Artherogenesis Flashcards
1
Q
Non-modifiable arterial disease risk factors (4):
A
- genetic abnormalities
- family history
- increasing age
- male
2
Q
Modifiable arterial disease risk factors (4):
A
- smoking
- hypertension (high blood pressure)
- high cholesterol levels
- diabetes mellitus
3
Q
Structure of the arterial wall
A
4
Q
Atherosclerosis structure consists of (2):
A
- fibrous cap
- necrotic core
5
Q
Atherosclerosis structure: fibrous cap:
A
- smooth muscle cells
- foam cells
- macrophages
- lymphocytes
- proteoglycans
- collagen
- elastin
- neurovascularisation
6
Q
Atherosclerosis structure: necrotic core:
A
- cell debris
- cholesterol crystals
- calcium salts
- foam cells
7
Q
Lipid Hypothesis:
A
- 1980s
- virchow specifically linked artherosclerosis
to high LDL cholesterol
8
Q
Lipid Oxidation Hypothesis:
A
- atherosclerosis as the consequence of free-radical driven oxidative modification of LDL cholesterol:
- OH radical (hydroxyl)
- O2- radical (superoxide)
- O2 radical (singlet) - modified LDL is taken up more rapidly by macrophages: LDL binds to non-specific scavenger receptors
- led to the hypothesis that: oxidative stress was a prerequisite for lipid uptake and thus a primary cause of atherosclerosis
9
Q
Reasons why lipid oxidation is a contributing factor but is not the primary cause of atherosclerosis:
A
- the distribution of atheroma in the arterial tree
- the role of non-lipid risk factors: hypertension, smoking, genetics
- the complications of atherosclerosis
- clinical trials with anti-oxidant drugs had no effect on the course of atherosclerotic disease
10
Q
Which experimental models does most atherosclerosis data come from? What are the disadvantages of these experiments?
A
- LDL receptor deficient mice
- Apolipoprotein E deficient mice
- the mice develop atherosclerosis on a
normal diet - may not be extrapolated correctly to
human disease
11
Q
Response to Injury Hypothesis Steps:
A
12
Q
Atherosclerosis is seen as an acute inflammatory response to endothelial injury.
True or False?
A
False
a chronic response
13
Q
Endothelial Injury Risk Factors:
A
- haemodynamic stress (high BP, arterial branch points)
- toxins (cigarette smoke)
- hyperlipidaemia
- aging
14
Q
In health, macrophages normally take up very little native LDL cholesterol.
True or False?
A
True
15
Q
What receptor deficiency results in the accumulation of large amounts of cholesterol in macrophages? Elaborate.
A
- LDL receptor deficiency causes a large
amount of cholesterol accumulation in
their macrophages - circulating LDL must undergo modification
to become atherogenic - these modifications allow LDL uptake via
scavenger receptors - modification = oxidation/ oxidative stress
16
Q
Why is atheroscleorsis more likely to occur at arterial branch points?
A
More likely to occur where there is turbulent flow
17
Q
Endothelial Injury Response:
A
- endothelial cells release cytokines
- endothelial cells express adhesion
molecules - allow leukocytes (monocytes) to bind and -
infiltrate (macrophages) - injury leads to reduced NO production
- Nitric Oxide (NO) was originally called EDFR endothelium derived relaxing factor
18
Q
What are the four classes of small molecules involved in atherosclerosis and what are their purposes?
A
- Cytokines: regulate inflammatory response
- Growth factors: stimulate the growth of
specific cell lines - Chemokines: attract monocytes
- Adhesion molecules: allow adhesion
19
Q
Two examples of the four classes of small molecules involved in atherosclerosis:
A
- Cytokines: IL-1, TNF-alpha
- Growth Factors: PDGF, VSMGF
- Chemokines: MCP1
- Adhesion molecules: ICAM-1, VCAM-1
20
Q
Response to Injury Hypothesis: Step 2:
- name
- common lipoprotein abnormalities lead to
(3) - endothelial injury causes
- in the intima — forms of lipid accumulates
(2) - which stimulates the release
A
- Lipoprotein Accumulation
- common lipoprotein abnormalities lead to:
- increased LDL cholesterol
- reduced HDL cholesterol
- increased Lipoprotein (a) - Endothelial Injury causes:
- increased O2 free radicals and
- reduced NO levels - in the intima two lipid forms accumulates:
- oxidised LDL
- cholesterol crystals - stimulates the release of inflammatory
mediators
21
Q
Foam Cell Development
A
- oxidised lipids are ingested by
macrophages - cells become foam cells
22
Q
What are monocytes that move into tissues called?
