PATHOLOGY 6020SYLLABUS

CARDIOVASCULARSCHEDULE 2005

December 2 FridayObjectives for Cardiovascular Course 1

10-11:00am HSEB 1730 CHF, CMP, Myocarditis Dr. Clayton 5

December 6 Tuesday11-12:00am HSEB 1730 Valvular Disease and Endocarditis Dr. Urie 11

December 8 Thursday8-9:00am HSEB 17370 Mandatory Olympus & PACS Training Dr. Clayton/Bown

11-12:00pm HSEB 1730 Atherosclerosis and Hypertension Dr. Urie 18

1-3:00pm HSEB 4300 Pathology Laboratory – Clayton/Staff 23Casepath Notes 24

December 12 Monday9-10:00am HSEB 1730 Ischemic Heart Disease Dr. Urie 38

10-11:00am HSEB 1730 Miscellaneous Cardiac Diseases Dr. Urie 45

December 15 Thursday10-12:00pm HSEB 4300 Pathology Laboratory Clayton/Staff 53

Congenital Hearts and Case Presentations

December 16 Friday8:00-11:00am Examination11:00-2:00pm

Be sure to check the web for changes that may have occurred after printing

Pathology 6020 – Year 2005Paul M. Urie, M.D., Ph.D.Frederic Clayton, M.D.December 2005

CARDIOVASCULAR PATHOLOGY

Suggested Reading and Study: This syllabus Webpath cardiovascular sections (Organ System and Lab Exercises) Pathologic Basis of Disease, Ch 11-12, pp. 512-618

OBJECTIVESA. Heart Failure

1. Outline the pathophysiologic mechanisms and cause of congestiveheart failure.

2. Compare and contrast:

"left-sided" and "right-sided" congestive heart failurecor pulmonale and cor bovinumcardiac tamponade and constrictive pericarditis

In terms of: defining featurespathogenesis and most frequent causesclinical manifestationscompensatory mechanismmorphologic finding

3. Compare the following congenital diseases of the great vessels: coarctation of aorta patent ductus arteriosus transposition of the great arteries

In terms of:developmentmajor morphologic featuresmajor alterations in blood flowlikely complicationseffect on arterial blood oxygenation

4. List the morphologic defects and abnormal blood flow patterns in: Tetralogy of Fallot

Transposition of great vessels Eisenmenger's complex

5. Describe forms of symptomatic congenital heart disease most commonly encountered in each of the following age groups:

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birth to two weeks1 month to 1 year10 years to 30 years

6. Describe forms of cyanotic congenital heart disease with and without pulmonary hypertension.

7. Define three syndromes in which congenital heart disease is associated with multiple non-heart congenital anomalies.

8. Describe forms of congenital heart disease manifest in the neonatal period in which adequate systemic perfusion is dependent upon patency of the ductus arteriosus.

B. Rheumatic Heart Disease: Compare acute and chronic stages of rheumatic heart disease:

pathogenesismorphologycomplications including extracardiac lesionspathophysiologysymptoms, signs and laboratory abnormalities

C. Chronic non-effective Valvular Disease: Define non-bacterial thrombotic endocarditis, know its pathogenesis, significance and complications.

D. Infective Valvular Disease: Discuss infective endocarditis in the context of:epidemiology, citing at least four common predisposing factorsorganisms that are responsibleclinical presentationgross appearancecharacteristic histopathology complications and prognosis

E. Miscellaneous Valvular Disease & Endocarditis1. Outline possible etiology and pathophysiology for:

pulmonary insufficiencytricuspid insufficiencyaortic stenosis and insufficiencymitral stenosis and insufficiency

F. Myocarditis and Cardiomyopathy1. Compare myocarditis with cardiomyopathy in terms of causes,

morphology, and diagnostic features.

2. Outline the classification of cardiomyopathies.

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G. Ischemic Heart Disease1. Describe pathogenetic sequences by which coronary

atherosclerosis produces:angina pectorisfatal arrhythmiamyocardial infarctionmyocardial ruptureventricular aneurysmmural thrombosiscongestive heart failurefibrinous pericarditis

In terms of:mechanismtemporal relationshipfrequencyprognosis

H. Myocardial Infarction1. Given a histologic section of infarcted myocardium, date the infarct

from the microscopic appearance.

2. List the tissue and serum enzyme changes in myocardial infarction, indicating when they appear and disappear.

3. Indicate the factors that determine the location and size of a myocardial infarct.

4. Describe the risk factors for myocardial infarction and how they can be modified.

I. Pericardial Disease1. Classify pericarditis according to causes.

2. Describe clinical findings with pericarditis and pericardial effusion.

J. Vasculitis1. Compare:

polyarteritis nodosasystemic lupus erythematosusgiant cell arteritis In terms of:

microscopic featureslaboratory findingssize and type of vessels involved, if anyorgans commonly involvedrelative frequency and prognosis

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2. Describe syphilitic aortitis in terms of:gross and microscopic appearancedistribution of the lesionspredisposing factorsusual clinical presentationcomplications

K. Arteriosclerosis - Clinical Aspects1. Describe the gross and microscopic appearances of the lesions of

atherosclerosis at different stages of development.

2. Discuss at least four predisposing factors in the development ofatherosclerosis in terms of evidence indicating the importance of each.

3. List the usual clinical manifestations of at least four common majorcomplications of atherosclerosis.

4. Compare the effects of aortic, coronary and cerebral arteriosclerosis.

L. Aneurysms1. Define and use in proper context:

true aneurysm false aneurysm mycotic aneurysm dissecting aneurysm

2. Compare thoracic and aortic aneurysms of the aorta by: causes incidence complications

M. Venous Diseases1. Define varicose veins indicating predisposing factors, pathogenesis

and complications.

2. Describe causes and consequences of venous thrombosis andemboli.

N. Cardiac Tumors - Compare and contrast the following neoplasms:hemangioma myxomaangiosarcoma metastatic carcinomaKaposi sarcoma

In terms of:frequency location consequences

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Pathology 6020 - Year 05Frederic Clayton, MDDec. 2, Friday10:00-11:00 am

CONGESTIVE HEART FAILURE, CARDIOMYOPATHY AND MYOCARDITISI. Congestive heart failure

A. Definition - the pathophysiologic state resulting from impaired cardiac function rendering the heart unable to maintain an output sufficient for the metabolic requirements of the tissues and organs of the body.

CHF occurs either because of a decreased myocardial capacity to contract or because an increased pressure-stroke-volume load imposed on the heart.

Systolic dysfunction - deterioration of myocardial contractility

Diastolic dysfunction - insufficient expansion to accommodate ventricular volume

B. Mechanisms of compensation1. Tachycardia

2. Frank-Starling mechanism - increased end-diastolic volume causes increased stroke volume (more venous return increases blood flow)

3. Myocardial hypertrophy - not hyperplasia

4. Catecholamines by the adrenal medulla – increase myocardial contractility

5. Renin-angiotensin-aldosterone system increases blood volume

6. Adrenergic-mediated redistribution of blood flow

7. Increased oxygen extract from hemoglobin

C. Left-sided failure1. Usual causes

a. Ischemic heart disease

b. Hypertension

c. Aortic and mitral valve disease

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d. Myocardial disease

2. Systemic effectsa. Lungs - pulmonary edema and congestion

dyspnea - breathlessness

orthopnea - dyspnea lying down (increased venous return)

paroxysmal nocturnal dyspnea - extreme dyspnea in bed, bordering on suffocation

cough - frothy, blood-tinged sputum

b. Kidneys - reduction in renal perfusion causes ischemic tubular necrosis and prerenal azotemia

c. Brain - cerebral hypoxia - irritability, loss of attention span, restlessness, stupor and coma

D. Right-sided heart failure1. Pathogenesis

a. Pure - cor pulmonale, tricuspid or pulmonic valve lesions

b. Consequence of left-sided failure - mitral stenosis and left-to-right shunts

c. Other - myocarditis, cardiomyopathy, constrictive pericarditis

2. Systemic effectsa. Liver - chronic passive congestion, central

hemorrhagic necrosis, cardiac sclerosis

b. Spleen - congestive splenomegaly

c. Kidneys - congestion and hypoxia

d. Subcutaneous tissue - peripheral edema, anasarca

e. Pleural spaces - effusions

f. Brain - venous congestion and hypoxia

g. Portal system - ascites

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II. MyocarditisA. Clinical significance

Frequency of the disease is unclear – symptoms are nonspecific so diagnosis is often missed. Most cases are probably of viral origin. Symptoms and signs depend on the etiology and severity - vary from sudden congestive heart failure to fatigue, dyspnea, palpitations and fever. ECG may show diffuse ST-T segment changes and chest x-ray may show cardiac dilatation.

