Download Valvular Heart Diseases

Pathology of
Cardiovascular System
Dr. Mohamad Nidal Khabaz
Valvular Heart
Diseases
Valvular Heart Diseases

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Stenosis: failure of the valve to open completely, so
impairing forward blood flow.
Insufficiency (Regurgitation): failure of the valve to
close completely so allowing reverse flow.
Valve abnormalities: congenital or acquired.
The most common abnormalities are acquired
stenosis of the mitral and aortic valves.
Valve abnormalities produce abnormal heart
sounds called murmurs.
Valvular Heart Diseases: Causes


Mitral Stenosis: almost all due to rheumatic fever
 Complications: Atrial fibrillation (the commonest),
Systemic embolization, Pulmonary hypertension,
Right ventricular failure, Chest infections
Mitral Regurgitation:
 mitral annulus:
 Dilatation : LV dilatation (Dilated
Cardiomyopathy) or repeated Myocardial
infarction
 Calcification: degenerative, chronic renal
failure (especially in elderly age group)
Valvular Heart Diseases: Causes

Mitral Regurgitation:
 mitral leaflets:
 Shortening, rigidity, deformity (rheumatic heart
disease)
 Destruction of the leaflet: systemic lupus
erythematosus, Trauma, infective endocarditis.
 Myxomatous degeneration (Mitral valve
prolapse)
 chordae tendineae
- Rupture: I.E., trauma, R.F., ischemia
 papillary muscles
- Dysfunction & Rupture: ischemia, dilatation.
Valvular Heart Diseases: Causes


Aortic Stenosis
 Calcific AS
 Rheumatic AS
 Congenital bicuspid aortic valve
Aortic Regurgitation
 Rheumatic fever
 Infective endocarditis
 Trauma
 Aortic root disease: dilatation of the ascending A.
 Marfan Syndrome, Syphilitic aortitis
Valvular Heart Diseases and
Rheumatic Fever



The most common cause of acquired valvular
disease in developed and underdeveloped
countries is rheumatic fever (R.F.)
Now in the western world R.F. is being eradicated,
but its still the common cause (in addition to CAD
and degenerative calcific diseases).
R.F. can be presented in many ways:
 arthritis without cardiac involvement
 rheumatic chorea (Sydenham's chorea) without
arthritis nor carditis
 carditis with or without arthritis
Acute Rheumatic Fever




Definition: an acute immunologically mediated,
inflammatory disease, which occurs as a sequel to
group A (beta-hemolytic) streptococcal pharyngitis
after an interval of 1- 4 weeks.
Multisystem disease involving the heart, joints,
brain, cutaneous and subcutaneous tissues.
Preventable disease
Major public health problem in heavily populated
underdeveloped and developing countries.
Rheumatic Fever: Incidence



Occurs in only 3% of patients with group A
streptococcal pharyngitis. Peak incidence: ages of
5-15 years. Girls>boys
Why not all patients that have GAS throat infection
will have R.F.? (different incidence)
Becaus there are microorganisms variables and
host variables:
 Microorganism variables: only certain strains (M
serotypes 1, 3, 5, 6, 14, 18, 24, 27, and 29) that
can produce the immunologically active Ag.
 Host variables: some will produce large amount
of Abs after each infection but others don’t.
Rheumatic Fever-Pathogenesis


Group A streptococcal(GAS) pharyngeal infection
 Body produce antibodies against streptococci,
these antibodies cross react with human tissues
because of the antigenic similarity between M
proteins of group A streptococci and human
connective tissues (molecular mimicry) there is
certain amino acid sequence that is similar
between GAS and human tissue.
Immunologically mediated inflamation & damage
(autoimmune disease) to human tissues which have
antigenic similarity with streptococcal components
like heart, joint, brain and connective tissues.


Bcs of the similsrity btw hyaluronic acid in GAS
capsule and in the connective tissue of the joints,
Ab produced agaist GAS capsule will start to attack
the joints and causes arthritis.
M-protein in GAS cell wall and the myocardium are
similar, thus Ab produced against GAS cell wall will
attack heart and will cause carditis and so forth.
Rheumatic Fever-Pathogenesis




There is no direct invasion to the tissue by the
microorganism, but it is an auotoimmune disease
that involves Ag-Ab interaction.
It must be pharyngeal infection not skin infection.
Always remember blood cultures of patients with
rheumatic fever are sterile.
Serological studies show elevated levels of
antibodies to streptococcal enzymes (streptolysin O
and DNAse B).
Rheumatic Fever:
Major Manifestations

Fever, migratory polyarthritis, pancarditis,
subcutaneous nodules, erythema marginatum of
skin, and sydenham’s chorea
Rheumatic Fever:
Major Manifestations
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Carditis (pancarditis): all 3 layers are involved
Arthritis: migratory polyarthritis (large joints)
Chorea:
spasmodic,
unintentional,
jerky
movements.
Subcutaneous nodule: painless, hard nodules
beneath skin, over bony prominence, tendons and
joints.
Erythema marginatum (rash): ring or crescent
shaped, transient patches over trunk and limbs.
Rheumatic Fever: Pathology



The characteristic lesion is a disseminated focal
inflammatory foci known as ( Aschoff bodies )
 A focus of fibrinoid necrosis surrounded by a
collection of lymphocytes, macrophages, few
plasma cells plus modified histiocytes known as
Anitschow cells (large amount of cytoplasm,
central nucleus, and prominent nucleolus), may
become multinucleated forming Aschoff giant
cells.
Inflammatory infiltrates in many tissues (synovium,
joints, skin, and heart).
Eventual fate is fibrosis (common in cardiac tissues).
Jones Criteria (Revised) for Guidance
in the Diagnosis of Rheumatic Fever
Major Manifestation
Carditis
Polyarthritis
Chorea
Erythema Marginatum
Subcutaneous Nodules
Minor
Manifestations
Clinical
Previous
rheumatic
fever or
rheumatic
heart disease
Arthralgia
Fever
Laboratory
Acute phase
reactants:
Erythrocyte
sedimentation
rate,
C-reactive
protein,
leukocytosis
Prolonged PR interval
Supporting Evidence
of Streptococal Infection
Increased Titer of AntiStreptococcal Antibodies ASO
(anti-streptolysin O),
others
Positive Throat Culture
for Group A Streptococcus
Recent Scarlet Fever
*The presence of two major criteria, or of one major
and two minor criteria, indicates a high probability of
acute rheumatic fever, if supported by evidence of
Group A streptococcal nfection.
Acute Rheumatic Carditis
(Pancarditis)


It is characterized by inflammatory changes
in all three layers of the heart.
Acute changes may resolve completely or
progress to scarring and chronic valvular
deformities.
Acute Rheumatic Heart Disease
Pathogenesis and Key Morphologic Changes
Pancarditis

Myocardium

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Endocardium: Common, affect mostly mitral and
aortic valves.



Scattered multiple foci of inflammation (Aschoff Bodies)
lie proximate to small vessels.
Diffuse interstitial inflammatory infiltrates.
Valves are edematous and thickened with foci of fibrinoid
necrosis. (Aschoff nodules uncommon).
Formation of small vegetations “fibrinous clots” along the
lines of valve closure (Verrucous Endocarditis).
Pericardium

Fibrinous Pericarditis: associated
serosanguinous pericardial effusion.
with
serous
or
Aschoff Body in Acute Rheumatic
Carditis
Aschoff body in acute rheumatic carditis.
Some large histiocytes with prominent
nucleoli, a prominent binuclear histiocyte,
and central necrosis.
Aschoff Body with “Caterpillar”
Nuclei
Verrucous Endocarditis
Fibrinous Pericarditis
Pancarditis
Clinical Manifestations


Symptoms:
 Pericardial friction rubs,
 Weak heart sounds,
 Tachycardia (rapid beating) and
 Arrhythmias.
In severe cases: myocarditis  cardiac
dilation

functional
mitral
valve
insufficiency or even congestive heart failure.
Chronic Rheumatic Heart
Diseases



It is characterized by irreversible deformity of
one or more cardiac valves. Usually mitral
valve is abnormal in 95% of cases.
Combined oartic and mitral valve disease is
present in 25% of cases. Aortic valve alone is
rarely affected.
Pulmonary and Tricuspid valves are extremely
rare to be affected.
Chronic Rheumatic Heart
Diseases
Pathological changes:
 Chronic scarring and calcification of the valve
leaflets → stiff and thickened structure →
stenotic valve orifice and Improper closure
(regurgitation).
 Shortening and fusion of the chordae
tendineae.
Chronic Rheumatic Heart
Diseases
Clinical manifestations: depend on which
valve is involved
 Cardiac murmurs,
 Arrhythmia,
 Hypertrophy,
 Dilation,
 Congestive heart failure,
 Thromboembolic complications
 Infective endocarditis
Chronic Rheumatic Mitral
Valvulitis
It is the most common cause of mitral stenosis
 It causes stenosis > regurgitation
 Occurs in females > males.
Mitral Stenosis:
 Leaflets are thick, rigid, and inter-adherent. And the
orifice is narrowed “fish mouth” deformity.
 Dilatation and hypertrophy of left atrium.
 Endocardium
is thickened particularly above
posterior mitral leaflet .
 Lungs: firm and heavy (result of chronic passive
congestion).

