Atherosclerosis Flashcards
Risk Factors
Potentially Modifiable:
Smoking
Lipids
Blood Pressure
Diabetes
Obesity
Lack of Exercise
Not Modifiable:
Age
Sex
Genetic Background
If you have two or three different risk factors then the risk associated is MULTIPLICATED
If risk factors are general, then why is atherosclerosis FOCAL?
Where do atheroscelorsises tend to arise?
Why do atherosclerotic lesions tend to appear on the outside of a bend rather than on the inside?
Where do LDLs deposit and what do they bind to?
Atherosclerosis is NOT evenly distributed - it tends to arise at specific places such as the bifurcation of the common carotid artery
Blood flow in arteries is LAMINAR so the blood flows fastest in the middle of the vessel and slower around the outside
When the blood goes around a corner too quickly it sets up EDDYs (turbulent flow)
Therefore, atherosclerotic lesions tend to appear on the outside of a bend rather than on the inside
LDLs deposit in the SUBINTIMAL SPACE and binds to matrix proteoglycans
Progression of Atherosclerosis
Once the LDLs enter the………………….. layer, a chain reaction is established
The lesion begins small and then ……………….. accumulate which brings in macrophages which eat up the endothelial fat and become …………………. ……………… and remove themselves from the viscinity
As fat deposition continues, the lesion accumulates pools of extracellular lipids (outside the macrophages) and the macrophages can no longer cope
The fat builds up further and you get a core of extracellular lipid - the pool of fats coalesce and forms a large mass of fat
The inflammation irritates the interior of the plaque to form a fibrous thickening
The macrophages produce ……………….. ……………….. that stimulate smooth muscle cells to grow, divide and make more ………………..
Eventually the plaque will RUPTURE which allows the lipid core (which is thrombogenic) to communicate with the lumen and stimulate ……………….. formation within the lumen
The photo on the right is of very advanced fibroatheroma
There is a layering effect - comes from repeat episodes of plaque destabilisation - small episodes of thrombus forming and then stopping - the thrombi form one after another to narrow the lumen a little bit at a time
Progression of Atherosclerosis
Once the LDLs enter the subintimal layer, a chain reaction is established
The lesion begins small and then LDLs accumulate which brings in macrophages which eat up the endothelial fat and become FOAM CELLS and remove themselves from the viscinity
As fat deposition continues, the lesion accumulates pools of extracellular lipids (outside the macrophages) and the macrophages can no longer cope
The fat builds up further and you get a core of extracellular lipid - the pool of fats coalesce and forms a large mass of fat
The inflammation irritates the interior of the plaque to form a fibrous thickening
The macrophages produce growth factors that stimulate smooth muscle cells to grow, divide and make more collagen
Eventually the plaque will RUPTURE which allows the lipid core (which is thrombogenic) to communicate with the lumen and stimulate clot formation within the lumen
The photo on the right is of very advanced fibroatheroma
There is a layering effect - comes from repeat episodes of plaque destabilisation - small episodes of thrombus forming and then stopping - the thrombi form one after another to narrow the lumen a little bit at a time
Describe the process for how a atherosclerosis occurs?
Progression of Atherosclerosis
Once the LDLs enter the subintimal layer, a chain reaction is established
The lesion begins small and then LDLs accumulate which brings in macrophages which eat up the endothelial fat and become FOAM CELLS and remove themselves from the viscinity
As fat deposition continues, the lesion accumulates pools of extracellular lipids (outside the macrophages) and the macrophages can no longer cope
The fat builds up further and you get a core of extracellular lipid - the pool of fats coalesce and forms a large mass of fat
The inflammation irritates the interior of the plaque to form a fibrous thickening
The macrophages produce growth factors that stimulate smooth muscle cells to grow, divide and make more collagen
Eventually the plaque will RUPTURE which allows the lipid core (which is thrombogenic) to communicate with the lumen and stimulate clot formation within the lumen
The photo on the right is of very advanced fibroatheroma
There is a layering effect - comes from repeat episodes of plaque destabilisation - small episodes of thrombus forming and then stopping - the thrombi form one after another to narrow the lumen a little bit at a time
List 5 main cell types for atheroscelrosis?
List two functions of Vascular endothelial cells for Atheroscelorosis?