B. Classification by etiology1. Viral - Coxsackie A and B, ECHO, influenza, poliomyelitis,

viral hepatitis, EBV, and cytomegalovirus

2. Chlamydia - C. psittaci

3. Rickettsia - R. typhi (typhus fever) and R. tsutsugamushi (scrub typhus)

4. Bacteria - diphtheria, salmonella, TB, strep, meningococcus, leptospira, Borrelia

5. Fungal and protozoa - trypanosoma (Chagas' disease), candida, toxoplasmosis, aspergillus, Blastomyces, cryptococci, and coccidiomycosis

6. Metazoa - echinococcus, trichinella

7. Hypersensitivity - RHD, SLE, systemic sclerosis, drugs

8. Physical agents - radiation, heat stroke

9. Idiopathic - giant cell myocarditis

C. General morphology1. Gross - cardiac dilatation, flabby myocardium with pale

patches of yellow-gray and hemorrhage on the cut surface

2. Microscopic - interstitial inflammatory infiltrate with focal myocyte necrosis and focal fibrosis. Type of infiltrate is suggestive of the etiology.

mononuclear - most types including idiopathic

neutrophils - bacteria

eosinophils - hypersensitivity, protozoa, Metazoa7

D. Specific entities1. Viral - most common etiology of myocarditis and is difficult to

diagnose - rising viral titers and endomyocardial biopsy viral cultures. EM has not been productive. May develop into congestive cardiomyopathy.

2. Bacteria - direct heart invasion with suppurative response.Diphtheria produces an exotoxin which causes myocyte necrosis.

3. Protozoa

Toxoplasmosis (infected soil passed to pets and man) affects young and immunocompromised host (heart transplant patients).

Trypanosoma (Chagas' disease) - passed in the feces of the Reduviidae bugs and penetrate broken skin or intact mucous membranes. Parasitization of myocytes with inflammatory infiltrate and the formation of pseudocysts. Fibrosis and congestive heart failure may be seen.

4. Hypersensitivity reactions - numerous drugs and toxins

5. Giant cell myocarditis - myocyte necrosis with multinucleate giant cells, lymphocytes, plasma cells, macrophages, and neutrophils. Often fulminant with rapid progression to death.

III. Cardiomyopathy - heart muscle disease of unknown etiologyA. Dilated or congestive cardiomyopathy

1. Morphology

Gross - increased weight, dilatation of ventricle, mild endocardial thickening, normal coronary arteries and valves

Microscopic - myocyte hypertrophy with large, bizarre nuclei; myofibrillar loss, and interstitial fibrosis

2. Etiology:

alcoholtoxinsselenium deficiency (Keshan's disease)viralgenetic

3. Clinical significance:

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cardiac failureatrial fibrillation with thrombosis and embolismdeath

B. Hypertrophic cardiomyopathy (IHSS, ASH)1. Morphology

a. Disproportional hypertrophy of ventricular septum (95%)

b. Myofiber disarray (100%)

c. Reduction in the volume of ventricular cavities (90%)

d. Endocardial thickening in the left ventricular outflow tract (75%)

e. Mitral valve thickening (75%)

f. Dilated atria (100%)

g. Abnormal intramural coronary arteries (50%)

2. Etiology - genetic – usually autosomal dominant, occasionally sporadic. Due to mutations of any of several contractile-related proteins.

3. Clinical significance

Symptoms - dizziness, syncope, LV failure, arrhythmias, reduction of cardiac output by obstruction and reduced LV volume, reduced LV compliance, sudden death rate 2-6% per year.

C. Restrictive/infiltrative/obliterative cardiomyopathy - restrict cardiac filling1. Endomyocardial fibrosis – children and young adults in

Africa with fibrosis of one or both ventricles. Subendocardial scarring involving inner third of myocardium. Unknown etiology, might be due to high food serotonin levels.

2. Loeffler's endocarditis - endomyocardial fibrosis, eosinophilic leukocytosis, myocardial necrosis and eosinophilic infiltrate, fibrosis, heart failure.

3. Endocardial fibroelastosis - focal or diffuse fibroelastic thickening of the endocardium without myocardial necrosis. Unknown etiology - hereditary, hypoxic, pressure overload, lymphatic obstruction, or viral.

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4. Infiltrative cardiomyopathies such as amyloidosis and hemochromatosis.

IV. Specific heart muscle diseaseA. Classification

1. Toxic - alcohol, cobalt, catecholamines, Cocaine, Adriamycin

2. Metabolic - hemochromatosis, nutritional deficiency, thyroid disease

3. Neuromuscular disease - Friedreich’s ataxia, muscular dystrophy

4. Storage disease - glycogen, Fabry's disease

5. Infiltrative - sarcoidosis

B. Sarcoidosis - noncaseating granulomata replacing heart muscle and healing with fibrosis (20-30% heart involvement).

C. Hemochromatosis - myocardium and conduction system with heart failure and arrhythmias either primary or secondary.

D. Rheumatoid heart disease - rheumatoid nodules within arteries, valves, myocardium, and pericardium.

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Pathology 6020 - Year 2005Paul M. Urie, MD, PhDDecember 6, Tuesday11:00-12:00 noon

VALVULAR HEART DISEASE AND ENDOCARDITIS

I. Definitions and classificationA. Stenosis - failure of a valve to open completely preventing forward

flow

Regurgitation (insufficiency) - failure of a valve to close completely allowing reverse flow

B. Classification based on etiology1. Aortic stenosis

a. Post-inflammatory scarring - RHD, infective endocarditis

b. Senile calcific aortic stenosis

c. Calcification of congenitally deformed valve

2. Aortic regurgitationa. Post-inflammatory scarring

b. Aortic disease

1. Syphilitic aortitis

2. Ankylosing spondylitis

3. Rheumatoid arthritis

4. Marfan's syndrome

3. Mitral stenosis – post-inflammatory scarring

4. Mitral regurgitationa. Leaflet abnormalities

1. Post-inflammatory scarring or infective endocarditis

2. Floppy mitral valve syndrome

b. Tensor apparatus abnormalities1. Rupture or dysfunction of papillary muscle

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2. Rupture of chordae tendineae

c. LV abnormalities1. LV dilatation

2. Calcification of mitral ring

II. Rheumatic fever and rheumatic heart disease

A. Definition - systemic disease characterized by migratory polyarthritis of the large joints, carditis, erythema marginatum of the skin, subcutaneous nodules, and Sydenham's chorea - a neurologic disorder with involuntary purposeless rapid movements.

B. Revised Jones' criteria for the diagnosis of rheumatic fever1. Major criteria

a. Carditis

b. Polyarthritis

c. Chorea

d. Erythema marginatum

e. Subcutaneous nodules

2. Minor criteriaa. Clinical

1. Previous rheumatic fever or RHD

2. Arthralgia

3. Fever

b. Laboratory1. Acute phase reactions - ESR, C-reactive

protein, leukocytosis

2. Prolonged P-R interval on ECG

3. Supporting evidence of strep infectiona. Increased titer of antistreptolysin O (ASO) and other

strep antibodies

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b. Positive throat culture for group A beta-hemolytic streptococcus weeks prior

c. Recent scarlet fever

C. Epidemiology1. Probability of RF is strongly correlated with severity and

duration or the pharyngitis and the magnitude of the immune response.

2. Risk factors include crowding, cold climates, poor living conditions, and inadequate medical care.

3. Mortality rate in 1940 20.6/100,000 to 2.2/100,000 in 1982

D. Pathogenesis1. Heart valve glycoproteins cross-react with hyaluronate

capsule of streptococci.

