Pathology: The Heart

Overview of Cardiac Pathology ............................................................................................................................................... 2

Myocardial Infarction: (pathophysiology & pathology) .......................................................................................................... 5
Pathology of Heart Muscle Disease ...................................................................................................................................... 13
Pathology of Heart Valves ..................................................................................................................................................... 17
Artificial Valves...................................................................................................................................................................... 22

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 Overview of Cardiac Pathology
Heart: two pumps PARTS OF THE HEART
1. bodyIVC/SVCRAtricuspid valve RV pulm valve  pulm artery  lungs (THAT GET DISEASE)
2. lungs pulm vein LAmitral valveLVaortic valveaortabody
1. coronary arteries*
2. valves
Coronary Arteries 3. conducting system
Normal Physiology 4. myocardium

2 main coronary arteries exit from aorta just above aortic valve (backflow pushes in) * most common
CA Major Branches Supplies
LAD: Left anterior descending LAD¨50% LV
Left main CA 70% LV
LCX: Left circumflex LCX: 20% / posterior LV
Right CA RV & 30% LV

Dominance: whoever gives rise to PDA (posterior descending) and PLA (posterior lateral) is “dominant”
 Right-dominant: RCA (70-80% hearts)
 Left-dominant: LCA (10%)
 Co-dominant: shared (10-20%)

Venous drainage via bunch of veins into great cardiac vein

Coronary Artery Disease

 Most common disease of heart
o 13.7M Americans, M>F, ↑ with older populations

“Atherosclerotic changes in arteries affecting blood flow to myocardium”

TX: SEVERE STENOSIS
 Narrowing of CA = CAD  ↓ oxygen, nutrients  ischemia 1. stents to open up
o Angina & sudden death (massive MI) can result the lumen wider
2. CABG (saphenous
If sudden (thromboembolus trapped in CA or dissection)  MI vein or internal
 ↓Blood flow distal to blockages mammary
 Which CA tells you where infarction happens (& vice versa) arteries) to bring
blood distal to
If gradual narrowing: blockage
 Collateral circulation can develop
 Compensatory Enlargement: vessel gets bigger to keep lumen size the
same (up to 40-50% obstruction!)

Heart Valves
Normal Physiology
 Tricuspid(RA/RV)
 Pulmonic (RV/PA)
 Mitral (LA/LV, 2 leaflets, others 3)
 Aortic (LV/aorta)

Valve  chordae tendinae to papillary mm, etc.

Thin, mobile pieces of tissue

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Valvular Disease
 Congenital (e.g. bicuspid aortic valve, most common, in 1-2% population) and acquired
 Most significant disease is LEFT SIDE (mitral /aortic)

Stenosis: thickening and calcification of valve

 Calcification/degenerative aortic stenosis most common in elderly (also HTN, smoking, males)
 Mitral stenosis often from rheumatic fever (young people!)

Regurgitation: blood flows in reverse through incompetent valve (aortic root dilation, floppy mitral valve changes)

Endocarditis: non-infectious or infectious (bacterial/fungal); plaques & vegetations can cause 2 problems:
 impact valve function
 risk to embolize (block artery  stroke) & seed infection

Tx by replacement
 mechanical: bileaflet used more often today; last longer but have to use antiplatelet drugs
 bioprosthetic: e.g. part porcine or bovine; don’t last as long but no anticoagulant therapy needed

Conducting System

Normal Physiology

SA Node  AV Node  bundle of His  Purkinje fibers

 SA & AV nodes are specialized myocardium
 Can use artery to SA node as clue to ID on path

Arrythmias (conducting system disease)

 Electrical conductance disturbance in heart
o E.g. Atrial fib, ventricular fib, blocks (blockage of electrical pulse)
 Can be benign or rapidly fatal
Tx:
 Pacemaker: electrical stim; pace the heart
 Automatic implantable cardioverter/defibrillator (AICD): electrical jolt ends arrhythmia; back to normal rhythm

Myocardium
Normal Physiology Dimensions
Heart weight F: 200-300 g
 Myocytes need lots of nutrients M: 230-420 g
 Endocardium: endothelial cells LV thickness 1.0-1.4 cm
RV thickness 0.3-0.5 cm

Myocardial Disease: Cardiomyopathies, Myocarditis, Ischemic Injury

Cardiomyopathies: 5 types, many are familial / genetic

 Dilated CM is most common (wide LV, can’t squeeze it closed
enough, turbulent flow  thrombus possibility)
 Hypertrophic CM: see myocyte disarray on path; often genetic (thick walls, esp. septum)
 Restrictive CM: usually secondary to infiltrative process (amyloid, sarcoidosis), more rare