Chronic Rheumatic mitral
valvulitis
Mitral Regurgitation:
 Valve leaflets are retracted
 Left ventricular dilatation and hypertrophy.
Rheumatic mitral stenosis demonstrates
diffuse fibrous thickening and distortion of the
valve leaflets, commissural fusion (arrow) "fish
mouth" shape.
Chronic Aortic Valvulitis
 Males > females and usually associated with mitral
valvulitis.
 May occur in congenital bicuspid aortic valve (2%)
Aortic stenosis:
 Valve cusps are thickened, firm and adherent to
each other  the aortic valve orifice is reduced to
a rigid triangular channel.
 Aortic stenosis increases the pressure load on left
ventricle causing hypertrophy.
 Subsequent left ventricular failure is associated
with dilation of the chamber.
Rheumatic aortic stenosis demonstrating
thickening and distortion of the cusps with
commissural fusion (rigid triangular channel)
Calcific Aortic Stenosis
degenerative calcific aorticstenosis

Degenerative changes in the cardiac valves are
part of normal aging process, but it can develop to
cause pathologic stenosis.

The aortic valve leaflets are rigid and deformed by
calcified masses.

Fibrosis and calcification of the valve cusps lead to
valve sclerosis.

The calcium deposits lie behind the valve cusps (at
the bases of the cusps).
Calcific Aortic Stenosis
(degenerative calcific aortic stenosis)

The free edges of the cusps are usually not
affected. Calcific stenosis does not fuse the
cusps.

Symptom: severe cases may cause angina,
syncope (fainting), congestive heart failure,
L.V. hypertrophy, sudden death due to
arrhythmia.
Degenerative calcific aortic stenosis of a normal
valve having three cusps.
Nodular masses of calcium are heaped up within
the sinuses of Valsalva (arrow). Note that the
commissures are not fused.
Mitral Valve Prolapse

It is a common cardiac disorder (3-5% of adult
population, mainly females, ages 20-40 years).

It is usually an isolated problem but it may arise as a
complication of certain connective tissue disorders
(e.g. Marfan syndrome).

It has been reported as an isolated autosomal
dominant condition that maps to chromosome 16p.

Less commonly, as an x-linked recessive disorders.
Mitral Valve Prolapse
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Most patients are asymptomatic
Some have palpitations and fatigue
Some have atypical chest pain, and mid-systolic
click with a late systolic murmur.
The valve leaflets (posterior cusp) are soft and
enlarged → ballooning of the leaflets into left atrium
during systole.
Chordae tendineae are elongated, fragile and may
rupture in severe cases.
The valve annulus may be dilated.
Mitral Valve Prolapse
Microscopic examination
 Excessive amounts of loose, edematous, faintly
basophilic tissue within the middle layer (spongiosa)
of the valve leaflets and chordae.
Complications
 Mitral regurgitation and congestive heart failure.
 Sudden death caused by ventricular arrhythmias.
 Infective endocarditis.
Left ventricle demonstrates ballooning
with prolapse of the posterior mitral leaflet
into the left atrium.
Endocarditis
Infective Endocarditis (IE)

Infection of the cardiac valves or the
endocardium, resulting in the formation of
vegetation (mass of thrombotic debris and microorganisms) on valve leaflets, mostly aortic and
mitral valves.

IE. is divided into two forms:

Acute Infective Endocarditis

Subacute Infective Endocarditis
Infective Endocarditis
Acute
Subacute
Organism
High virulant
staphylococcus
Low virulant hemolytic
streptococcus
Valve
Normal and deformed
valves
Deformed valve
Progression
Rapid
Slow
Response
Little local reaction,
lession is destructive
Local inflammation,
lession is less
destructive
Resolution
Death (50%)
Recovery (antibiotics)
Infective Endocarditis
Etiology and Pathogenesis
Bacteremia
 Obvious hematogenous infection as with:
 Intravenous drug abusers,
 Elsewhere infection,
 Previous
dental, surgical or interventional
procedure (urinary catheterization).
 Occult source of bacteremia
 Small injuries to skin or mucosal surfaces such as
brushing the teeth.
Infective Endocarditis
Etiology and Pathogenesis
Causative Organisms

-Hemolytic
(viridans)
streptococci
deformed valves (50-60%).
attacks

Staphylococcus aureus attacks healthy or
deformed valves (intravenous drug abusers) (1020%) .

Coagulase-negative staphylococci (S. epidermidis)
attacks prosthetic valve.
Infective Endocarditis
Risk Factors

Cardiac abnormalities: such as chronic valvular
diseases and high pressure shunts within the heart
(small ventricular septal defects).

Prosthetic heart valves (10% to 20%).

Intravenous drug abusers (right side of the heart)
Pathology of Acute
Endocarditis


Gross: vegetations may obstruct valve orifice and
cause rupture of the leaflets, cordae tendineae, or
papillary muscles.
 May cause abscess in perivalvular tissue (ring
abscess).
 Vegetations may become systemic emboli 
infarcts (brain, kidneys, myocardium) and
abscesses.
Micro: vegetations consist of large number of
organisms, fibrin and blood cells.
Pathology of Subacute
Endocarditis

Gross: vegetations are firmer and less destructive
(ring abscess uncommon).


Systemic emboli may develop
infarcts, without abscesses.
and
cause
Micro: granulation tissue is seen at the base of the
vegetations.

Later: fibrosis, calcifications
inflammatory infiltrates.
and
chronic
Infective Endocarditis
Clinical Manifestation



Onset: gradual or explosive (organisms).
 Organism of low virulence cause low-grade fever,
malaise, weight loss.
 Organism of high virulence cause high fever,
shaking chills.
Cardiac murmurs, enlargement of spleen, clubbing
of digits (particularly in subacute cases), and
petechiae.
Blood culture is important (only minority of cases
remain negative).
Infective Endocarditis
Complications

Regurgitation leading to congestive heart failure.

Myocardial abscess (ring abscess).

Extension of infection to root of aorta (mycotic
aneurysm).

Systemic emboli, also pulmonary emboli in rightsided endocarditis.

Renal complications
Infarction).
(glomerulonephritis
and
Bacterial Endocarditis Remote Embolic
Effects
Endocarditis of the mitral valve
(subacute, caused by streptococcus
viridans)
Acute endocarditis of a congenitally
bicuspid aortic valve with severe cuspal
destruction and ring abscess (arrow).
Nonbacterial Thrombotic Endocarditis
(NBTE), Marantic Endocarditis




Characterized by sterile small nodules less than 5
mm, (fibrin, platelets and other blood components)
on the valve leaflets along the line of closure.
The valve leaflets are normal, no inflammation or
fibrosis.
Mitral valve is the most common site, followed by
aortic valve
It has been found to be associated with endothelial
abnormalities, deep venous thrombosis, and
malignancy (adenocarcinoma).
Libman-Sacks Endocarditis
(LSE)

Small sterile vegetations on ventricular or
both surfaces of mitral & tricuspid valves in
some patients with Systemic Lupus
Erythematosus.
Nonbacterial Thrombotic Endocarditis (NBTE).
Nearly complete row of thrombotic vegetations
along the line of closure of the mitral valve leaflets.
RHD: row of small vegetations along the lines of closure of the
valve leaflets.
IE: large, irregular masses on the valve cusps that extend onto
the cords.
NBTE: small, bland vegetations, usually attached at the line of
closure.
LSE: has small or medium-sized vegetations on either or both
sides of the valve leaflets.
Myocardial Diseases
Primary Myocardial
Diseases

A group of diseases intrinsic to myocardial fibers,
including mainly:

Myocarditis: inflammatory conditions
myocardium result in myocardium injury

Cardiomyopathies:
primary
abnormalities in the myocardium.
 Dilated
cardiomyopathy
 Obstructive
 Restrictive
cardiomyopathy
cardiomyopathy
of
the
non-infectious
Myocarditis

The heart may be of normal size, but more
commonly it is dilated.

The myocardium is flabby, pale and often contains
small areas of hemorrhage.

In most cases, myocarditis appears to be self-limited

Clinical features range from an asymptomatic state
to severe congestive heart failure at late stage

Arrhythmia:
lethal
ventricular
arrhythmias
accounting for most sudden cardiac deaths.
Myocarditis: Major Causes


Infections
Immune-Mediated Reactions
Myocarditis: Major Causes

Infections
Viruses: the most common cause in USA (e.g.,
coxsackievirus, echovirus).
 Chlamydia (e.g., C. psittaci)
 Rickettsia (e.g., R. typhi [typhus fever])
 Bacteria (e.g., Corynebacterium [diphtheria],
Neisseria [meningococcus], Borrelia [Lyme
disease])
 Fungi (e.g., Candida)
 Protozoa (e.g., Trypanosoma [Chagas disease],
the most common cause in South America)
 Helminths (e.g., trichinosis)

Myocarditis: Major Causes

Immune-Mediated Reactions
 Postviral and Poststreptococcal (rheumatic
fever)
 Systemic lupus erythematosus
 Drug hypersensitivity (e.g., methyldopa,
sulfonamides)
 Transplant rejection
Unknown : Sarcoidosis, and Giant cell myocarditis
Myocarditis: Microscopically

Viruses: edema and inflammatory infiltrate
dominated by lymphocytes, myocyte degeneration
and necrosis.

