CVR Atherosclerosis and peripheral vascular disease Flashcards
modifiable risk factors for artheroscleoris (6)
smoking lipid intake blood pressure diabetes obesity sedentary lifestyle
nonmodifiable risk factors for artheroscleoris
sex at birth
age
Genetic background
What is the risk of atherosclerosis if you have hypertension smoking and high cholesterol?
Individual risk and grouped?
Hypertension: x3
Smoking: x1.6
High cholesterol: x4
All 3: x16
How has atherosclerosis epidemiology changed over time? (5)
- Reduced hyperlipidaemia (statin treatment)
- Reduced hypertension (antihypertensive treatment)
- Increased obesity -> Increased diabetes
- New improvements in diabetes treatment have doubtful effect on macrovascular disease
- Changing pathology of coronary thrombosis possibly related to altered risk factors
What happens to lipids deposited in the subintimal space?
LDL deposit in subintimal space and binds to matrix proteoglycans -> Oxidised-> engulfed by macrophages -> foam cells
stages of artherosclerosis (6)
- coronary artery at lesion prone location has adaptive thickening (SMC)
- types II lesion (fatty streak)
- Type III (preatheroma/intermediate lesion)
- Type IV (atheroma)
- Type V (fibroatheroma)
- Type VI (complicated lesion)
main cell types involved in atherosclerosis and their roles(5)
- vascular endothelial cells (barrier function and leukocyte recruitment)
- platelets (thrombus generation and cytokine and GF release)
- monocytes-macrophages (foam cell formation, cytokine and GF release, source of free radicals, metalloproteinases)
- vascular smooth muscle cells (collagen producing, migration and proliferation, remodelling and fibrous cap formation)
- T cell (macrophage activation)
the two types of macrophages
- inflammatory macrophages (for killing pathogens)
- resident macrophages
where is LDL synthesised?
liver
- > carries cholesterol from liver to rest of the body
- including arteries
HDL function?
carrier cholesterol from peripheral tissues including arteries back to the liver
Oxidised LDL comes from where? What properties does it have?
due to action of free radicals on LDL
It’s a family of highly inflammatory and toxic forms of LDL
familial hyperlipidemia:
- What is is?
- signs
- event that could occur
- causative genetics?
- Failure to remove LDL from blood
- xanthomas and early atherosclerosis
- fatal MI before age 20 if untreated
- autosomal gene causing massively elevated cholesterol
what happens to LDL R negative patient?
macrophages accumulate cholesterol
What is the purpose of inflammatory macrophages with scavenger receptor?
Scavenger receptors are a family of pathogen receptors that ‘accidently’ bind OxLDL
How do LDLs get modified?
LDLs leak through the endothelial barrier by uncertain mechanisms.
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification.
Best studied modification is oxidation - represents partial burning
LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation!
what does macrophage scavenger receptor A bind?
(aka CD204)
- oxidised LDL
- Gram-positive bacteria like Stapylococi and streptococci
- binds to dead cells
what does macrophage scavenger receptor B bind?
(aka CD36)
- oxidised LDL
- malaria parasites
- dead cells
what oxidative enzymes (free radicals) do Macrophages have that can modify native LDL (2)?
a) NADPH Oxidase, for example superoxide O2-.
b) Myeloperoxidase, for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite.
stages of macrophage apoptosis (4)
OxLDL derived metabolites are toxic eg 7-keto-cholesterol.
- Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading.
- Once overwhelmed, macrophages die via apoptosis
- They then release macrophage tissue factors and toxic lipids into the central death zone - called the lipid necrotic core
- Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.
Nuclear Factor kappa B (NFkB)
What is it?
a transcription factor
Nuclear Factor kappa B (NFkB)
What is its role?
Master regulator of inflammation
Nuclear Factor kappa B (NFkB)
What activates it?
Activated by numerous inflammatory stimuli
- Scavenger receptors
- Toll-like receptors
- Cytokine receptors e.g. IL-1
Nuclear Factor kappa B (NFkB)
What does it switch on?
numerous inflammatory genes
- Matrix metalloproteinases
- Inducible nitric oxide synthase
- Interleukin-1
what event does plaque rupture cause?
myocardial infarction and stroke
- closely related to damange from activated macrophages, particularly activation of collagen degradation
