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Pathobio Exam 1
Set 16: Atherosclerosis
102
Pathology
Graduate
10/19/2011

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Term
What is the most common disease affecting blood vessels?
Definition
atherosclerosis
Term
def

atherosclerosis
Definition
a form of arteriosclerosis (hardening of the arteries) - thickening & loss of elasticity of the vessel wall
Term
What causes atherosclerosis?
Definition
formation of atheromas (lipid plaques)
Term
What are the consequences of atherosclerosis?
Definition
stenosis, occlusion of vessel lumen, or aneurysm => damage to organs by altering blood flow
Term
What are the 4 important clinical manifestations of atherosclerosis?
Definition
1) IHD (ischemic heart disease)
2) MI
3) PVD (peripheral vascular disease)
4) cerebrovascular disease (inc. stroke)
Term
Sx

atherosclerosis
Definition
usually subclinical until complications of late-stage leisons lead to overt disease s.a.
transient vascular insufficiency
infarct
acute hemorrhage from ruptured aneurysm
Term
What vessels are affected by atherosclerosis?
Definition
elastic large to medium sized muscular arteries
Term
Where in vessels does atherosclerosis tend to affect?
Definition
branch points & origins of exiting vessels
Term
What are the 3 classical divisions of atherosclerosis?
Definition
1) fatty streaks
2) atherosclerotic plaques (fibrous or fibroatheromatous)
3) complicated plaques
Term
What is the earliest atherosclerotic leison?
Definition
fatty streaks
Term
def

fatty streaks
Definition
subendothelial lipid deposits
Term
In fatty streaks, where does lipid accumulate?
Definition
"foam cells" (monocytes, macrophages, smooth muscle cells)
Term
What are the predominant cells in fatty streaks?
Definition
monocytes/macrophages
Term
What is the hallmark of atherosclerotic disease?
Definition
atherosclerotic plaques
Term
How do atherosclerotic plaques form?
Definition
evolve from fatty streaks by progressive accumulation of lipid & smooth muscle cells
Term
What is at the core or atherosclerotic plaques?
Definition
necrotic center with cellular debris, lipids, & plasma proteins
Term
What covers the atherosclerotic plaque on the luminal surface?
Definition
fibrous capsule
Term
Where does neovascularization occur in an atherosclerotic plaque?
Definition
periphery of leisons
Term
Where in an atherosclerotic plaque are inflammatory cells found?
Definition
base & sides of the plaque
Term
What are the cells in plaques embedded into in an atherosclerotic plaque?
Definition
CT matrix produced by smooth muscle cells (SMCs)
Term
What are the 3 essential components of the atherosclerotic plaque?
Definition
1) cells (SMCs, monocytes/macrophages, T cells)
2) CT (ECM, collagen, elastic, & proteoglycans)
3) lipids (intracellular & extracellular including cholesterol & cholesterol crystals)
Term
What is the primary cell type in an atherosclerotic plaque?
Definition
SMCs
Term
def

stable plaques
Definition
have dense fibrous caps
Term
def

unstable plaques
Definition
have prominent lipid core
Term
What are the 3 critical features of the atherosclerotic plaque that is responsible for expasion of the leisons => clinically overt disease?
Definition
1) proliferation of intimal SMCs
2) accumulation of lipid & ECM in intima
3) on-going inflammation & collagen deposition
Term
What is the advanced leison in atherosclerosis?
Definition
complicated leison
Term
What does it mean that complicated leisons are "advanced"?
Definition
plaques have undergone one of the following alterations:
1) calcification
2) ulceration (focal rupture)
3) thrombosis
4) hemorrhage into the plaque
5) aneurysmal dilation of the vessel wall
Term
Effect

calcification of plaque
Definition
reduce flexibility of vessel wall
Term
Effect

ulceration of plaque
Definition
embolization of plaque contents
Term
Effect

thrombosis of plaque
Definition
partial or complete occlusion
Term
Effect

hemorrhage into plaque
Definition
acute expansion or rupture of plaque
Term
Effect