Chronic cases: ventricular dilation, inflammation is
less obvious, myocardial fibrosis becomes more
prominent

Parasites:
the
organism
is
demonstrable
histologically, (Chagas disease, trypanosomes
directly infect cardiac muscle fibers).
Myocarditis: Microscopically
(Cont......)

Bacteria: neutrophilic infiltrate, and sometimes
abscess.

Cardiac transplant rejection: interstitial lymphocytes
and myocyte degeneration.

Giant cell myocarditis is characterized by an
inflammatory infiltrate in which multinucleated giant
cells are prominent.
Lymphocytic Myocarditis:
Dense mononuclear inflammatory cell
infiltrate and associated myocyte injury.
Hypersensitivity Myocarditis:
interstitial inflammatory infiltrate composed
largely of eosinophils and mononuclear
inflammatory cells.
Giant Cell Myocarditis:
Mononuclear inflammatory infiltrate
(lymphocytes and macrophages), with
extensive loss of muscle, and multinucleated
giant cells, apparently derived from muscle.
Myocarditis:
Trypanosoma cruzi (Chagas disease).
Intracellular organisms inside a myocyte, no
inflammatory reaction.
Cardiomyopathies
Cardiomyopathies

Cardiomyopathies has been classified into three
forms:

Dilated Cardiomyopathy

Hypertrophic Cardiomyopathy

Restrictive Cardiomyopathy
Dilated Cardiomyopathy
(DCM)

Characterized by progressive cardiac hypertrophy,
dilation and contractile (systolic) dysfunction
(ineffective contraction, patients may have an
ejection fraction of less than 25%).
Dilated Cardiomyopathy (DCM)

Exact cause is unknown in 90% of cases, but can
result from:
 Viral myocarditis: presence of nucleic acids of
coxsackievirus B and other enteroviruses.
 Toxic chemicals:
 Alcohol abuse (ethanol toxicity)
 Cobalt
 Chemotherapeutic agents (Doxorubicin).
 Pregnancy: peripartum cardiomyopathy occurs
late in pregnancy or several weeks post partum.
DCM: Genetic and familial conditions




Inherited genetic abnormalities are responsible for
(20% to 30%) of cases of dilated cardiomyopathy.
Mutations in genes coding for cytoskeletal proteins:
 Mutations
in the dystrophin gene on X
chromosome (responsible for Becker and
Duchenne muscular dystrophy).
 Abnormalities
in genes encoding desmin,
merosin, and dystrophin-associated proteins
termed sarcoglycans.
Abnormalities in certain mitochondrial enzymes.
Mutations in certain sarcomere protein genes (e.g.,
β-myosin and cardiac troponin T).
DCM: Pathology
The heart is enlarged and flabby, weights 900 g (23X normal), this is caused by dilation and
hypertrophy of all chambers.
 Dilation and poor contractile function cause stasis of
blood in the cardiac chambers and predispose to the
development of fragile mural thrombi and
subsequent emboli.
Microscopic features are non-specific
 Myocyte hypertrophy
 Interstitial fibrosis, wavy fiber change
 Scanty mononuclear infiltrate (sometimes)

DCM: Clinical Features






DCM is the most common form, accounting for about
90% of cases.
Most common between ages of (20-60 years), men >
women.
Most cases arise sporadically (except familial
cases).
Patients develop progressive congestive heart
failure.
Prognosis is very poor (except peripartum DCM):
 50% die within 2yr, 75% within 5yr due to (CHF,
embolic complications or ventricular arrhythmias).
Cardiac transplantation is the only mode of therapy
DCM: Four-chamber dilation and
hypertrophy.
DCM: Histology demonstrating variable
myocyte hypertrophy and interstitial
fibrosis
Hypertrophic Cardiomyopathy (HCM)
Asymmetric septal hypertrophy or
Idiopathic hypertrophic subaortic stenosis
It is characterized by:
 Myocardial hypertrophy which causes powerful
contractions that rapidly expel blood from the
ventricular cavities.
 Abnormal (impaired) diastolic filling because of the
stiff, thick wall of the ventricle.
 The basic problem is an inability to fill a
hypertrophic left ventricle during diastole. Ejection
is forceful but ineffective because the amount of
blood in the left ventricle is greatly reduced.
Hypertrophic Cardiomyopathy (HCM)
Asymmetric septal hypertrophy or
Idiopathic hypertrophic subaortic stenosis
Pathogenesis:
 50% of cases, HCM inherited as an autosomal
dominant trait
 Mutations in genes encoding sarcomeric contractile
proteins.
 -myosin heavy chain (commonest 30%)
 Troponin I and T, -tropomyosin, and myosin
light chains
 Allelic heterogeneity
HCM: Pathology




The heart weights 800
gm
Hypertrophy of LV and
interventricular septum
“IVS”, without dilation
(the left atrium may be
dilated).
IVS is thicker than the
free (lateral) wall of the
left ventricle.
IVS hypertrophy is most
evident
in
subaortic
region
HCM: Pathology

It is often associated with ventricular outflow
obstruction during systole which is caused by
abnormal anterior motion of the mitral valve leaflet
during systole.

This motion lead to recurrent, forceful contact
between the septum and the anterior mitral leaflet
causing thickening of the anterior mitral leaflet and
adjacent septal endocardium.
HCM: Pathology
Microscopically

Irregular arrangement
of hypertrophied
abnormally branching
myocytes

Myocardial fibrosis (late
stage)
HCM: Clinical


Characterized by:
 Exertional dyspnea
 Harsh systolic ejection murmur
 Myocardial ischemia is common, and thus anginal
pain is frequent.
 Ventricular arrhythmias and sudden death
 Increased risk of infective endocarditis
 Later, progressive myocardial fibrosis may cause
congestive heart failure.
Prognosis: varies with the genetic defect, so
molecular diagnosis is useful
Restrictive Cardiomyopathy
(RCM)





Characterized by primary decrease in ventricular
compliance, resulting in impaired ventricular filling
during diastole.
The problem is a stiff and inelastic ventricle that can
be filled only with great effort, but the systole is not
forceful.
Myocardial contractility, although often normal early
in the course of the disease, usually declines,
causing congestive heart failure in later stages.
Symptoms: fatigue, exertional dyspnea, chest pain,
and arrhythmias
It is the least common type of Cardiomyopathy.
RCM: Causes




Endomyocardial fibrosis (the most common cause)
accounts for up to 10% of cases of childhood heart
disease in tropical areas.
Eosinophilic endomyocardial fibrosis (Löffler
syndrome), is rare.
Genetic factors are not clearly defined, but may
account for some cases (desmin mutations)
Additional
important
causes:
amyloidosis,
endocardial fibroelastosis,
hemochromatosis,
radiation injury to the heart.
RCM: Pathology

Tropical endomyocardial fibrosis and Löffler
syndrome:
 The atria are dilated, and the ventricles of
normal size
 The endocardium is thick and solid (left
ventricle).
 Microscopically: dense fibrosis in endocardium
& myocardium.
RCM: Pathology (Cont...)


Eosinophilic endomyocardial fibrosis:
 infiltration by eosinophils (early stages).
Endocardial fibroelastosis (uncommon):
 Occurs mostly in children < 2 years of age,
 Abundant
fibroelastic
tissue
in
the
endocardium
revealing
porcelain-like
appearance).
Pericarditis
Pericarditis

Primary: uncommon, mostly viral and sometimes by
other organisms (pyogenic bacteria, mycobacteria
and fungi).

Secondary to:
 Acute
myocardial infarction, cardiac surgery, or
radiation to the mediastinum.
 Associated
with systemic disorders, mostly with
uremia, rheumatic fever, systemic lupus
erythematosus
(SLE),
and
metastatic
malignancies (bloody effusions).
Pericarditis Outcomes

Pericarditis may

Cause immediate hemodynamic complications if
a significant effusion is present

Resolve without significant sequelae

Progress to a chronic fibrosing process.
Acute Pericarditis: Morphology





In uremia, and acute rheumatic fever: the exudate is
fibrinous and impart a shaggy irregular pericardial
surface (bread and butter pericarditis).
Viral pericarditis  fibrinous exudate.
Acute bacterial pericarditis  fibrinopurulent
exudate.
Tuberculosis caseous materials and hemorrhagic
pericarditis
Pericardial metastases: irregular nodules with a
shaggy fibrinous exudate and a bloody effusion .
Fibrinous Pericarditis
The pericardial surface shows strands
of pink fibrin extending outward.
There is underlying inflammation.
Chronic Pericarditis:
Morphology

Ranges from delicate adhesions to dense fibrotic
scars.

