Transcript 01. CVS, Atherosclerosis

Slide 12.1
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ECs comprise the single cell-thick,
continuous lining of the entire cardiovascular
system, collectively called the endothelium.
Endothelial structural and functional integrity
is fundamental to the maintenance of vessel
wall homeostasis and normal circulatory
function.
Slide 12.3
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SMCs are predominant cellular element of the
vascular media
SMCs are responsible for vasoconstriction and
dilation in response to normal or pharmacologic
stimuli.
They also synthesize collagen, elastin, and
proteoglycans; and elaborate growth factors and
cytokines. They migrate to the intima and
proliferate following vascular injury.
Thus, SMCs are important elements of both normal
vascular repair and pathologic processes such as
atherosclerosis.
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Vascular injury ( endothelial
injury/dysfunction) stimulates SMC growth.
Reconstitution of the damaged vascular wall
is a physiologic healing response that
includes the formation of a neointima, in
which SMCs (1) migrate from the media to the
intima, (2) multiply as intimal SMCs, and (3)
synthesize and deposit ECM
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During the healing response, SMCs undergo
changes that resemble dedifferentiation. In
the intima they lose the capacity to contract
and gain the capacity to divide.
Intimal SMCs may return to a
nonproliferative state when either the
overlying endothelial layer is re-established
following acute injury or the chronic
stimulation ceases.
Arteriosclerosis (literally, "hardening of the
arteries") is a generic term for thickening and
loss of elasticity of arterial walls. Three
patterns of arteriosclerosis are recognized;
they vary in pathophysiology and clinical and
pathological consequences.
1)Atherosclerosis, the most frequent and
important pattern
2)Mönckeberg medial calcific sclerosis is
characterized by calcific deposits in
muscular arteries in persons older than age
50. They do not encroach on the vessel
lumen.
3)Arteriolosclerosis affects small arteries and
arterioles. There are two anatomic variants,
hyaline and hyperplastic, both associated
with thickening of vessel walls with luminal
narrowing that may cause ischemic injury.
Most often associated with hypertension
and diabetes mellitus.
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Atherosclerosis is characterized by intimal
lesions called atheromas, or atheromatous or
fibrofatty plaques, which protrude into and
obstruct vascular lumens and weaken the
underlying media. They may lead to serious
complications
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Fatty streaks are the earliest lesion of
atherosclerosis. They are composed of
lipid-filled foam cells. They are not
significantly raised and thus do not cause
any disturbance in blood flow. Fatty streaks
begin as multiple yellow, flat spots less
than 1 mm in diameter that coalesce into
elongated streaks, 1 cm long or longer.
They contain T lymphocytes and
extracellular lipid in smaller amounts than
in plaques.
Fatty streak—a collection of foam cells in the intima.
A. Aorta with fatty streaks ( arrows), associated largely with the ostia of branch vessels.
B. Close-up photograph of fatty streaks from the aorta of an experimental hypercholesterolemic rabbit
shown after staining with Sudan red, a lipid-soluble dye, again illustrating the relationship of the lesions to
the two-branch vessel ostia.
C. Photomicrograph of fatty streak in an experimental hypercholesterolemic rabbit, demonstrating intimal
macrophage-derived foam cells ( arrow).
Slide 12.9
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The key processes in atherosclerosis are
intimal thickening and lipid accumulation. An
atheroma or atheromatous plaque consists of
a raised focal lesion initiating within the
intima, having a soft, yellow, grumous core of
lipid (mainly cholesterol and cholesterol
esters), covered by a firm, white fibrous cap.
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The atheromatous plaques appear white to
whitish yellow and impinge on the lumen of
the artery. They vary in size from
approximately 0.3 to 1.5 cm in diameter but
sometimes coalesce to form larger masses.
Atherosclerotic lesions usually involve only a
partial circumference of the arterial wall
("eccentric" lesions) and are patchy and
variable along the vessel length.
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The most heavily involved vessels are the
abdominal aorta then coronary arteries, the
popliteal arteries, the internal carotid arteries,
and the vessels of the circle of Willis.
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Atherosclerotic plaques have three
principal components:
(1) cells, including SMCs, macrophages, and
other leukocytes
(2) ECM, including collagen, elastic fibers,
and proteoglycans
(3) intracellular and extracellular lipid .
These components occur in varying
proportions.