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Myocarditis: most often after viral infection (coxsackie B virus);
 can also be parasitic (Chagas dz; not in USA) or idiopathic (Giant
cell; deadly)
 Results in poor contractility (lower ejection fraction)
 Paradoxical outcome: typical myocarditis  often have
sequelae; fulminant myocarditis  often do very well

Myocardial infarctions: result from ischemic injury to he heart

 Often secondary to CA occlusion; more rarely general
hypotension or anemia
 Myocytes die: lack of oxygen & nutrient supply
o Acute: sudden death of myocytes; replaced with yellow
pus / PMNs, then Mϕ  Heals, collagen scar forms, Cardiomyopathies
other side thickens to compensate
 Histology: see contraction bands from post-infusion reperfusion injury; big scar / fibroblasts lay down collagen

Cardiac transplant
Used in treatment of heart failure (secondary to many of these processes)
 If heart can’t pump blood to lungs/body effectively Cardiac Transplant Facts
 Indications: Heart failure with marked
Failure of transplanted hearts: limitations or bed rest (NYHA class III/IV)
 Often from transplant vasculopathy (coronary vessels narrowed)  10-20/yr at JHH
o different from atherosclerotic CA dz: diffuse process / no  50% chance of 10 yr survival
way to do bypass  Most transplant failures due to:
o Rejection (short-term)
o Transplant vasculopathy (long-term)

Remember that all of these processes work together!

 Concurrent CA dz & calcific aortic stenosis (share risk factors)
 Can cause one another secondarily (examples):
o Aortic stenosis  increased LV pressure  2° hypertrophy of ventricular wall
o Recover from MI  thin scar where myocardium was  2° dilation (dilated cardiomyopathy)
o MI  arrhythmia (destroy part of conducting system) + valvular dz (papillary mm injured)

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 Myocardial Infarction: (pathophysiology & pathology)

ISCHEMIA
 Temporary imbalance: myocardial O2 supply & demands
 Complete reversibility of derangements
o cell metabolism, electrical, contractile
 “stunned myocardium”, full recovery can take weeks
INFARCTION
 Happens when ischemia is severe enough and for long enough time
 Myocyte death
 Irreversible derangements (cellular, electrical, contractile)

TIME IS MUSCLE: the amount of salvageable myocardium ↓ rapidly after occlusion!

Pathophysiology of “acute coronary syndromes”: KNOW THIS

1. Rupture of “vulnerable” atherosclerotic plaque
2. Exposure of subendothelial matrix
3. Platelet adhesion / activation / aggregation
4. Intraluminal thrombus
5. Total or subtotal occlusion

WHAT PREDISPOSES A PLAQUE TO RUPTURE?

INTRINSIC PROPERTIES OF LESION
 Large, soft atheromatous core
 Thin fibrous cap (especially “shoulder”)
 Cap inflammation (activated Mϕ)
 Most often MILD-MODERATE severity/stenosis
EXTRINSIC TRIGGERS
 Circumferential wall stress (HTN)
 Sympathetic surge (↑MI in morning, winter with
shoveling, emotional stress, vigorous exercise)
 Thrombotic risk factors

Approach to the Patient with Ischemic Discomfort

Vast majority of patients with acute coronary syndrome present with chest pressure / pain

Workup: Working Dx  ECG, look for cardiac biomarkers  final Dx

 ST depression:Unstable Angina, Non-ST-elevation MI (NSTEMI)
 ST Elevation MI: most emergent (others urgent too)
o Represents acute total CA occlusion
 Looking at anterior leads (V2-V4)

Anterior ST segment elevation Anterior ST segment depression

Unstable Angina (no biomarkers)
STEMI (biomarkers present)
NSTEMI (biomarkers present)

Etiologies of MI
 Coronary thrombosis: the primary cause of MI
 Coronary artery embolus: most often from heart
 Coronary vasospasm (Prinzmetal’s angina): vasoconstriction, will totally resolve with nitrates to vasodilate!
 Ao Dxn (with coronary artery obstruction)
 Coronary arteritis (inflammation)
 Congenital coronary artery anomalies
 Severe, prolonged hypotension

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 Pathology of MI
 Yellowish eccentric atherosclerotic plaque; can still have big lumen with no symptoms

Thrombosis:
 Superficial thrombosis with endothelial erosion (turbulence & exposed substrate for
thrombosis; thrombus forms on surface of lumen)
 Deep thrombosis with plaque disruption (rupture of plaque, blood hemorrhages
underneath to find substrate; plaque disrupted & pushes cap out into lumen)
 Some can do both (push up from underneath & thrombus forms on surface as well)