In extreme cases the heart cannot expand normally
during diastole, a condition called constrictive
pericarditis.
Pericarditis: Clinical




Atypical chest pain (worse on reclining),
Friction rub.
Significant exudate  signs and symptoms of
cardiac tamponade  faint distant heart sounds,
distended neck veins, declining cardiac output, and
shock.
Chronic constrictive pericarditis  venous
distension and low cardiac output.
Pericardial Effusions

Accumulation of fluid in the pericardium, fluid nature
varies with cause, major types and their causes are:
 Serous:
congestive
heart
failure,
hypoalbuminemia
 Serosanguineous:
blunt
chest
trauma,
malignancy
 Chylous: mediastinal lymphatic obstruction
 Fibrinous / Serofibrinous: RF, connective tissue
diseases, MI and post-MI, trauma & uremia
 Blood
(Hemopericardium): ruptured aortic
aneurysms,
ruptured
myocardial
infarcts,
penetrating traumatic injury to the heart.
Cardiac Tumors


Heart tumor are rare
Metastatic Neoplasms: metastases may reach the
heart via lymphatic, venous, or arterial channels.
 seen in up to 10% of patients dying of
disseminated
cancer,
mostly
involving
pericardium.
 The most common primary neoplasms that
metastasize to the heart are:
 carcinomas of the lung and breast,
 malignant melanomas,
 lymphomas & leukemias.
Cardiac tumors
Primary tumors include:

Myxoma: is commonest heart tumor in adults,
benign, 90% in Lt atrium. They appear as sessile or
pedunculated gelatinous mass covered by
endothelium

Microscopically: multinucleated stellate (Starshaped) cells, edema and mucoid stroma.
Cardiac tumors



Rhabdomyoma
 Common (infancy and children)
 Associated with tuberous sclerosis
 Grossly: myocardial masses project into the
ventricular lumen solitary or multifocal.
 Microscopically:
eosinophilic, polygonal cells
(contain
large,
glycogen-rich
cytoplasmic
granules).
Lipoma, and Papillary Elastofibromas,
Sarcomas: Angiosarcomas, and Rhabdomyosarcomas.
Vascular Diseases
Vasculitis

Inflammation of blood vessels of any size,
affecting one or few vessels in a limited
area or it could be systemic affecting
multiple organ systems.
Vasculitis

Mostly immune reaction related:
 Immune complexes.
(SLE, cryoglobulinemic vasc.)
(hypersensitivity)
(viral infection, hepatitis)
 Antineutrophil cytoplasmic antibodies (ANCAs).
 p-ANCAs (perinuclear  myeloperoxidase)
(microscopic polyangiitis, Churg-Strauss
syndrome)
 c-ANCAs (cytoplasmic  proteinase 3)
(Wegener granulomatosis)
Vasculitis


Mostly immune reaction related:
 Immune complexes.
 Antineutrophil cytoplasmic antibodies (ANCAs).
 Antiendothelial Cell Antibodies: induced by
defects in immune regulation (SLE, Kawasaki)
Infection
Direct Infection
Bacterial (e.g., Neisseria)
Rickettsial (e.g., Rocky Mountain spotted fever)
Spirochetal (e.g., syphilis)
Fungal (e.g., aspergillosis, mucormycosis)
Viral (e.g., herpes zoster-varicella)
Classification of
Vasculitis
Based on
Pathogenesis
Immunologic
Immune complex-mediated
Infection-induced (e.g., hepatitis B and C virus)
Henoch-Schönlein purpura
Systemic lupus erythematosus and rheumatoid arthritis
Drug-induced
Cryoglobulinemia
Serum sickness
Antineutrophil cytoplasmic autoantibody-mediated
Wegener granulomatosis
Microscopic polyangiitis (microscopic polyarteritis)
Churg-Strauss syndrome
Direct antibody attack-mediated
Goodpasture syndrome (anti-glomerular basement membrane antibodies)
Kawasaki disease (antiendothelial antibodies)
Cell-mediated
Allograft organ rejection
Inflammatory bowel disease
Paraneoplastic vasculitis
Unknown
Giant cell (temporal) arteritis
Takayasu arteritis
Polyarteritis nodosa (classic polyarteritis nodosa)
Classification of vasculitis


The systemic vasculitides are classified on the
basis of the
 Size and
 Anatomic site of the involved blood vessels,
 Histologic characteristics of the lesion, and
 Clinical manifestations.
There is considerable clinical and pathologic
overlap among these disorders,
Classification of vasculitis




Polyarteritis nodosa:
 Medium - sized & small arteries.
Wegener’s granulomatosis:
 Arterioles,venules,capillaries and small blood
vesseles.
Microscopic polyarteritis (hypersensitivity
vasculitis):
 Venules, capillaries & arterioles.
Temporal (giant cell,cranial) arteritis:
 Mainly affects large blood vesseles.
Giant Cell (Temporal) Arteritis

The most common of the vasculitis, is an acute
and chronic, often granulomatous inflammation of
arteries of large to small size (mainly in the headespecially the temporal arteries but also the
vertebral and ophthalmic arteries (Blindness).

Lesions have also been found in other arteries
throughout the body, including the aorta (giant cell
aortitis).
Giant Cell (Temporal) Arteritis:
Morphology


Characteristically, segments of affected arteries
develop nodular thickenings with reduction of the
lumen and may become thrombosed.
Common variant:
 granulomatous inflammation of the inner half of
the media centered on the internal elastic
membrane marked by
 a lymphocytic infiltrate,
 multinucleate giant cells,
 fragmentation of the internal elastic lamina,
 macrophages are seen close to the damaged
elastic lamina.
Giant Cell (Temporal) Arteritis
(Morphology Cont..)


Less common pattern, a nonspecific panarteritis
with a mixed inflammatory infiltrate (lymphocytes,
macrophages, neutrophils and eosinophils).
Healed stage of both of these patterns reveals
collagenous thickening of the vessel wall;
organization of the luminal thrombus sometimes
transforms the artery into a fibrous cord.
Giant Cell (Temporal) Arteritis:
Pathogenesis


Evidence points to a T-cell-mediated immune
response to an unknown, possibly vessel wall,
antigen.
Supporting this hypothesis are a granulomatous
inflammatory response with the presence of CD4+
T cells.
Giant Cell (Temporal) Arteritis:
Clinical Features




Rare before the age of 50 (F:M = 2:1) .
Symptoms are constitutional fever, fatigue, weight
loss-without localizing signs or symptoms
The diagnosis depends on biopsy and histologic
confirmation.
Treatment with anti-inflammatory agents is
remarkably effective.
Temporal (giant cell) arteritis.
Giant cells at the degenerated internal elastic
membrane in active arteritis and intimal
thickening.
Temporal (giant cell) arteritis.
Elastic tissue stain demonstrating focal
destruction of internal elastic membrane (arrow)
and intimal thickening (IT) characteristic of longstanding or healed arteritis.
Polyarteritis Nodosa (PAN)


Systemic
vasculitis
(segmental
transmural
necrotizing inflammation) of small or medium-sized
muscular arteries (but not arterioles, capillaries, or
venules), typically involving kidneys, heart, liver,
and gastrointestinal tract, but sparing the pulmonary
circulation.
Individual lesions may involve only a portion of the
vessel circumference with preference for branching
points.
Polyarteritis Nodosa (PAN)
(Cont...)



Inflammatory process causes segmental erosion
with weakening of the arterial wall which may cause
aneurysm or rupture.
Impairment of perfusion, causing ulcerations,
infarcts, ischemic atrophy, or hemorrhages.
Sometimes the lesions are exclusively microscopic
with no gross changes.
Polyarteritis Nodosa (PAN):
Histologically




The acute phase demonstrates neutrophils,
eosinophils, and mononuclear cells and is
frequently accompanied by fibrinoid necrosis. The
lumen may become thrombosed.
Later, the acute inflammatory infiltrate disappears
and is replaced by fibrous thickening of the vessel
wall that may extend into the adventitia.
Firm nodularity sometimes marks the lesions.
All stages of activity may coexist in different vessels
or even within the same vessel.
Polyarteritis Nodosa:
Clinical Course



> young adults <, Acute, subacute, or chronic and is
frequently remittent and episodic.
Malaise, fever of unknown cause, and weight loss;
hypertension, abdominal pain and melena (bloody
stool), diffuse muscular aches and pains, and
peripheral neuritis.
Renal involvement is often prominent and a major
cause of death. There is no glomerulonephritis
because small vessel involvement is absent.
Polyarteritis Nodosa:
Clinical Course