2. Cross reactivity is present between cardiac muscle and strep antigens - streptococcal cell wall M proteins.

3. Cytotoxic T lymphocytes sensitized to strep antigens lyse heart cells.

4. Immunoglobulins and complement are fixed to sarcolemmal sheaths of cardiac myocytes and are found in Aschoff bodies.

E. Morphology1. Aschoff body - most distinctive feature found in interstitial

connective tissue either perivascular, subendocardial, or rarely subepicardium and valves

a. Exudative lesion - fibrinoid necrosis

b. Classic proliferative cellular lesion - fibrinoid necrosis, cardiac histiocytes (Anitschkow cell) and plasma cells, lymphocytes, neutrophils and mast cells

c. Progressive fibrosis or healed lesion

2. Cardiac - 50-75% in children 2-16 years and 35% in adultsa. Pericarditis - diffuse fibrinous inflammatory reaction

b. Myocarditis - interstitial connective tissue

c. Endocarditis13

mitral valve 40-50% aortic valve 15-20% mitral and aortic valves 35-40% mitral, aortic, tricuspid 2-3% friable vegetations (verrucae) along lines of closure of

leaflets - fibrinoid necrosis with leukocyte infiltrate leading to fibrous scarring and calcifications

3. Other sites - joints, skin, arteries, lung and pleura

III. Infective endocarditisA. Definition - infection of heart valves, A-V shunts, coarctations of

aorta, mural endocardium and prosthetic heart valves

B. Classification1. Acute

a. Causative agent - Staphylococcus aureus and streptococci are most frequent, Pseudomonas in some with intravenous drug use as a risk; others include: gonococci and coliforms; Candida and Aspergillus in immunocompromised patients.

b. Usually normal hearts; also previous cardiac surgery, immunodeficiency, or immunosuppression.

c. Metastatic foci of infection common

d. Symptoms - high fever, shaking chills, weakness, embolic manifestations

e. Mortality can reach 70% and often results in permanent valve damage

f. Associated with chronic alcoholism and drug addiction

2. Subacutea. Causative agent - Streptococcus viridans group and

Enterococcus

b. Most hearts have underlying cardiac disease

c. Metastatic foci of infection rare

d. Symptoms - progressive weakness, weight loss, fever, anemia, night sweats, splenomegaly

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e. Mortality 10-40%

C. Pathogenesis1. Occurs at sites of alteration of blood flow - jet effect causing

endothelial injury and low pressure sinks favoring deposition of fibrin and clumps of organisms

2. Bacteremia may follow dental, urological manipulations, IV drug abuse or vascular catheters

3. Agglutinating antibodies develop causing clumping of organisms and allowing them to precipitate on valve.

4. Pathogenesis of acute bacterial endocarditis is less clear

D. Morphology1. Sites of involvement - mitral valve 25-30%, aortic valve 25-

35%, tricuspid valve 10%, valve prosthesis 10%, congenital defects 10%

2. Friable, bulky vegetations containing platelets, red cells, fibrin, inflammatory cells, bacteria with neovascularization at the base and occasional fibrosis and calcification

3. Cardiac complicationsa. Coronary artery embolization

b. Abscess formation

c. Erosion or perforation of valve or chordae tendineae

4. Non-cardiac complicationsa. Septic emboli producing splinter hemorrhages of

nails, Osler nodes and Janeway lesions on skin; emboli lodged in arteries may produce mycotic aneurysms.

b. Immune complex deposits - glomerular lesions and vasculitis

IV. Nonbacterial thrombotic endocarditis - marantic endocarditisA. Morphology - sterile, small (1-5 mm) vegetations containing fibrin

and platelets along the line of closure of the aortic or mitral valve leaflets

B. Clinical significance - predisposing conditions include metastatic malignancy, hypercoagulable states, chronic debilitating diseases, and

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endocardial trauma. May become secondarily infected and may be a source of arterial emboli.

V. Nonbacterial verrucous endocarditis (Libman-Sacks disease)Mitral and tricuspid valvulitis with active systemic lupus erythematosus with mucoid pooling, fibrinoid necrosis, and fibrosis within the connective tissue of the valves.

VI. Calcific aortic valve stenosisA. Pathogenesis and morphology - usually follows infective

endocarditis or rheumatic fever but occurs more often in congenital bicuspid valve or in normal valves with advancing age. Fibrosis and calcification obliterate the sinuses of Valsalva and valve leaflets.

B. Clinical significance – critical obstruction is a reduction of valve area by 2/3 or 50 mmHg pressure gradient (<1 cm2 opening). Results in pressure overload, LV hypertrophy and heart failure.

Increased incidence of sudden death.

VII. Calcification of mitral valve annulusIrregular stony hard beading (2-5 mm in thickness) in the mitral valve annulus; often associated with ischemic heart disease.

May narrow lumen and impinge on the conduction system. Elderly individuals, especially women.

VIII. Mitral valve prolapseA. Morphology - excessively large leaflets or excessively long chordae

tendineae; myxomatous change within the valve leaflet usually affects posterior leaflet.

B. Etiology - unknown - Marfan's syndrome, hereditary disorders of connective tissue.

C. Clinical significance - 5-7% of general population most commonly young women; complications include regurgitation, arrhythmias, susceptibility of infective endocarditis and psychiatric manifestations.

IX. Complications of artificial valvesA. Thrombosis/thromboembolism

B. Anticoagulant-related hemorrhage

C. Infective endocarditis16

D. Structural or biologic deterioration (bioprosthesis)

E. Nonstructural dysfunction - tissue entrapment, paravalvular leaks, anemia

X. Phentermine (Fastin) and Fenfluramine (Pondimin) valvular disease.A. Morphology similar to carcinoid valvular disease with fibrous

plaques on valve leaflets, primarily the mitral valve resulting in mitral regurgitation.

B. Treatment is surgical repair or replacement of the valve.

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Pathology 6020 - Year 2005Paul M. Urie, MD, PhD Dec. 8, Friday11:00-12:00 noon

ATHEROSCLEROSIS AND HYPERTENSIONI. Normal Vessels

A. Types of arteriesLarge or elasticMedium or muscularSmall arteriesArterioles

B. Layers of arteriesIntimaMediaAdventitia

II. Arteriosclerosis - hardening of the arteriesAtherosclerosis

Mönckeberg’s medial calcific sclerosis

Arteriolosclerosis

A. Atherosclerosis1. Risk factors

a. Major

Diet and hyperlipidemiaHypertensionCigarette smokingDiabetes

b. Minor

ObesityPhysical inactivityMale genderIncreasing ageFamily historyHigh carbohydrate intakeHyperhomocysteinemia

2. Morphology

a. Fatty streak18

b. Atheromatous plaque - fibrous plaque, fibrolipid and fibrofatty

Cellular component - smooth muscle, macrophages, leukocytes

Connective tissue extracellular matrix component

Intracellular and extracellular lipid component

c. Complicated lesion

1. dystrophic calcification within media or plaque

2. ulceration with rupture and cholesterol emboli

3. superimposed thrombosis with vascular occlusion

4. hemorrhage into the plaque

5. atrophy of media and loss of elastic tissue with aneurysmal dilatation

3. Theories of pathogenesis:

Response-to-injury hypothesisa. Chronic endothelial cell injury, increased

endothelial permeability, endothelial dysfunction.

b. Monocyte emigration in the intima with accumulation of oxidized LDL.

c. Smooth muscle cell proliferation and extracellular matrix deposition with smooth muscle cell lipid accumulation.

d. Platelets adhere to damaged endothelium with organization of thrombi.

Biomechanical hypothesisa. Uniform laminar shear stress stimulus up-

regulates the expression of a subset of “atheroprotective genes” in endothelial cells.

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b. Locally protective in “lesion-protected areas” to offset effects of systemic risk factors.

4. Clinical significancea. narrowing of the vascular lumen causing

ischemia

b. sudden occlusion of the lumen by thrombosis or hemorrhage producing infraction

c. site of thrombosis and embolism

d. weakening of the wall of the vessel followed by aneurysm or rupture

B. Mönckeberg’s arteriosclerosis

Basic lesion - ringlike calcification within the media of medium-sized to small muscular arteries in individuals over 50 years of age. Bone and bone marrow might be seen in the calcified media.

Lesions do not produce narrowing or occlusion of the vascular lumen.

Site of involvement - femoral, tibial, radial and ulnar arteries

Pathogenesis - unknown but related to prolonged vasotonic influence

III. ArteriolosclerosisA. Hyaline arteriolosclerosis

1. Morphology - homogeneous pink, hyaline thickening of the walls of arterioles with loss of underlying structure and narrowing of the lumen. Lesions are related to diabetes and hypertension and may reflect leakage of plasma proteins across vascular endothelium. Hyaline consists of collagen and precipitated plasma proteins.

2. Clinical significance - associated with benign hypertension and diabetes mellitus.

B. Hyperplastic arteriolosclerosis1. Morphology - concentric, laminated, onionskin thickening of

the walls of arterioles with proliferation of smooth muscle cells and layer of collagen narrowing of the lumen frequently accompanied by deposits of fibrin and acute necrosis.

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2. Clinical significance - associated with malignant or accelerated phase hypertension.

3. Pathogenesis - vasoconstriction and increased blood pressure causes endothelial injury, platelet thrombosis, intravascular coagulation and vessel necrosis

IV. Hypertensive heart diseaseA. Definition - left ventricular hypertrophy, usually concentric in the

absence of other cardiovascular pathology and a history of hypertension >160/95

B. Morphology

Gross - concentric hypertrophy with left ventricular wall thickness greater than 2.0 cm and total weight of heart greater than 500 gm; decompensation of cardiac function produces dilatation of the left ventricle.

Microscopic - increase in myofiber volume and mean diameter; nuclei are enlarged, hyperchromatic and rectangular and have bizarre shapes; interstitial fibrosis is present; arterioles show wall thickening.