The longitudinal view

 Downstream from plaque is where blockage often occurs
 Thrombus forms after plaque (where turbulence is)
 Cholesterol deposits there too (swept downstream)

Ischemic Heart Disease: Reversible & Irreversible Injury

 If you reperfuse within 15m in animal studies: all reversible

 After that, longer occlusion  less reversal (bigger infarct) METABOLIC EFFECTS OF MYOCARDIAL ISCHEMIA
 ↓ O2 and substrate delivery
Impaired O2 / Substrate Delivery  ↓ removal of endproducts
 Can’t generate ATP via ox-phos  switch to anaerobic glycolysis  Electrolyte imbalances
 Glycogen gets used up
 Creatine phosphate (CP) and ATP fall (ATP used up, then CP gives up its phosphates to ATP)  PPi increases

Decreased Removal of Endproducts This process is really fast

 Lactate accumulation Big changes in first few seconds!
 Decreased intracellular pH: lactic acid ↑  CP drops first; ATP more slowly
(CP replenishes ATP at first)
Functional manifestations of ischemia  Lactate rises over next few hours
 ATP is about 2/3 gone at 15 min
 Rapid loss of contractility
(point of irreversible change – so
 Contractile dysfunction persists during you can lose a lot of ATP and still
reperfusion; slowly reversible (“stunning”) reverse changes)
 If only part of heart is affected: can see a loss of
segment shortening (“shortening” actually goes negative during systole - expansion!)
o Means that that part of heart is bulging out because of the pressure the rest of the heart’s generating
o Gradually restored over next few days (slow)

Electrolyte imbalances: stuff flows down its gradient

 K+ flows out (decreased membrane potential)
 Na+ flows in (↑[Na+]in)
 Ca+2 flows in (↑[Ca+2]in)

Notes on the picture to the right: remember ↓ATP


+2
Can’t sequester Ca in SR: no ATP!
 Can’t maintain Na/K gradients (no ATP for Na/K ATPase)
 Lactic acid building up inside: more H+ inside, so more Na co-
transported in to get rid of the H (further disruption)
 Normally Ca influx triggers release from SR on each beat; this
whole process is now disrupted because of these imbalance

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  pH↓ with time (lactic acid building up)
 K+↑ (efflux from cells), then plateaus
o then ↑ again (cells starting to die, release more K+)

Cells start to swell:

 Na+ flows in, Cl- comes along, H2O follows
 Tissue osmolality ↑ (catabolism within ischemic cells  ↑ # stuff)

Morphologic changes in myocardial ischemia:

histological changes subtle, not too useful, cell swelling & chromatin margination but not useful or reliable for diagnosis)

Ischemic Heart Disease (reversible  irreversible injury / MI)

Earliest morphologic changes best on electron microscopy

 look for cell death (blebbing of sarcolemma, disruption of plasma membrane)
 Cytoskeletal damage: disruption of attachment complexes between Z-bands and plasma membranes
o PMs lift up off of Z-bands & form vesicles
 Mitochondrial changes: “amorphous matrix densities” (black blobs in mito) & calcium deposits (donut shaped)

Reperfusion: contraction-band necrosis

 At edge of infarcts or where they’ve been reperfused
 Ischemic myocytes that just made transition to irreversible injury
o Hypercontract when re-exposed to oxygen
o Calcium rises, cell contracts but can’t relapse
o Form contraction bands (proteins of lots of sarcomeres
compacted into single bands)

Dx of MI
1. Symptoms:
 “Typical” chest pain (substernal  neck/jaw, etc, worse on
exercise, etc., etc.)
 Also syncope, dyspnea, orthopnea (SOB on laying down), cough

2. EKG changes: ST elevation or depression

3. Release of cardiac-specific proteins

 Creatine kinase (CK, MB is myocardial-specific isotype)
 Troponin I or T (TnI/TnT; depends on hospital)

 TIME COURSE OF CHANGES (important!)