List two functions of platelets for atherosclerosis?
List 4 roles of macrophages in atherosclerosis?
List 3 roles of vascular smooth muscle cells for atherosclerosis?
List the role of T lymphocytes for atherosclerosis?
What are the two systems responsible for haemostasis?
What are Foam cells?
What are macrophages a key source of and name 2 things they release?
What are matrix metalloproteinases?
Vascular Smooth Muscle Cells, in an abnormal artery with an atherosclerotic plaque, can synthesise and secrete ……………….. which contributes to the stabilisation of the …………. and ……………..
Main Cell Types and their Roles
There are TWO systems responsible for haemostasis:
Clotting Cascade
Platelet Aggregation
Platelet aggregation and the coagulation cascade generate normal clotting but they can also generate abnormal clotting (thrombosis)
Foam Cells are macrophages that have consumed fat
Macrophages secrete cytokines and growth factors and are a key source of free radicals which the immune system makes as part of the natural immune function to kill microbes
Because of the abnormal inflammatory action in advancing lesions, they then become an inappropriate source of free radicals
Matrix Metalloproteinases - degrade major extracellular proteins such as collagen
Vascular Smooth Muscle Cells, in an abnormal artery with an atherosclerotic plaque, can synthesise and secrete COLLAGEN which contributes to the stabilisation of the plaque and fibrous cap
T cells - the feedback of macrophages activates T cell and the activated T cells, in turn, activate macrophages
Macrophages
- White blood cells can injure host tissue if they are activated excessively or inappropriately
- In atherosclerosis, the main inflammatory cells are ………………….
- Macrophages are derived from blood ……………….
- There are many different types of macrophages
- Macrophage subtypes are regulated by combinations of………………. ………………. binding to regulatory sequences on DNA
- We do not yet understand the regulation
- Two main classes - ………………. or inflammatory macrophages
•………………. macrophages adapted to kill microorganisms (germs)
•………………. macrophages – normally homeostatic
–suppressed inflammatory activity
–Alveolar resident macrophages (surfactant lipid homeostasis)
–………………. (calcium and phosphate homeostasis)
–Spleen (iron homeostasis)
–
Macrophages
- White blood cells can injure host tissue if they are activated excessively or inappropriately
- In atherosclerosis, the main inflammatory cells are macrophages
- Macrophages are derived from blood monocytes
- There are many different types of macrophages
- Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory sequences on DNA
- We do not yet understand the regulation
- Two main classes - resident or inflammatory macrophages
•Inflammatory macrophages adapted to kill microorganisms (germs)
•Resident macrophages – normally homeostatic
–suppressed inflammatory activity
–Alveolar resident macrophages (surfactant lipid homeostasis)
–Osteoclasts (calcium and phosphate homeostasis)
–Spleen (iron homeostasis)
–
Where are LDLs synthesised and what is its roles
Where are HDLs synthesised and what is its roles?
What causes Oxidised LDL(s), modified LDL(s) ?
•Low density lipoprotein (LDL)
–‘bad’cholesterol
–synthesised in liver
–carries cholesterol from liver to rest of body including arteries
•High density lipoprotein (HDL)
–‘good cholesterol’
–carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
•Oxidised LDL(s), modified LDL(s)
–Due to action of free radicals on LDL (see later)
–Not one single substance
–families of highly inflammatory and toxic forms of LDL found in vessel walls.
How is LDL trapperd in the sub endothelial layer?
What is trapped LDL sisceptiable to?
Modification of subendothelial trapped LDL
- LDL becomes oxidatively modified by ………….. …………..
- Oxidised LDL is ………….. by macrophages and stimulates ………….. …………..
- Best studied modification is oxidation
- Chemically represents partial burning
- LDL becomes oxidatively modified by free radicals
- Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
Name a genetic illness which predisposes you to Atheroscelrosis?
What type of genetic illness is it?
How does it predispose you to atheroscelosis?
Patients’ skin and their arteries contain deposits of fat with the accumulations of foam cells- what is this called?
What are its clinical features?
