Title: Rosalind Franklin University of Medicine and Science
1Rosalind Franklin University of Medicine and
Science
2ARTERIOSCLEROSIS
-
- Arthur S. Schneider, M.D.
- Department of Pathology
- Chicago Medical School at
- Rosalind Franklin University of Medicine and
Science
3ARTERIOSCLEROSIS
- general term
- rigidity (sclerosis), often with thickening, of
blood vessels - three major entities included
- Mönckeberg's arteriosclerosis (medial calcific
sclerosis) - arteriolosclerosis
- atherosclerosis
4MÖNCKEBERG'S ARTERIOSCLEROSIS (MEDIAL CALCIFIC
SCLEROSIS)
- involves media of medium sized muscular arteries
- ring-like calcifications
- amorphous basophilic staining material in
sections - visualized in living patients by x-ray
5MÖNCKEBERG'S ARTERIOSCLEROSIS cont.
- patients usually older than age 50
- radial, ulnar, femoral and tibial arteries
- does not obstruct arterial flow
- intima not involved
- term "pipestem artery" describes stiff, calcific
vessels - distinct and unrelated to atherosclerosis which
may coexist
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7ARTERIOLOSCLEROSIS
- characterized by proliferative changes or hyaline
thickening of small arteries and arterioles - kidney most characteristic site
- often associated with hypertension or diabetes
mellitus - when associated with hypertension termed benign
and malignant nephrosclerosis
8HYALINE ARTERIOLOSCLEROSIS
- characterized by hyaline thickening of afferent
arterioles in hypertensive disease - similar changes in both afferent and efferent
arterioles in diabetes mellitus - lesions thought due to production of
extracellular matrix material by vascular smooth
muscle cells - response to endothelial injury with leakage of
plasma components into the vessel wall
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11HYPERPLASTIC ARTERIOLOSCLEROSIS
- characterized by proliferative or hyperplastic
changes - concentric, laminated, onion-skin thickening of
arteriolar walls - often demonstrates fibrinoid necrosis of vessel
wall (necrotizing arteriolitis) - associated with malignant hypertension
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13ATHEROSCLEROSIS
- most important disease of the vascular system
- focal plaques (atheromas) within intima of
arteries - central core of cholesterol and cholesterol
esters, lipid laden histiocytes (foam cells),
calcium, and necrotic debris
14ATHEROSCLEROSIS
- covered by subendothelial fibrous cap consisting
of smooth muscle cells, foam cells, and
extracellular matrix material - become larger, more numerous, often confluent
- sometimes cover entire surface of severely
affected vessels
15NECROTIC CENTER
FIBROUS CAP
MEDIA
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20DISTRIBUTION OF LESIONS
- abdominal aorta most frequent site
- favored sites of involvement
- about ostia of major aortic branches
- proximal portions of the coronary arteries
- carotid arteries
- circle of Willis
- large vessels of the lower extremities
- renal and mesenteric arteries
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25FATTY STREAK
- appears in all populations
- independent of race, sex or environment
- appears in very young children
- characterized by intimal lipid laden foam cells
- anatomic distribution different than atheromas
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28PROGRESSION AND COMPLICATIONS
- enlarging plaques impinge upon underlying media
and cause narrowing of vascular lumens - often complicated by ulceration, hemorrhage, or
calcification - thrombus formation at site of plaque results in
obstructive disease - embolization from plaque or overlying thrombus
- aneurysmal dilatation from weakened vessel walls
29AHA Classification Types I and II have onset
from first decade types III and IV from third
decade and types V and VI from fourth decade
- Type I (initial) lesion
- Isolated macrophage foam cells (fatty dot)
- Type II (fatty streak) lesion
- Mainly intracellular lipid accumulation
- Type III (intermediate) lesion
- Type II changes and small extracellular lipid
pools
30AHA Classification Types I and II have onset
from first decade types III and IV from third
decade and types V and VI from fourth decade
- Type IV (atheroma) lesion
- Type II changes and core of exracellular lipid
- Type V (fibroatheroma) lesion
- Lipid core and fibrotic layer, or multiple lipid
cores and fibrotic layers, or mainly calcific, or
mainly fibrotic - Type VI (complicated) lesion
- Surface defect, hematoma-hemorrhage, thrombus
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39INCIDENCE
- world-wide
- highest in industrialized societies
- especially high in Finland, Great Britain, many
other northern European countries, United States,
and Canada - much less common in the Orient, India, Africa,
and in South and Central America - incidence more than 10 fold greater in Finland
than in Japan
40CLINICAL MANIFESTATIONS
- silent without evident manifestations for many
years - becomes apparent because of occlusive disease
- about 50 percent of total deaths in the United
States, about half of these due to ischemic heart
disease (IHD) - IHD most common illness of western populations
41CLINICAL MANIFESTATIONS cont.
