PBL 5 - Coronary Heart Disease Flashcards
what is atherosclerosis?
= a chronic inflammatory process triggered by the accumulation of cholesterol-containing LDL particles in the arterial wall
= plaque formation; the build up of gruel-like substances such as fats and cholesterol in our artery walls which can restrict or block the blood flow
what is ischaemia?
lack of oxygen due to restriction of blood supply
what are 2 non-modifiable risk factors for myocardial infarction?
- age
- gender
MI is not common in what ages for each gender?
men < 40
women < menopause
name 2 modifiable risk factors for MI
- smoking
2. dyslipidaemia = high level of total cholesterol. LDL cholesterol is associated worth increased risk of CAD
what conditions can predispose you to a higher CAD risk?
- hypertension
- diabetes mellitus
- psychosocial factors
- excess adiposity and metabolic syndrome
what 2 things are recommend to people with a BP over 120/80mmHg?
- decrease salt intake
- weight loss
why does diabetes increase risk of CAD?
- tend to have a higher BP
- dyslipidaemia
- increase glucose levels
- inflammatory markers
what are hydrophobic fact molecules (eg. triglycerides and cholesterol) transported to all cells and tissues of the body in?
lipoprotein particles
describe lipoprotein particle structure
- triglyceride and cholesterol centre
- surrounded by a phospholipid outer shell
- apolipoprotein is embedded in the outer shell
what is the function of apolipoprotein in lipoprotein particles?
- stabilise the complex
- give it a functional identity
what are the 2 main types of lipoprotein and how do they influence risk of CAD?
- bad LDL = increases risk
2. good HDL = decreases risk
what apolipoprotein is embedded in LDL?
apolipoprotein B (ApopB) = ApopB100
what apolipoprotein is embedded in HDL?
apolipoprotein A1 (ApopA1)
what can take LDL in circulation to the artery wall across endothelial cells?
scavenger receptors
at the artery wall, what happens to LDL? what does this lead to?
taken by macrophages to become foam cells, leading to plaque formation
what does HDL do?
transports the cholesterol back to liver through reverse cholesterol transport (RCT)
what is cholesterol converted to for the ease of transporting via reverse cholesterol transport?
cholesteryl ester
what happens to cholesterol in the liver?
excreted through the biliary route
what is resveratrol?
a polyphenolic compound in red wine/grapes known for its antioxidant and anti-inflammatory products
at a particular single nucleotide morphism (SNP) what do CAD patients show?
tend to have C instead of T
what does a high peak on a Manhattan Plot tell us?
high peak = high significance of the genomic region
in GWAS for CAD, a high peak was always found on what chromosome location?
chromosome 9 but not on any gene — Gp21 (named by location)
what is shown without the Gp21 region?
proliferation and senescence of aortic smooth muscle cells are increased — both characteristics of smooth muscle cells in CAD
non-coding regions in the genome can modulate gene expression by acting as what?
regulatory elements
name the different layers of a normal blood vessel
what type of endothelium lines blood vessels?
simple squamous epithelial cells
what does the intima contain?
collagen and proteoglycans
what does the media layer contain?
smooth muscle cells and elastic fibres
what does the adventitia layer contain?
thick collagenous and elastic tissue
where does atherosclerosis tend to occur?
where the artery bifurcates and when the calibre of the artery changes
why is atherosclerosis more prone to occur in birfurcation or calibre changes hotspots?
turbulent flow can happen and cause local recirculating an increase of local concentration of plasma LDL
- frictional force (due to disturbed flow)
- endothelial injury
what is the first stage of atherosclerosis?
infiltration of ApopB-containing LDL in the arterial wall
describe the first stage of atherosclerosis
- LDL transports into the arterial wall and is retained by proteoglycans (in intima)
- disturbed flow creates frictional force on endothelial cells so pro-inflammatory activation
- endothelial dysfunction (due to frictional injury and pro-inflammatory activation) leads to increased influx of cholesterol-containing lipoprotein into the arterial intima
- endothelial cells lose its function as a barrier — more influx of cholesterol-containing lipoprotein
how can retained LDL in the intima be modified by eg. oxidation?
serve as an initiating stimulus for inflammatory reactions, by being recognised as a danger-associated-molecular-pattern (DAMP)
what is the second stage in the development of atherosclerosis?
endothelial adhesion molecule expression and leukocyte adhesion & recruitment
what do oxLDL particles induce?
endothelial surface expression of leukocyte adhesion molecules
expression of what provides a sophisticated regulation of the inflammatory process?
endothelial adhesion molecules and leukocyte integrins and selectins
what do leukocytes recruited to the developing atherosclerotic lesion do?
- produce a number of inflammatory mediators amplifying the inflammatory reaction through a continuous activation of both leukocytes and endothelial cells and by
- recruiting further immune cells to the forming lesion
what is the 3rd stage in the development of atherosclerosis?
monocytes to macrophage differentiation
monocytes differentiate into tissue macrophages under the influence of what?
monocyte-colony stimulating factor (M-CSF) present in forming lesions
what 2 types of macrophages are activated in the 3rd stage of atherosclerosis development
- classically activated/M1 macrophages — sustain inflammatory responses and result in tissue damage
- alternatively activated/M2 macrophages — promote tissue repair and healing by secreting anti-inflammatory mediators
what is the 4th stage in the development of atherosclerosis?
oxLDL uptake and foam cell formation
describe 4th stage of atherosclerosis development
- oxLDL and other modified forms of LDL particles can bind to scavenger receptors expressed on resident macrophages
- uptake of lipoprotein particles will induce the conversion of macrophages into foam cells — results in the microscopic appearance of lipid-laden macrophages
what is the 5th stage in the development of atherosclerosis?
antigen presentation — internalisation of oxLDL by macrophages and dendritic cells will lead to not only foam cell formation, but also antigen presentation (adaptive immune system)
what recruits effector CD4+ T cells to the atherosclerotic region in the 5th stage of atherosclerosis development?
leukocyte adhesion molecules and chemotactic factors produced as a consequence of the innate immune activation
what do CD4+ T cells differentiate into?