Autosomal recessive genetic disease
People with FH have a massively elevated choleterol (20 mmol/L)
There is failure to clear LDL from the blood
Patients’ skin and their arteries contain deposits of fat with the accumulations of foam cells (when this happens in the skin it is called a xanthoma)
Clinical Features: xanthomas and early atherosclerosis (if untreated, fatal myocardial infarction before the age of 20)
Macrophages accumulate cholesterol
What happens in LDLR negative patients in terms of macrophages?
What is the Scavanger receptor?
Macrophages accumulate cholesterol
In LDLR negative patients, macrophages continue to accumulate cholesterol
It was deduced that there is a SECOND LDL receptor (on the macrophages) which is not under feedback control in atherosclerotic lesions
This receptor was called the SCAVENGER RECEPTOR because it hoovers up chemically modified LDL (oxidised LDL)
It is now known that scavenger receptors are a family of pathogen receptors that accidentally bind to oxidised LDLs
Macrophage Scavenger Receptors
How the macrophage reacts is dependent on how much arterial OxLDL there is
Arterial OxLDL deposits can have TWO different effects:
Explain them
Macrophage Scavenger Receptors
How the macrophage reacts is dependent on how much arterial OxLDL there is
Arterial OxLDL deposits can have TWO different effects:
Interaction of OxLDL with macrophages can lead to the abnormal materials being scooped up by the macrophage and removed from the artery (this is a form of safe clearance and leads to reverse cholesterol transport and is a form of homeostasis)
In the second pathway, higher levels of OxLDL will activate bug-detector pathways and pathogen pattern recognition pathways which have evolved to detect anything with fat in it that isn’t us - inflammatory
The bug detector pathways are macrophage scavenger receptors (A and B)
A - binds to OxLDL but evolved to bind to Gram positive bacteria and dead cells
B - binds to OxLDL but also bind to malaria parasites and dead cells
Oxidised LDL in an Atherosclerotic Plaque
Bottom arrow shows an accumulation of OxLDL in a foam cell
Macrophages have oxidative enzymes that can modify native LDL
Name two of them?
•Phagocytose/scavenge modified lipoproteins, and become foam cells
Macrophages have oxidative enzymes that can modify native LDL
NADPH Oxidase
Takes oxygen and reduces it (adds an electron) forming an oxygen molecule with an extra negative charge which is extremely reactive
SUPEROXIDE (O2-)
Superoxide sits at the top of a cascade of highly reactive oxygen species to form the oxygen that goes into HOCL (hypochlorous acid) which happens by the action of myeloperoxidase from hydrogen peroxide and chloride
When trying to kill pathogens, macrophages produce hypochlorous acid (domestos (bleach)) which is extremely toxic and rapidly degrades the surface
Activating macrophages basically makes the macrophages secrete hypochlorous acid in the arteries - this highlights a lot of the problems that happen in atherosclerosis
Peroxynitrite - MORE UNSTABLE than HOCL and is formed from nitric oxide
MYELOPEROXIDASE - involved in making hypochlorous acid (HOCL) and peroxynitrite (HONOO)
Macrophages accumulate modified LDLs to become enlarged foam cells
When macrophages enter the subendothelial layer they start off small but as they get further and further in they get bigger and bigger
These foam cells end up getting very sick because they are bloated with fat
They become so bloated with fat that the fat comes out of solution forming fat globules within the macrophage which eventually kills it
–Cytokine mediators (eg IL-1, MCP-1) that recruit more monocytes
–Chemoattractants and growth factors for VSMC
Name 2 and list there funtions. One has 2 functions and one has 3 functions?
They have a secondary function where they can repair the damaged interior
PDGF and TGF-beta can influence the VSMC to turn become the synthetic phenotype
The atherosclerotic VSMC can make more ECM and have fewer contractile filaments
Macrophages proteolyse extracellular matrix
Macrophages degrade plaque ………….. through a set of enzymes called ………… …………………..
They activate each other in a …………
They degrade collagen and the mechanism is based on …………
In the image - where there are macrophages, there is no collagen - because the macrophages can degrade the ………… themselves
This degradation weakens the ………… ………… and once it becomes weak enough it ruptures and triggers ………… formation
This may lead to an occlusive ………… and cessation of blood flow
Macrophages proteolyse extracellular matrix
Macrophages degrade plaque collagen through a set of enzymes called matrix metalloproteinases
They activate each other in a cascade
They degrade collagen and the mechanism is based on Zinc
In the image - where there are macrophages, there is no collagen - because the macrophages can degrade the collagen themselves
This degradation weakens the fibrous cap and once it becomes weak enough it ruptures and triggers thrombus formation
This may lead to an occlusive thrombus and cessation of blood flow
What might blood coagulation at the site of rupture lead to?
Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow
This is a histology image of a thrombosis
Normally, in this person, the coronary artery would be defined by the internal elastic lamina (around the green line)
This thrombus has arisen because of a crack
The physical crack in the superficial cap of the artery is full of activated macrophages
It also contains lots of small vessels which have erythrocytes within them
The small vessels have been the source of a second problem which is the bleed
When ruptured- forms instantaneous thrombus
List 5 characterisitcs of vulnerable and stable plaques?
Reduced collagen content goes hand in hand with a thin fibrous cap
Matrix metalloproteinases degrade the collagen in the plaque making it weaker
LEFT - died of an occlusion in the left anterior descending coronary artery
There are THREE main coronary arteries:
To begin with they come off as the Right Coronary Artery and the Left Main Coronary Artery
The right coronary artery runs down the right ……………………. ……………. and supplies most of the right side of the heart (mainly the right ventricles)
LEFT divides into the ………… ………. ………………… and ……………….. …………………
LAD supplies the ………………… ………….. …………… and the ……………….
…………. …………….. supplies the left ventricular free wall
This person has blocked off their left anterior descending coronary artery which has resulted in the death of the myocardium in the anterior free wall and the septum
LEFT - died of an occlusion in the left anterior descending coronary artery
There are THREE main coronary arteries:
To begin with they come off as the Right Coronary Artery and the Left Main Coronary Artery
The right coronary artery runs down the right atrioventricular sulcus and supplies most of the right side of the heart (mainly the right ventricles)
LEFT divides into the Left Anterior Descending and Left Circumflex
LAD supplies the anterior free wall and the septum
Left Circumflex supplies the left ventricular free wall
This person has blocked off their left anterior descending coronary artery which has resulted in the death of the myocardium in the anterior free wall and the septum
What causes the macrophages to die from apoptosis?
They release macrophage ……………. …………… and …………….. ………… into the central death zone called the ……………. ………………… …………….
How does apoptosis of macrophages contribute to thrombosis?
Macrophage Apoptosis
Happens, in part, because the OxLDL derived metabolites are TOXIC (e.g. 7-keto cholesterol)
Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
When they are finally overwhelmed by the amount of fat, they die by apoptosis
They release macrophage tissue factor and toxic lipids into the central death zone called the LIPID NECROTIC CORE
The thrombogenic and toxic materials accumulate in the lipid necrotic core until plaque rupture allows them to meet the blood
Endothelial loss- exposure of calagen- formation of thrombus
What is Nuclear Factor Kappa B?
Nuclear Factor Kappa B
Transcription Factor
Master regulator of inflammation
Activated by numerous inflammatory stimuli:
Scavenger receptors
Toll-like receptors
Cytokine receptors
Switches on numerous inflammatory genes:
Matrix metalloproteinases
Inducible nitric oxide synthase
Diagramatic Summary - Macrophages in Atherosclerosis
Severe pain, nausea and vomiting are signs of MI
Various risk factors summate to activate endothelial cells which make them more sticky for monocytes
There is an increase in endothelial permeability which allows LDLs into the peripheral section of the arterial wall
In the subendothelial layer, the LDLs are readily oxidised
Macrophages will oxidise more LDLs which starts a viscious cycle
The macrophages phagocytose OxLDL turning them into foam cells
The foam cells will release more cytokines and chemokines that recruit more monocytes
Macrophages also secrete matrix metalloproteinases which degrade collagen in the artery wall and secrete growth factors which increase the number of smooth muscle cells and increase collagen synthesis
The macrophages are capable of removing fat from the artery wall - reverse cholesterol transport
If the macrophages, however, are overwhelmed by the intracellular fat, they can die by apoptosis and release the toxic lipids and macrophage tissue factor into the necrotic core
What are the major inflammatory cell type in atherosclerosis?
Name 2 protective functions macrophages have in the plaque?
List 4 deterious functions they have in the plaque?