Note that liver enzymes (LDH / AST) can also rise in MI

(nonspecific for MI, but if you see it, don’t assume pt’s liver is bad)

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  Total CK and CK-MB peak early (first 48 hrs)
o draw multiple times early in hosp to capture

 Troponin takes longer to return to normal

 If you REPERFUSE, enzymes PEAK HIGHER AND EARLIER

Anatomy of Myocardial Infarction

CA INFARCT COMPLICATIONS
 Shock
 Anterior
LAD  BBB
 Septum
 VSD
Posterior papillary
LCX Lateral
muscle rupture  MR
 Posterior papillary
 Inferior
muscle rupture  MR
Right  Right
 AV block
Ventricle
 VSD

BBB=bundle branch block, VSD = ventral septal defect, MR =

mitral regurgitation, LAD = left anterior descending,
LCX = left circumflex

Anatomy & Prognosis

Prognosis is inversely related to infarct size
 Bigger infarct: ↑ arrhythmias, ↑ hemodynamic complications, ↑ short-term mortality
 Cardiogenic shock: associated with > 30% LV infarction

What determines MI Size?

 Duration of coronary occlusion
 Size of territory that CA supplies (LAD = “widowmaker”)
 Presence / absence of collaterals
 Myocardial oxygen demands (↑HR, BP, contractility can make MI larger!)

Collaterals:
 normally not too many / tiny in everybody
o if you have gradual stenosis of CA (e.g. long-term angina) you can develop collaterals (protective!)
o Can have virtually complete occlusion with collateral: but occlude second artery  massive MI
 Collateral flow highest in outer layer of myocardium
o If enough collateral flow: won’t get a transmural infarct regardless of duration!

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 Morphologic Stages of MI (Inflammatory Response & Repair)

RESPONSE & REPAIR (WITHOUT REPERFUSION)

0-6 hrs No changes (gross/microscopic)
Endocardium on right, then intact myocytes
(oxygen can diffuse in to a limited extent), and
Coagulative necrosis starts then necrotic, hypereosinophilic region of
6-24 hrs  Cytoplasmic eosinophilia myocytes (where the vessels are); karyolitic +
 Nuclear karyolysis (no nuclei!) maybe starting to see some PMNs in blood
vessel

Anucleate myocytes (karyolysis) with tons of

PMNs
acute inflammatory response (+ coagulative necrosis)
1-4 days
 Lots of PMNs  die & disintegrate by 3-4d

5-7 days Mϕ activity: clean up dead myocytes & PMNs

Right side have nuclei (OK); granulation tissue
forming in middle, cells on left side are dead /
Granulation tissue around rim karyolitic. Blood vessels start to form (tons of
7-10 days capillaries in middle granulation area).
(fibroblasts  collagen, PMNs, capillary formation)

1-6 wks Organization of infarct

1-3 mo Collagen deposition (scar)

Aneurysmal Thinning: when a scar forms after a transmural infarct, the previously infracted
area can become very thin: predispose to aneurysm in that area

Reperfusion: speeds things up

 Accelerates disintegration of irreversibly-injured myocytes (contraction-band necrosis)
 Can accentuate hemorrhage into areas of microvascular injury (hemorrhagic infarct)
 May or may not cause lethal reperfusion injury
 Limits size of MI
 Supports slow metabolic and contractile recovery of viable myocytes

Reperfusion Therapy:
1. Thrombolytics
2. Mechanical (Stent and/or balloon angioplasty, usually both) reperfusion

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Remember: TIME IS MUSCLE with reperfusion therapy
 Wait 0-1 hours: save 35 extra lives per 1000 patients
 Wait 2-3h: save 25
 Wait 13-24h: only save 5 (big drop)

Consequences of Acute Myocardial Infarction

1. L/R ventricular dysfunction
2. Mural thrombosis  systemic embolism Morbidity & Mortality of MI
3. Arrythmias (mess up wiring)  In-hospital mortality: 7%
4. Mechanical complications (rarer but most feared)  One year mortality: 35%
a) Free wall rupture (hemopericardium; burst through wall  Arrythmias = 40-50% deaths
of heart  blood into pericardium)  Pump failure = 40-45% deaths
b) Papillary muscle rupture  mitral regurgitation o Cardiogenic shock
o CHF (20% of pts who survive MI)
c) Septal rupture  VSD

Killip class: can be used to grade (no heart failure = I, cardiogenic shock = IV): worse outcome with ↑ class

Mural thrombus
LV aneuyrism & thrombus: need a large transmural infarct
1. Infarct thins, elongates (expansion)  LV volume ↑, EF↓, heart failure
2. LV remodeling can be prevented (reduce infarction size, restore patency, reduce afterload with ACE inhibitors)
3. Can be nidus for thrombus formation (dilation  stasis)  embolization

Arrhythmias
Arrythmia Characteristics Treatment
Ventricular premature beats (VPBs) Common None
Accelerated idioventricular rhythm (AIVRs) Common with reperfusion None
Ventricular tachycardia / fibrillation (VT/VF) Cause of sudden death Shock
Drugs
Block 1,2,3°, can be permanent or temporary ± Pacer