C. Pathogenesis

Hypertension places pressure overload on the left ventricle and causes vascular disease which increases peripheral vascular resistance. The heart must hypertrophy to maintain a normal cardiac output in the face of increased vascular resistance.

Hypertrophy with left ventricular wall thickening increases myocardial oxygen demand. Eventual hypoxia of the cardiac myocytes may induce decompensation and dilatation.

V. Cor Pulmonale (pulmonary hypertensive heart disease)A. Definition - right ventricular hypertrophy and dilatation in response

to pulmonary hypertension not secondary to left heart failure or congenital heart disease.

B. Acute - right ventricular dilatation following massive pulmonary embolism

C. Chronic - right ventricular hypertrophy1. Diseases of the Lungs

a. Chronic obstructive pulmonary disease21

b. Diffuse pulmonary interstitial fibrosis

c. Extensive persistent atelectasis

d. Cystic fibrosis

e. Idiopathic - primary pulmonary hypertension

2. Diseases of pulmonary vesselsa. Pulmonary embolism

b. Primary pulmonary vascular sclerosis

c. Diffuse pulmonary arteritis

d. Drug, toxin, or radiation induced vascular sclerosis

e. Extensive pulmonary tumor micrometastases

3. Disorders affecting chest movementa. Kyphoscoliosis

b. Neuromuscular dystrophies

c. Marked obesity

4. Disorders inducing pulmonary arteriolar constrictiona. metabolic acidosis

b. hypoxemia1. Chronic altitude sickness

2. Obstruction to major airways

3. Idiopathic alveolar hypoventilation

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Pathology Lab HSEB 4300Dr. Clayton/Staff

Access labs at: www.path.utah.edu/class.htm

Cardiovascular Pathology Cases

Laboratory I - Thursday 12/8/05 1:00-3:00pmLaboratory II - Thursday 12/15/04 10:00-12:00noon

Goals and Objectives:

Following the participation in lab sessions one and two the student will be able to:

1. Use the electronic medical record and/or computer to gather data on patients

2. Use the library electronic reference system to research data on diseases, therapies and drugs

3. Understand the basic pathology, presentation, and treatment of cardiac disorders including:a. Atherosclerosisb. Myocardial infarctionc. Amyloidosisd. Cor Pulmonalee. Hypertensionf. Sudden deathg. Valve replacementsh. Endocarditisi. Cardiomegaly

4. Understand the basic pathology, presentation, and treatment of vascular disorders including:a. Polyarteritis nodosab. Diabetic ischemic vasculopathy

5. Compile data on a patient and present it in the form of a Clinical Pathological Correlation .

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Cardiovascular Casepath Notes

Case 1

Part 1

1. What is your differential diagnosis?

2. Why is this patient at risk for peripheral vascular disease?

Part 2

1. What was the organism recovered from the wound?

2. Why is this patient having problems with recurrent infections?

3. Review the white cell count trends, what does this tell you about the infection?

Part 3

1. Is the graft patent?

2. How do the native vessels appear?

3. What do you think about the graft cultures?

4. A CXR and EKG were performed on 8-31 prior to surgery. Are there any signs of cardiac disease?

Part 4

1. What do the premortem labs suggest?

2. What was the cause of her sudden death?

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Part 5

1. Discuss the diagnosis and management of Insulin dependent Diabetes Mellitus.

2. Discuss the mechanism of accelerated atherosclerosis including glycosylation of proteins and lipids.

3. What are the incidence of amputations and peripheral vascular disease in DM?

4. Describe the increased risk of infection in DM.

5. What is the treatment of an infected graft?

6. What populations are at increased risk for DM in the U.S.?

7. What are the EKG findings in Myocardial Infarction?

Case 2

Part 1

1. What is your differential diagnosis?

2. What tests would you want to get?

3. What does an elevated sedimentation rate mean?

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Part 2

1. What is polyarteritis nodosa?

2. What additional risks does Factor V Leiden impose on this patient?

3. Review the EKG from this admission; are there any signs of cardiac ischemia?

4. An x-ray of the foot was performed to rule out osteomyelitis of the great toe, do you see any bone loss?

Part 3

1. What do these CBC findings have to do with his underlying vasculitis?

2. What changes are seen on CXR?

Part 4

1. Are the autopsy findings consistent with polyarteritis nodosa?

2. What vessels are involved in this disorder?

3. What other vasculitides may present like this patient?

Part 5

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1. Describe polyarteritis nodosa, its diagnosis and treatment.

2. Is atherosclerosis associated with vascular damage?

3. How does Factor V Leiden affect atherosclerosis?

4. Describe the etiology of ischemic infarcts of the tissues in this case

5. How does immunosuppression increase the risk of infection?

Case 3

Part 1

1. What is your differential diagnosis?

2. How might the diagnosis of the lung biopsy have added to his current situation?

Part 2

1. The patient had an aortogram on 10-18-03. How do his vessels look?

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2. A CT scan with contrast performed on this admission is shown here. Are there any signs of leakage in his AAA?

Part 3

1. Review the EKGs below. What changes occurred in the heart since the last admission?

Part 4

1. What was the cause of death?

2. What underlying causes of amyloidosis should be looked for at autopsy?

3. Is the aneurism related to the amyloid?

Part 5

1. What are the etiologies of amyloidosis and how does amyloid present?

2. How does amyloid affect the heart and vessels?

3. What is the relation of bundle branch block with amyloid?

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4. How do you diagnose abdominal aortic aneurism and what is the treatment?

Case 4

Part 1

1. What are the cardiac causes of shortness of breath?

2. How does lung disease affect the heart?

3. Review the admission laboratory results how did these help rule out the possibility of a pulmonary embolus?

4. What do you see on his EKG?

5. What is your differential diagnosis?

Part 2

1. Look at the patient’s O2 trends to get an idea of his lung function and how treatment with intubation helped.

2. What effect does oxygenation have on the heart?

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Part 3

1. What is this heart disease called?

2. What is the cause of death?

3. What is the significance of the patent foramen ovale?

Part 4

1. What are the effects of lung disease on the heart?

2. How is the diagnosis of cor pulmonale made?

3. How do you diagnosis and manage right heart failure?

4. What is a patent foramen ovale, why does it occur in cor pulmonale and what risk does it impose on the patient?

Case 5Part 1

1. What is your differential diagnosis?

2. What is the extent of damage?

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Part 2

1. What are the patient's risk factors for coronary artery disease? What should his children be tested for?

2. Review the EKG, what abnormalities do you see? What is a bundle branch block?

3. Are there any abnormalities on CXR?

Part 3

1. What is an intra-aortic balloon pump and how does it increase the cardiac output?

2. Review the chest films following balloon placement. What do you see?

3. What is the rhythm on the EKG?

Part 4

1. The Admission H&P of 6-22-03 reveals the concern for epigastric pain. What could be causing this?

2. What does the troponin tell you?

3. Review the EKG from this admission, are there any changes?

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4. Review the CT scan performed on 6-23-03, what do you see?

5. What could be the cause of death?

Part 5

Part 6

1. Explain the diagnosis and treatment of acute myocardial infarction.

2. What are the risk factors for acute myocardial infarction?

3. What are the risks for cardiac rupture (consider timing and location of infarct)?

4. Discuss congestive heart failure following infarction.

Case 6Part 11. What do you note in the iliac artery runoff?

2. What do you see on the renal artery injections?

Part 2

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1. Review the labs on admission. What is her PaO2?

2. Review the EKG. Do you see any abnormalities?

3. Review her Chest X-ray on admission. Is the heart size normal? How do the lungs look?

Part 3

1. What is the outlook for this patient?

2. What risk factors did this patient have for developing a deep venous thrombosis?

3. What serious sequela of DVT is she at risk for?

Part 41. What is going on in her heart?

2. Is this acute or chronic?

3. What is a possible cause of death?

Part 51. What is the diagnosis and treatment for renal artery stenosis?

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2. How does renal artery stenosis cause hypertension?

3. Describe the development of left ventricular hypertrophy in hypertension.

4. What are the causes of sudden cardiac death?

Case 7Part 1

1. Review the patient’s pre-operative labs. Does there appear to be any contraindication to surgery?

2. Review the pre-operative EKG. What are the findings?

3. Why does this patient have LVH?

4. Review her pre-operative Chest X-Ray 6-4-02. Are there any abnormalities?

Part 2

1. Review the post-operative Chest X-Ray 6-5-03. What changes do you see?

2. Why might an aortic valve replacement affect the functioning of the myocardium?

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Part 3 1. What does the post operative blood gas tell you about her heart function?

Part 41. What abnormalities do you see?

