Fundamentals of Atherogenesis Flashcards
what is atherosclerosis?
Is the principal cause of heart attack, stroke and gangrene of the extremities
what is the main problem of atherosclerosis?
is plaque rupture leading to thrombus formation, partial/complete arterial blockage leading to a heart attack
what are the risk factors For Atherosclerosis?
Age
Tobacco Smoking
High Serum Cholesterol
Obesity
Diabetes
Hypertension
Family History
which is the best-known risk factor for coronary artery disease
1. Obesity
2. Diabetes
3. Gender
4. Age
AGE
where are atherosclerosis plaques distributed?
Found within peripheral and coronary arteries
Focal distribution along the artery length
describe how Distribution may be governed by haemodynamic factors
Changes in flow/turbulence (eg at bifurcations) cause the artery to alter endothelial cell function. Wall thickness is also changed leading to neointima. Altered gene expression in the key cell types is key.
Q: Which of the following is not in artery walls?
1.Tunica intima
2.Tunica media
3.Epithelial cells
4.Neutrophils
EPITHELIAL CELLS
what does an atherosclerotic plaque consist of:
- Lipid
-Necrotic core
-Connective tissue
-Fibrous “cap”
what will the plaque eventually do to the vessel?
will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may “rupture” (thrombus formation – death).
what initiates atherosclerosis?
- Initiated by an injury to the endothelial cells which leads to endothelial dysfunction.
2.Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall. - Inflammation ensues
name 4 examples of good inflammation
Pathogens
Parasites
Tumors
Wound healing
name 8 examples of bad inflammation
Myocardial reperfusion injury
Atherosclerosis
Ischaemic heart disease
Rheumatoid arthritis
Asthma
Inflammatory bowel disease
Shock
Excessive wound healing
what ignites inflammation in the arterial wall?
LDL
Endothelial dysfunction- in response to injury hypothesis
what ignites inflammation in the arterial wall-LDL?
can pass in and out of the arterial wall
in excess it accumulates in arterial wall, and undergoes oxidation and glycation
once inflammation is initiated what occurs to the chemoattractants?
are released from endothelium and send signals to leukocytes.
AND/OR
are released from site of injury and a concentration-gradient is produced.
what are the inflammatory cytokines found in plaques
IL-1 - canakinumab
IL-6 – tocilizumab**
IL-8
IFN-g
TGF-b
MCP-1
(C reactive protein)
Leukocyte recruitment to vessel walls - summary
capture
rolling
slow rolling
firm adhesion
transmigration
describe the fatty streak stage of Progression of Atherosclerosis
-Earliest lesion of atherosclerosis
-Appear at a very early age (<10 years)
-Consist of aggregations of lipid–laden macrophages and T lymphocytes within the intimal layer of the vessel wall
describe the intermediate lesions (2) stage of Progression of Atherosclerosis
Composed of layers of :
-Lipid laden macrophages (foam cells)
-Vascular smooth muscle cells
-T lymphocytes
-Adhesion and aggregation of platelets to vessel wall
-Isolated pools of extracellular lipid
describe the fibrous plaques stage (3) of Progression of Atherosclerosis
Impedes blood flow
Prone to rupture
Covered by dense fibrous cap made of ECM proteins including collagen (strength) and elastin (flexibility) laid down by SMC that overlies lipid core and necrotic debris
May be calcified
Contains: smooth muscle cells, macrophages and foam cells and T lymphocytes
describe the plaque rupture (4 )stage of Progression of Atherosclerosis
Plaques constantly grow and recede.
Fibrous cap has to be resorbed and redeposited in order to be maintained.
If balance shifted eg in favour of inflammatory conditions (increased enzyme activity), the cap becomes weak and the plaque ruptures.
Basement membrane, collagen, and necrotic tissue exposure as well as haemorrhage of vessels within the plaque
Thrombus (clot) formation and vessel occlusion
describe the plaque erosion (5)stage of Progression of Atherosclerosis
-Second most prevalent cause of coronary thrombosis
-Lesions tend to be small ‘early lesions’
- A thickened fibrous cap may lead to collagen triggering thrombosis rather than tissue factor (as in plaque rupture)
- A platelet-rich clot may overlie the luminal surface.
-There is usually a small lipid core
what are the treatments used for coronary artery disease?
PCI - Percutaneous Coronary Intervention
More than 90% of patients require stent implantation
Restenosis was a major limitation, no longer though due to drug eluting stents
Q: What are coronary stents used in patients today made of?
1. Metal
2. Plastic
3. Polymers
metal
describe aspirin
irreversible inhibitor of platelet cyclo-oxygenase
describe Clopidogrel/Ticagrelor
inhibitors of the P2Y12 ADP receptor on platelets and other drugs with antiplatelet actions
describe statins
inhibit HMG CoA reductase, reducing cholesterol synthesis
describe PCSK9 inhibitors
monoclonal antibodies that inhibit PCSK9 protein in the liver which leads to improved clearance of cholesterol from the blood.
