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Rosalind Franklin University of Medicine and Science

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Title: Rosalind Franklin University of Medicine and Science


1
Rosalind Franklin University of Medicine and
Science
2
ARTERIOSCLEROSIS
  • Arthur S. Schneider, M.D.
  • Department of Pathology
  • Chicago Medical School at
  • Rosalind Franklin University of Medicine and
    Science

3
ARTERIOSCLEROSIS
  • general term
  • rigidity (sclerosis), often with thickening, of
    blood vessels
  • three major entities included
  • Mönckeberg's arteriosclerosis (medial calcific
    sclerosis)
  • arteriolosclerosis
  • atherosclerosis

4
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

5
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

8
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

14
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

15
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

29
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

30
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

40
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

41
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

42
RISK FACTORS
  • non-modifiable
  • age
  • male gender
  • family history
  • genetic abnormalities
  • modifiable
  • hyperlipidemia
  • hypertension
  • cigarette smoking
  • diabetes mellitus

43
RISK FACTORS
  • other, less certain
  • obesity
  • physical inactivity
  • type A personality
  • homocysteine
  • postmenopausal state
  • alcohol
  • lipoprotein (a)
  • hardened (trans) unsaturated fat intake
  • Chlamydia pneumoniae

44
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

45
AGE
  • premature atherosclerosis refers to clinically
    apparent disease occurring earlier in life
  • characteristic of famililal hyperlipidemias,
    diabetes mellitus, and hypertension

46
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

47
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

48
DIABETES MELLITUS
  • associated with premature atherosclerosis
  • course is more rapid and severe, especially in
    women
  • gangrene of the lower extremities almost
    restricted to diabetics

49
CIGARETTE SMOKING
  • well established major risk factor

50
LESS FIRMLY ESTABLISHED RISK FACTORS
  • obesity, especially in combination with diabetes
  • sedentary lifestyle
  • personality and stress factors

51
LESS FIRMLY ESTABLISHED RISK FACTORS
  • hyperhomocysteinemia
  • hyperuricemia
  • oral contraceptive agents (in association with
    cigarette smoking)

52
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)

53
ROLE OF INFECTION?
  • suggested factors (much interest, but nothing
    definitive as yet)
  • Chlamydia pnemoniae
  • Cytomegalovirus

54
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

55
HYPERCHOLESTEROLEMIA
  • hypercholesterolemia secondary to hypothyroidism
    or nephrotic syndrome also associated with
    increased atherosclerotic disease

56
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

57
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

58
LABORATORY TESTING
  • LDLHDL ratio should be 41 or less
  • frequent test panel includes triglycerides, total
    cholesterol, HDL, and LDL
  • lipoprotein phenotyping sometimes useful

59
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

60
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

72
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.
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