Part 5

1. What are the attachments of the RVAD and the coronary grafts?

2. What are the microscopic findings in the heart?

3. What is the cause of death?

Part 61. Describe the diagnosis and treatment of congenital bicuspid valve.

2. Describe aortic stenosis and its effects on the heart.

3. Is myocardial ischemia and infarction a risk of surgery?4. Describe how the right ventricular assist device and aortic balloon pump help support a failing heart.

Case 8Part 1

1. What is your differential diagnosis?

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2. Review the chest film from 4-4-03 on admission. Are there any abnormalities?

3. Review the labs from 4-4-03. Are there any clues to his illness

Part 2

1. Should there have been follow up to the frozen section report of the mediastinal biopsy?

2. What is your differential diagnosis now?

Part 3

1. What is the rhythm on the EKG?

2. What are the findings on the CT of the head?

Part 4

1. What is your diagnosis now?

Part 5 1. What is the diagnosis and treatment of endocarditis?

2. What are the etiologies of endocarditis?

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3. What is the difference between marantic and infectious endocarditis?

4. Describe Trousseau Syndrome in adenocarcinoma.

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Pathology 6020 - Year 2005Paul Urie, M.D., Ph.D.Dec. 12, Monday

9:00-10:00 AM

ISCHEMIC HEART DISEASE AND CARDIAC ENZYMES

Reading: Robins Pathologic Basis of Disease 7th edition: pages 571-587; or in the 6th edition pages 550-564.

I. Incidence

Accounts for 80% of deaths caused by heart disease or 30% of the total mortality in the United States. Mortality from IHD in the U.S. has decreased by 50% since 1963.

II. Pathogenesis

IHD is caused by an imbalance between the myocardial blood flow and the metabolic demand of the myocardium.

A. Reduced coronary blood flow

Reduction in coronary blood flow is due to progressive stenosis by atherosclerosis in 90% of patients with IHD. Other etiologic factors are: vasospasm, thrombosis, or circulatory changes leading to hypoperfusion.

Basic principle - coronary artery perfusion depends on the pressure differential between the ostia (aortic diastolic pressure) and coronary sinus (right atrial pressure). Blood flow is reduced during systole because of Venturi effects at the coronary orifices and compression of intramuscular arteries during ventricular contraction.

Factors reducing coronary blood flow1. Decreased aortic diastolic pressure

2. Increased intraventricular pressure and myocardial contraction

3. Coronary artery stenosis - transient or fixeda. Fixed coronary stenosisb. Acute plaque change

-Not dependent on percent of fixed stenosis-Role of Inflammation and C-reactive protein

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c. Coronary artery thrombosis

d. Vasoconstriction

4. Aortic valve stenosis and regurgitation

5. Increased right atrial pressure

Coronary artery distribution patterns and frequency of stenosis

Left anterior: (40-50%)

anterior wall left ventricle, apex descending, anterior IV septum

Right:(30-40%)

posterior wall left ventricle, posterior IV septum

Left circumflex:(15-20%)

lateral wall left ventricle

Intramyocardial collateral vessels are present in all hearts with pressure gradients permitting flow despite occlusion of major vessels.

The cross-sectional area of the coronary artery lumen must be reduced by more than 75 percent to significantly affect perfusion. Coronary atherosclerosis is segmental, and usually involves the proximal 2 cm of arteries (epicardial).

B. Increased myocardial oxygen demand Tachycardia Hypertrophy Hypermetabolism - exercise Infection Pregnancy Hyperthyroidism Drugs

C. Availability of oxygen in the blood Anemia Carboxyhemoglobin Pulmonary disease Right to left shunting of blood

III. Patterns of ischemic heart disease

A. Angina pectoris - a symptom complex of IHD characterized by paroxysmal attacks of chest pain, usually substernal or precordial,

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caused by myocardial ischemia that falls short of inducing infarction.1. Stable angina (typical) - paroxysms of pain related to

exertion and relieved by rest or vasodilator, subendocardial ischemia. Chronic, fixed atheromatous plaques that are >75%.

2. Variant or Prinzmetal's angina - angina that classically occurs at rest and is caused by reversible spasm of the coronary arteries.

3. Unstable angina - prolonged pain, pain at rest in a person with stable angina, or worsening of pain in stable angina. Abrupt disruption, fissure, or thrombosis that is nonocclusive. This may be the prodrome to MI.

B. Sudden cardiac death - Unexpected death from cardiac causes usually within one hour after cardiac symptoms or without the onset of symptoms. Most common is plaque disruption and acute thrombus, platelet aggregates or thromboemboli. It strikes 300,000-400,000 persons annually. (Also includes other cardiac disorders (10-20%): congenital abnormalities, aortic stenosis, MVP, myocarditis, cardiomyopathies, pulmonary hypertension, conduction defects)

Death is due to ventricular electrical instability (arrhythmia).

C. Myocardial infarction1.5 million people in US affected annually. 30% die - half in the first hour. 250,000 people/year die before reaching hospital. Women are relatively protected during reproductive years, but estrogen replacement does not slow atherosclerosis after menopause.

Transmural infarct - usually involves the LV or in 15-30% it may involve septum with extension into the RV. Isolated infarcts of RV and right atrium are extremely rare. Infarct is within area fed by one coronary vessel.

Pathogenesis of transmural infarcts (most common type of MI)a. Occlusive coronary thrombus overlying an ulcerated

or fissured stenotic plaque causes 90% of transmural AMI.

b. Vasospasm with or without coronary atherosclerosis and possible association with platelet aggregation.

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c. Emboli from left sided mural thrombi, vegetative endocarditis, or paradoxic emboli from the right side of heart through a patent foramen ovale.

Subendocardial infarct - multifocal areas of necrosis or circumferential necrosis confined to the inner 1/3-1/2 of the LV wall. May be caused by hypotension, global ischemia, etc. and does not follow distribution of a single vessel.

1. Key Events in MI

Time FeatureSeconds Onset of ATP depletion<2 minutes Loss of contractility20-40 minutes Irreversible cell injury> 1 hour Microvascular injury

2. Morphology of MI

Time Gross Features Microscopic FeaturesReversible0-1/2 hour

None EM only relaxation of myofibrils; glycogen loss; mitochondrial swelling

Irreversible½ - 4 hours

None Waviness of fibers

4-12 hours Dark mottling Edema, hemorrhage, early coagulative necrosis

12-24 Dark mottling Coagulative necrosis, neutrophils infiltrate, pyknosis, contraction bands in reperfusion injury

1-3 days Mottling with yellow infarct center

Complete coagulative necrosis with loss of nuclei and striations; interstitial neutrophils

3-7 days Hyperemic border, central yellow softening

Dying neutrophils, macrophages begin phagocytosis of dead myocytes at border

7-10 days Maximally yellow and soft, depressed red margins

Phagocytosis of dead cells; early granulation tissue

10-14 days Red-gray depressed infarct borders

Granulation tissue with new vessels and collagen deposition

2-8 weeks Gray-white scar, Increased collagen and

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progressive from border to center of infarct

decreased cellularity and vascularity

>2 months Scarring complete Dense collagenous scar

3. Complications of MIa. none (10-20%), death (7-13% of those receiving

aggressive reperfusion therapy)

b. arrhythmias and conduction defects (75-95%)

c. congestive heart failure, pulmonary edema (60%)

d. cardiogenic shock (10-15%)

e. pericarditis (50%)

f. mural thrombosis (40%) and thromboembolism (15%)

g. rupture of ventricle, papillary muscle or ventricular aneurysm formation (4-8%)rupture usually occurs at 3-7 days

4. Therapeutic modalitiesa. Infarct modification by thrombolysis

b. PTCA - balloon dilatation

c. Directional atherectomy

d. Coronary bypass surgery

e. Coronary artery stents

5. Reperfusion modification of infarction<20 minutes get salvage of myocardium, may have stunning

2-4 hours get partial salvage with central necrosis

> 6 hours of no benefit in reducing infarct size

Gross findings show hemorrhage in infarcted and reperfused regions.

Microscopic shows contraction bands and interstitial RBCs.

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D. Chronic IHD with heart failure, hypertrophy and interstitial fibrosis (ischemic cardiomyopathy). These patients make up 50% of heart transplant recipients.1. Morphology

Gross - LV usually dilated, moderate-severe atherosclerosis, focal small scars confined to the LV wall, pericardial fibrous adhesions

Microscopic - myocyte hypertrophy and focal atrophy with myocytolysis of single and clusters of cells; focal small interstitial scars; coronary atherosclerosis

2. Clinical significance

Slow, progressive heart failure with or without previous MI or angina, sometimes referred to as ischemic cardiomyopathy

Responsible for 40% of the mortality in IHD

IV. Diagnostic laboratory testing in acute MIA. Serum enzymes - leak from necrotic cells, there is a more rapid

rise with reperfusion treatment

1. Creatine kinase (CK, CPK) - composed of two subunits "M" and "B" which combine to yield three isoenzymes MM, MB, BB

Tissue BB MB MMSkeletal muscle 0% 2% 98%Myocardium 0% 15-40% 60-85%Brain 90% 0% 10%Bladder 95% 0% 5%Bowel 100% 0% 0%

CK-MB begins to rise in 2-4 hours, peaks at 24 hours and returns to normal by 72 hours.

