Atherosclerosis & Peripheral Vascular disorder Flashcards
how is the burden of IHD and CVD changing worldwide?
increasing
what are the modifiable risk factors for atherosclerosis?
- Smoking
- Lipids intake
- Blood pressure
- Diabetes
- Obesity
- Sedentary lifestyle
what are the non-modifiable risk factors for atherosclerosis?
age
sex
genetic background
how do different risk factors contribute to atherosclerosis risk?
combined risk factors in individual causes risk factor multiplication (synergistic)
what changes have happened in epidemiology that alter the risk of atherosclerosis?
- Reduced hyperlipidaemia (statin treatment)
- Reduced hypertension (antihypertensive treatment)
- Increased obesity à increased diabetes
- New improvements in diabetes treatment have doubtful effect on macrovascular disease
- Changing pathology of coronary thrombosis possibly related to altered risk factors
where does atherosclerosis occur?
in one cell thick narrow intima within thick smooth wall
where does LDL deposition occur?
in subintimal space and bind to matrix proteoglycans
what are the types of initial lesions due to atherosclerosis progression and what are their features?
what is the window of opportunity for primary prevention from lesions?
what is the role of vascular endothelial cells?
barrier function (e.g to lipoproteins)
leukocyte recruitment
what is the role of monocyte-macrophages?
foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteineinases
what is the role of vascular smooth muscle cells?
migration and proliferation
collagen synthesis
remodelling and fibrous cap formaiton
what is the role of platelets?
thrombus generation
cytokine and growth factor release
what is the role of T lymphocytes
macrophage activation
what is the role of inflammation in atherosclerosis?
atherosclerosis has an inflammatory basis
patients at high risk atherosclerosis complications are injected with antibodies to IL-1 (have fewer major adverse CV events)
mechanisms include cholesterol crystal formation
what are the main inflammatory cells in atherosclerosis?
macrophages (derived from blood monocytes)
what are the classes of macrophages?
inflammatory
resident
what are inflammtory macrophages?
adapted to kill microorganisms (germs) at expense of some host damage
what are resident macrophages?
normally homeostasis- suppress inflammatory activity
alveolar resident macrophages- surfactant lipid homeostasis
osteoclasts- calcium and phosphate homeostasis
spleen- iron homeostasis
what are the types of lipoproteins?
LDL
HDL
oxidised LDLs, modified LDLs
where is LDL synthesised?
in liver
what is LDL?
low density lipoprotein
bad cholesterol
what does LDL do?
carries cholesterol from liver to rest of body including arteries
what is the composition of LDL?
what is the risk from LDL?
high LDL= increased risk CVD and atherosclerosis
do we need LDL?
yes- need some to survive
what is HDL?
high density lipoprotein
good cholesterol
what is the role of HDL?
carries cholesterol from peripheral tissues including arteries back to liver
(= reverse cholesterol transport)
how are oxidised LDLs/ modified LDLs created?
due to the action of free radicals on LDL
not one single substance
where are oxidised LDLs/modified LDLs found?
families of highly inflammatory and toxic forms of LDL found in vessel walls
how are modified LDLs created?
- LDLs leak through endothelial barrier
- LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in sub-endothelial layer and becomes susceptible to modification
- Best studies modification= oxidation
- LDL becomes oxidatively modified by free radicals
- Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation!
what is familial hyperlipidaemia?
autosomal genetic disease
characteries by massively elevated cholesteral- failure to clear LDLS from blood
xanthomas and early atherosclerosis
what happens if Familial hyperlipidaemia is untreated?
fatal myocardial infarction before age 20
what can be used to lower plasma cholesterol?
HMG-CoA reductase inhibitors= statins
what are the types of LDL receptors?
LDL receptor
scavenger receptor
what is the scavenger receptor
LDL receptor
not under feedback control
pathogen receptors that bind OxLDL
what are the types of macrophage scavenger receptors?
macrophage scavenger receptor A
macrophage scavenger receptor B
what does macrophage scavenger receptor A do?
known as CD204
binds oxidised LDLs
binds to gram-positive bacterial like staphylococci & streptococci
binds to dead cells
what does macrophage scavenger receptor B do?
known as CD36
binds to oxidised LDL
binds to malaria parasites
binds to dead cells
what is the role of macrophages within plaques?
generate free radicals that further oxides lipoproteins
phagocytose modified lipoproteins and become foam cells
express cytokine mediators that recruit monocytes
express chemo-attractant and growth factors for VSMC
express proteinases that degrade tissue
how do macrophages generate free radicals?
have oxidative enzymes that can modify native LDL
NADPH oxidase- e.g superoxide O2-
myeloperoxidase- HOCL hypochlorous acid from ROS + Cl-, HONOO peroxynitrite
how do macrophages become foam cells?
accumulate modified LDLs to become enlarged foam cells
what is a cytokine?
protein immune hormones that activate endothelial cell adhesion molecules
what are some examples of cytokines involved in atherosclerosis?
Interleukin-1 = upregulates vascular cell adhesion molecule 1 VCAM-1
VCAM-1= mediates tight monocyte binding
atherosclerosis is reduced in mice without IL-1 or VCAM-1
what are chemokines?
small proteins chemoattractant to monocytes
what are some chemokines important in atherosclerosis?
monocyte chemotactic protein1- (MCP-1)
MCP-1 binds to a monocyte G-protein coupled receptor CCR2
atherosclerosis is reduced in MCP-1 or CCR-2 deficient mice
what is the role of platelet-derived growth factor?
VSMC chemotaxis
VSMC survival
VSMC division (Mitosis)
what is the role of transforming GF beta?
increases collagen synthesis
matrix deposition
what is the role of macrophages in expressing chemo-attractants and GF for VSMC?
“Wound healing” role of the macrophage in atherosclerosis -
Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix
PDGF and TGF-b causes decreased contractile filaments and increased matrix deposition geners= atherosclerosis
what proteinases do macrophages express that degrade tissue?
MMPs
what are MMPs?
matrix metalloproteinases
family of 28 homologous enzymes
activate each other by proteolysis
degrade collagen
catalytic mechanism based on Zn
what are the characteristics of vulnerable plaques
TCFA- thin cap fibrous atheroma
- Large soft eccentric lipid rich necrotic core
- Increased VSMC apoptosis
- Reduced VSMC & collagen content
- Thin fibrous caps
- Infiltrate of activated macrophages expressing MMPs
how does macrophage apoptosis occur in atherosclerosis?
- 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
what happens on foam cell apoptosis?
- Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
- Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood
what is nuclear factor kappa B (NFkB)?
transcription factor
master regulator of inflammation
switches on numerous inflammatory genes
what is NFkB activated by?
- Scavenger receptors
- Toll-like receptors
- Cytokine receptors e.g. IL-1
what doe3s NFkB activate?
inflammatory genes
- Matrix metalloproteinases
- Inducible nitric oxide synthase
- Interleukin-1