Mechanical complications
1. Free wall rupture (hemopericardium; burst through wall of heart  blood into pericardium)
a. Usually fatal: hemopericardium + cardiac tamponade
b. Rarely: leads to pseudoaneurysm
i. Rupture contained by adherent pericardium
ii. See narrow neck / wide body aneuyrism on echo / acth
Treatment of Acute MR
iii. Need urgent cadiac surgery
 Aggressive use of diuretics & inotropes
 Vasodilator therapy
2. Papillary muscle rupture  mitral regurgitation  Intraaortic balloon counterpulsation
a. Can occur with either ST or non-ST segment elevation MI (balloon pump)
b. Usually an inferior MI (posteromedial papillary muscle  Emergent cath to
supplied only by RCA; anterolateral has dual supply) o Confirm dx
c. Causes pulmonary congestion ± hypotension; can o Define anatomy
sometimes be heard as MR (systolic murmur at apex)  Repair/replace with immediate surgery

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 Treatment of VSD (a lot like MR Tx)
3. Septal rupture  VSD, blood flows back into RV instead of aorta  Aggressive use of diuretics & inotropes
a. Anteroseptal or inferior MI  Vasodilator therapy
b. Frequently at first MI (no collaterals)  Intraaortic balloon counterpulsation
c. Causes pulmonary congestion ± hypotension (balloon pump)
d. ± systolic murmur + thrill at L. sternal border)  Emergent cath to
o Confirm dx
o Visualize VSD
o Define anatomy
 Fix with immediate surgery

Balloon pump (intraaortic balloon counterpulsation)

 Insert through femoral artery, snake up aorta.
 Inflate during diastole, relax on systole
o Increases perfusion through CA (push blood out by increasing backpressure against Ao valve)
o Increases blood flow out to other tissues too

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 Pathology of Heart Muscle Disease
Myocarditis
Key feature: Myocarditis Leukocytes Why?
Type of WBC helps you ID the etiology Chagas Dz / T. cruzi T-cell rich mononuclear Intracellular parasite
Coxsackievirus B3 Lymphocitic Virus (or autoimmune after)
Myocarditis: leukocytic infiltration of Rheumatic fever Anitschkow cells Autoimmune post-strep
heart muscle associated with myocyte (weird histiocytes) (won’t see PMNs, etc)
necrosis. (Aschoff bodies too)
Fungal No WBC Seen in immunocompromised pts
(Generally excludes MI-related inflammation) Drugs (cocaine, etc) Eosinophils Hypersensitivity
Various causes: idiopathic, infectious - hypersensitivity
(parasitic, viral, bacterial, fungal),
rheumatic fever (infectious  autoimmune), drugs Clinical features of myocarditis
• Acute presentation:
heart failure, arrhythmia or death
Infectious Myocarditis • ↑ ESR
• Leukocytosis
Chagas’ Disease (trypanosoma cruzi): parasitic • ↓LV function with ↓ EF
 South America: transmitted by reduvid bug
 16-18M infected; 3M have Chagas’ dz of heart Pathologic findings
• Pale, flabby hearts
 See T-cell-rich mononuclear cell infiltrate: parasite • WBC infiltrate + myocyte necrosis
takes over cytoplasm (by definition)
• WBC infiltrate: may be patchy
Coxsackievirus: picornavirus, fecal-oral or resp trans
 Most common cause in USA
 Coxsackievirus B3 is #1
 Biphasic course:
o initially URI / GI illness; sensitization of immune system
o 7-14d later myocarditis (but virus no longer detectable –
IMMUNOLOGIC RESPONSE is to blame)
 Lymphocitic infiltrate + myocyte necrosis

Why does Coxsackie B3 myocarditis happen? Various theories (may all play a role)
1. Immune system overdoes it while trying to kill virally-infected cardiomyocytes
o Lots of proinflammatory cytokines; persistent infiltration (can be detrimental to remote heart areas too)
2. Autoimmune-mediated destruction (molecular mimicry / similar host-viral epitopes)
o May be immune response against self-antigens, or
o maybe virus injures cells, exposing normally hidden antigenic epitopes to immune system (not recognized as “self”)
3. Direct virus-induced cardiomyocyte injury
In any case immune system is key: immunosuppressive therapy can be used to treat viral myocarditis!