2. Troponin - cardiac muscle specific enzymes, Troponin I and Troponin T appear within 2-4 hours, peak at 48 hours and remain elevated 7-10 days. Normally there is no troponin in the serum.

3. Aspartate aminotransferase (AST, SGOT) - found in the cytoplasm and mitochondria of a variety of tissues including liver, heart, and skeletal muscle

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4. Lactate dehydrogenase (LD, LDH) - composed of four subunits of two different types "H" and "M," and yields five isoenzymes.

LD-l (HHHH) 19-39% Myocardium, erythrocytes, kidneyLD-2 (HHHM) 25-50% Erythrocytes, kidneyLD-3 (HHMM) 16-31% LungLD-4 (HMMM) 2 - 9% Skeletal muscleLD-5 (MMMM) 2 -17% Liver, skeletal muscle

LD-2 (most abundant), LD-l, LD-3, LD-4, LD-5 (least abundant)

LD-l/LD-2 < 1 (normally)

V. C-reactive protein (CRP) may predict the risk of MI in patients with angina. A highly sensitive CRP of >3 mg/L is associated with high risk of cardiovascular disease.

VI. Hyperhomocysteinemia - independent risk factor for vascular disease including coronary artery disease. Patients with an inborn error of metabolism causing homocystinuria have premature atherosclerosis. Other patients may have increased homocysteine due to decreased folate and B6 intake.

A. Homocysteine plasma levels are increased by 15-40% in patients with CAD (levels >100 micromols/L). Normal <16 micromol/L.

B. Treated with folic acid, pyridoxine or vitamin B12

VII. BNP – Brain natriuretic peptide (B-type natriuretic peptide) marker for CHF

A. Neurohormone predominately produced in the left ventricle in response to pressure and volume expansion. Synthesis and secretion is a protective response that is up regulated in patients with heart failure, resulting in vasodilation and diuresis/natriuresis. Elevated BNP are seen in hypertension, tachycardia, cardiomyopathy, MI, mitral and aortic stenosis.

B. Clinical utility

Detect asymptomatic CHFObjectively assess heart failure severity – correlating with NYHA

classification

Monitor therapy and disease progressionPredict 30-day and 10-month mortality after AMI

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C. BNP < 100 pg/ml – no heart failureBNP 100-300 pg/ml – heart failure is presentBNP 300-600 pg/ml – mild heart failureBNP 600-1000 pg/ml – moderate heart failureBNP >1000 pg/ml – severe heart failure

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Pathology 6020 - Year 2005Paul Urie, M.D., Ph.D.Dec. 12, Monday 10-11 am

ANEURYSMS, VASCULITIS, PERICARDIAL DISEASE AND TUMORS

Reading: Robins Pathologic Basis of Disease 7th edition: pages 530-553 and 610-615; or in the 6th edition pages 515-540 and 589-591.

I. AneurysmsA. Arteriosclerotic

Site of involvement - abdominal aorta, common iliac arteries or arch and descending thoracic aorta

Clinical significance - rupture, impingement of adjacent structure, occlusion of a vessel, embolism, abdominal mass

B. Syphilitic aneurysms

Site of involvement - thoracic aorta and arch

Morphology - saccular, fusiform, and cylindroid types with destruction of the media. Obliterative endarteritis of the vasa vasorum by lymphocytes and plasma cells causing ischemic injury to the media with intimal and subintimal scarring. Aortic valve ring dilatation and insufficiency causing volume overload hypertrophy, "cor bovinum"

C. Mycotic aneurysm - infection of major artery which weakens the wall.

II. Aortic dissections This is most common in 40-60 year olds related to hypertension (90%). Also seen in Marfan’s Syndrome as an abnormality of fibrillin or as an iatrogenic disorder (catheterization).

Site of involvement - ascending aorta and aortic arch

Morphology - intimal tear with hematoma within media

Cystic medial necrosis - focal separation of the elastic and smooth muscle of the media by ground substance of connective tissue with accompanying focal fibrosis of media.Clinical significance - external hemorrhage and occlusion of arteries.

Type A involves ascending aorta and Type B does not.

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III. VasculitisA. Classification based on vessel size

1. Large vessela. Giant cell arteritisb. Takayasu’s arteritis

2. Medium-sized vessela. Polyarteritis nodosa (PAN)b. Kawasaki disease

3. Small vessela. Wegner’s granulomatosisb. Churg-Strauss syndromec. Microscopic polyangiitisd. Henoch-Schönlein purpurae. Essential cryoglobulinemic vasculitisf. Cutaneous leukocytoclastic angiitis

B. Classification based on pathogenesis1. Infectious - bacterial, fungal, and viral

2. Immunologica. Immune complex mediated - Henoch-Schönlein, SLEb. Direct antibody mediated - Kawasaki diseasec. ANCA associated - Wegner’s granulomatosisd. Cell-mediated - Allograft organ rejection

3. Unknowna. Giant cell arteritisb. Takayasu’s arteritisc. Polyarteritis nodosa

C. Polyarteritis nodosa (PAN)Immune mediated disorder, associated with Chronic Hepatitis B in 30% of patients. There is no association with ANCA.

Site of involvement - kidneys 85%, heart 75%, liver 65%, GI 50%

Medium sized muscular arteries affected by segmental and transmural lesions usually at branch points

Morphology of lesions (varying ages)

Acute - fibrinoid necrosis and transmural neutrophil, mononuclear, and eosinophil infiltrate, +/- thrombosis

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Healing - fibroblastic proliferation with continued necrosis

Healed - fibrotic thickening, scattered lymphocytes and plasma cells with calcium deposits

Clinical signs - fever, malaise, weakness, leukocytosis, and symptoms of specific organ involvement

Treatment – steroids and cyclophosphamide results in 90% response

D. Microscopic polyangiitis (leukocytoclastic)Immune mediated disorder, usually in response to a foreign antigen, drug, bacteria etc.

It involves small vessels (arterioles, venules and capillaries) of the skin mucous membranes, lungs, brain, heart, GI tract, kidneys, and muscle (palpable purpura).

Morphology - fibrinoid necrosis with neutrophil infiltrate, all lesions are of the same age. Pauci-immune vasculitis means there are little or no deposits on immunofluorescence.

Diagnosis – skin biopsy

p-ANCA positive in 70% of patients

Treatment is removal of antigenic source

E. Wegener's granulomatosisProbably a cell-mediated immunity to an inhaled agent; immune complexes may be seen in the vessels in some patients. M>F; age 40-50

Site of involvement - acute necrotizing or granulomatous vasculitis of the upper and lower respiratory tract, and renal disease with necrotizing glomerulonephritis present in small arteries and veins

Morphology - focal acute necrosis surrounded by a zone of fibroblastic proliferation with giant cells and leukocyte infiltrate.

c-ANCA present in 95% of patients with active disease

Treatment is immunosuppression

F. Giant cell (temporal) arteritis

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T-cell mediated, antigen driven immune response is most likely cause. It is the most common of the vasculitides; often have very high erythrocyte sedimentation rate.

Site of involvement - focal granulomatous inflammation of arteries of large to small size that affects cranial vessels in older individuals

Morphology – patchy granulomatous lesions with giant cells and fragmentation of elastic fibers, fibrosis results in nodular thickening

Diagnosis – arterial biopsy (2-3 cm length)

Treatment – high dose steroids

Clinical significance - Involvement of ophthalmic arteries may lead to blindness and aortic involvement can lead to aneurysm

G. Raynaud’s disease - paroxysmal pallor or cyanosis of digits of hands or feet due to intense vasospasm without organic changes.

H. Raynaud’s phenomenon - arterial insufficiency of extremities secondary to arterial narrowing induced by various diseases.

