Term
| What is the most common disease affecting blood vessels? |
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Definition
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Term
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Definition
| a form of arteriosclerosis (hardening of the arteries) - thickening & loss of elasticity of the vessel wall |
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Term
| What causes atherosclerosis? |
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Definition
| formation of atheromas (lipid plaques) |
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Term
| What are the consequences of atherosclerosis? |
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Definition
| stenosis, occlusion of vessel lumen, or aneurysm => damage to organs by altering blood flow |
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Term
| What are the 4 important clinical manifestations of atherosclerosis? |
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Definition
1) IHD (ischemic heart disease)
2) MI
3) PVD (peripheral vascular disease)
4) cerebrovascular disease (inc. stroke) |
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Term
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Definition
usually subclinical until complications of late-stage leisons lead to overt disease s.a.
transient vascular insufficiency
infarct
acute hemorrhage from ruptured aneurysm |
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Term
| What vessels are affected by atherosclerosis? |
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Definition
| elastic large to medium sized muscular arteries |
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Term
| Where in vessels does atherosclerosis tend to affect? |
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Definition
| branch points & origins of exiting vessels |
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Term
| What are the 3 classical divisions of atherosclerosis? |
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Definition
1) fatty streaks
2) atherosclerotic plaques (fibrous or fibroatheromatous)
3) complicated plaques |
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Term
| What is the earliest atherosclerotic leison? |
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Definition
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Term
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Definition
| subendothelial lipid deposits |
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Term
| In fatty streaks, where does lipid accumulate? |
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Definition
| "foam cells" (monocytes, macrophages, smooth muscle cells) |
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Term
| What are the predominant cells in fatty streaks? |
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Definition
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Term
| What is the hallmark of atherosclerotic disease? |
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Definition
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Term
| How do atherosclerotic plaques form? |
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Definition
| evolve from fatty streaks by progressive accumulation of lipid & smooth muscle cells |
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Term
| What is at the core or atherosclerotic plaques? |
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Definition
| necrotic center with cellular debris, lipids, & plasma proteins |
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Term
| What covers the atherosclerotic plaque on the luminal surface? |
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Definition
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Term
| Where does neovascularization occur in an atherosclerotic plaque? |
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Definition
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Term
| Where in an atherosclerotic plaque are inflammatory cells found? |
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Definition
| base & sides of the plaque |
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Term
| What are the cells in plaques embedded into in an atherosclerotic plaque? |
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Definition
| CT matrix produced by smooth muscle cells (SMCs) |
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Term
| What are the 3 essential components of the atherosclerotic plaque? |
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Definition
1) cells (SMCs, monocytes/macrophages, T cells)
2) CT (ECM, collagen, elastic, & proteoglycans)
3) lipids (intracellular & extracellular including cholesterol & cholesterol crystals) |
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Term
| What is the primary cell type in an atherosclerotic plaque? |
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Definition
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Term
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Definition
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Term
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Definition
| have prominent lipid core |
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Term
| What are the 3 critical features of the atherosclerotic plaque that is responsible for expasion of the leisons => clinically overt disease? |
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Definition
1) proliferation of intimal SMCs
2) accumulation of lipid & ECM in intima
3) on-going inflammation & collagen deposition |
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Term
| What is the advanced leison in atherosclerosis? |
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Definition
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Term
| What does it mean that complicated leisons are "advanced"? |
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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 |
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Term
Effect
calcification of plaque |
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Definition
| reduce flexibility of vessel wall |
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Term
Effect
ulceration of plaque |
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Definition
| embolization of plaque contents |
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Term
Effect
thrombosis of plaque |
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Definition
| partial or complete occlusion |
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Term
Effect
hemorrhage into plaque |
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Definition
| acute expansion or rupture of plaque |
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Term
Effect
aneurysm dilation of vessel wall due to plaque |
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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 |
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Term
| What determines the clinical significance of advanced atherosclerosis? |
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Definition
| vascular occlusion or rupture |
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Term
