Coronary Heart Disease Flashcards
what are the modifiable risk factors of artherosclerosis?
- smoking
- lipid intake
- blood pressure
- diabetes
- obesity
- sedentary lifestyle
what are the non-modifiable risk factors of atherosclerosis?
- age
- sex
- genetic background
How much does only hypertension increase your risk of developing atherosclerosis?
x 3
How much does only high cholesterol increase your risk of developing atherosclerosis?
x 4
How much does only smoking increase your risk of developing atherosclerosis?
x 1.6
How much does both hypertension and smoking increase your risk of developing atherosclerosis?
x 4.5
How much does both hypertension and high cholesterol increase your risk of developing aetherosclerosis?
x 9
How much does both smoking and high cholesterol increase your risk of developing atherosclerosis?
x 6
How much does smoking, hypertension and high cholesterol increase your risk of developing atherosclerosis?
x 16
Where does atherosclerosis tend occur?
at branches, bends and bifurcations
Why does atherosclerosis occur at branches and bends?
turbulent blood flow vortices cause damage to artery and causes inflammation
What does the endothelium do?
- controls contraction
- maintain the blood pressure
What happens in atherosclerosis?
LDLs deposit in the subintimal space and binds to matrix proteoglycans
How does atherosclerosis start?
adaptive thickening of the smooth muscle cells
What happens in a Type II lesion?
macrophage foam cells enter the adaptive thickening and ‘eat up’ the collected LDLs
What happens in a Type III (preatheroma) lesion?
the macrophage foam cells die due to fat overload, causing the formation of small pools of extracellular lipid
What happens in Type IV (atheroma) lesions?
the small pools of extracellular lipid join to for a core of extracellular lipid
What happens in Type V (fibroatheroma) lesions?
the core of extracellular lipid causes a inflammatory reaction which triggers the smooth muscle cells forming a fibrous thickening using collagen
What happens in Type VI (complicated) lesions?
the fibrous thickening breaks down killing the collagen cells - fissure and hematoma which eventually causes the formation of a thrombus.
Cholesterol crystals can form too.
Stratificiation due
What happens in Type V lesions in terms of plaque disruption?
stratification caused by the multiple breaking and reformation of different plaques
When is the window of opportunity for primary intervention of atherosclerosis?
Intermediate and advanced lesions (WITHOUT complications)
- life style changes
- risk factor management
What clinical interventions are available when complications of atherosclerosis occur?
- secondary prevention
- catheter based interventions
- revascularisation surgery
- heart failure treatment
What are the main cell types involved in the inflammation of the arteries and the progression of atherosclerosis?
- vascular endothelial
- monocyte-macrophages
- vascular smooth muscle cells
- T lymphocytes
- Platelets
What are the role of vascular endothelial cells?
- barrier function (lipoproteins)
- leukocyte recruitment
What are the role of platelets?
- thrombus generation
- secrete cytokines and growth factor release
What are the role of monocyte-macrophages?
- foam cell formation
- cytokine and growth factor release
- major source of free radicals
- metalloproteinases
What are the role of vascular smooth muscle cells?
- migration and proliferation (from media to plaque) - collagen synthesis (strengthens the plaques) - remodelling and fibrous cap formation - can lead to unstable angina due to narrowing lumen
What are the role of T-lymphocytes?
macrophage activation
What is the relationship between macrophages and the T lymphocytes?
both activation each other
What are the 2 main functions of macrophages?
- inflammatory
- resident
What do inflammatory macrophages do?
adapted to kill microorganisms
What do resident macrophages do?
- homeostatic (suppress anti-inflammatory activity)
- alveolar resident macrophages (lipid surfactant homeostasis)
- osteoclasts (calcium and phosphate homeostasis)
- spleen (iron homoeostasis)
What characterises atherosclerosis?
macrophage inflammatory cells
What do LDLs do?
carries cholesterol from the liver to the rest of the body (including arteries)
What do HDLs do?
carries cholesterol from peripheral tissues (including arteries) back to the liver
What are oxidised/modified LDLs?
families of highly inflammatory and toxic forms of LDLs found in the vessel wall - caused by the action of free radicals on LDLs
How are LDLs modified?