aneurysm dilation of vessel wall due to plaque
Definition
erosion of plaque into media => loss of elastic tirrue & smooth muscle due to: pressure, ischemic atrophy, or inflammatory damage => focal ballooning out of vessel wall
Term
What determines the clinical significance of advanced atherosclerosis?
Definition
vascular occlusion or rupture
Term
When will atherosclerosis remain subclinical until?
Definition
1) acute occlusion => infarction
2) chronically diminished arterial flow => progressive organ dysfunction
or
3) hemorrhage occurs
Term
When does progressive stenosis reach a critical phase?
Definition
~70%
Term
When does acute arterial occlusion usually occur?
Definition
setting of plaque ulceration/rupture or hemorrhage into plaque with thrombosis
Term
Which plaques are particularly vulnerable to acute arterial occlusion?
Definition
high lipid content
thin fibrous cap
Term
What causes aneurysms?
Definition
progressive damage to vessel wall with loss of elastic fibers & SMCs => impinge on adjacent structures or rupture acutely
Term
Where are atherosclerotic aneurysms most common?
Definition
abdominal aorta
Term
What are the 6 subclassification of atherosclerotic leisons as detailed by the AHA?
Definition
I: initial leison (1st decade - silent)
II: fatty streak
III: intermediate leison (3rd decade)
IV: atheroma ( - silent or overt)
V: fibroatheroma (4th decade)
VI: complicated leison
Term
What are the major NON-modifiable risk factors for atherosclerosis (AS)?
Definition
Age: increasing
Sex: M>F (Estrogen = premenopausal protecton)
Family Hx (inherited genetic abnormalities)
Term
Whata are the major modifiable risk factors for AS?
Definition
Hyperlipidemia
DM
HTN
Smoking
Increased C-reactive protein level
Term
What are the minor, uncertain, or non-quantified risk factors for AS?
Definition
obesity
physical inactivity
stress
diet: high CHO or trans fat intake
increased lipoprotein
chronic inflammatory diseasea (chlamydia)
increased homocysteine level
EtOH
Term
Where in the world is AS more prevalent?
Definition
developed nations
Term
Why is there multiplicative effect of risk factors for AS?
Definition
Risk factors of AS are shared among other diseases s.a. ICD, HTN, DM, MI, stroke, renal disease, neurodegenerative diseases.
Term
What lipids play a role in AS?
Definition
cholesterol & other steroids, fatty acids, triglycerides
Term
What protein is used to transport lipids?
Definition
lipoproteins
Term
What proteins synthesized in the liver form lipoproteins?
Definition
apoproteins
Term
How are lipoproteins classified?
Definition
electrophoresis
Term
What are the 5 lipoproteins?
Definition
1) chylomicrons
2) VLDL
3) IDL
4) LDL
5) HDL
Term
What 4 lipoprotein abnormalities were found in MI survivors?
Definition
1) increased LDL
2) increased chylomicron remnant & IDL
3) increased abnormal lipoproteins
4) decreased HDL
Term
[image]
Definition
1) chylomicron
2) chylomicron remnant
3) VLDL
4) IDL
5) LDL
6) HDL
Term
What happens to cholesterol when it's metabolized in the liver?
Definition
Becomes free cholesterol =>
1) storage
2) synthesizing membranes
3) inhibits lipoprotein synthesis
4) inhibits synthesis of more cholesterol
Term
What types of lipoproteins are associated with high rish AS?
Definition
LDL, VLDL, & IDL
IIa (LDL) - β
IIb (LDL & VLDL) - β & pre-β
III (IDL) - broad β
Term
What does high levels of LDL, VLDL, & IDL imply about blood cholesterol & triglyceride levels?
Definition
increased
Term
What causes hypercholeseremia?
Definition
Genetic or acquired abnormalities in synthesis or degradation of plasma lipoproteins
Term
What implicates cholesterol as a risk factor for AS?
Definition
1) increased dietary intake of cholesterol => increased risk
2) lipoprotein abnormalities seen in CVD
3) lipid genetic syndromes are associated with increased incidence AS
4) lab models derived from these observations
Term
What autosomal type is familial hypercholesterolemia?
Definition
autosomal dominant
Term
What abnormality is caused by familial hypercholesterolemia?
Definition
defect in LDL receptor protein or apoproteins (deficiency or functional impairment)
Term
Sx

