Coronary Artery Disease and Atherosclerosis Flashcards
Describe the expected burden of IHD
By 2020, will be the highest global killer. Increasing because of the epidemiological shift- developing countries have more westernised lifestyles.
What is atherosclerosis
A progressive, inflammatory disease of large and medium sized arteries.
Describe the areas of medicine that atherosclerosis involves
Neurology (cerebrovascular disease) Cardiology (coronary disease) Cardiac Surgery (revascularization) Vascular Surgery (revascularization) Endocrinology (diabetes) Metabolic medicine (lipids) Acute Medicine (Heart attack Stroke)
What are the modifiable risk factors for atherosclerosis
Smoking
Lipid intake- can be controlled by pharmacological means and diet
Blood pressure- diet control (low salt) and medications
Diabetes- low sugar, lose weight, pharmacological (metformin, sulphonylurea)
Obesity- diet, exercise, drugs (lipid absorption, appetite, gastric bands)
Sedentary Lifestyle - exercise
What are the non-modifiable risk factors for atherosclerosis
Age- increased age increases number and severity of lesions
Sex- men are affected to a much greater extent than women, until the menopause when the incidence in women increases- cardioprotective effects of oestrogen.
Genetic background- at least 50% of risk.
What are we concerned with in the clinic
Modifiable risk factors.
Explain the interaction of the risk factors
Have a multiplicative effect
Describe the changes in the epidemiology over the past decade
Reduced hyperlipidaemia (statin treatment
Reduced hypertension (antihypertensive treatment
New improvements in diabetes treatment have doubtful effect on macrovascular disease
Increased obesity Increased diabetes
Changing pathology of coronary thrombosis possibly related to altered risk factors
What are the clinical trials for SGLT2 inhibitors indicating
Diabetes drugs- still ongoing- little effect on microvascular disease.
Where do atherosclerotic plaques tend to form
Bifurcations
Due to haemodynamic
Create eddys in blood- more turbulent flow in these areas.
Describe the deposition of LDL
Low density lipoproteins (LDL) deposit in the subintimal space and binds to matrix proteoglycans.
Describe the progression of atherosclerosis
lesion prone location- adaptive smooth muscle thickening following LDL deposition
Type 2 lesion- becomes inflammatory- population of foam cells (fat filled macrophages)
Type 3 -preatheroma- foam cells release fat as they die- small pools of extracellular lipid on artery wall
Type 4 (atheroma)- small pools of lipid coalesce to form necrotic core of extracellular lipid.
Type 5 (fibroatheroma)- fibrous thickening (collagen) lies over core, beneath the endothelium
Type 6 (complicated lesion)- if fibrous thickening not enough and cap cracks apart, triggering thrombus that can occlude artery
Describe the appearance of the type 6 lesion
Stratified appearance
As development is stepwise
Grows incrementally in small steps as you age.
What does the stability of the plaque depend on
The stability of the plaque is dependent on the strength and thickness of the fibrous cap, which relies on the balance between inflammation and repair. If this balance is disturbed and inflammation predominates, the cap may become thinner, less stable and may rupture.
Counterintuitively, we want a thick, fibrous cap as it prevents MI.
Where does the window of opportunity for lifestyle interventions lie
Intermediate and advanced lesions
lifestyle changes and risk factor management during intermediate/advanced lesion stage
Describe the clinical interventions for complicated plaques
Secondary prevention
Catheter based interventions
Revascularisation surgery
Treatment of heart failure
Describe percutaneous coronary intervention
Number of procedures to relieve stenosis in the coronary arteries.
Performed by the insertion of a catheter- usually via the femoral artery.
Balloon angioplasty: compresses the plaque; expands the lumen
Metal stent- positioned within the stenosis- expanding vessel walls and restoring vessel patency- should be coated with immuno-suppressive agents- to reduce the risk of re-stenosis.
Describe coronary artery bypass graft
The procedure uses autologous veins and/or arteries to bypass stenosis in coronary arteries.
Describe the role of vascular endothelial cells
surface for leukocyte recruitment Barrier function (e.g. to lipoproteins)
Describe the roles of platelets
Thrombus generation
Cytokine and growth factor release - causing smooth muscle cell migration from the media to the intima
Describe the roles of monocytes/macrophages
Foam cell formation- macrophages take up oxidised LDL
Cytokine and growth factor release - monocyte and smooth muscle infiltration.
Major source of free radicals
Metalloproteinases- degrade fibre cap (cofactor is zinc)- more prone to thrombus.
Describe the roles of the vascular smooth muscle cells
Migration and proliferation- move from media to the intima
Collagen synthesis
Remodelling & fibrous cap formation
Describe the roles of T lymphocytes
Macrophage activation
Describe the regulation of macrophages
Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory sequences on DNA. However, we do not yet understand the regulation!