III. VeinsA. Varicose veins

Site of involvement - superficial veins of lower extremities

Clinical significance - stasis dermatitis and ulcers, NOT embolism

B. Phlebothrombosis and thrombophlebitis

Site of involvement - deep leg veins

Clinical significance - pulmonary embolism

Variants - Phlegmasia alba dolens - painful white leg due to venous inflammation compressing the lymphatics

Migratory thrombophlebitis - migrating venous thrombi

IV. Lymphatics

A. Acute lymphangitis

B. Obstructive lymphedema - tumors, surgery, radiation or fibrosis

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V. Pericardial Effusion - normally 30-50 ml in pericardial sacA. Serous - straw-colored or clear watery fluid from congestive heart

failure or hypoproteinemia or scleroderma

B. Serosanguineous - blood-tinged watery fluid from blunt chest trauma, cardiopulmonary resuscitation, metastatic tumor or tuberculosis

C. Chylous - watery fluid with lipid droplets due to lymphatic obstruction from either benign or malignant mediastinal tumors

D. Hemopericardium - accumulation of pure blood in pericardial sac; usually due to traumatic perforation of heart wall, rupture secondary to acute MI, rupture of intrapericardial aortic aneurysm, or rarely bleeding diatheses - leukemia or thrombocytopenia

Cardiac tamponade (reduce diastolic filling) may occur with rapid accumulation of 200-300 ml

VI. Pericarditis - inflammation of the pericardiumA. Etiology

1. Infectious agentsa. Viral - Coxsackie, ECHO, influenza, adenovirus or

mumps

b. Bacteria

c. M. tuberculosis or fungal

d. Parasites

2. Immunologically-mediated

Rheumatic fever, SLE, Scleroderma, postcardiotomy, or drugs

3. Miscellaneous - MI, uremia, neoplasia, trauma, radiation

B. Acute pericarditis1. Serous pericarditis

a. Etiology - virus, rheumatic fever, SLE, scleroderma, tumors, or uremia.

b. Morphology - 50-200 ml exudate with scant numbers of neutrophils, lymphocytes, and histiocytes and rare development of fibrous adhesions or organization.

2. Fibrinous or serofibrinous pericarditis

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a. Etiology - MI, uremia, radiation, trauma, SLE, viral, bacterial, or cardiac surgery.

b. Morphology - serous fluid with fibrin, inflammatory cells, and red cells. Fibrous organization with adhesive pericarditis rarely restricting cardiac motion.

c. Symptoms and signs - pain, fever, and pericardial friction rub.

3. Purulent or suppurative pericarditisa. Etiology - bacterial, mycotic, or parasitic from direct

invasion, hematogenous seeding, lymphatic seeding or direct introduction.

b. Morphology - thin to creamy pus, 400-500 ml in volume with reddened, granular coated serosal surfaces.

Organization is the usual outcome with constrictive pericarditis.

4. Hemorrhagic pericarditis - blood mixed with fibrinous exudatea. Etiology - M. tuberculosis, neoplasms, or bacterial

infection.

b. Morphology - resolution or organization with or without calcification.

5. Caseous pericarditis - TB and the most frequent cause of fibrocalcific, chronic constrictive pericarditis.

C. Healed pericarditis1. Little clinical significance

a. "Soldier's plaque" - thickened non-adherent epicardial plaque.

b. diffuse or focal obliterative pericarditis

2. Serious clinical importancea. Adhesive mediastinopericarditis - consequence of

caseous or suppurative pericarditis or previous cardiac surgery with obliteration of the pericardial sac and adherence to the surrounding structures.

Increased cardiac work with systolic retractions of rib cage and pulsus paradoxus.

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b. Constrictive pericarditis - dense fibrous or fibrocalcific scar that limits diastolic expansion and restricts cardiac output.

Small quiet heart with reduced pressure and cardiac output without hypertrophy or dilatation.

May be a consequence of tuberculous pericarditis.

VII. Cardiac tumorsA. Primary cardiac tumors

Incidence - 0.0017-0.33%

Myxomaa. Site of involvement - 90% in atria with 4:1 left to right ratio

and covered by endothelium.

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Adults (>16 years) Children (1-15) Infants (<l year)

Benign

Myxoma Rhabdomyoma RhabdomyomaLipoma Fibroma TeratomaPapillary fibroelastoma Myxoma Fibroma

Malignant

Angiosarcoma Malignant Teratoma FibrosarcomaRhabdomyosarcoma Rhabdomyosarcoma RhabdomyosarcomaMesothelioma

b. Morphology - Stellate or globular myxoma cells, macrophages, and smooth muscle in acid mucopolysaccharide ground substance. Neoplasm derived from primitive mesenchymal cells.

c. Clinical significance - "wrecking ball," ball-valve obstructions, or embolism.

B. Secondary tumors - more commonly involving pericardium than myocardium. Blood or lymphatic-borne metastasis from carcinomas or malignant lymphomas.

VIII. VASCULAR TUMORSA. Classification of Tumors of Blood Vessels

1. Benigna. Hemangiomab. Vascular ectasias

2. Intermediatea. Hemangioendothelioma

3. Malignanta. Hemangiopericytomab. Kaposi’s sarcomac. Angiosarcoma

B. Hemangioma - most common vascular tumor, usually in infancy or childhood; usually small; most often seen on skin but can occur in visceral organs.

Capillary or cavernous subtypes composed of clusters of endothelial lined spaces filled with RBCs.

C. Kaposi’s sarcoma - associated with AIDS or transplantation; occurs in the setting of human herpesvirus 8 infection; can be seen on skin or in visceral organs.

Spindle cell neoplasm with many slit-like vascular channels.

D. Angiosarcoma - highly malignant, bulky tumor. Morphology varies widely.

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CONGENITAL HEART DISEASE LABCase PresentationsHSEB 4300 Teaching LaboratoryDecember 15 2005 Thursday10:00-12:00noon

CASE 1History: A 2870 gm baby is born at 37 weeks gestation to a 23 year old primagravida. The pregnancy was uncomplicated, and no ultrasound was performed during gestation. The baby initially does well, but then approximately 12 hours following delivery develops respiratory difficulty. The baby has a poor color, weak pulses, and oxygen saturation of only 90%.

Examine the gross specimen and slide 1.1. What are the findings?

What is the diagnosis?

What is the outcome?

CASE 2History: Before the era of cardiac surgery, a 10 year old girl lived with her parents in the highlands above Butte, Montana. She was only half the size of her 4th grade classmates, and she did not go out to play at recess because she tired easily. Her skin always had an ashen grey to pale bluish tint.

Examine the gross specimen from a similar case. What are the findings?

What is the diagnosis:

Explain the pathophysiology of this condition, and why was the child eventually sent to live with relatives in Florida?

CASE 3History: At 18 weeks gestation, an ultrasound reveals a cardiac defect, along with a “double bubble” sign suggesting duodenal atresia. Maternal serum alpha-

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fetoprotein is low and the beta-HCG is high. The parents elect to proceed with the pregnancy. The baby is born at 36 weeks. A systolic murmur is present.

Examine the gross specimen and slides 3.1 and 3.2. What are the findings?

Dr. Leonard (a clinical geneticist) is asked to see the baby. She points out the features seen in slide 3.3. What do you see?

What additional test would help to diagnose the baby’s underlying condition?

What happens if this lesion is not repaired?

CASE 4History: A 15 year old male is noted on physical examination to have more development of his upper body than lower body. Physical examination reveals bounding 4+ radial pulses, but weak 1+ dorsalis pedis pulses. A chest radiograph reveals clear lung fields, normal cardiac shadow, and rib notching.

What is the abnormality seen in slides 4.1 and 4.2 from other patients with a similar condition?

Describe the pathophysiology of this condition.

CASE 5History: A 65 year old male develops increasing orthopnea and exercise intolerance over the past year. A chest radiograph reveals pulmonary edema and congestion. The left heart shadow is increased, particularly the left ventricle.

Compare the lesions seen in slides 5.1 and 5.2. What is present?

What are these conditions?

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CASE 6History: A neonate born at term develops cyanosis within the first day of life. A systolic murmur is audible on auscultation. Arterial oxygen saturation is only 82%.

Examine the gross specimen. What are the findings?

What is the diagnosis:

Explain the pathophysiology of this condition:

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PATHOLOGY 6020 YEAR 2005CONGENITAL HEART DISEASEDirected Study HandoutLaboratory Session: December 15 10:00-12:00 HSEB 4300

Pathology of Congenital Heart Disease

Acyanotic Cardiac Malformation:

Left-to-Right Shunts

1. Ventricular Septal Defects (“VSD”)

Defects in the ventricular septum may be single (90%) or multiple, they may be located in the membranous septum (90%), the muscular septum, or in the conus (subpulmonic).

How does the presence of a VSD alter the hemodynamics? (Hint: What happens to the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) after birth?)

2. Patent Ductus Arteriosus (“PDA”)

Why does the ductus stay open in the fetus and close immediately after birth?

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How does a PDA alter hemodynamics? (Hint: How does aortic pressure compare to pulmonary artery pressure?)

3. Atrial Septal Defects (“ASD”)

Defects in the atrial septum are usually (90%) at the foramen ovale (ostium secundum) or in the lowermost portion of the atrial septum (ostium primum).