familial hypercholesterolemia
Definition
1) early onset AS
2) deposits of lipid-laden macrophages in skin (xanthomas)
3) elevated cholesterol & LDL
4) Lipid profiles IIa (LDL) & IIb (vLDL & LDL)
Term
What other genetic mutation => increased risk for AS?
Definition
plasma lipoprotein mutations
Term
What does high HDL (or more specifically low total cholesterol/HDL ratio) correlate with?
Definition
decreased AS risk
Term
What results in intracellular deposition of lipoprotein-derived cholesterol?
Definition
oxidative modification of LDL (lipid peroxidation) => enhanced clearance by subendothelial macrophages (foam cells)
Term
What is one of the end products of lipid peroxidation?
Definition
malondialdehyde
Term
What are the 7 ways LDL peroxidation => increased AS leison?
Definition
1) readily ingested by scavenger cells => foam cell formation
2) chemotactic for circulating blood monocytes
3) increased monocyte adhesion
4) inhibiting migration of foam cells
5) stimulating release of GFs & cytokines
6) toxic to EC & SMCs
7) serve as Ag => Ab formation
Term
What increased in dietary intake can reduce risk of AS?
Definition
omega-3 PUFAs
antioxidants
Term
How does omega-3 PUFAs decrease AS risk?
Definition
inhibits EC synthesis of PDGF
Term
What drugs lower cholesterol?
Definition
statins
Term
Function

macrophages/monocytes in AS plaque
Definition
1) phagocytose lipid to become foam cell
2) release mediators to interact with other cells
Term
Function

SMCs in AS plaque
Definition
1) migrate from media & proliferate
2) imbibe lipid to become foam cells
3) release mediators to interact with other cells
Term
Function

T cells in AS plaque
Definition
release mediators to interact with other cells
Term
What is a key component of AS plaque formation that occurs early?
Definition
SMC proliferation
Term
What accounts for the progressive growth of AS leisons?
Definition
SMC proliferation & ECM deposition in intima
Term
Why happens when SMCs take up lipid in AS plaque?
Definition
turned into foam cells
Term
What stimulatory GFs are secreted in an AS plaque?
Definition
PDGF via ECs, SMCs, monocytes/macrophages, platelets
bFGF via macrophages, ECs, & lymphocytes
Term
What inhibitory GFs are have decreased secretion in an AS plaque?
Definition
heparin-like compounds via EC
Term
How may SMC determine it's own proliferation?
Definition
1)ability to proliferate changes with age
2)altered SMC kinetics may predispose to myointimal hyperplasia following endothelial injury
Term
What is considered the key event in the pathogenesis of AS?
Definition
endothelial injury
Term
What role does endothelial injury play in AS?
Definition
1) endothelial injury + high lipid diet => atheroma
2) most leisons develop under "normal" endothelium
Term
What is the relationship b/w endothelium & monocytes in early AS & late AS?
Definition
early: recruitment of monocytes => protective
late: accumulated macrophages => recruitment of more inflammatory cells/produce toxic oxygen radicals
Term
What is the relationship b/w macrophages & T cells in AS?
Definition
=> chronic inflammatory state & fibrosis
Term
Why is high levels of CRP indicative of increased AS risk?
Definition
biomarker of inflammation
Term
Why is it hypothesized that chlamydia can lead to increased AS risk?
Definition
produces local endothelial injury + chronic inflammation
Term
What 5 central questions should be addressed by any AS pathogenesis hypothesis?
Definition
1) What is the basis for SMC proliferation?
2) By what mech. does lipid enter the plaque?
3) What are the characteristics and/or functions of the cells involved in AS
4) What is the role of AS risk factors?
5) What accounts for the anatomic location of the AS leisons?
Term
What is the earliest hypothesis of AS pathogenesis?
Definition
insudation
Term
def

insudation hypothesis
Definition
LDL enters endothelium via receptor-mediated uptake or non-specific uptake via pinocytosis.