- cerebral ischemia with infarction
- ischemic bowel disease
- peripheral vascular occlusive disease with
claudication, ischemic necrosis and gangrene - renal arterial ischemia with secondary
hypertension - weakening of vessel walls can lead to aneurysm
- abdominal aorta most frequent site
42RISK FACTORS
- non-modifiable
- age
- male gender
- family history
- genetic abnormalities
- modifiable
- hyperlipidemia
- hypertension
- cigarette smoking
- diabetes mellitus
43RISK FACTORS
- other, less certain
- obesity
- physical inactivity
- type A personality
- homocysteine
- postmenopausal state
- alcohol
- lipoprotein (a)
- hardened (trans) unsaturated fat intake
- Chlamydia pneumoniae
44AGE
- incidence increases with age
- long period required to develop occlusive disease
- increased collagen content makes intima less
elastic and more likely to develop small surface
defects - usual earliest age of manifestation of clinical
disease - about 35 or later in men
- about ten years later in women
45AGE
- premature atherosclerosis refers to clinically
apparent disease occurring earlier in life - characteristic of famililal hyperlipidemias,
diabetes mellitus, and hypertension
46GENDER
- more common in men
- incidence in women increases after menopause
- incidence approaches that of men by age sixty to
seventy - postmenopausal hormone replacement therapy no
longer thought to be protective
47HYPERTENSION
- major risk factor
- weakens media with disruption of elastic tissue
and resultant shearing stress to the overlying
endothelium - leads to endothelial injury and eventual
atheromatous plaque formation
48DIABETES MELLITUS
- associated with premature atherosclerosis
- course is more rapid and severe, especially in
women - gangrene of the lower extremities almost
restricted to diabetics
49CIGARETTE SMOKING
- well established major risk factor
50LESS FIRMLY ESTABLISHED RISK FACTORS
- obesity, especially in combination with diabetes
- sedentary lifestyle
- personality and stress factors
51LESS FIRMLY ESTABLISHED RISK FACTORS
- hyperhomocysteinemia
- hyperuricemia
- oral contraceptive agents (in association with
cigarette smoking)
52OTHER RISK INDICATORS
- markers of hemostatic and thrombotic function and
inflammation - plasminogen activator inhibitor-1
- C-reactive protein see below)
- lipoprotein Lp(a) (an altered form of LDL that
contains the apolipoprotein B-100 portion of LDL
linked to apolipoprotein A)
53ROLE OF INFECTION?
- suggested factors (much interest, but nothing
definitive as yet) - Chlamydia pnemoniae
- Cytomegalovirus
54HYPERCHOLESTEROLEMIA
- plaques are rich in cholesterol and cholesterol
esters - dietary induced hypercholesterolemia in animals
leads to atheromatous lesions - inherited hypercholesterolemic disorders lead to
premature atherosclerosis with increased
mortality and morbidity
55HYPERCHOLESTEROLEMIA
- hypercholesterolemia secondary to hypothyroidism
or nephrotic syndrome also associated with
increased atherosclerotic disease
56HYPERCHOLESTEROLEMIA cont.
- population studies clearly demonstrate
correlation of serum cholesterol level with the
risk of atherosclerotic disease and its
complications - serum cholesterol can be decreased by restricted
dietary intake of cholesterol and saturated fat
dietary modification or combination of diet and
cholesterol-lowering drugs - reduces incidence of IHD
57LABORATORY TESTING
- LDL
- "bad cholesterol"
- predictive significance same as total cholesterol
- HDL
- good cholesterol
- inverse relationship to risk of atherosclerosis
- probably protects by removing cholesterol from
tissues and plaques
58LABORATORY TESTING
- LDLHDL ratio should be 41 or less
- frequent test panel includes triglycerides, total
cholesterol, HDL, and LDL - lipoprotein phenotyping sometimes useful
59NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP)
- All persons over 20 should have cholesterol
checked - Below 200 mg/dl desirable--check again in 5 years
- 200-239 mg/dl borderline high -further evaluation
is indicated - 240 mg/dl and above high--associated with
significant risk
60NCEP DEFINITIONS
- very high-risk patients
- cardiovascular disease together with
- multiple risk factors (especially diabetes)
- severe and poorly controlled risk factors (e.g.,
continued smoking) - metabolic syndrome (a constellation of risk
factors associated with obesity including high
triglycerides and low HDL - patients hospitalized for acute coronary
syndromes such as heart attack
61NCEP DEFINITIONS
- high-risk patients
- coronary heart disease or
- disease of vessels to brain or extremities
- diabetes mellitus
- multiple (2 or more) risk factors (e.g., smoking,
hypertension)
62NCEP DEFINITIONS
- moderately high-risk patients
- multiple (2 or more) risk factors for coronary
heart disease together with a 10 to 20 percent
risk of heart attack within 10 years. - lower/moderate risk
- moderate risk (2 or more risk factors plus an
under 10 percent risk of a heart attack in 10
years) - 0 to 1 risk factor (lower levels of risk are less
clear cut)
63NCEP RECOMENDATIONS
- high and very high risk
- recommended LDL-C goal is 100 mg/dL, but when
risk is very high, an LDL-C goal of 70 mg/dL is a
therapeutic option - moderately high-risk patients
- goal is LDL under 130 mg/dL, with therapeutic
option to set lower LDL goal of under 100 mg/dL - low risk
- goal is LDL under 160 mg/dl
64OLD INSUDATION THEORY
- infiltration of intima with lipid and plasma
proteins is primary atherogenic event
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66OLD ENCRUSTATION OR THROMBOGENIC THEORY
- organization of repeated mural thrombi on intimal
surface of vessel leads to formation of thickened
plaques filled with lipid derived from breakdown
of platelets and leukocytes
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68OTHER OLDER THEORIES
- smooth muscle migration and proliferation is
primary and not secondary event - stimuli such as hyperlipidemia may be inciting
causes for hyperproliferation - smooth muscle proliferations within atheromas are
often monoclonal - "monoclonal hypothesis encompasses a number of
speculative concepts
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70RESPONSE TO INJURY HYPOTHESIS
- considers atherosclerosis to be chronic
inflammatory response of arterial wall initiated
by injury to endothelium.