30% of PAN patients have hepatitis B antigen in
their serum.
There is no association with ANCA.
Poor prognosis: death if not treated, but therapy with
corticosteroids and cyclophosphamide results in
remissions or cures in 90%.
Clinical diagnosis by biopsy of the suspected area of
involvement.
Polyarteritis nodosa with segmental fibrinoid
necrosis and thrombotic occlusion of the lumen of
this small artery. Note that part of the vessel wall at
the upper right (arrow) is uninvolved.
Wegener’s Granulomatosis


Necrotizing vasculitis characterized by the triad of:
 Acute necrotizing granulomas of the upper
respiratory tract (ear, nose, throat), or the lower
respiratory tract (lung) or both.
 Necrotizing or granulomatous vasculitis affecting
small to medium-sized vessels (capillaries,
venules, arterioles, and arteries), mostly in the
lungs and upper airways.
 Renal disease (focal necrotizing, often crescentic,
glomerulonephritis).
Limited forms, or more widespread WG (eye, skin).
Wegener’s Granulomatosis




Pathogenesis
 Immunologic mechanisms of Cell Mediated type.
 > 95% c-ANCA positive.
 May be hypersensitivity to an inhaled agent.
Clinical picture
 overlaps with PAN and occurs more in males
 peak 5th decade
Diagnosis (Lung biopsy)
Prognosis: 80% die within a year
 90% respond to treatment
Wegener granulomatosis.
There is inflammation (vasculitis) of a small artery
along with adjacent granulomatous inflammation,
in which epithelioid cells and giant cells (arrows)
are seen.
Micoscopic Polyangiitis
(Microscopic Polyarteritis, Hypersensitivity,
or Leukocytoclastic Angiitis)


Necrotizing vasculitis: (Arterioles, capillaries,
venules). All lesions tend to be of the same age.
Involve
 skin (palpable purpura),
 mucous membranes,
 lungs (capillaritis: hemoptysis),
 brain, heart,
 GI (bowel pain or bleeding),
 kidneys
(necrotizing
glomerulonephritis:
hematuria, proteinuria), and
 muscle (muscle pain or weakness).
Micoscopic Polyangiitis
(Microscopic Polyarteritis, Hypersensitivity,
or Leukocytoclastic Angiitis)



Precipitating cause: immunologic reaction to an
antigen
 drug: penicillin
 microorganisms: strept ococcus
 heterlogous proteins and tumor antigens.
Removal of the offending agent improve the case
p-ANCAs are present in 70-80% of patients.
Micoscopic Polyangiitis
(Microscopic Polyarteritis, Hypersensitivity,
or Leukocytoclastic Angiitis)
Morphology
 The transmural necrotizing lesions of microscopic
polyangiitis often resemble those of PAN with
segmental fibrinoid necrosis of the media.
 Macroscopic infarcts similar to those seen in PAN
are uncommon.
 In some lesions the change is limited to infiltration
with neutrophils, which become fragmented as they
follow the vessel wall, giving rise to the term
leukocytoclastic angiitis.
Leukocytoclastic vasculitis in a skin.
Fragmentation of neutrophil nuclei in and
around vessel walls.
Kawasaki’s disease
(mucocutaneous lymph node syndrome)






Acute illness of infants and children characterized by
fever, lymphadenopathy, skin rash, oral/ conjunctival
erythema.
Associated with an arteritis affecting large, mediumsized, and small vessels.
Its clinical significance stems from the involvement of
coronary arteries.
20% have coronary vasculitis, often with aneurysm.
Histology like PAN
Etiology ; unknown, it is self-limited disease, rarely
fatal(1%) due to complications of coronary
involvement.
Thromboangiitis Obliterans
(Buerger’s disease)



Distinctive disease leads to vascular insufficiency,
is characterized by segmental, thrombosing, acute
and chronic inflammation of medium and small
arteries, (tibial and radial arteries and adjacent
veins and nerves).
It almost always affects males (ages 20 to 40 ) who
have a history of smoking or chewing tobacco,
however, a higher percentage of women and
people over the age of 50 have been recognized to
have this disease.
May leads to gangrene.
Thromboangiitis Obliterans
(Buerger’s disease)


Pathogenesis: derivative of tobacco or tobacco
smoke may cause endothelial cell injury or incite an
immunologic reaction in predisposed persons.
Microscopically, acute and chronic inflammation
permeates the arterial walls, accompanied by
thrombosis of the lumen, which may undergo
organization and recanalization.
 The thrombus contains small microabscesses
with a central focus of neutrophils surrounded by
granulomatous inflammation
Thromboangiitis obliterans (Buerger disease)
The lumen is occluded by a thrombus containing
two abscesses (arrows). The vessel wall is
infiltrated with leukocytes.
Arteriosclerosis
Arteriosclerosis


Hardening of arteries (Thickening and loss
of elasticity of arterial walls).
Three pattern
 Atherosclerosis
 Monckeberg
 Arteriolosclerosis
Monckeberg Medial Calcific Sclerosis

Focal dystrophic Calcific deposits in the media.

It occurs in old age group >50 in:

Small to medium-sized muscular arteries of
 Lower
 Head
 Pelvis
limb
and neck
(especially the uterine arteries).

Of unknown
significance
etiology
and
of
little
clinical

There is higher incidence in diabetic individuals.
Monckeberg Medial Calcific Sclerosis





No lumenal narrowing, No ischemic and embolic
phenomena
In advanced cases, stenosis and atheroma may
occur, but
the lumen usually remains patent
(open), and vessels may become rigid and lose
their distensibility leading to "pipe-stem" rigidity.
Calcified arteries may be visualized on
radiographs.
Histology: Ring like or plate calcification in media.
Asymptomatic, however, it may co-exist with
atherosclerosis.
Monckeberg's Medial Calcific Sclerosis
Calcification affects only the media.
Arteriolosclerosis

Affects small arteries and arterioles

Cause thickening of vessel walls with luminal
narrowing that may induce ischemic injury, and is
best demonstrated in the renal arterioles.

Most often associated with hypertension and
diabetes mellitus.

Two anatomic variants

Hyaline arteriolosclerosis

Hyperplastic arteriolosclerosis
Hyaline Arteriolosclerosis


Characterized by

Diffuse, homogeneous, pink hyaline thickening of
the walls of arterioles.

Loss of underlying structural detail and narrowing
of the lumen

Occurs typically in elderly patients.

Advanced lesions are seen in persons with
diabetes mellitus and/or with hypertension.
Hyaline arteriolosclerosis
kidneys.
is typically seen in
Hyaline Arteriolosclerosis

Endothelial injury causes leakage of plasma
components across vascular endothelium, and
excessive extracellular matrix production by smooth
muscle cells.

This process is associated with lumenal narrowing
that may induce ischemic injury

Afferent & efferent arterioles in kidney→benign
nephrosclerosis
Hyaline Arteriolosclerosis
Markedly thickened arteriole to the lower right of
this glomerulus
Hyaline Arteriolosclerosis
Arteriolar wall is hyalinized and the lumen is
markedly narrowed
Hyperplastic Arteriolosclerosis

Concentric laminated (onion skin) arteriolar
thickening with reduplicated basement membrane
and smooth muscle cells proliferation.
 Commonly
associated
with
malignant
hypertension
 Leads to lumenal narrowing
 Frequently associated with fibrinoid necrosis
(necrotizing arteriolitis).
 Later, the vascular walls hypertrophy due to
hyperplasia of SMCs and sometimes this occurs
along with necrosis of the vessel wall.
Hyperplastic Arteriolosclerosis
Onion skin appearance
Narrow Lumen
Onion Skin Thickening
Of arterioles.
Hyperplastic Arteriolosclerosis
(Onion-Skinning) causing luminal obliteration (arrow)
Hyperplastic Arteriolosclerosis
Fibrinoid necrosis
Atherosclerosis (ATH)

Systemic disease at multiple sites affects vital
organs, in which ATH is revealed at:

Elastic arteries

Large arteries

Medium sized arteries.

It is common worldwide, almost everyone in U.S is
subject to ATH if they live long enough. Accounting
for about 50% of all deaths in West.

The characteristic lesion of ATH is called atheroma
ATH: Atheroma (fibrofatty plaques)

Atheroma is focal lesion of intima, that is
characterized by intimal deposition of lipids,
intruding into the lumen (0.3 to 1.5 cm in
diameter),

Atheroma leads to intimal thickening, scarring, and
reducing the lumen size causing stenosis, which
ends with ischemia and infarction.
Atheroma: Gross


Atheroma consist of lipid core covered by a firm
white fibrous cap, and have three main
components:

Cells:
including
leukocytes
SMCs,
macrophages,

Extracellular matrix, including collagen, elastic
fibers, and proteoglycans

Intracellular and extracellular lipid.
Around the lesions, there is neovascularization.
Foam cells are large lipid-laden cells that derive predominantly
from blood monocytes (tissue macrophages), but SMCs can
also absorb lipid to become foam cells.
Two type of atheromatous plaques
Soft plaques (abundant lipid).
Solid or fibrous plaques (SMCs and fibrous tissue).
Atheroma


Plaques
through
change
and
progressively
enlarge

Cell death and degeneration,

Synthesis and degradation of extracellular
matrix,

Organization of thrombus.