(provides hypothesis for how lipid is accumulated, but not SMC proliferation. studies have concluded that lipids are engulfed by macropahges & then transported across vascular wall)
Term
def

encrustation hypothesis
Definition
small mural thrombi represent the initial event & organization of these thrombi => plaque formation.

Thus SMC proliferation is a reaction to the passage of lipids & proteins from blood to vessel wall.

(studied have concluded mural thrombosis is not an initial event)
Term
def

monoclonal hypothesis
Definition
an alteration in growth control of one a few SMC underlies the pathogenesis of AS. This alteration can be caused by some unknown factor s.a. mutagen, virus, etc.

(studies have shown many AS plaques are monoclonal)
Term
def

response-to-injury hypothesis
Definition
the def. of endothelium injury was changed to include changes s.a. alteration in cell surface constituents, increased permeability, & increased endothelial turnover since endothelium is retained & remains intact in most AS plaques
Term
def

oxidative-modification hypothesis
Definition
reduced severity of AS is a result of the production of LDL resistant to oxidation.

(studies have shown that cellular antioxidants protect against AS damage, esp. endothelial dysfunction)
Term
def

hemodynamic hypothesis
Definition
hemodynamics plays a role since there is increased AS occurance at sites of prominent hemodynamic fluctuations & prominence of HTN as a risk factor.

hemodynamic forces can induce gene expression in EC (but can also induce gene expression of anti-atherogenic agents)
Term
What are the 3 stages of a unifying hypothesis of AS?
Definition
1) initiation & formation
2) adaptation
3) clinical
Term
What occurs in the initiation & formation stage of a unifying hypthesis?
Definition
1) initial intimal leison
2) lipid accumulation due to EC or SMC disruption
3) monocyte/macrophage response to injury
4) local mural thrombus incorporated into leisons
5) necrosis in deeper portions of thickened intima
6) fibroinflammatory lipid plaque
Term
What occurs in the adaptation stage of a unifyong hypothesis?
Definition
Luminal encroachment => hemodynamic changes & changes in vascular caliber
Term
What occurs in the clinical stage of a unifying hypothesis?
Definition
1) plaque progression
2) complications
Term
def

primary prevention of AS
Definition
delaying formation of atheroma
(adjusting all modifiable risk factors)
Term
def

secondary prevention of AS
Definition
preventing recurrance of symptomatic events
Term
What are the 4 aims of interventions at plaque regression?
Definition
1) interfere with initiation of plaque formation (statins)
2) interfere with plaque progression (statins)
3) enhance plaque stability & thromboresistance => reduced likelihood of rupture, vasoreactivity or thrombosis (anticoagulants)
4) removal of plaque constituents (lipids, fibrin, collagen) (endarterectomy, angioplasty)
Term
Increased CT matrix in fibrous plaques is:

A) of blood-borne origin
B) synthesized by smooth muscle cells
C) secreted by lipid-laden macrophages
D) not subject to proteinase activity
Definition
B
Term
Characteristic features of fatty streaks include all of the following EXCEPT:

A) lipid-laden smooth muscle cells
B) thrombosis
C) lipid-laden macrophages
D) thickened intima
E) insignificant narrowing of the lumen
Definition
B
Term
Which of the following processes converts a fibrous plaque into a complicated plaque?

A) cholesterol condenses into crystals
B) foam cells accumulate
C) neovascularization at the periphery of the leison
D) endothelial surface ulcerates
E) smooth muscle cells proliferate
Definition
D
Term
Which of the following is most likely to be associated with an increased incidence of myocardial infarction due to coronary artery atherosclerosis?

A) an elevated HDL
B) a diet rich in omega-3 PUFAs
C) program of exercise & moderate EtOH consumption
D) elevated blood homocysteine level
E) normal blood level of lipoprotein Lp(a)
Definition
D
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