Describe inflammatory macrophages
Adapted to kill microorganisms (germs
Describe resident macrophages
Normally homeostatic - suppress inflammatory activity
Alveolar resident macrophages - surfactant lipid homeostasis
Osteoclasts - calcium and phosphate homeostasis
Spleen - iron homeostasis
Describe the white cell response in atherosclerosis
Excessive and inappropriate
Describe LDLs
‘Bad’ cholesterol - Synthesised in liver.
Carries cholesterol from liver to rest of the body including arteries.
Describe HDLs
Good’ cholesterol
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
Describe oxidised/modified LDLs
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.
Describe the structure of lipoproteins
Docking molecule ‘molecular addresses for fat delivery’ (apoprotein) Lipid monolayer (like cell membrane) but one molecule thick Cargo fat for fuel (triglycerides and cholesterol esters)
Describe the modification of subendothelial LDLs
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
Describe familial hyperlipidaemia
Autosomal genetic disease.
Massively elevated cholesterol (20mmol/L).
Failure to clear LDL from blood.
Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20
Failure to remove LDL from blood to liver.
What is the LDL receptor and cholesterol synthesis regulated by
LDL receptor (expression negatively regulated by intracellular cholesterol). Cholesterol synthesis is also negatively regulated by cellular cholesterol. Led to the discovery of HMG-CoA reductase inhibitors (= “statins”) for lowering plasma cholesterol.
What happens in LDLR-negative patients
In LDLR-negative patients, macrophages accumulate cholesterol
Deduced a second LDL receptor - not under feedback control - in atherosclerotic lesions. Called them ‘scavenger receptor’ since they hoover up chemically modified LDL.
Now known that scavenger receptors are a family of pathogen receptors that ‘accidentally’ bind OxLDL.
What were scavenger receptors intended to bind to
Germs and not oxLDL
Hep B- actively protective- receptor binds to Hep B and not oxLDL
Describe macrophage scavenger receptor A
Known as CD204 Binds to oxidised LDL Binds to Gram-positive bacteria like Staphylococci & Streptococci Binds to dead cells Cause inflammation and destruction
Describe macrophage scavenger receptor B
Known as CD36 Binds to oxidised LDL Binds to malaria parasites Binds to dead cells safe clearance and reverse cholesterol transport
Describe the macrophage function of generating free radicals
Macrophages have oxidative enzymes that can modify native LDL
a) NADPH Oxidase, for example superoxide O2-
b) Myeloperoxidase, for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite.
Further oxidation- vicious cycle of positive feedback loop.
bleach secreted to walls to oxidise LDLs
Describe the role of macrophages in Phagocytosing modified lipoproteins, & become foam cells
Macrophages accumulate modified LDLs to become enlarged foam cells
Describe the role of macrophages in Expressing cytokine mediators that recruit monocytes
Plaque macrophages express inflammatory factors that are involved in monocyte recruitment.
Cytokines – protein immune hormones that activate endothelial cell adhesion molecules
VCAM-1 mediates tight monocyte binding
Atherosclerosis is reduced in mice without IL-1 or VCAM-1
Chemokines - small proteins chemoattractant to monocytes
Monocyte chemotactic protein-1 (MCP-1
MCP-1 binds to a monocyte G-protein coupled receptor CCR2.
Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice.
Describe the roles of macrophages in expressing chemo-attractants and growth factors 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
Platelet derived growth factor
Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)
Transforming growth factor beta
Increased collagen synthesis
Matrix deposition
Describe the difference between the normal and atherosclerotic media
High Contractile filaments
Low Matrix deposition genes
Low Contractile filaments
High Matrix deposition genes
What are the metalloproteinases
Family of ~28 homologous enzymes.
Activate each other by proteolysis.
Degrade collagen.
Catalytic mechanism based on Zn.
What may blood coagulation at the site of rupture lead to
Effect of plaque erosion/rupture - Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.
Plaque full of pro-coagulation factors
once it touches the blood it will thrombose
MI or stroke risk
Describe ruptures plaques
macrophages mean fibrous cap becomes so thin that will break and rupture, allowing necrotic core to contact blood and cause thrombus formati
Describe the characteristics of vulnerable plaques
Large soft eccentric lipid-rich necrotic core Increased VSMC apoptosis Reduced VSMC & collagen content Thin fibrous cap Infiltrate of activated macrophages expressing MMPs
Describe macrophage apoptosis
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.
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
Describe NFkB
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
Summarise the role of NFkB
Integrator
Activates a variety of downstream mechanisms from a variety of different stimuli (switching on inflammatory genes (e.g. Matrix metalloproteinases and inducible nitric oxide synthase) - can be activated by many stimuli and coregulate multiple genes
What can inflammation be
prothrombogenic