71RESPONSE TO INJURY HYPOTHESIS
- interaction between modified lipoproteins,
monocyte-derived macrophages, T lymphocytes, and
normal cellular constituents of arterial wall - chronic endothelial injury, usually subtle, with
resultant endothelial dysfunction, yielding
increased permeability, leukocyte adhesion, and
thrombotic potential - accumulation of lipoproteins, mainly LDL
- modification of lesional lipoproteins by
oxidation
72RESPONSE TO INJURY HYPOTHESIS
- interaction between modified lipoproteins,
monocyte-derived macrophages, T lymphocytes, and
normal cellular constituents of arterial wall - adhesion of monocytes (and other leukocytes) to
endothelium, followed by migration into the
intima and transformation into macrophages and
foam cells - adhesion of platelets
73RESPONSE TO INJURY HYPOTHESIS
- release of factors from activated platelets,
macrophages, or vascular cells that cause
migration of smooth muscle cells from media into
intima
74RESPONSE TO INJURY HYPOTHESIS
- proliferation of smooth muscle cells in intima
- elaboration of extracellular matrix, leading to
accumulation of collagen and proteoglycans - enhanced accumulation of lipids both intra- and
extra-cellularly
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77ROLE OF INFLAMMATION
- damaged endothelium expresses adhesion molecules
(such as VCAM-1) that bind monocytes and T
lymphocytes - monocytes
- migrate between endothelial cells and localize in
intima - transform into macrophages and engulf oxidized
LDL - macrophages
- produce IL-1 and TNF which increase adhesion of
leukocytes - several chemokines recruit more leukocytes
- produce toxic oxygen species that cause oxidation
of LDL - elaborate growth factors that contribute to
smooth muscle cell proliferation and migration - T lymphocytes recruited to intima by
chemoattractants - activated leukocytes and intrinsic arterial cells
- release fibrogenic mediators that can promote
replication of smooth muscle cells and
elaboration of extracellular matrix
78HYPERLIPIDEMIA AND ATHEROGENESIS
- hypercholesterolemia, may directly impair
endothelial cell function through increased
production of oxygen free radicals that
deactivate NO (endothelial-relaxing factor) - lipoproteins accumulate within intima at sites of
increased endothelial permeability - free radicals generated by macrophages or
endothelial cells ? chemical change of lipid in
arterial wall to oxidized LDL - oxidized LDL
- ingested by macrophages through scavenger
receptor - increases monocyte accumulation in lesions
- stimulates release of growth factors and
cytokines - cytotoxic to endothelial cells and smooth muscle
cells
79SMOOTH MUSCLE CELLS
- migrate from media to intima
- take up modified lipids, contributing to foam
cell formation - proliferate and deposit extracellular matrix
- several growth factors implicated in
proliferation of smooth muscle cells - PDGF
- FGF
- TGF-a
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81Hypothetical sequence of cellular interactions in
atherosclerosis Hyperlipidemia and other risk
factors are thought to cause endothelial injury,
resulting in adhesion of platelets and monocytes
and release of growth factors, including
platelet-derived growth factor (PDGF), which lead
to smooth muscle cell migration and
proliferation. Foam cells of atheromatous
plaques are derived from both macrophages and
smooth muscle cells-from macrophages via the
very-low-density lipoprotein (VLDL) receptor and
low-density lipoprotein (LDL) modifications
recognized by scavenger receptors (e.g., oxidized
LDL), and from smooth muscle cells by less
certain mechanisms. Extracellular lipid is
derived from insudation from the vessel lumen,
particularly in the presence of
hypercholesterolemia, and also from degenerating
foam cells. Cholesterol accumulation in the
plaque reflects an imbalance between influx and
efflux, and high-density lipoprotein (HDL) likely
helps clear cholesterol from these accumulations.
Smooth muscle cells migrate to the intima,
proliferate, and produce extracellular matrix,
including collagen and proteoglycans. From
Robbins Text
82MULTIFACTORIAL PATHOGENESIS OF ATHEROSCLEROSIS
- chronic inflammatory response
- initiated early in life
- multiple mechanisms contribute to plaque
formation and progression - endothelial dysfunction
- monocyte adhesion and infiltration
- lipid accumulation and oxidation
- smooth muscle proliferation
- extracellular matrix deposition
- thrombosis.
83Thank you for your attention.