Rheumatic Fever:
 Acute, recurrent, multisystem inflammatory disease
 Autoimmune complication: 1-5 wks post-infection with group A strep (pharyngitis)
o (common epitope with cardiac myosin M protein; Ab formed)
o Treat strep pharyngitis to prevent it!
Path features:
 Aschoff bodies (perivascular round / oval foci of fibrinoid necrosis surrounded by lymphocytes and Mϕ)
 Anitschkow cells: weird looking (like little caterpillers) – modified histiocytes

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Fungal myocarditis
 Rare; generally seen in immunocompromised pts
 Aspergillus and cryptococcal infection (candida too)
 NO WBC (because of patient – immunosuppresed!)

L to R in picture: Aspergillus (branching septate hyphae), Candida (yeast &

hyphae), Cryptococcus (capsule)

Hypersensitivity myocarditis
 Various drugs (incl cocaine, e.g. Len Bias)

 EOSINOPHILS predominante: intense infiltrate of cells with bilobed

nuclei & eosinophilic granulated cytoplasm (L picture)

 Cocaine: 14% Americans >12yo have tried at least once!

o Sudden death, myocarditis
o Contraction band necrosis in isolated cells (diffuse in
reperfusion post-MI) (R picture)
 (maybe via microvascular spasm? Cocaine prevents
NE reuptake)

Giant cell myocarditis

 FULMINANT disease
 Serpiginous (snake-like) areas of necrosis;
 Big, multinucleated giant cells at margins
 Contrast to sarcoid: other organs free of granulomatous
inflammation

Cardiomyopathies
Pathology doesn’t help in determining etiology, but genetics can help with prognostication
Dilated Cardiomyopathy:
Clinical features of DCM
 Big, flabby, hypocontracting hearts • Chronic progressive heart failure with ↓LVEF
 Boxcar nuclei (hypertrophy of myocytes themselves) • Arrhythmia, embolic episodes
• Mitral/ tricuspid regurgitation
Presentations • CXR: cardiac enlargement and pulmonary
vascular congestion
Alcoholic cardiomyopathy:
ETOH & acetaldehyde Pathologic findings of DCM
interfere with calcium • Biventricular hypertrophy & 4-chamber
transport; relationship to dilation
cardiomyopathy unknown • Mural thrombi
• Myocyte hypertrophy
Beer drinkers’ • Interstitial fibrosis
cardiomyopathy (Canadians
put cobalt in beer to stabilize head, toxic to heart)
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Peripartum cardiomyopathy:
 onset of CHF in 3rd trimester or 1st 6 mo post-partum
 Risks: multiparity, eclampsia, twins, mom > 30yo, poor nutrition, exact etiology unknown, non-specific biopsy
 Outcome: about 50% pts have heart return to normal size within 6 mo

Andriamycin (doxorubicin) cardiomyopathy

 Intercalating chemotherapeutic agent (anthracycline)
 Dose-related injury; degeneration begins before any clinical abnormality
seen; need to FOLLOW PT with biopsy!
 Classic finding: DILATED SMOOTH ENDOPLASMIC RETICULUM
o (only cardiomyopathy where pathology helps determine
etiology)

Inherited cardiomyopathies: need to take a good FHx‼

 Lamin A/C mutations (one example)
o Type IV IF proteins (between inner nuclear membrane & chromatin)
o Regulate nuclear shape / transcriptional regulation
o Inherited Lamin A/C mutations = 5.9% of all cases of dilated cardiomyopathy!
 (esp. pts with conduction system disease)
o Correlate with survival: worse prognosis!

Hypertrophic Cardiomyopathy:
Clinical features of HCM
 Heavy hypercontracting hearts  Exertional angina
 Dyspnea, fatigue, syncope
 Wide septum (top), myocytes in  Sudden death
disarray (bottom)
Pathologic findings of HCM
 Classic: young athletes! • Asymmetric septal hypertrophy
• Catenoidal configuration to the septum
Genetic mutations are important in HCM • Disarray of the myoctyes
(like in DCM) • Systolic anterior motion of the
anterior leaflet of the mitral valve
β -myosin heavy chain gene • Endomyocardial plaque on the
 1/3 of all HCM outflow tract of the left ventricle
 50% families with HCM have (where MV anterior leaflet keeps
identifiable mutation (can make in bumping against it)
all family members)
 Mutations that change charge of altered AA have shorter survival
 Good prognostic indicator: test family members; take precautions or treat before sudden death occurs

Restrictive Cardiomyopathy:
 LV contracts normally but rigid (ventricle filling is impaired)
 Very rare
 Endomyocardial fibrosis in Africa (fibrosis of ventricular endocardium);
 Lofler’s syndrome (myocyte necrosis + eosinophilic infiltrate)
 Note fibrous ring around LV; RV hypertrophy