| When will atherosclerosis remain subclinical until? |
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Definition
1) acute occlusion => infarction
2) chronically diminished arterial flow => progressive organ dysfunction
or
3) hemorrhage occurs |
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Term
| When does progressive stenosis reach a critical phase? |
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Definition
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Term
| When does acute arterial occlusion usually occur? |
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Definition
| setting of plaque ulceration/rupture or hemorrhage into plaque with thrombosis |
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Term
| Which plaques are particularly vulnerable to acute arterial occlusion? |
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Definition
high lipid content
thin fibrous cap |
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Term
|
Definition
| progressive damage to vessel wall with loss of elastic fibers & SMCs => impinge on adjacent structures or rupture acutely |
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Term
| Where are atherosclerotic aneurysms most common? |
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Definition
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Term
| What are the 6 subclassification of atherosclerotic leisons as detailed by the AHA? |
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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 |
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Term
| What are the major NON-modifiable risk factors for atherosclerosis (AS)? |
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Definition
Age: increasing
Sex: M>F (Estrogen = premenopausal protecton)
Family Hx (inherited genetic abnormalities) |
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Term
| Whata are the major modifiable risk factors for AS? |
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Definition
Hyperlipidemia
DM
HTN
Smoking
Increased C-reactive protein level |
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Term
| What are the minor, uncertain, or non-quantified risk factors for AS? |
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Definition
obesity
physical inactivity
stress
diet: high CHO or trans fat intake
increased lipoprotein
chronic inflammatory diseasea (chlamydia)
increased homocysteine level
EtOH |
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Term
| Where in the world is AS more prevalent? |
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Definition
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Term
| Why is there multiplicative effect of risk factors for AS? |
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Definition
| Risk factors of AS are shared among other diseases s.a. ICD, HTN, DM, MI, stroke, renal disease, neurodegenerative diseases. |
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Term
| What lipids play a role in AS? |
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Definition
| cholesterol & other steroids, fatty acids, triglycerides |
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Term
| What protein is used to transport lipids? |
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Definition
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Term
| What proteins synthesized in the liver form lipoproteins? |
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Definition
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Term
| How are lipoproteins classified? |
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Definition
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Term
| What are the 5 lipoproteins? |
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Definition
1) chylomicrons
2) VLDL
3) IDL
4) LDL
5) HDL |
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Term
| What 4 lipoprotein abnormalities were found in MI survivors? |
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Definition
1) increased LDL
2) increased chylomicron remnant & IDL
3) increased abnormal lipoproteins
4) decreased HDL |
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Term
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Definition
1) chylomicron
2) chylomicron remnant
3) VLDL
4) IDL
5) LDL
6) HDL |
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Term
| What happens to cholesterol when it's metabolized in the liver? |
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Definition
Becomes free cholesterol =>
1) storage
2) synthesizing membranes
3) inhibits lipoprotein synthesis
4) inhibits synthesis of more cholesterol |
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Term
| What types of lipoproteins are associated with high rish AS? |
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Definition
LDL, VLDL, & IDL
IIa (LDL) - β
IIb (LDL & VLDL) - β & pre-β
III (IDL) - broad β |
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Term
| What does high levels of LDL, VLDL, & IDL imply about blood cholesterol & triglyceride levels? |
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Definition
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Term
| What causes hypercholeseremia? |
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Definition
| Genetic or acquired abnormalities in synthesis or degradation of plasma lipoproteins |
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Term
| What implicates cholesterol as a risk factor for AS? |
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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 |
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Term
| What autosomal type is familial hypercholesterolemia? |
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Definition
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Term
| What abnormality is caused by familial hypercholesterolemia? |
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Definition
| defect in LDL receptor protein or apoproteins (deficiency or functional impairment) |
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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) |
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Term
| What other genetic mutation => increased risk for AS? |
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Definition
| plasma lipoprotein mutations |
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Term
| What does high HDL (or more specifically low total cholesterol/HDL ratio) correlate with? |
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Definition
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Term
| What results in intracellular deposition of lipoprotein-derived cholesterol? |
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Definition
| oxidative modification of LDL (lipid peroxidation) => enhanced clearance by subendothelial macrophages (foam cells) |
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Term
| What is one of the end products of lipid peroxidation? |
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Definition
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Term
| What are the 7 ways LDL peroxidation => increased AS leison? |