Atheroma often undergo calcification.
Complication: rupture (ulceration or erosion),
hemorrhage, thrombosis, aneurysmal dilation




Large BV :
 Abdominal aorta
 Iliac
In descending order
 Coronary
 Popliteal
 Carotid
 Circle of Willis.
Vessels of the upper
extremities are usually
spared,
The severity of AS in one
artery does not predict its
severity in another
Atherosclerosis: Complications


Major consequences
 Coronary arteries: IHD (myocardial infarction)
 Cerebrovascular
system: Cerebral infarction
(stroke)
 Aorta: Hypertension and aneurysm formation
 Peripheral vascular system
 Decreased perfusion to extremities (gangrene
of the legs)
More consequences (diminished arterial perfusion)
 Mesenteric occlusion, Sudden cardiac death,
Chronic IHD, Ischemic encephalopathy
Atherosclerosis: Fatty streaks





Fatty streaks, (composed of foam cells), are not
significantly raised and thus do not cause any
disturbance in blood flow.
They begin as multiple yellow, flat spots (fatty
dots) less than 1 mm, then combine into
elongated streaks.
Fatty streaks appear in the aortas of children
regardless of geography, race, sex, or
environment.
Coronary fatty streaks begin to form in
adolescence.
The relationship of fatty streaks to atherosclerotic
plaques is uncertain.
Gross views of atherosclerosis in the aorta.
A. Mild atherosclerosis composed of fibrous plaques,
one of which is denoted by the arrow.
B. Severe disease with diffuse, complicated lesions.
Morphologic types
Fatty dots
Atheroma Plaques
Complicated
Histologic features of atheromatous plaque
in the coronary artery.
Histologic features of
atheromatous plaque in the
coronary artery.
The plaque shown in A,
stained for elastin (black)
demonstrating that the
internal and external elastic
membranes are destroyed
and the media of the artery
is thinned under the most
advanced plaque (arrow).
Histologic features of
atheromatous plaque in the
coronary artery.
The junction of the fibrous
cap and core showing
scattered inflammatory cells,
calcification (broad arrow),
and neovascularization (small
arrows)
Atherosclerosis:
Risk Factors

Non-modifiable risk factors (Constitutional)


Modifiable risk factors (Major)


Age, Sex, Genetics
Hyperlipidemia,
Diabetes
Hypertension,
Smoking,
Modifiable risk factors (Other)

Diet (obesity), life style (stress), personal habits
(lack of regular exercise)
Atherosclerosis
Constitutional Risk Factors

Age: it is clinically evident after middle age, between
ages 40-60 increases the incidence of MI 5 fold.

Sex: men > premenopausal women, but men = women
by 7th-8th decades (↓ postmenopausal estrogen).

Genetics: familial predisposition (polygenic)

Well-defined hereditary genetic derangement in
lipoprotein
metabolism
(familial
hypercholesterolemia)

Familial clustering of other risk factors: hypertension
or diabetes
Atherosclerosis: Major Risk Factors
Hyperlipidemia (Hypercholesterolemia)



LDL increases the risk of ATH.
HDL has a protective effect (negative risk factor).
 It mobilizes the cholesterol from tissues to liver,
 It is increased by exercise and ethanol use
High dietary intake
 Bad fats: cholesterol and saturated fats (egg yolk,
animal fats, and butter)
 Good fats such as omega-3 fatty acids (fish oils),
unsaturated fats)
 Low ratio of saturated to polyunsaturated fats
lowers risk.
Atherosclerosis: Major Risk Factors
Hypertension



Hypertension: Men ages 45-62 with (BP 169/95) →↑
X 5 of IHD than men with (BP 140/90).
Cigarette smoking increases the incidence and
severity of ATH in M &F and decreases HDL
 1 pack +/day for years→↑ X2-3 of death rate
from IHD
Diabetes mellitus
 Induces hypercholesterolemia
 MI (X 2)
 stroke
 gangrene (X100- 150)
Atherosclerosis: Other Risk Factors

Decrease physical activity (lack of regular exercise)

Life style (competitive, stressful with type A
personality)

Obesity (decrease HDL)

Multiple risk factors have multiplicative effect.
ATH may develop in absence of known risk factor.

Atherosclerosis: Other Risk Factors
(Cont…)

Hyperhomocystenemia: homocysteine increases
platelet adhesion and coagulation abnormalities,
resulting in increased arterial and venous clots,
leading to strokes and heart attacks

Can be caused by low intake of Folic acid,
vitamin B
Atherosclerosis – Pathogenesis
The Response to Endothelium Injury Hypothesis
1. ATH is considered to be a chronic inflammatory
response of the arterial wall initiated by injury to the
endothelium (focal areas of chronic endothelial
injury (slight), because of

derivatives of cigarette smoke,

homocysteine,

viruses and other infectious agents,

hyperlipidemia
Atherosclerosis – Pathogenesis
The Response to Endothelium Injury Hypothesis
2. Result in endothelial dysfunction that causes

↑endothelial permeability,

enhanced leukocyte adhesion

alteration in expression of EC gene products
(ICAM-1) & (VCAM-1) that mediate adhesion of
circulating monocytes, lymphocytes and platelets.
(thrombotic potential)
Atherosclerosis – Pathogenesis
The Response to Endothelium Injury Hypothesis
3.Depositions of lipoproteins in the vessel wall, mainly
LDL with its high cholesterol content. Then
modification of lesional lipoproteins by oxidation.
4.Adhesion of blood monocytes (and other
leukocytes) to the endothelium, followed by their
migration into the intima and their transformation
into macrophages and foam cells.
5.Adhesion of platelets.
Atherosclerosis – Pathogenesis
The Response to Endothelium Injury Hypothesis
6. Release of factors from activated platelets and
macrophages that cause migration of SMCs from
media into the intima.
7. Proliferation of SMCs in the intima, and elaboration
of extracellular matrix, leading to accumulation of
collagen and proteoglycans.
8. Enhanced accumulation of lipids both within cells
(macrophages and SMCs) and extracellularly.
Atherosclerosis - Pathogenesis
The Role of Endothelial Injury

Determinants of endothelial alterations

Homodynamic disturbances

Effects of hypercholesterolemia

Tendency for plaques to occur at ostia of exiting
vessels, branch points and along the posterior
wall of the abdominal aorta (where there are
disturbed flow patterns).
Atherosclerosis - Pathogenesis
The Role of Lipids

Evidence linking hypercholestrolemia & ATH

Increased LDL cholesterol levels, decreased
HDL cholesterol levels, and increased levels of
the abnormal Lp(a)

Lipids in atheromas (plaques) are plasmaderived cholesterol and cholesterol esters.

Relationship between increased LDL level and
the severity of ATH
Atherosclerosis - Pathogenesis
The Role of Lipids ( Cont…)

Genetic or acquired
hypercholesterolemia.
 familial
conditions
result
in
hypercholesterolemia
 diabetes
mellitus
 hypothyroidism
 nephrotic
syndrome
 alcoholism

Lowering levels of serum cholesterol by diet or
drug slows the rate of progression of ATH, and
causes regression of plaques.
Atherosclerosis - Pathogenesis
The Role of Lipids (mechanisms)

Hyperlipidemia, may directly impair EC function
through increased production of oxygen free
radicals (in macrophages or EC) that deactivate
nitric oxide (the major endothelial-relaxing factor).

Free radicals induce chemical changes of lipid in
the arterial wall by oxidizing LDL, leading to:

Accumulation of lipoproteins (mainly LDL or
oxidized LDL) in intima at sites of increased
endothelial permeability.
Atherosclerosis - Pathogenesis
The Role of Lipids (mechanisms)

Role of oxidized LDL in atherogenesis
 Oxidized LDL is ingested through scavenger
receptor of macrophages thus forming foam
cells.
 Increases monocytes accumulation in lesion
(adhesion)
 Stimulates release of GF & cytokines
 Oxidized LDL is cytotoxic to ECs and SMCs
 Oxidized LDL can induce endothelial cell
dysfunction
The Role of
Monocytes, Macrophages and Platelets



Adhesion of monocytes to ECs, then migration into
the intima, followed by transformation into
macrophages which engulf lipoproteins largely
oxidized LDL to become foam cells.
 Macrophages
produce IL-1 & TNF which
increase adhesion of leukocytes
 Macrophages produce toxic O2 species
 Macrophages elaborate GF that contribute in
SMC proliferation.
Adhesion of platelets
Release of factors from activated platelets and
macrophages that cause migration of SMCs from
media into the intima.
Atherosclerosis - Pathogenesis
The Role of Smooth Muscle Cell Proliferation

Proliferation of SMCs in the intima and elaboration
of ECM, leading to accumulation of collagen and
proteoglycans.

Convert fatty streak into a mature fibrofatty
atheroma and contribute to the progression of
ATH.

