12. Atherosclerosis Flashcards
Atherosclerosis
Slow progressive disease (large to medium size muscular elastic arteries) where intimal based plaque develops composed of SMC, inflammatory cells and increased extra cellular matrix
Most frequent and clinically important
Narrowing (stenosis) of blood vessels
Major cause of CVD and peripheral vascular disease
Arteriosclerosis
Arterial wall thickening/loss of elasticity
Arterioloscleorsis
Affects small arteries and arterioles
Associated with ischemia
Structure of atherosclerosis plaques
Fibrous cap: SMC macrophages, foam cells (macrophages engulfing oLDL)
Necrotic center: cell debris, cholesterol crystals, foam cells, calcium
Atherosclerotic cardiovascular diseases
Coronary heart disease
Cardiovascular disease
Peripheral artery disease
Aortic atherosclerosis and aneurysm
Non modifiable risk factors
Family history
Increasing age
Male gender
Modifiable risk factors
Hyperlipidemia - increase of bad LDL cholesterol and decrease in good HDL cholesterol
Hypertension = caused by vasoconstriction - stress on circulation and EC injury
Smoking - decrease NO synthesis therefore increase pro inflammatory cytokines and pro thrombotic (blood clot formation encouraged)
Diabetes - hyperlipidemia with type 2 and excess insulin, insulin decreases bioavailability of NO
Pathogenesis
- EC injury causing increase vascular permeability, leukocyte adhesion
- Accumulation of lipoproteins (mainly LDL) in vessel wall - become oxidized when moving into intima by ROS
- Platelets adhesion
- Monocytes adhesion to endothelium - migration into intima and become macrophages
- Macrophages injest oxidized LDLs and become foam cells
- Lipid accumulation increase in inflammatory cytokines
- SMC recruitment/proliferation and ECM production
Response to injury
EC loss results in intima thickening (EC dysfunction)
EC dysfunction caused mostly by
Hemodynamics disturbances
Hyperlipidemia
Hemodynamics disturbances
Laminar flow - through vessels except where there is a split, activated endothelial genes whose functions are protective against atheroscleosis
Turbulent flow - flow is obstructed vessel turns or blood flows over rough surface - plaques develop at these branch points and other areas of disturbed blood flow
Chylomicrons
Lipoprotein
Deliver triglyceride to cells in the body
Very low density lipoprotein (VLDL)
Deliver triglycerides to cells in body
Low density (LDL)
Bad cholesterol
Delivers cholesterol from liver to cells in the body
High density (HDL)
Good
Reverse cholesterol transport
HDL takes cholesterol from cells back to liver
Dyslipoproteins
Increase LDL levels bad
Decrease HDL levels good
Chronic hyperlipidemia contributing to atherosclerosis
Excess LDLs travel through tunica intima and become oxidized
oLDLs = when engulfed by macrophages form foam cells, toxic to endothelial cells and SMC, release cytokines and chemokines
Cholesterol crystals = “danger signals” activate innate immunity
In plaques they are dangerous because they can produced DAMP signals (endogenous danger signals)
LDL role in atherosclerosis
Too much circulating in blood
Become deposited into tunica intima and are oxidized by ROS
Oxidized LDL causes endothelial activation and express CAMs (ahesion receptors)
Leukocytes move into tunica intima (monocytes to macrophages) who take up oLDL and become foam cells
Vulnerable plaques
Larger area of foam cells and lipid
Thin fibrous cap
Increased inflammatory cells
More likely to rupture
Stable plaques
Smaller area of foam cells and lipid
Thick fibrous cap
Few inflammatory cells
Less likely to rupture
Atherosclerotic plaque - clinical outcomes
Rupture, ulceration, erosion
Hemhorrage
Atheroembolism
Aneurysm formation
Consequences of atherosclerotic disease
Anyuerism/rupture : plaque makes blood vessel wall weak
Occlusion by thrombus: blood forms inside plaque causing clot
Critical stenosis: over 80% occlusion
Thrombus
Forms over disrupted plaque or contents of atherosclerotic plaque
Can embolism and obstruct down stream vessels
Thrombin- pre-blood clot