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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 |
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Term
| What increased in dietary intake can reduce risk of AS? |
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Definition
omega-3 PUFAs
antioxidants |
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Term
| How does omega-3 PUFAs decrease AS risk? |
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Definition
| inhibits EC synthesis of PDGF |
|
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Term
| What drugs lower cholesterol? |
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Definition
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Term
Function
macrophages/monocytes in AS plaque |
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Definition
1) phagocytose lipid to become foam cell
2) release mediators to interact with other cells |
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Term
Function
SMCs in AS plaque |
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Definition
1) migrate from media & proliferate
2) imbibe lipid to become foam cells
3) release mediators to interact with other cells |
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Term
Function
T cells in AS plaque |
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Definition
| release mediators to interact with other cells |
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Term
| What is a key component of AS plaque formation that occurs early? |
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Definition
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Term
| What accounts for the progressive growth of AS leisons? |
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Definition
| SMC proliferation & ECM deposition in intima |
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Term
| Why happens when SMCs take up lipid in AS plaque? |
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Definition
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Term
| What stimulatory GFs are secreted in an AS plaque? |
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Definition
PDGF via ECs, SMCs, monocytes/macrophages, platelets
bFGF via macrophages, ECs, & lymphocytes |
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Term
| What inhibitory GFs are have decreased secretion in an AS plaque? |
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Definition
| heparin-like compounds via EC |
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Term
| How may SMC determine it's own proliferation? |
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Definition
1)ability to proliferate changes with age
2)altered SMC kinetics may predispose to myointimal hyperplasia following endothelial injury |
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Term
| What is considered the key event in the pathogenesis of AS? |
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Definition
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Term
| What role does endothelial injury play in AS? |
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Definition
1) endothelial injury + high lipid diet => atheroma
2) most leisons develop under "normal" endothelium |
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Term
| What is the relationship b/w endothelium & monocytes in early AS & late AS? |
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Definition
early: recruitment of monocytes => protective
late: accumulated macrophages => recruitment of more inflammatory cells/produce toxic oxygen radicals |
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Term
| What is the relationship b/w macrophages & T cells in AS? |
|
Definition
| => chronic inflammatory state & fibrosis |
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Term
| Why is high levels of CRP indicative of increased AS risk? |
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Definition
| biomarker of inflammation |
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Term
| Why is it hypothesized that chlamydia can lead to increased AS risk? |
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Definition
| produces local endothelial injury + chronic inflammation |
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Term
| What 5 central questions should be addressed by any AS pathogenesis hypothesis? |
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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? |
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|
Term
| What is the earliest hypothesis of AS pathogenesis? |
|
Definition
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Term
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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) |
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Term
def
encrustation hypothesis |
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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) |
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Term
|
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) |
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Term
def
response-to-injury hypothesis |
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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 |
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Term
def
oxidative-modification hypothesis |
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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) |
|
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Term
def
hemodynamic hypothesis |
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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) |
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Term
| What are the 3 stages of a unifying hypothesis of AS? |
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Definition
1) initiation & formation
2) adaptation
3) clinical |
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Term
| What occurs in the initiation & formation stage of a unifying hypthesis? |
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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 |
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Term
| What occurs in the adaptation stage of a unifyong hypothesis? |
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Definition
| Luminal encroachment => hemodynamic changes & changes in vascular caliber |
|
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Term
| What occurs in the clinical stage of a unifying hypothesis? |
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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 |
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Definition
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|
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 |
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Definition
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|
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 |
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Definition
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|
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) |
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Definition
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