Enhanced accumulation of lipids both within cells
(macrophages and SMCs) and extracellularly.
Ischemic Heart
Diseases
Ischemic Heart Diseases (IHD)

A group of closely related syndromes caused by an
imbalance between the myocardial oxygen
demands and blood supply.
 It accounts for 80% of cardiac death and nearly
1/3 of all deaths in developed countries .
 The most common cause of IHD is luminal
narrowing of the C.A. by atherosclerosis and the
following contributing factors:
 Acute plaque changes
 Coronary artery thrombosis
 Coronary artery vasospasm
Ischemic Heart Diseases (IHD)

Clinical syndromes of IHD
 Angina
pectoris
 Myocardial
infarction
 Sudden
cardiac death
 Chronic
IHD
Angina Pectoris (AP)

Characterized by episodic attacks of crushing or
squeezing substernal pain, radiating to precordium
and left arm.

Types of Angina

Typical stable AP

Prinzmetal or variant angina

Unstable Angina
crescendo angina)
(preinfarction
angina
or
Angina Pectoris (AP)

Typical stable AP

Chest pain associated with exertion, stress
and emotion.

Usually there is fixed atherosclerotic
narrowing (75%) of C.A (stenosis).

Relieved by rest and nitroglycerine.
Angina Pectoris (AP)

Prinzmetal or variant angina

Occurs at rest, less frequently related to effort

Caused by C.A. spasm
atherosclerotic plaque.

Respond to nitroglycerine
usually
near
Angina Pectoris (AP)

Unstable Angina
crescendo angina)
(preinfarction
angina
or

More frequent, more intense and provoked by
less effort or emotion

Increased frequency of anginal pain and Lasts
longer

Caused by acute plaque change with
superimposed partial thrombosis or vasospasm

Nitroglycerine is required more but it is less
effective
What is your diagnosis

Severe, crushing substernal chest pain, which
may radiate to the neck, jaw, epigastrium,
shoulder, or left arm.

This pain lasts several hours to days and is not
significantly relieved by nitroglycerin.

The pulse is generally rapid and weak

Patient is diaphoretic
breathing (dyspnea).
(sweating)
with
short
Myocardial Infarction (MI)

An area of myocardial necrosis caused by local
ischemia.

Acute MI is the most common cause of death in
the west. 1.5 million MI/ year in USA, with 1/2
million deaths, 50% do not reach hospital.

Ages 45-54, M>F (Risk factors same as of
atherosclerosis).
Myocardial Infarction (MI)

Pathogenesis

Most acute MIs are caused by coronary artery
thrombosis.

Important contributing factors are:
 Acute
plaque
thrombosis.
 Vasospasm
changes
followed
by
and platelet aggregation may
contribute to coronary artery occlusion.
Acute myocardial infarction (MI)


MI typically begins in the subendocardial region
and extends over the next (3-6) hours to involve
the mid- and subepicardial areas of the
myocardium
Two types of M I
 Transmural: full thickness infarction > 2.5 cm in
diameter caused by sever atheroma with acute
plaque changes leading to complete occlusion.
 Subendocardial: limited to inner 1/3 of wall
thickness, caused by ischemia due to diffuse
coronary atherosclerosis (stenosis).
Morphology of MI


Size of MI depends on segment of C.A. blocked
and collateral circulation
The location of MI depends on site of occlusion and
type of coronary circulation
 Left anterior descending coronary artery (LAD)
(40%- 50%)
 Anterior and apical LV+ ant 2/3 of IVS
 Right coronary artery (RCA) (30% - 40%)
 Posterior LV + post 1/3 of IVS( in right
dominance)
 Left circumflex coronary artery LCA (15% - 20%)
 Lateral LV + post wall ( in left dominance)
0-12 hours
There are no morphological changes yet.
12-18 hours
Coagulation necrosis begins, the cytoplasm of the necrotic myocytes becomes
eosinophilic, loss of cross striations, pyknosis and karyorrhexis. Wavy fiber
change at the periphery of the infarct.
18-72 hours
The area shows a slight pallor. Neutrophils begin to show up and peak about 3
days and subsequently diminish. Hemmhorage is rare because MIs are
ischemic by definition. contraction bands at the periphery of the infarct
produced by hypercontraction of myofibrils in dying cells.
4-7 days
The infarct will appear pale firm with a hyperemic boarder. Macrophages,
fibroblasts and capillaries first appear at the margins then begin to migrate
into center. Macrophages begin to phagocytize the necrotic myocytes.
10 days
The necrotic area is yellow, soft; the granulation tissue is visible grossly at the
edge of the infarct as a red-purple zone. Collagen fibers are seen and many
macrophages with remnants of myocytes.
4-8 weeks
Vascularity diminishes and most infarcts have been replaced by dense scar
tissue. The ventricular wall is thinned, firm, and gray at the site of the
healed infarct
Myocardial Infarct, early changes
(Wavy Fibers)
Early Acute Myocardial Infarct
(Few PMN’s)
Acute Myocardial Infarct
Coagulative Necrosis
Organizing Myocardial Infarct
Granulation Tissue
Old Myocardial Infarct
(Collagen Scar)
Organizing Myocardial Infarct
Complications of MI





Infarcted papillary muscle rupture is most common
at third day. It causes acute left ventricular failure
and is associated with a high mortality rate.
External rupture usually towards the end of the week
1 as blood dissects through the myocardium. It
causes hemopericardium and cardiac tamponade. It
can also dissect through the IV septum.
Mural thrombi are potential sources for systemic
emboli.
Acute pericarditis occurs in (15%) of patients with MI
within 2 to 4 days.
Ventricular aneurysm is a late complication
Complications of MI


After infarction about 25% of patients experience
sudden death due to fatal arrhythmia.
If patients survive the acute event, 80% to 90%
develop complications.
 Arrhythmias (75% - 95%)
 Left ventricular failure with mild to severe
pulmonary edema (60%)
 Cardiogenic shock (10%) if infarct > 40% of LV
mass.
 Thromboembolic phenomena (15%-49%).
MI - Laboratory diagnosis

Creatine kinase (MB fraction) rises within 4-6
hours, peaks early and is normal within 4 days.

LDH rises in about 24 hours, peaks in 3-6 days
and may be abnormal for 14 days. The most
sensitive is the ratio of LDH1 to LDH2 (normally <
1.0 ; ratio "flipped" in infarction).

Troponin I & T, troponin levels remain elevated for
4 to 7 days after the acute event
Sudden cardiac death

Unexpected death from cardiac causes within one
hour of the onset of symptoms.

Majority are complication of IHD.

75 - 95 % have marked coronary atherosclerosis.

Ultimate cause of death is fatal arrhythmias.
Sudden cardiac death
Coronary Artery Diseases
Coronary atherosclerosis
Developmental abnormalities (anomalous origin, hypoplasia)
Coronary artery embolism
Other (vasculitis, dissection)
Myocardial Diseases
Cardiomyopathies
Myocarditis and other infiltrative processes
Right ventricular dysplasia
Valvular Diseases
Mitral valve prolapse
Aortic stenosis and other forms of left ventricular outflow obstruction
Endocarditis
Conduction System Abnormalities
Hypertensive heart disease (HHD)


Basics for diagnosis

History of hypertension

Left ventricular hypertrophy in the absence of
other causes accounting for hypertrophy
The stimulus for hypertrophy is pressure overload
Hypertensive heart disease (HHD)

Stages of HHD

Compensated HHD:
 With
hypertrophy an adequate cardiac output
is maintained.

Decompensated HHD:
 Thickness
of muscle wall increase demand for
oxygen, decrease compliance, and role of
hypertension on atheroma, all contribute to
decompensated HHD and eventual dilatation.
Hypertensive heart disease (HHD)

Gross

Compensated stage ..... Concentric hypertrophy

Decompensated stage ......... Dilatation
 Both

stages, heart weight increased
Histology: Large fibers with large nuclei, later
interstitial fibrosis.
Hypertensive heart disease (HHD)


Causes of death in HHD
 CHF
 Increased risk of sudden cardiac death
 Renal disease , stroke
Drug control leads to regression of hypertrophy.
Aneurysms
Aneurysms


Abnormal dilations of blood vessel or the heart.
Develop where there is marked weakening of
the wall (congenital, infections, trauma,
systemic diseases).
True aneurysms (Atherosclerotic, syphilitic,
congenital vascular aneurysms and the left
ventricular aneurysm) are of two shapes:
Fusiform and Saccular.
Aneurysms (Cont…)


False aneurysm is a tear in the vascular wall
leading to an extravascular hematoma that
freely communicates with the intravascular
space (pulsating hematoma).
 Aortic dissection (dissecting hematoma),
patients
with
hypertension
or
with
abnormality of connective tissue that affects
the aorta (Marfan syndrome).
Complications: Thrombosis, Embolism, Rupture
Proximal
aortic
dissection
demonstrating a small, oblique
intimal tear (demarcated by the
probe), allowing blood to enter
the
media,
creating
an
intramural hematoma (narrow
arrows).
Note that the intimal tear has
occurred in a region largely
free
from
atherosclerotic
plaque, and that propagation of
the intramural hematoma is
arrested at a site more distally
where atherosclerosis begins
(broad arrow).
Abdominal Aortic Aneurysm (AAA)
Causes

Atherosclerosis causes arterial
through medial destruction.