- LDLs leak through the endothelial barrier
- LDLs are trapped by binding to the sticky matrix proteoglycans in the sub-endothelial layer
- LDL becomes oxidatively modified by free radicals
How can oxidised LDLs cause chronic inflammation?
it is phagocytosed by macrophages (making them foam cells) which stimulates chronic inflammation
What is familial hyperlipidemia?
- massively elevated cholesterol (>20mmol/L)
- autosomal genetic disease (dominant)
What causes familial hyperlipidemia?
failure to clear LDL from the blood
What the effects of familial hyperlipidemia?
- xanthomas
- early atherosclerosis
untreated: - fatal MI <20
What gene causes familial hyperlipidemia?
LDLR (accidently bind OxLDL) + scavenger receptor
What does macrophage scavenger receptor A (CD204) do?
- binds to oxidised LDL
- binds to gram positive bacteria
- binds to dead cells
What does macrophage scavenger receptor B (CD36) do?
- binds to oxidised LDL
- binds to malaria parasites
- binds to dead cells
What oxidative enzymes activated macrophages can modify LDL?
NADPH oxidase (superoxide) Myeloperoxidase (hypochlorous acid)
What are the negative impacts of macrophages
- generate free radicals that further oxidise lipoproteins
- phagocytose modified lipoproteins and become foam cells
- express cytokine mediators that recruit monocytes
- express chemoattractants and growth factors
- express proteinases that degrade tissue
What are cytokines?
protein immune hormones that activate endothelial cell adhesion molecules
What are chemokines?
small proteins chemoattractant to monocytes
What cytokines are released by macrophages?
IL-1 stimulate endothelial cells over the plaque to express called VCAM-1 (mediates tight monocyte binding)
What happens if IL-1 or VCAM-1 aren’t present?
no atherosclerosis formed (seen in mice)
What chemokines are released by macrophages and what do they do?
MCP-1 binds to G protein coupled receptor CCR2
What happens if MCP-1 or CCR2 aren’t present?
atherosclerosis is reduced (in mice)
What is the wound healing role of macrophages?
release of complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit matrix
What is the impact of platelet derived growth factor (PDGF)?
- vascular smooth muscle cell chemotaxis
- vascular smooth muscle cell survival
- vascular smooth muscle cell division (mitosis)
What is the impact of transforming growth factor beta (TGF-b)?
- increased collagen synthesis
- matrix deposition
What are the main 2 types of growth factors released?
- platelet derived growth factor
- transforming growth factor beta
What happens in atherosclerotic vascular smooth muscle cells?
- reduced contractile filaments
- increased matrix deposition genes
Which proteinases are expressed by macrophages?
metalloproteinases (MMPs)
What are Metalloproteinases?
- family of 28 homologous enzymes
- zinc based enzymes
What do Metalloproteinases do?
- activate eachother via proteolysis
- degrade collagen
- catalytic mechanism based on zinc
What happens when MMPs breakdown collagen?
- plaque erosion/rupture
(no longer trapped in smooth muscle) - blood coagulation may cause an occlusive thrombus
What are the characteristics of vulnerable and stable plaques?
- large, soft eccentric lipid-rich necrotic core
- increased VSMC apoptosis
- reduced VSMC and collagen content
- thin fibrous cap
- infiltrate of activated macrophages expressing MMPs
What happens in macrophage apoptosis?
- Ox LDLs are toxic
- Macrophage foam cells have protective systems that maintain survival when toxic lipid loading
- when overwhelmed, apoptosis
- then release tissue factors and toxic lipids forming a lipid necrotic core
- thrombogenic and toxic material accumulates until plaque rupture
What is Nuclear Factor kappa B (NFkB)?
transcription factors that regulates inflammation
What activates NFkB?
- scavenger receptors
- toll-like receptors
- cytokine receptors (IL-1)
- cholesterol crystals
- toxic OxLDL
- cell stress
What genes does NFkB activate?
- matrix metalloproteinases
- inducible nitric oxide synthase
- IL-1
What happens in atherosclerotic inflammation?
- LDLs are converted into OxLDLs that activate macrophages
- activated macrophages damage artery walls
- all regulated by NFkB