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Typically, the superficial fibrous cap is
composed of SMCs and relatively dense
ECM. Beneath and to the side of the cap (the
"shoulder") is a cellular area consisting of
macrophages, SMCs, and T lymphocytes.
Deep to the fibrous cap is a necrotic core,
containing a disorganized mass of lipid
(primarily cholesterol and cholesterol
esters), cholesterol clefts, debris from dead
cells, foam cells, fibrin, variably organized
thrombus, and other plasma proteins.
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Foam cells are large, lipid-laden cells that
derive predominantly from blood
monocytes (tissue macrophages), but SMCs
can also imbibe lipid to become foam cells.
Around the periphery of the lesions, there is
usually evidence of neovascularization
(proliferating small blood vessels). Typical
atheromas contain relatively abundant lipid.
Atheromas often undergo calcification.
Major components of well-developed atheromatous plaque:
fibrous cap composed of proliferating smooth muscle cells, macrophages,
lymphocytes, foam cells, and extracellular matrix. The necrotic core consists
of cellular debris, extracellular lipid with cholesterol crystals, and foamy
macrophages.
Slide 12.6
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 and complicated lesions.
Slide 12.7
Histologic features of atheromatous plaque in the coronary artery.
A. Overall architecture demonstrating a fibrous cap (F) and a central lipid core (C) with typical cholesterol clefts. The
lumen (L) has been moderately narrowed. Note the plaque-free segment of the wall ( arrow). In this section, collagen
has been stained blue (Masson trichrome stain).
B. Higher-power photograph of a section of 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).
C. Higher-magnification photomicrograph at the junction of the fibrous cap and core showing scattered inflammatory
cells, calcification ( broad arrow), and neovascularization ( small arrows).
Slide 12.8
American Heart Association classification of human atherosclerotic lesions from the fatty dot (type I) to the
complicated type VI lesion. The diagram also includes growth mechanisms and clinical correlations.
Slide 12.11
The advanced lesion of atherosclerosis is at
risk for the following pathological changes
that have clinical significance:
1) Focal rupture, ulceration, or erosion of the
luminal surface of atheromatous plaques
may result in exposure of highly
thrombogenic substances that induce
thrombus formation or discharge of debris
into the bloodstream, producing
microemboli composed of lesion contents
(cholesterol emboli or atheroemboli).
2) Hemorrhage into a plaque, especially in the
coronary arteries, may be initiated by
rupture of either the overlying fibrous cap
or the thin-walled capillaries that
vascularize the plaque. A contained
hematoma may expand the plaque or
induce plaque rupture.
3)Superimposed thrombosis, the most feared
complication, usually occurs on disrupted
lesions (those with rupture, ulceration,
erosion, or hemorrhage) and may partially or
completely occlude the lumen. Thrombi may
heal and become incorporated into and
thereby enlarge the intimal plaque.
4)Aneurysmal dilation may result from ATHinduced atrophy of the underlying media,
with loss of elastic tissue, causing weakness
and potential rupture
5) Calcifications.
Natural history of atherosclerosis
Slide 12.5
Major
Nonmodifiable
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Increasing age
Male gender
Family history
Genetic abnormalities
PotentiallyControllable
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Hyperlipidemia
Hypertension
Cigarette smoking
Diabetes
Lesser, Uncertain, or Nonquantitated
 Obesity
 Physical inactivity
 Stress ("type A" personality)
 Postmenopausal estrogen deficiency
 High carbohydrate intake
 Alcohol
 Lipoprotein Lp(a)
 Hardened (trans)unsaturated fat intake
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Chlamydia pneumoniae
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Low-density lipoproteins (LDLs):
When too much LDL (bad) cholesterol
circulates in the blood, it promotes atheroma
formation in the arteries.LDLs contribute to
heart disease because they carry large
amounts of cholesterol.
Very-low-density lipoproteins (VLDLs): is also
considered to be a type of bad cholesterol
because it helps cholesterol build up on the
walls of arteries
Chylomicrons also promote atherosclerosis.
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High-density lipoproteins (HDLs): is known
as “good” cholesterol, because high levels of
HDL seem to protect against heart
attack. Low levels of HDL (less than 40
mg/dL) also increase the risk of heart
disease. HDLs help to reverse the effects of
high cholesterol by collecting cholesterol
from other lipoproteins and transporting it to
places where it can be utilized by the cells
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This concept, called the response to injury
hypothesis, considers atherosclerosis to be a
chronic inflammatory response of the arterial
wall initiated by injury to the endothelium.