Cystic medial degeneration of the arterial media

wall
thinning
Focal loss of elastic and muscle fibers in the
aortic media and replacement by cystic spaces
filled with myxoid material (hypertension,
Marfan’s syndrome)
Abdominal Aortic Aneurysm (AAA)
Sites

Common site is abdominal aorta below the renal
arteries and above the bifurcation of the aorta. But
the common iliac arteries, the arch, and descending
parts of the thoracic aorta can be involved.

AAAs are saccular or fusiform, and thrombus
frequently fills at least part of the dilated segment .
Abdominal Aortic Aneurysm (AAA)



Two variants: Inflammatory AAAs and Mycotic
AAAs
Males > 50 years old, (50% of patients are
hypertensive).
Complications: depend primarily on location and
size:
 Rupture
into
the
peritoneal
cavity
or
retroperitoneal tissues with massive hemorrhage.
 Obstruction of a vessel, particularly of the iliac,
mesenteric, renal, or vertebral branches.
 Embolism from atheroma or mural thrombus.
 Pressure on an adjacent structure (ureter or
vertebrae).
Abdominal aortic aneurysm that ruptured.
A. Cross-section of aortic media with marked elastin
fragmentation and formation of areas devoid of elastin that
resemble cystic spaces, from a patient with Marfan syndrome.
<cystic medial necrosis>
B. Normal aortic media, showing the regular layered pattern of
elastic tissue.
In both A and B the tissue section is stained to highlight elastin
as black.
Aortic Dissection (Dissecting
Hematoma)

Entry of blood into the arterial wall, through an
intimal tear, usually in the aortic arch, dissecting the
media between the middle and outer third, causing
massive hemorrhage.
 Aortic dissection (dissecting hematoma), occurs
in patients with hypertension (90%) or with
abnormality of connective tissue that affects the
aorta (Marfan syndrome).
 Dissection of the aorta or other branches
(coronary) may occur during or after pregnancy
(rare).
Histologic view of the dissection demonstrating
an aortic intramural hematoma (asterisk). Aortic
elastic layers black and blood red in this section,
stained with Movat stain.
Aortic Dissection (Dissecting
Hematoma)

Sudden onset of severe pain, beginning in the
anterior chest, radiating to the back, and moving
downward as the dissection progresses. (Not MI).

Aortic dissections are classified into two types:

Proximal lesions: more common (dangerous),
involving the ascending aorta or both the
ascending and the descending aorta (called type
A).

Distal lesions begin distal to the subclavian artery
(called type B)
Aortic dissections
are classified into
two types: A and B.
Aortic Dissection (Dissecting Hematoma)
Complication

The most common cause of death is rupture of the
dissection outward into any of the three body
cavities (pericardial, pleural, or peritoneal).

Retrograde dissection into the aortic root can cause
disruption of the aortic valve causing cardiac
tamponade, aortic insufficiency, and myocardial
infarction.

Extension of the dissection into the great arteries of
the neck or into the coronary, renal, mesenteric, or
iliac arteries, causing critical vascular obstruction.
Varicose Veins
Varicose Veins




Varicose Veins are abnormally dilated, tortuous
veins produced by prolonged, increased pressure
and loss of wall support. Most common in lower
limbs.
The condition is common in (age >50, obese and
women).
Clinically: lead to venous stasis, congestion,
edema, pain, and thrombosis. Embolism is rare
Pathogenesis: damage to valves  Stagnation 
Increased pressure  dilatation.
Varicose Veins- Morphology


Gross
 Veins with varicosities are dilated, tortuous,
elongated and scarred, with thinning at the
points of dilatation.
 Thrombosis and valve deformities (thickening
and shortening of the cusps).
Microscopically:
 variations in the thickness of the wall caused by
dilatation
in
areas
and
compensatory
hypertrophy and subintimal fibrosis in others.
Varicose veins
of the leg.
Thrombophlebitis &
Phlebothrombosis



Two designations for venous thrombosis and
inflammation.
The deep leg veins account for about 90% of cases
of venous thrombosis.
The most important clinical causes.
 Cardiac failure,
 Neoplasia,
 Pregnancy,
 Obesity,
 Postoperative state, and
 Prolonged bed rest or immobilization
Vascular Tumors
Classification of Vascular Tumors
Benign Neoplasms, Developmental and Acquired Conditions
Hemangioma
Capillary hemangioma
Cavernous hemangioma
Pyogenic granuloma (lobular capillary hemangioma)
Lymphangioma
Simple (capillary) lymphangioma
Cavernous lymphangioma (cystic hygroma)
Glomus tumor
Intermediate-Grade Neoplasms
Kaposi sarcoma
Hemangioendothelioma
Malignant Neoplasms
Angiosarcoma
Hemangiopericytoma
Benign tumors:
Hemangiomas



Characterized by increased numbers of normal or
abnormal vessels filled with blood.
Mostly localized but may involve large segments
of the body (entire extremity) and called
angiomatosis.
The majority are superficial lesions often of the
head and neck, possible in liver.
Benign tumors:
Hemangiomas (Cont...)



Common in childhood and constitutes 7% of all
benign tumors. May present at birth.
Capillary Hemangiomas are the most common
type. Mostly in the skin, subcutaneous tissues, and
mucous membranes of the oral cavity and lips.
Many regress spontaneously
The strawberry type of the skin of the newborn is
common (juvenile hemangioma).
Capillary Hemangiomas



Color (bright red to blue), size varies (mm to
centimeters), flat or slightly elevated
Lobulated but unencapsulated aggregates of
closely packed thin walled capillaries which are
filled with blood and lined by flat benign
endothelium
The Lumina may contain thrombi
Hemangioma of the tongue
Cavernous Hemangiomas





Less common, and characterized by large vascular
spaces.
Are soft, red-blue measuring 1-2 cm. Sharply
defined but not encapsulated. Composed of large
cavernous vascular spaces filled with blood.
Cavernous Hemangiomas are less circumscribed
and more frequently involve deep structures.
Rarely giant forms occur, that affects large
subcutaneous areas of the face or extremities.
Are mostly of little clinical significance.
Cavernous hemangioma
Pyogenic Granuloma
(Lobular capillary hemangioma)






Polypoid form of capillary hemangiomas.
Occurs as rapidly growing red nodule attached by a
stalk to the skin and oral mucosa , which bleeds
easily and is ulcerated.
One third of the lesions develop after trauma.
The proliferating capillaries are accompanied by
edema and inflammatory cells
The appearance resembles granulation tissue.
Pregnancy tumor ( granuloma gravidarum) is a
pyogenic granuloma that occurs in the gingival of
pregnant ladies and regresses after delivery
Pyogenic granuloma of the lip
Pyogenic granuloma
Lobular capillary hemangioma
Borderline Malignancies:
Hemangioendotheliomas



A wide spectrum of vascular neoplasms showing
histologic
features
and
clinical
behavior
intermediate between benign hemangiomas and
angiosarcomas.
The most common is epithelioid hemangioendotheliomas which occurs around medium sized
and large veins in the soft tissues of adults.
Most are cured by excision but up to 40% recur
and 30% metastasize.
Epithelioid
hemangioendothelioma.
Epithelioid hemangioendothelioma.
Prominent intracytoplasmic lumen
formation
Kaposi Sarcoma


A. Chronic type:
 Called classic or European mainly occurs in
elderly
 Red to purple nodules in the distal lower
extremities, increasing in size slowly and locally
persistent.
B. Lymphadenopathic:
 Called African or endemic mainly among children
of south Africa
 Localized or generalized lymphadenopathy. It is
an aggressive tumor
Kaposi Sarcoma


C- Transplant Associated:
 Occurs several months to a few years
postoperatively in solid organ transplant recipient
who receive high doses of immunosuppressive
therapy.
 Lesions are localized or generalized
 Skin lesions may regress.
D. AIDS associated:
 In one fourth of AIDS patients especially
homosexuals
 Common to involve lymph nodes and the gut.
Kaposi sarcoma
A. Gross photograph illustrating coalescent red-purple
macules and plaques of the skin.
B. Histologic view of the nodular form demonstrating
sheets of plump, proliferating spindle cells and
vascular spaces.
Malignant tumors:
Angiosarcomas





Occur in both sexes ant tend to affect adults
Mostly affects skin, soft tissues, breast and liver.
Hepatic angiosarcomas are associated with
carcinogens like arsenic.
Shows local invasion and metastatic spread.
Has poor outcome.
Angiosarcoma
A. Gross photograph of angiosarcoma of the heart (right ventricle).
B. Moderately well differentiated angiosarcoma with dense clumps of
irregular, moderate anaplastic cells and distinct vascular lumens.
C. Immunohistochemical staining of angiosarcoma for the endothelial cell
marker CD31, proving the endothelial nature of the tumor cells.