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 Infiltrative processes

Amyloid
 Various proteins can be the cause; deposited in tissues & form β-pleated sheets abnormally
 Immunocyte-derived disease (AL): from light chains (from plasma cell disorders!)
 Senile cardiac amyloid: from transthyretin (prealbumin)

Path findings:
 heart is enlarged & firm
 amorphous eosinophilic hyaline deposits in blood vessels / within
interstitium
 stain with Congo red (see picture to right; would see greenish
bands if polarized)

Others:
 hemochromotosis: can get iron deposits in heart
 glycogen storage disease: congenital; myocytes filled with glycogen

Heart transplants
Remember autograft / isograft / allograft / xenograft (diagram)
 Xenograft: risk of transmission of new disease to humans!

Heart transplants: most often performed for CARDIOMYOPATHIES

 ABO match donor / recipient
 5 year survival: > 60%
 Anastamosis of PA, aorta, atria (don’t want to mess with thin
pulmonary veins)
 Immunosuppression afterwards (but can lead to fungal, cryptococcal,
viral infection, etc)

Rejection: by the time it’s clinically apparent, irreversible damage may have
been done to the myocardium – use heart biopsy to detect before Sx start!
 If you see myocarditis starting (e.g. lymphs) – titrate your
immunosuppresion!

Accelerated graft arteriosclerosis is a problem too (after initial complications of rejection, still 50% lose heart by 13yrs)
 diffuse, concentric process, not a localized eccentric plaque like normal atherosclerosis
 Can’t treat with CABG or stent (because it’s not just in one place)

Endomyocardial biopsy
 Allows histologic diagnosis of myocarditis in living patients!
 Serial biopsys  can document natural history of cardiac disease
 Can improve therapy: better response by titrating doses, etc.

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 Pathology of Heart Valves
Normal Valves

Embryology (gasp!) of valve development

 (pulmonic + aortic) and (mitral / tricuspid) start out together
(outflow tracts & AV valves grouped)
 PV/Ao rotate, then both split
 Who cares? Can see defects sometimes in how they segregate & separate
Most severe disease: LEFT SIDE (Ao & MV)

Semi-lunar valves (aortic & pulmonic) – far right, upper

 Nodule of arantius = part of leaflet above line of closure; not a big deal if it
gets damaged (not involved in closing)
 Coronary orifices behind cusps of aortic valve (fill with backpressure
generated in diastole in aortic root)

Mitral valve: right

 2 leaflets (anterior & posterior), etc.

Tricuspid valve - far right, lower

 Chordae tendinae connecting to papillary
muscle, etc.

Normal histology:
 Bland & unremarkable (No
inflammatory cells or blood
vessels)
 Zona spongiosa, zona fibrosa,
zona ventricularis

Normal valve function: one way door

(blood goes in one way only)

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 Stenotic Valve Disease
Stenosis: valve becomes rigid, obstructs blood flow
 Results in severe pressure gradient across the valve

Etiologies: see slide (right)

Aortic Stenosis
 Most common valve to be stenotic

Congenital bicuspid aortic valves (1-2% pop)

 Often stenotic @ 50-60 yo
 Have raphe in middle (valve cusps never separated)

Tricuspid Ao valves can calcify too (60-80yo)

 See big calcifications – obstruct opening
 Histology: see calcifications, no acute inflammation

Bicuspid aortic valve (raphe at top) Calcified tricuspid aortic valve

2 2
Normal valve: 3-4cm , critical stenosis at 0.75 cm

Mitral Stenosis
Post-Rheumatic fever almost exclusively (don’t see too much anymore in US)

Acute rheumatic fever

 Group A strep pharyngitis  rheumatic fever 4-6wks later
o Acute pancarditis (murmurs, rubs, long PR interval)
o Vegetations (gross)
o Aschoff bodies on histology 
(granuloma-type structures with multinucleated cells)

Chronic rheumatic valve disease

 Sequelae of ARF 
 mitral & aortic valve stenosis (30-40yrs)
 ↑collagen & calcification with stiffening of valve

Mitral > Mitral & aortic > Aortic (frequency)

 Classic “fishmouth appearance” for mitral valve
2 2 2
o Nml 4-6cm , Sx @ 2cm , <1cm is critical

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Carcinoid heart disease

From CARCINOID TUMOR of GI TRACT

 Release vasoactive substances
(serotonin, histamine, bradykinin, prostaglandins)

Plaque-like deposits on RIGHT SIDE heart valves

 Tricuspid and pulmonic stenosis
 Lung inactivates vasoactive substances  left side spared