Moreover, lesion progression is sustained by
interaction between modified lipoproteins,
monocyte-derived macrophages, T
lymphocytes, and the normal cellular
constituents of the arterial wall.
Processes in the response to injury hypothesis.
1, Normal.
Slide 12.13
2, Endothelial injury with adhesion of monocytes and platelets (the
latter to denuded endothelium).
Slide 12.14
3, Migration of monocytes (from the lumen) and smooth muscle
cells (from the media) into the intima.
Slide 12.15
4, Smooth muscle cell proliferation in the intima.
Slide 12.16
5, Well-developed plaque.
Slide 12.17
Slide 12.18
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Central to this thesis are the following:
Accumulation of lipoproteins, mainly LDL,
with its high cholesterol content, in the vessel
wall
Chronic endothelial injury, usually subtle,
increased permeability, leukocyte adhesion,
and thrombotic potential.
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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
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Adhesion of platelets
Release of factors from activated platelets,
macrophages, or vascular cells that cause
migration of SMCs from media into the
intima
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Proliferation of smooth muscle cells in the
intima, and elaboration of extracellular
matrix, leading to the accumulation of
collagen and proteoglycans
Enhanced accumulation of lipids both within
cells (macrophages and SMCs) and
extracellularly.
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primary prevention programs, aimed at
either delaying atheroma formation or
causing regression of established lesions in
persons who have never suffered a serious
complication of atherosclerotic coronary
artery disease
secondary prevention programs, intended
to prevent recurrence of events such as
myocardial infarction in patients with
symptomatic disease.
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based on risk factor modification: abstention
from or cessation of cigarette smoking,
control of hypertension, weight reduction and
increased exercise, moderation of alcohol
consumption, and, most importantly,
lowering total and LDL blood cholesterol
levels while increasing HDL. on
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Definition: rheumatic fever is an acute,
immunologically mediated, multi-system
inflammatory disease that follows, after a
few weeks, an episode of group A beta
hemolytic streptococcal pharyngitis (3% of
patients).
The incidence and mortality of rheumatic
fever has declined over the past 30 years
(due to improved socioeconomic condition
and rapid diagnosis and treatment of strep.
pharyngitis.
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Affect the heart during its acute phase 
acute rheumatic carditis.
Cause chronic valvular deformities (many
years after the acute disease.
Hypersensitivity
reaction induced by
group A strept. (ab.
Against protein M
Cross-reaction /
Autoimmune
response
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Inflammatory infiltrates occur in a wide
range of tissues: synovium, joints, skin,
heart.
Focal fibrinoid necrosis  mixed
inflammatory reaction (diffuse or localized)
 Fibrosis (chronic rheumatic heart disease) .
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Pancarditis (endo- myo- pericarditis).
Multiple foci of inflammation within the
connective tissue of the heart. (Aschoff
bodies: central fibrinoid necrosis,
surrounded by chronic mononuclear
inflammatory infiltrate and occasional large
histiocytes).
Diffuse interstitial inflammatory infiltrates
(may lead to generalized dilation of the
cardiac chambers).
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Pericardial involvement: fibrinous
pericarditis, sometime associated with
serous or serosanguinous effusion.
Endocardium:
◦ Mostly mitral and aortic valve.
◦ Valves are edematous and thickened with foci
of fibrinoid necrosis. (Aschoff nodules
uncommon).
◦ Verrucous endocarditis (small vegetations
along lines of valve closure).
Acute changes may resolve completely or
progress to scarring and chronic valvular
deformities.
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Arthritis: large joints, self limited, no chronic
deformities.
Lung: uncommon, chronic interstitial
inflammation and fibrinous pleuritis.
Skin: skin nodules, erythema marginatum.
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Irreversible deformity of one or more cardiac
valves (previous acute valvulitis).
Left side of heart > right.
Reduction of diameter (stenosis), or improper
closure (regurgitation), or both.
May lead to cardiac failure (overload)
May predispose to infective endocarditis.
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Stenosis > regurgitation.
Females > males.
In stenosis:
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Leaflets are thick, rigid, and interadherent.
Dilatation and hypertrophy of left atrium.
Mural thrombi may be present systemic emboli.