Th cells
what T cells are considered atheroprotective and why?
effector T cells of the Treg cells inhibit immune responses and inflammation
what do Th1 cells promote?
macrophage activation and inflammation
what do Th17 cells promote?
fibrosis through il-17 — enhances formation of the lesion’s fibrous cap and plaque stability
what is the 6th stage of atherosclerosis development?
macrophage apoptosis and necrotic core formation
describe stage 6 of atherosclerosis
- several factors, such as oxidative stress, in the atherosclerotic lesions induce macrophage death through apoptosis
- apoptotic cells are normally cleared by a specific phagocytosis process, efferocytosis = an immune response essential for normal steady state of a tissue and a critical phenomenon in the resolution of inflammation
- defective clearance of lipid-laden apoptotic macrophages in the atherosclerotic region creates a lipid necrotic core
what are F and C?
F = fibrous cap C = necrotic core
name some inflammatory cells seen in the adventitia of atherosclerotic vessels
- dendritic cells
- macrophages
- mast cells
- lymphocytes
what are activated in the adventitia of atherosclerotic vessels?
T and B cells
what may develop in advanced stages of atherosclerosis in the adventitia?
large lymphoid structures called adventitia tertiary lymphoid organs
what do adventitia tertiary lymphoid organs do?
sites of antibody production, including antibodies to plasma lipoproteins
after injury, what do endothelial cells reduce the release of and what is the effect of this?
- reduce release of vasoactive hormones such as nitric oxide and prostacyclin
- these hormones relax blood vessels and inhibit platelet activation — therefore this is reduced
what happens to smooth muscle cells in the media in atherosclerosis?
proliferate and move to intima
what is formed due to matrix deposition and smooth muscle cell proliferation and migration?
fibrous cap
what do muscle cells also play a key role in?
calcification
what secretes platelet-derived growth factor (PDGF) and what does it lead to?
endothelial cells, vascular smooth muscle cells and macrophages
leads to proliferation of smooth muscle cells
what kind of scans can be used to visualise arterial plaques?
CT scans and PET scans
describe how PET scans work and what they do
= Position Emission Tomography (PET) scan
- used to show which plaque is more inflammatory
- use a radioactive drug or tracer - 18F Flurodeoxyglucose - to label inflammatory activities
- this is a radioactive glucose molecule as inflammation needs energy
- 18F Flyrodeoxyglycose uptake correlates with macrophage density
what are the most common cholesterol-lowering drugs?
statins
what do statins inhibit?
- the biosynthesis pathway of cholesterol — the melavonate pathway
- particularly target HMG-CoA reductsase in this pathway
what happens when intracellular cholesterol is low?
body tries to increase amount of LDL
—> a TF called SREPB-2 is matured to upregulate LDL receptor + PCSK9
what do LDL receptors do?
uptake the circulatory LDLs on the liver cell membrane to reduce the LDL level in circulation
what does PCSK9 do?
controls the amount of LDL receptors by degrading them
- mediates the lysosomal degradation of the complex formed by the PCSK9, LDL receptor + LDL
what if we could inhibit PCSK9 by using inhibitors?
LDL receptors will not be degrade as and can be recycled to uptake more circulatory LDL
what are 3 reasons for the bifurcation or calibre change of arteries being the atherosclerotic hotspots?
- increased local conc of cholesterol
- frictional force
- endothelial injury
what serves as an initiating stimulus for inflammatory reactions in atherosclerosis?
retained oxidises LDL
monocytes differentiate into macrophages under the influence of what present in forming lesions?
monocytes-colony stimulating factor (M-CSF)
uptake of lipoprotein particles induces conversion of macrophages into what?
foam cells
CD4+ T cells are activated/differentiated into Th cells through what?
antigen presentations by macrophages and dendritic cells
what are the 3 stages of atherosclerosis? describe each
- fatty streak — younger age. made up of smooth muscle cells, cholesterol and macrophages
- fibrous plaque — develops within the inner layer of the vessel, made up of smooth muscle cells, macrophages and lymphocytes with cholesterol in them. as the plaque grows, it begins to produce into the vessel where the blood is flowing
- complicated lesion — fibrous plaque breaks apart, exposing cholesterol and connective tissue underneath it — platelets sent to area — blood flow restricted — ruptured plaque in combination with the blood clot = complicated lesions
where do monocytes differentiate into macrophages?
intima
what is the MOA of statins?
inhibit HMG CoA reductase
what is the role of Lecithin-cholesterol acyl transferase?
esterifies free cholesterol in LDLs and HDLs
what type of angina is caused by vasospasms?
Prinzmetal variant
name 4 roles of NO
- inhibiton of transcription of adhesion molecules in the endothelium
- inhibition of platelet aggregation
- inhibiton of vascular smooth muscle proliferation
- vasodilation
it does not increase vascular permeability
which cholesterol transporter is the body’s main source of energy during prolonged fasting?
VLDLs
smoking one cig per day puts you at a __ % higher chance of developing CHD?
30%
what is Prinzmetal’s variant angina characterised by?
angina that occurs without provocation
what causes ST elevation in MIs?
opening of K+ channels
what is the main mechanism by which NO relieves an attack of angina?
dilating peripheral capacitance vessels
what is the fibrous cap of an atheroma mostly made up of?
smooth muscle cells and collagen