A
Macrophages
23
Q
Response to Injury Hypothesis in detail:
A
- chemical/oxidative stress causes
endothelial dysfunction - allows low density lipoproteins to move
into the intima and become modified - the injured endothelium allows monocytes
to adhere to the endothelium and migrate
into the intima where they become
macrophages - the macrophages take up the
modified/oxidised low-density lipoproteins
to form foam cells - the foam cells release more inflammatory
mediators, cytokines, growth factors and
chemoattractants - which causes the migration of smooth
muscle cells from the media into the intima - these cells mix together forming a fatty
streak - extracellular matrix formation: made by
smooth muscle cells that secrete collagen,
elastin and proteoglycans - extracellular matrix stabalises the
atherosclerotic plaque
24
Q
Fatty Streak Formation:
A
- ***smooth muscle cells migrate from the
media - ***foam cells and smooth muscle cells
produce fatty
streaks - foam cells eventually undergo apoptosis,
when they mix with smooth muscle cells - visible in almost everyone from early teens
- does not obstruct flow but may progress
- visible in almost everyone from early teens
25
Fatty streaks are found in which part of the vessel?
- the intima
- hence do not obstruct flow
26
What is the first visible manifestation of atherosclerosis?
Fatty streak (in intima)
27
Atherogenesis
28
Plaque Stabilisation:
- cells?
- consists of?
- what stabilises the atherosclerotic plaque?
- controlled by a mumber cytokines/growth
factors?
- smooth muscle cells migrate from the
media and proliferate
- smooth muscle cells and synthesise
extracellular matrix:
- mainly collagen
- also elastin and proteoglycans
- **extracellular matrix stabilises the
atherosclerotic plaque
- controlled by a number of cytokines/growth factors:
- Platelet-derived growth factors (PDGF)
- Fibroblast growth factor (FGF)
- Tissue Growth Factor alpha (TGF-
alpha)
29
Plaque Development: what forms the fibrous cap of an atherosclerotic plaque
- smooth muscle cells and extracellular
matrix
30
What forms the necrotic core of an atherosclerotic plaque?
- foam cells degenerate forming a lipid rich
necrotic core
31
Atherosclerotic Plaque Progression:
- plaque grows: becomes raised from the
vessel wall
- calcium salts deposited: calcium phosphate and calcium hydroxyapitite, hardening of arteries
- new vessels grow into the edges of the
plaque (Neovascularisation)
- tunica media is thinned and weakened
32
What is neovascularisation?
when new vessels grow into the edges of the atherosclerotic plaque - can bleed into the plaque
33
Occlusive atherosclerotic plaques can cause
angina
34
Unstable Occlusive Atherosclerotic Plaques :
- activated inflammatory in plaques can
cause:
- smooth muscle cell apoptosis
- breakdown of extracellular matrix
- ***thinning of fibrous cap will lead to
rupture
- development of unstable of vulnerable
plaques
35
unstable plaques diagram
36
Unstable plaques can lead to clinical events:(3)(3)
- rupture/erosion/ulceration will expose
collagen and the lipid core which is
thrombogenic
- Thrombus may:
- occlude the artery (MI)
- partially occlude the artery (unstable
angina)
- become organised into the plaque,
plaque progression (stable angina)
- Occlusions or progression can also follow bleeding into the plaque (neovasculature)
37
ST elevation myocardial infarc occurs when
- occlusion atherosclerotic plaque in a coronary artery
38
Stroke occurs when
occlusion atherosclerotic plaque in the brain
39
Aneurysm formation:
- weakening of the media, thinning of
adventitia leads to arterial dilation
- eventually leads to dissection, and vessel
rupture
40
Where does aneurysm commonly occur and why
- abdominal aorta
- tension in the wall is greatest
- progressive dilation
41
Athero-embolism:
- ruptured plaque material discharged into
the circulation
- lands in small vessels (eg legs)
- necrotic toes
42
Clinical consequences of atherosclerosis: aorta:
- aneurysm formation (abdomen>thorax)
- renal artery stenosis (hypertension)
43
Clinical consequences of atherosclerosis: coronary arteries:
- angina
- MI
- heart failure
44
Clinical consequences of atherosclerosis: cerebral arteries:
- stroke
- vascular dementia
45
Clinical consequences of atherosclerosis: leg arteries:
- claudication
- foot ulcers
- gangrene
46
Atherosclerosis is a degenerative process.
True or False?
False
Inflammatory
47
How many deaths in the UK are due to atherosclerosis?
1 in 5 deaths in the UK is due to atherosclerosis
48
Plaque instability occurs when the
lipid rich necrotic core expands and the fibrous cap thins
49
Plaque - related clinical events most commonly occur due to
thrombosis following plaque rupture