Lungs are firm and heavy (chronic passive congestion).
Right heart may be affected later.
In regurgitation:
◦ Retracted leaflets.
◦ Left ventricular hypertrophy and dilatation.
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Males > females.
Associated with mitral valvulitis.
Aortic stenosis:
◦ Valve cusps are thickened, firm and interadherent
 rigid triangular channel.
◦ Left ventricular hypertrophy.
◦ Subsequent left ventricular failure and dilation.
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Aortic regurgitation: retraction of leaflets.
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Occurs 10 days to 6 weeks after pharyngitis.
? Of genetic susceptibility.
Peak incidence: 5-15 years.
Pharyngeal culture may be negative, but anti
streptolysin O (ASO) titer will be high.
Arthritis: large joints, migratory.
Acute carditis: pericardial friction rubs, weak
heart sounds, tachycardia and arrhythmias.
myocarditis  cardiac dilation  functional
mitral valve insufficiency or even congestive
heart failure.
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Manifestation after years or decades after the
initial episode of rheumatic fever.
Signs and symptoms depend on which
involved valve(s): cardiac murmurs,
hypertrophy, dilation, congestive heart
failure, arrhythmia, thromboembolic
complications and infective endocarditis.
A. Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible
along the line of closure of the mitral valve leaflet (arrowheads). Previous episodes of rheumatic valvulitis have caused fibrous
thickening and fusion of the tendinous cords.
Slide 13.34
B. Microscopic appearance of an Aschoff body in a patient with acute
rheumatic carditis. The myocardial interstitium has a circumscribed collection
of mononuclear inflammatory cells, including some large histiocytes with
prominent nucleoli, a prominent binuclear histiocyte, and central necrosis.
Slide 13.35
C. & D. Mitral stenosis with diffuse fibrous thickening and distortion of the valve leaflets, commissural fusion (arrow in C),
and thickening and shortening of the tendinous cords. Marked dilation of the left atrium is noted in the left atrial view ( C).
Slide 13.36
D. Opened valve. Note the neovascularization of the anterior mitral leaflet (arrow).
Slide 13.37
E. Surgically removed specimen of rheumatic aortic stenosis demonstrating
thickening and distortion of the cusps with commissural fusion ( E from
Schoen FJ, St. John-Sutton M:
Contemporary issues in the pathology of valvular heart disease. Hum Pathol
18:568, 1967.)
Slide 13.38
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Characterized by the deposition of small
masses of fibrin, platelets, and other blood
components on the leaflets of the cardiac
valves (sterile).
Pathogenesis/ association:
◦ Subtle endothelial abnormalities.
◦ Hypercoagulability.
◦ Association with malignancy (50%).
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Gross:groups of small nodules on the lines
of valve closure (similar to those of acute
rheumatic fever), valve leaflets are normal.
Aortic valve most common site.
Micro: fibrin and platelets aggregates, no
inflammation or fibrosis.
Clinically asymptomatic, if large: may
embolize, may become infected.
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Definition: infection of the cardiac valves
or mural surface of the endocardium,
resulting in the formation of an adherent
mass of thrombotic debris and organisms.
Divided into:
◦ Acute: high virulent organisms (staphylococcus
aureus), infect even normal valves, progress
rapidly, little local host reaction.
◦ Subacute: infection of previously abnormal
valves by organisms of low virulence (hemolytic streptococci-viridans), progress
slowly, induce local inflammatory reaction.
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Bacteremia: i.v. drug abusers, elsewhere
infection, previous dental, surgical or
interventional procedure (catheterization).
In some cases the source of bacteremia is
occult.
Infective endocarditis is a particularly
difficult infection to eradicate because of the
avascular nature of the heart valves.
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Cardiac abnormalities: chronic valvular
diseases, high pressure shunts within the
heart (small ventricular septal defects).
Prosthetic heart valves.
Intravenous drug abusers.
Most common of non prosthetic valves (5060%):
-Hemolytic (viridans) streptococci, which
attack previously damaged valves and causes
subacute IE.
 Staphylococcus attack healthy or deformed
valves (10-20%).
 Prosthetic valve endocarditis is caused
commonly by coagulase-negative
staphylococci (e.g., S. epidermidis).
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Valvular vegetations containing bacteria or
other organisms.
