1b Atherosclerosis Flashcards
How is the world disease burden of coronary heart disease changing?
Increasing levels of obesity and diabetes globally
What are the modifiable risk factors of coronary heart disease?
Smoking, Lipids intake, blood pressure, diabetes, obesity and sedentary lifestyle
What are the non-modifiable risk factors for atherosclerosis?
Age
Sex
genetic background
What are the three risk factors which contribute to the risk factor multiplication?
Hypertension
High Cholesterol
Smoking
Why has hyperlipidaemia reduced over the last decade?
Statin treatment
How has hypertension changed over the last few decades?
Lowered due to anti-hypertensive treatment
What are the function of vascular endothelial cells?
barrier function eg to lipoproteins
involved in leukocyte recruitment
What is the role of platelets in atherosclerosis?
Thrombus generation
Cytokine and growth factor release
What are monocyte-macrophages involved in?
Foam cell formation, and the release of cytokines and growth factors
What are a major source of free radicals?
Monocytes/macrophages
What are the roles of vascular smooth muscle cells?
Migration and proliferation
Collagen Synthesis
Remodelling and fibrous cap formation
Which T lymphocytes are involves in macrophage activation?
CD4 Th1
Which T lymphocytes are involved in macrophage de-activation?
CD4 Treg
What is the main basis of atherosclerosis?
Inflammation
What is the connection between lipids and inflammation in atherosclerosis?
Cholesterol crystal formation connects lipids and inflammation in atherosclerosis
What happens if white blood cells are activated excessively?
White blood cells can damage host tissue if they are activated
What are the main inflammatory cells in atherosclerosis?
Macrophages - derived from blood monocytes
What regulates macrophages?
Combination of transcription factors binding to regulatory sequences on DNA
What are the two types of macrophages?
Inflammatory macrophages and non-inflammatory / resident
macrophages
What are inflammatory macrophages adapted to do?
Kill micro-organisms 9germs)
What are the functions of non-inflammatory macrophages?
Normally homeostatic functions
Alveolar resident macrophages = involved in surfactant lipid homeostasis
Spleen = involved in iron homeostasis
What is LDL?
Low density lipoprotein - the “bad” cholesterol which is made in the liver
What is the function of LDL?
Carries cholesterol from the liver to the rest of the body including the arteries
What is HDL?
High density lipoprotein - carries. cholesterol from the peripheral tissues including arteries back to the liver = involved in reverse cholesterol transport
What causes modified LDLs to form?
Free radicals, enzymes and aggregations
What do modified LDLs form?
Families of high inflammatory and toxic forms of LDL found in vessel walls
What is the surrounding layer of lipoproteins like?
Lipid monolayer which is one molecule thick - separates fat from water
Contains apoproteins on the surface
What is carried in the center of an LDL?
triglycerides
Why do LDLs leak through the endothelial barrier?
Due to activation in areas of vortex
What traps the LDL in the sub-endothelial layer?
It binds to sticky matrix carbohydrates (proteoglycans) and sticks in the sub-endothelial layer - becomes susceptible to modification
What type of modification might a LDL undergo?
oxidation - through free radical attack from activated macrophages
What happens to the LDL once it has been oxidatively modified?
Phagocytosed by macrophages which stimulates chronic inflammation
What do the engulfed oxidised LDL’s become?
Foam cells = leads to chronic inflammation
What is seen in children with familial hyperlipidaemia?
Xanthoma - lesions containing cholesterol and fat
What are the chemical features of patients with familial hyperlipidaemia?
Massively elevated cholesterol levels, resulting in xanthomas and early atherosclerosis - if untreated can lead to risk of myocardial infarction before the age of 20
What is the problem in patients with familial hyperlipidaemia?
It is an autosomal genetic disease which leads to a failure to clear LDL from the blood
How is cholesterol synthesis regulated?
By cellular cholesterol
What is the general mechanism of action of statins?
HMG-CoA reductase inhibitors
What happens to cholesterol in LDLR-negative patients?
Macrophages accumulate cholesterol
What are the types of LDL receptors and how do they differ?
LDL Receptor = under negative feedback with cholesterol levels
Scavenger receptors = hoover up chemically modified LDL = accidently bind OxidisedLDL
Where do atherosclerotic plaques commonly form?
Bifurcation of carotid artery
Bifurcation of abdominal aorta into iliac arteries
Origins of the subclavians and the carotids
Renal arteries
In large and medium calibre arteries, where are plaques likely to form in the blood vessel structure itself?
Subintima space - LDLs deposit in this space and bind to matrix proteoglycans
Explain the progression of atherosclerosis
Coronary artery at lesion prone location
Smooth muscle in between endothelium and media
Type II lesion
As LDL enters the neo intima, it attracts monocytes from blood differentiating into tissue forms to form macrophages
Type III (preatheroma)
As LDL builds up, it releases extracellular lipid droplets in the artery wall
Type IV (atheroma)
Droplets of lipid fuse and fat kills macrophages so these are dead
Type V (fibroatheroma)
Fibrous thickens and starts to look as abscess from the exterior
Type VI (complicated lesion)
Breakdown of plaque → this material enters the blood → forming clots in the blood
If an atherosclerotic plaque breaks down, what could happen?
myocardial infarction or stroke
What primary prevention would you attempt in intermediate and advanced lesions?
