium fused to chest wall/pleura/diaphragm
• Systolic drag: heart tethered; each contraction pulls rib cage + diaphragm
• Signs: visible systolic retraction of rib cage + diaphragm; pulsus paradoxus
• Results in cardiac hypertrophy + dilation from increased workload

• Heart encased in rigid thick fibrous/fibrocalcific shell (up to 1 cm thick)
• Ventricles CAN contract during systole but CANNOT expand during diastole → filling completely blocked
• Concretio cordis: extensive calcification turns scar into hard white plaster mold encasing heart
• Fixed output trap: cannot increase output with exercise or increased venous return
• No cardiac hypertrophy possible (rigid shell confines muscle mass)
• Signs: muffled heart sounds, markedly elevated JVP, peripheral edema
• Treatment: surgical pericardiectomy

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22. CARDIAC TUMORS

Primary Benign Tumors (90% of all primary cardiac neoplasms):

A. Cardiac Myxoma (Most common primary cardiac tumor in adults)

• Origin: primitive multipotent mesenchymal cells of endocardium

• Sporadic majority (no consistent cytogenetic alterations)
• Familial: McCune-Albright syndrome (activating GNAS1 mutations = Gsα protein)
• Carney Complex (null PRKAR1A mutations = regulatory subunit of cAMP-dependent protein kinase)

• 90% in atria; left:right ratio 4:1
• Most common site: margin of fossa ovalis (interatrial septal wall)

• Solitary; variable size (<1 cm to >10 cm)
• Two configurations: (1) sessile (broad-based, hard, globular, hemorrhagic mottling); (2) pedunculated (slender stalk, soft, translucent, villous, gelatinous)
• Microscopy: globular or stellate myxoma cells in pale blue acid mucopolysaccharide ground substance; primitive vessel-like/gland-like structures; mononuclear inflammation + old hemorrhage

• During diastolic filling, gravity-dependent mass swings forward on stalk → plugs mitral valve opening
• Position-dependent syncope + dyspnea + classic diastolic "tumor plop" sound

1. Ball-valve mitral obstruction
2. Systemic embolization (friable villous fingers fragment → stroke/limb ischemia in young patients)
3. Constitutional syndrome: fever + malaise + weight loss from tumor secretion of IL-6

B. Papillary Fibroelastoma (Most common primary tumor of cardiac valves)

• Gross: small nodules (dry state); in fluid → distinctive multi-fronded "sea anemone" appearance
• Morphologically resembles Lambl excrescences, but clonal cytogenetic abnormalities confirm true neoplasm
• Anatomy: >80% on cardiac valves; semilunar valves (aortic/pulmonary) → ventricular surfaces; AV valves (mitral/tricuspid) → atrial surfaces
• Size: 1-2 cm; hair-like projections up to 1 cm
• Histology: surface endothelium layer + inner myxoid connective tissue rich in elastic fibers
• Clinical danger: delicate fronds → platelet aggregation → systemic thromboembolism → MI, stroke, or sudden death

C. Cardiac Rhabdomyoma (Most common primary tumor of pediatric heart)

• Discovered in first years of life; presents with unexplained murmur/mechanical blockage/outflow obstruction
• Many may be congenital hamartomas (spontaneous regression as child grows)

• 50% sporadic; 50% linked to tuberous sclerosis (mutations in TSC1/hamartin or TSC2/tuberin)
• Loss of TSC1/TSC2 → unconstrained mTOR activation → massive myocyte overgrowth

• Gross: firm, gray-white myocardial masses; typically multiple; ventricular wall preference (not atrial like myxoma)
• Microscopy: massively enlarged, glycogen-stuffed cardiomyocytes
• "Spider cell": standard histologic processing dissolves glycogen → thin web-like strands of structural protein stretching from nucleus to membrane (spider sitting in web)

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23. METASTATIC NEOPLASMS OF THE HEART

• Carcinomas: lung, breast
• Hematologic: leukemias, lymphomas
• Cutaneous: melanomas

1. Retrograde lymphatics (carcinomas via mediastinal channels)
2. Hematogenous seeding (highly vascular tumors e.g., melanoma)
3. Direct extension from intrathoracic tumors

1. Pericardial spread: most common cause of symptomatic cardiac metastases; large bloody hemorrhagic effusions → cardiac tamponade
2. Myocardial metastases: usually clinically silent; compromises contractility/compliance; if near pacing nodes → arrhythmias

• SVC syndrome: bronchogenic carcinoma or malignant lymphoma massively infiltrates mediastinum → encases/compresses/invades SVC → obstructs blood draining from head, neck, upper extremities
• IVC/RA plugging: Renal Cell Carcinoma (RCC) invades renal vein → grows as solid column up IVC → protrudes into RA → plugs right-sided inflow tract

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24. CARDIAC TRANSPLANTATION & ALLOGRAFT PATHOLOGY

1. Effective immunosuppression: calcineurin inhibitors (cyclosporine, tacrolimus) + mTOR inhibitors + glucocorticoids
2. Rigorous candidate selection: size, blood type, antibody screening
3. Endomyocardial biopsy surveillance: routine right ventricular septal biopsies - only reliable mechanism to diagnose acute rejection BEFORE irreversible injury

Acute Rejection Archetypes:

• Mechanism: host T-lymphocytes infiltrate donor organ
• Histology: dense interstitial lymphocytic inflammation + myocyte necrosis/apoptosis (mimics acute viral myocarditis)
• Secondary: interstitial edema; cytokines can stun contractility without visible structural dropout

• Mechanism: donor-specific antibodies (against donor MHC proteins) activate complement cascade → endothelial injury
• Histology: subtle perivascular edema + inflammatory cells adherent to capillaries
• Diagnostic anchor: C4d immunohistochemistry - C4d is a stable catabolic fragment of complement permanently gluing itself to damaged capillary endothelium

Allograft Vasculopathy (Most important long-term limitation):

• Timeline: 50% at 5 years; virtually 100% at 10 years
• Pathogenesis: chronic low-grade immune responses → growth factor production → massive intimal smooth muscle cell proliferation + ECM synthesis
• Pattern: diffuse, concentric, uniform intimal thickening throughout entire coronary tree (vs. conventional CAD: focal, eccentric, localized plaques in proximal arteries)
• Silent infarction danger: transplanted heart is permanently denervated (surgical severance); patients CANNOT feel angina → silent MIs, progressive CHF, or SCD without warning pain

• Opportunistic infections (unusual bacterial/fungal/viral pathogens)
• Post-transplant malignancies: EBV-associated B-cell lymphomas (PTLD) - T-cell suppression eliminates surveillance against EBV-infected B-lymphocytes

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