Artherogenesis Flashcards
Non-modifiable arterial disease risk factors (4):
- genetic abnormalities
- family history
- increasing age
- male
Modifiable arterial disease risk factors (4):
- smoking
- hypertension (high blood pressure)
- high cholesterol levels
- diabetes mellitus
Structure of the arterial wall
Atherosclerosis structure consists of (2):
- fibrous cap
- necrotic core
Atherosclerosis structure: fibrous cap:
- smooth muscle cells
- foam cells
- macrophages
- lymphocytes
- proteoglycans
- collagen
- elastin
- neurovascularisation
Atherosclerosis structure: necrotic core:
- cell debris
- cholesterol crystals
- calcium salts
- foam cells
Lipid Hypothesis:
- 1980s
- virchow specifically linked artherosclerosis
to high LDL cholesterol
Lipid Oxidation Hypothesis:
- 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
Reasons why lipid oxidation is a contributing factor but is not the primary cause of atherosclerosis:
- 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
Which experimental models does most atherosclerosis data come from? What are the disadvantages of these experiments?
- LDL receptor deficient mice
- Apolipoprotein E deficient mice
- the mice develop atherosclerosis on a
normal diet - may not be extrapolated correctly to
human disease
Response to Injury Hypothesis Steps:
Atherosclerosis is seen as an acute inflammatory response to endothelial injury.
True or False?
False
a chronic response
Endothelial Injury Risk Factors:
- haemodynamic stress (high BP, arterial branch points)
- toxins (cigarette smoke)
- hyperlipidaemia
- aging
In health, macrophages normally take up very little native LDL cholesterol.
True or False?
True
What receptor deficiency results in the accumulation of large amounts of cholesterol in macrophages? Elaborate.
- 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
Why is atheroscleorsis more likely to occur at arterial branch points?
More likely to occur where there is turbulent flow
Endothelial Injury Response:
- 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
What are the four classes of small molecules involved in atherosclerosis and what are their purposes?
- Cytokines: regulate inflammatory response
- Growth factors: stimulate the growth of
specific cell lines - Chemokines: attract monocytes
- Adhesion molecules: allow adhesion
Two examples of the four classes of small molecules involved in atherosclerosis:
- Cytokines: IL-1, TNF-alpha
- Growth Factors: PDGF, VSMGF
- Chemokines: MCP1
- Adhesion molecules: ICAM-1, VCAM-1
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
- 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
Foam Cell Development
- oxidised lipids are ingested by
macrophages - cells become foam cells
What are monocytes that move into tissues called?
Macrophages
Response to Injury Hypothesis in detail:
- 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
Fatty Streak Formation:
- ***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
Fatty streaks are found in which part of the vessel?
- the intima
- hence do not obstruct flow
What is the first visible manifestation of atherosclerosis?
Fatty streak (in intima)
Atherogenesis
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)
Plaque Development: what forms the fibrous cap of an atherosclerotic plaque
- smooth muscle cells and extracellular
matrix
What forms the necrotic core of an atherosclerotic plaque?
- foam cells degenerate forming a lipid rich
necrotic core
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
What is neovascularisation?
when new vessels grow into the edges of the atherosclerotic plaque - can bleed into the plaque
Occlusive atherosclerotic plaques can cause
angina
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
unstable plaques diagram
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)
ST elevation myocardial infarc occurs when
- occlusion atherosclerotic plaque in a coronary artery
Stroke occurs when
occlusion atherosclerotic plaque in the brain
Aneurysm formation:
- weakening of the media, thinning of
adventitia leads to arterial dilation - eventually leads to dissection, and vessel
rupture
Where does aneurysm commonly occur and why
- abdominal aorta
- tension in the wall is greatest
- progressive dilation
Athero-embolism:
- ruptured plaque material discharged into
the circulation - lands in small vessels (eg legs)
- necrotic toes
Clinical consequences of atherosclerosis: aorta:
- aneurysm formation (abdomen>thorax)
- renal artery stenosis (hypertension)
Clinical consequences of atherosclerosis: coronary arteries:
- angina
- MI
- heart failure
Clinical consequences of atherosclerosis: cerebral arteries:
- stroke
- vascular dementia
Clinical consequences of atherosclerosis: leg arteries:
- claudication
- foot ulcers
- gangrene
Atherosclerosis is a degenerative process.
True or False?
False
Inflammatory
How many deaths in the UK are due to atherosclerosis?
1 in 5 deaths in the UK is due to atherosclerosis
Plaque instability occurs when the
lipid rich necrotic core expands and the fibrous cap thins
Plaque - related clinical events most commonly occur due to
thrombosis following plaque rupture