Lifestyle changes
Risk factor management
What is the explanation for LDLR-negative patients, where macrophages accumulate cholesterol?
There is a second LDL receptor (scavenger receptor) which is not under feedback control, in the atherosclerotic lesions
These receptors accidentally bind to OxLDL and so this leads to macrophages which are also in the atherosclerotic lesions to hoover up this modified LDL
What are macrophage scavenger receptors A and B also known as?
Macrophage scavenger receptor A - CD204
Macrophage scavenger receptor B - CD36
What binds to both the two macrophage scavenger receptors?
Oxidised LDL
What type of bacteria binds to macrophage scavenger receptor A?
gram positive bacteria = like staphlyococci and Streptococci
What microorganism binds to macrophage scavenger receptor B?
Malaria parasites
When arterial Ox-LDL is deposited, what is there a balance between when activating macrophages?
Inflammation (activation of bug-detector pathways) and Homeostasis (safe clearance and reverse cholesterol transport)
What are the two oxidising enzymes that can modify native LDL?
NADPH Oxidase
Myeloperoxidase
What is an example of myeloperoxidase?
HOCl hypochlorous acid (bleach)
How can myeloperoxidase release then result in damage to the artery walls?
If inflammatory cells are in our vessels and primed to secrete this enzyme each time we eat anything with cholesterol which is then taken by LDL and deposited into our vessels, then this triggers hypochlorite bleach release (HOCl) from ROS + Cl-
What cytokines are released from plaque macrophages?
IL-1
What chemical do macrophages trigger the generation of?
Hydrogen peroxide
What changes might be seen in the lumen when foam cells form?
cholesterol crystals, zone of sick and dying foam cells, fat globules and foam cell debris
What happens when macrophages accumulate modified LDL’s
Become foam cells
What is expressed by plaque macrophages which helps with monocyte recruitment?
inflammatory factors
What are cytokines?
protein immune hormones that activate endothelial cell adhesion molecules
What are chemokines?
Small protein chemoattract to monocytes
What is the main cytokine in atherosclerosis?
Interleukin 1
What does interleukin 1 do?
triggers eg intracellular cholesterol crystals and NFkB. Coordinates multiple processes including cell death and cell proliferation; and elevated CRP
What is the main chemokine involved in atherosclerosis?
monocyte chemotactic protein-1
MCP-1
What does MCP-1 bind to?
binds to a monocyte G-protein coupled receptor CCR2.
Describe the wound healing role of macrophages?
Macrophages release growth factors that recruit VSMC and stimulate them to migrate, survive, proliferate and deposit extracellular matrix e.g. structurally strong collagen
What does platelet derived growth factor do?
Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)
What does TGF-beta do?
Increased collagen synthesis
Matrix deposition
Describe the changes that occur in vascular smooth muscle cells to go from normal medial to atherosclerotic?
PDGF + TGF-b
decreased Contractile filaments
increased Matrix deposition genes
What is the effect of plaque erosion/rupture?
Blood coagulation at the site of rupture - may lead to an occlusive thrombus and cessation of blood flow
How do macrophages degrade collagen which leads to plaque ruptures?
Metalloproteinases -
How do metalloproteins get activated?
Activate each other by proteolysis and degrade collagen
What do metalloproteinases require to work?
Zinc
What are the characteristics of vulnerable and stable plaques?
Large, soft eccentric lipid rich core
Increased VSMC apoptosis
Reduced VSMC and Collagen content
Thin fibrous cap
Infiltrate of activated macrophage expressing MMP’s
What is meant by a fibrous cap?
Layer of fibrous connective tissue which is thicker and less cellular than the normal intima, found in atherosclerotic plaques
Contains macrophages and smooth muscle cells
A rupture of unstable plaque in what artery usually causes an anteroseptal myocardial infarction?
Left anterior descending coronary artery
Describe what is seen on an ECG with a coronary artery thrombosis and myocardial infarction
ST-segment elevation anterior leads (T wave aversion seen later), also VE
What is an example of an OxLDL derived metabolite?
7-keto-cholesterol
What are macrophage foam cells protected against?
Maintain survival in the face of toxic lipid loading
What happens to macrophages once they become overwhelmed?
Die via apoptosis - release macrophage growth factors and toxic lipids into the central death zone called the liquid necrotic core
What are the functions of macrophages in atherosclerotic pathophysiology?
Secrete inflammatory cytokines and chemokines
Phagocytose, process and export cholesterol to reverse cholesterol transport (HDL)
Secrete oxidants that damage cells and LDL
Accumulate cholesterol and become sick and activated by cholesterol overload
Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core.
Secrete matrix metalloproteinases
What are the signs and symptoms of atherosclerosis?
Death of downstream tissue
Loss of function of one side of the body - major ischaemic stroke
Severe central crushing chest pain with fear, dizziness and nausea - MI
Angina
Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.
What is the master regulator of inflammation?
Nuclear Factor kappa B (NFkB)
What are the three things which activate Nuclear Factor kappa B (NFkB) ?
Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1
What genes does Nuclear Factor kappa B (NFkB) switch on?
Numerous inflammatory genes
Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1
What regulates macrophage activation?
nuclear factor kappa B