Aortic and mitral valves are the most
common sites. (right side valves in i.v.users)
Vegetations may be single or multiple,
involve one or more valve(s), differ in
appearance according to the causative
agent.
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Vegetations: may obstruct valve orifice, lead
to rupture of ( the leaflets, cordae
tendineae, or papillary muscles), abscess in
perivalvular tissue (ring abscess), friable
vegetations may become systemic emboli
infarcts + abscesses.
Micro: large number of organisms + fibrin
and blood cells. Neutrophilic inflammatory
reaction occurs the infection extends
beyond the avascular valves.
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Vegetations are firmer, less destructive, and
ring abscess are uncommon.
Micro: Granulation tissue is seen at the base
of the vegetations, later: fibrosis,
calcifications and chronic inflammatory
infiltrates. Systemic emboli may develop but
they don’t undergo suppuration.
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Onset: gradual or explosive (~organisms).
◦ Low-grade fever, malaise, weight loss.
◦ High fever, shaking chills.
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Cardiac murmurs.
Enlargement of spleen, clubbing of digits (particularly in subacute
cases).
Systemic emboli (neurologic deficits, retinal abnormalities, necrosis
of digits, and infarcts of the myocardium.
Pulmonary emboli in right-sided endocarditis.
Mycotic aneurysms.
Petechiae (due to micro emboli or deposition of immune complexes.
Renal lesions: renal infarcts and glomerulonephritis.
Valvular regurgitation and congestive heart failure due to progressive
valvular destruction.
Blood culture for aerobic and anaerobic organisms is very important
(only minority of cases remain negative).
Endocarditis of the mitral valve (subacute, caused by Streptococcus viridens). The irregular, large friable vegetations are denoted by arrows.
Slide 13.40
B. Acute endocarditis of a congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with severe cuspal destruction and ring abscess (arrow).
Slide 13.41
C. Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were
demonstrated by tissue Gram stain.
Slide 13.42
D. Gross photograph illustrating healed endocarditis with perforations on bicuspid aortic valve
Slide 13.43
Diagrammatic comparison of the lesions in the four major forms of vegetative
endocarditis. The rheumatic fever phase of RHD (rheumatic heart disease) is
marked by a row of warty, small vegetations along the lines of closure of the
valve leaflets. IE (infective endocarditis) is characterized by large, irregular
masses on the valve cusps that can extend onto the cords (see Fig. 13–18 A).
NBTE (nonbacterial thrombotic endocarditis) typically exhibits small, bland
vegetations, usually attached at the line of closure. One or many may be
present (see Fig. 13–20). LSE (Libman-Sacks endocarditis) has small or
medium-sized vegetations on either or both sides of the valve leaflets.
Slide 13.44
Nonbacterial thrombotic endocarditis (NBTE).
A. Nearly complete row of thrombotic vegetations along the line of closure of
the mitral valve leaflets.
B. Photomicrograph of NBTE showing bland thrombus, with virtually no
inflammation in the valve cusp (c) or the thrombotic deposit. The thrombus is
only loosely attached to the cusp (arrow).
Slide 13.45
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Primary: mostly viral, sometimes by other
microorganisms (pyogenic bacteria,
mycobacteria and fungi.
Secondary to: acute myocardial
infarction, cardiac surgery, or radiation
to the mediastinum.
Associated systemic disorders, mostly
with uremia.
Less common 2ndry causes: rheumatic
fever, SLE, and metastatic malignancies
(bloody effusions).
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Cause immediate hemodynamic
complications, if significant effusion is
present.
Resolve without significant sequelae.
Progress to chronic fibrosing process.
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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
pericarditis.
Tuberculosis caseous materials.
Pericardial metastases: irregular nodules.
Exudate usually resolve unless there is excessive
suppuration or caseation, where healing leads to
chronic pericarditis.
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Ranges from delicates adhesions to dense
fibrotic scars that obliterate the pericardial
space.
In extreme cases the heart can’t expand
during diastole : constrictive pericarditis.
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Atypical chest pain (worse on reclining).
High pitch friction rub.
Significant exudate cardiac tamponade
 faint distant heart sounds, distended
neck veins, declining cardiac output, and
shock.
Chronic constrictive pericarditis  venous
distension and low cardiac output.
Acute suppurative pericarditis
as an extension from
pneumonia. Extensive
purulent exudate is evident in
this in situ photograph.
Slide 13.56