Regurgitant valve disease

 Valve becomes “two way door”
 Blood flows backwards because of valvular insufficiency
1. Valve leaflet dysfunction
2. Root enlargement
3. Leaflet apparatus failure

Aortic Regurgitation

Etiologies: see slide

1. Cusp disease:
normal diameter valve but leaflets have something on them
2. Root enlargement:
enlarged diameter; stretches valve leaflets

Chronic Rheumatic Dz Dilated Aortic Root

Thickening, fusion of 2 leaflets at Very taut cusps; no way this can
bottom right – can’t close close completely

Mitral Regurgitation

Etiologies:
1. Cusp disease
2. Ring abnormalities (dilated or rigid)
3. Chordae Tendineae
(short vs long/broken)
4. Papillary muscle injury (MI, CM)

Note: MV prolapse isn’t uncommon in young women, but only some develop true regurgitation / floppy valves

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 Floppy Mitral Valve Myxoid Degeneration Rheumatic Mitral Regurgitation
Floppy cusp (top) won’t make Normal zona fibrosa but myxoid Crazy shortened thickened chordae tendininae,
a good seal (lots of mucousy stuff )mixed in definitely won’t let valve close

Calcific Mitral Annulus Fibrosis

(both sides)

Calcification itself is pretty normal,

but valve can get stuck on it (more
rare, causes regurgitation)

Tricuspid Regurgitation
 Pretty rare
 Can get from old rheumatic fever, carcinoid heart disease, bacterial endocarditis, or dilated annulus (from
right-sided CHF; like MV problems in left CHF)

Endocarditis
The “door stopper” – has two main problems
1. Stops leaflets from closing (regurgitation)
2. Thrombus formation (seeds infection; can embolize)

Non-infectious endocarditis

NBTE (non-bacterial thrombotic endocarditis)

 Thrombotic deposits on line of closure on valve leaflets
 Pts with hypercoagulable state (neoplasia, autoimmune disorders too)
 Organize into “Lambl’s excrescences”- hairy whisker appearance
 Not infectious but can become secondarily infected and/or embolize
o In general, need a damaged valve for infection to set up shop

NBTE Histology:
 Fibrin, platelets, fibroblasts, vegetations
(some Mϕ and Fe too)
 No acute inflammatory cells
(PMNs, etc.) or bacteria

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Libman-Sacks Endocarditis
 4% of patients with lupus (SLE)
 Often doesn’t cause disease

Infectious endocarditis
More common in:
INFECTIOUS CAUSES OF ENDOCARDITIS
 IV drug users (usually RIGHT SIDED)
o shoot up in veins  R heart, hit damaged valve  #1 is STAPH AUREUS
o Others are in left side valves  Viridans group strep, enterococci, coag-
 Pts w/ prosthetic heart valves neg staph, HACEK organisms fungi,
 Pts w/ structural heart disease others (pretty much everything)
 HACEK: common board question, group
Complications: valve dysfunction & thromboemboli of Gram (-)s, grow slowly (watch
culture 2-3 wks)

Gross view: friable (can break off), growing on line of closure (regurgitation)
 Some can actually eat away at valve leaflet (S. aureus)

Histology:
 Large view: see vegetation overlying valve (arrow)
 Ulceration, some normal valve, colonies with acute inflammation
(PMNs, lymphs, etc)

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 Artificial Valves
Bioprosthetic or Mechanical?
Material? Anticoagulants? Lifespan?
Bioprosthetic Bovine, pig valve in prosthetic strut No anticoagulants Limited life / need replacement
Mechanical Carbon alloys Need warfarin Last 20+ years

Mechanical: cage & ball was loud & drove you crazy, Poe-style  tilting disk (leaked)  bileaflet / St. Jude (used today)
 Earlier designed – more turbulence  more thrombus formation

Bioprosthetic: possible to get

endocarditis, etc.

Valvuloplasty:
• Severe mitral (and rarely tricuspid) regurgitation or stenosis

Stenotic? Balloon valvuloplasty

(inflate a balloon in the valve space to “crack” it open)

Regurgitant? Artificial cord replacement and ring annuloplasty

Review questions
1. Which of the following is a major cause of aortic 3. This picture is an example of? (shows picture of big
valvular stenosis? root with taut leaflets)
a. Carcinoid heart disease a. Aortic regurgitation due to root
b. Marfan enlargement
c. Syphilis
d. Calcified congenital bicuspid valve 4. The most common infectious cause of
endocarditis is?
2. What is the order most frequently noted for a. Staph aureus
affected valves by chronic rheumatic valve disease
a. Mitral > mitral & aortic > aortic

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