How does an atrial septal defect alter hemodynamics? (Hint: What happens to left ventricular (LV) compliance and right ventricular (RV) compliance after birth?)

4. Atrioventricular Septal Defect (“A-V septal defect”, “A-V canal”, “Endocardial Cushion Defect”)

An ostium primum defect plus a VSD in combination makes a large, continuous defect. The mitral and tricuspid valves are joined together as one common A-V valve which crosses the ventricular septum.

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Hemodynamically, it acts like a large ASD plus a large VSD.

This is the most common cardiac malformation found in Down syndrome (Trisomy 21).

Acyanotic Obstructive Cardiac Malformations

1. Aortic Stenosis (“AS”)

There are three levels of obstruction:

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1) Valvular: Bicuspid, unicuspid, or tricuspid leaflets

2) Subvalvular: Fibrous ring, fibromuscular, or muscular (e.g., Idiopathic Hypertrophic Subaortic Stenosis, or “IHSS”)

3) Supravalvular: Hour glass, fibrous ring, or hypoplastic segment. This can be found in William’s Syndrome.

What are the hemodynamic-anatomic consequences of left ventricular (“LV”) obstruction?

2. Pulmonic Stenosis (“PS”)

There are three levels:

1) Valvular: Bicuspid, unicuspid, tricuspid, dysplastic

2) Subvalvular or infundibular (muscular) is frequently secondary to valvular, most commonly with tetralogy of Fallot.

3) Supravalvular: Usually seen with tetralogy of Fallot, William’s Syndrome, or congenital rubella syndrome.

What are the hemodynamic-anatomic consequences of right ventricular (“RV”) obstruction?

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3. Coarctation of the Aorta

Typically, discrete constriction of the aorta just distal to the origin of the left subclavian artery. Other types: tubular hypoplasia, preductal, and postductal.

Collateral circulation from the arch vessels and thoracic arteries supplies the descending aorta.

What is the role of the PDA in hemodynamic alterations and manifestations of coarctation?

The metamorphosis of coarctation is shown at the right: (A) fetal prototype with no flow obstruction, (B) late gestation, aortic ventricle increases output, antegrade aortic flow bypass via ductal orifice, (C) neonate, increasing antegrade arch flow, (D) Mature juxtaductal stenosis, (E) Infantile type, fetal prototype persists

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Cyanotic Cardiac Malformations with Decreased Pulmonary Flow

Flow from the right ventricle to the lungs is obstructed so that some desaturated blood bypasses the lungs and enters the aorta either through intracardiac defects or aortico-pulmonary communication.

1. Tetralogy of Fallot (“T of F” or “Tet”)

Dr. Fallot described four features:

a. VSD (large, nonrestrictive, perimembranous)

b. Pulmonic stenosis (“PS”) (mild to severe to atresia)

c. RV hypertrophy (“RVH”)

d. Overriding aorta (aorta overrides the VSD)

How does the severity of PS with tetralogy of Fallot affect hemodynamics?

Why is there right-to-left shunting?

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2. Pulmonic Atresia-Hypoplastic RV

This is a syndrome of tricuspid valve and RV hypoplasia, atresia of the pulmonic valve, and intact ventricular septum (“IVS”)

What happens to blood which enters the RV? How does blood get from the vena cavae to the lungs? (Remember there is total obstruction to RV ejection into the pulmonary artery).

Cyanotic Cardiac Malformations with Increased Pulmonary Flow

1. Transposition of Great Arteries (“TGA”)Aorta arises from RV and PA arises from LV. Right and left heart circulations are in parallel. There is no mixing of saturated and desaturated blood unless there is a VSD, PDA, or ASD.

TGA usually occurs with intact ventricular septum (“IVS”).

TGA may be associated with a VSD, PS, or both.

If there is no mixing, what palliative procedures can be utilized to allow adequate mixing? How can we create communications between the right and left hearts?

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2. Truncus Arteriosus

Failure of development of the spiral septum results in persistence of the truncus and absence of part of the conus musculature. This causes a VSD with overriding trunk from which the pulmonary trunk arises.

Hemodynamically, this situation is similar to a large VSD and PDA, but both ventricles empty into the truncus so there is admixture of ejected blood.

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3. Hypoplastic Left Heart Syndrome

There is usually severe hypoplasia of LV, mitral valve, ascending aorta, and aortic valvular atresia. Blood from RV is ejected into the PA and passes through the lungs as well as through the PDA into the descending aorta, and retrograde into the aortic arch and descending aorta.

How does pulmonary venous blood returning to the left atrium get to the RV?

Why do these newborns die within days after birth?

Eisenmenger Complex

When a cardiac malformation, such as a large ASD or VSD, with a left-to-right shunt, has been present for a long time, there can be reversal of the shunt. This occurs because of the increased pulmonary blood flow that produces increasing pulmonary hypertension.

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Answer to congenital heart disease questions:

How does the presence of a VSD alter the hemodynamics? (Hint: What happens to the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) after birth?)

At birth, there is relatively high pulmonary vascular resistance. Resistance drops as the pulmonary circulation assumes a more adult configuration. This causes decreased pressures on the right, so that there is shunting of oxygenated blood from left to right. The larger the shunt, the greater the workload for the left ventricle and the more likely congestive heart failure will occur. Over time, the increased flow to the right results in increasing pulmonary vascular resistance (pulmonary hypertension).

Why does the ductus stay open in the fetus and close immediately after birth?

In fetal life, the pulmonary vascular resistance is high and blood from the pulmonary artery is shunted via the ductus into the aorta. After birth, pulmonary pressures drop and there is no longer the right to left shunt, and the ductus closes.

How does a PDA alter hemodynamics? (Hint: How does aortic pressure compare to pulmonary artery pressure?)

Aortic pressure is higher than pulmonary arterial pressure, so that a PDA creates a left to right shunt.

How does an atrial septal defect (ASD) alter hemodynamics? (Hint: What happens to left ventricular (LV) compliance and right ventricular (RV) compliance after birth?)

An ASD creates a left to right shunt following birth because the left-sided pressures are higher than the right. However, the pressure differential across an ASD is lower than that for a VSD, because atrial pressures are lower.

What are the hemodynamic-anatomic consequences of left ventricular (“LV”) obstruction?

LV outflow obstruction leads to increased workload on the left ventricle, resulting in LV hypertrophy, then dilation. The same situation exists with systemic hypertension. When the LV fails, the left-sided failure causes pulmonary edema.

What are the hemodynamic-anatomic consequences of right ventricular (“RV”) obstruction?

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RV outflow obstruction leads to increased workload on the right ventricle, resulting in RV hypertrophy, then dilatation. The same situation exists when the pulmonary vascular bed is decreased with pulmonary diseases such as pulmonary emphysema or pulmonary fibrosis, leading to cor pulmonale. When the RV fails, the right-sided failure leads to hepatic passive congestion, peripheral edema, and body cavity effusions.

What is the role of the PDA in hemodynamic alterations and manifestations of coarctation?

The presence of a PDA with the coarctation makes a difference. A pre-ductal coarctation along with a PDA means that unoxygenated blood can be shunted to the aorta. A post-ductal coarctation with a PDA can create a left to right shunt. If no PDA is present, the symptoms may not be severe, and the condition is diagnosed by relative hypertension in upper extremities compared to lower extremities.

How does the severity of pulmonic stenosis (PS) with tetralogy of Fallot affect hemodynamics?

The greater the outflow obstruction, the greater the load on the right ventricle and the greater the right to left shunt. If the amount of PS is minimal, then there may in fact be a left to right shunt across the VSD.

Why is there right-to-left shunting with tetralogy of Fallot?

If the degree of pulmonic obstruction is moderate to severe, then the pressure exceeds that of the left ventricle, leading to a right to left shunt across the VSD and cyanosis from mixing of unoxygenated blood.

With pulmonic atresia, what happens to blood which enters the RV? How does blood get from the vena cavae to the lungs? (Remember there is total obstruction to RV ejection into the pulmonary artery).

Blood has to shunt via an ASD (foramen ovale remains patent) and a PDA.

In transposition of the great arteries (TGA), if there is no mixing, what palliative procedures can be utilized to allow adequate mixing? How can we create communications between the right and left hearts?

Create a surgical ASD or VSD.67

With a hypoplastic left heart, how does pulmonary venous blood returning to the left atrium get to the RV?

A PDA is essentially the only connection

Why do newborns with hypoplastic left heart die within days after birth?

There is not enough systemic cardiac output to sustain life in many cases. The severity depends upon the degree of hypoplasia. The baby may survive for variable periods of time. There may be time to consider options such as repair (Norwood procedure) or transplantation.

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