Rosalind Franklin University of Medicine and Science

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Rosalind Franklin University of Medicine and
Science
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ARTERIOSCLEROSIS

• Arthur S. Schneider, M.D.
• Department of Pathology
• Chicago Medical School at
• Rosalind Franklin University of Medicine and
  Science

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ARTERIOSCLEROSIS

• general term
• rigidity (sclerosis), often with thickening, of
  blood vessels
• three major entities included
• Mönckeberg's arteriosclerosis (medial calcific
  sclerosis)
• arteriolosclerosis
• atherosclerosis

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MÖNCKEBERG'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

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MÖNCKEBERG'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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ARTERIOLOSCLEROSIS

• 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

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HYALINE 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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HYPERPLASTIC 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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ATHEROSCLEROSIS

• 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

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ATHEROSCLEROSIS

• 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

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NECROTIC CENTER
FIBROUS CAP
MEDIA
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DISTRIBUTION 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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FATTY 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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PROGRESSION 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

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AHA 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

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AHA 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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INCIDENCE

• 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

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CLINICAL 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

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CLINICAL 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

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RISK FACTORS

• non-modifiable
• age
• male gender
• family history
• genetic abnormalities
• modifiable
• hyperlipidemia
• hypertension
• cigarette smoking
• diabetes mellitus

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RISK FACTORS

• other, less certain
• obesity
• physical inactivity
• type A personality
• homocysteine
• postmenopausal state
• alcohol
• lipoprotein (a)
• hardened (trans) unsaturated fat intake
• Chlamydia pneumoniae

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AGE

• 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

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AGE

• premature atherosclerosis refers to clinically
  apparent disease occurring earlier in life
• characteristic of famililal hyperlipidemias,
  diabetes mellitus, and hypertension

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GENDER

• 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

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HYPERTENSION

• 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

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DIABETES MELLITUS

• associated with premature atherosclerosis
• course is more rapid and severe, especially in
  women
• gangrene of the lower extremities almost
  restricted to diabetics

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CIGARETTE SMOKING

• well established major risk factor

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LESS FIRMLY ESTABLISHED RISK FACTORS

• obesity, especially in combination with diabetes
• sedentary lifestyle
• personality and stress factors

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LESS FIRMLY ESTABLISHED RISK FACTORS

• hyperhomocysteinemia
• hyperuricemia
• oral contraceptive agents (in association with
  cigarette smoking)

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OTHER 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)

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ROLE OF INFECTION?

• suggested factors (much interest, but nothing
  definitive as yet)
• Chlamydia pnemoniae
• Cytomegalovirus

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HYPERCHOLESTEROLEMIA

• 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

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HYPERCHOLESTEROLEMIA

• hypercholesterolemia secondary to hypothyroidism
  or nephrotic syndrome also associated with
  increased atherosclerotic disease

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HYPERCHOLESTEROLEMIA 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

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LABORATORY 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

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LABORATORY TESTING

• LDLHDL ratio should be 41 or less
• frequent test panel includes triglycerides, total
  cholesterol, HDL, and LDL
• lipoprotein phenotyping sometimes useful

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NATIONAL 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

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NCEP 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

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NCEP 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)

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NCEP 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)

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NCEP 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

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OLD INSUDATION THEORY

• infiltration of intima with lipid and plasma
  proteins is primary atherogenic event

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OLD 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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OTHER 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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RESPONSE TO INJURY HYPOTHESIS

• considers atherosclerosis to be chronic
  inflammatory response of arterial wall initiated
  by injury to endothelium.

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RESPONSE 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

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RESPONSE 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

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RESPONSE TO INJURY HYPOTHESIS

• release of factors from activated platelets,
  macrophages, or vascular cells that cause
  migration of smooth muscle cells from media into
  intima

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RESPONSE 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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ROLE 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

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HYPERLIPIDEMIA 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

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SMOOTH 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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Hypothetical 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
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MULTIFACTORIAL 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.

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Thank you for your attention.