14 - Atherosclerosis Flashcards
What is atherosclerosis?
Progressive narrowing of large arteries through a process of intimal thickening and lipid accumulation
- Decreasing in developed world, increasing in developing world
- Successful drug treatment
- Focus on prevention
List the layers of a normal blood vessel from lamina outwards
- Endothelium (intima)
- Internal elastic lamina
- Media (myocytes)
- External elastic lamina
- Adventitia (connective tissue)
Give very broad steps for the progression of atherosclerotic lesions from fatty streak to fibrous plaque
- LDL passes through endothelium of blood vessel and lodges in the intima
(due to injury, fluid shear stress (High BP), smoking) - LDL gets oxidized
- Oxidized LDL causes the release of MCP-1 (monocyte chemoattractant protein to be released from endothelial and SM cells) - these attract monocytes to move into the intima
- Oxidized LDL also causes monocytes to differentiate into macrophages. These macrophages will release cytokines (INF-alpha, IL-1) which will cause the expression of adhesion molecules (P-selectin, VCAM-1) on the endothelial cells to allow more monocytes to move into the cell.
- Oxidized LDL also causes the release of the growth factor M-CSF (macrophage colony stimulating factor). This M-CSF causes the expression of the scavenger receptor on the macrophage - which then takes up oxidized (modified) LDL to form a foam cell (macrophage with tons of cholesterol lipids)
- Foam cells release cytokines that cause smooth muscle cell proliferation.
- The formation of a fibrous cap occurs (due to collagen deposition from the smooth muscle) - this hardens, and can exert a lot of pressure on the endothelial cells (fibroatheroma, stage V)
- Unstable fibrous plaques can rupture and thrombosis occurs as a result as platelets try to fix the rupture (complicated stage VI).
What is the role of HDL in atherosclerosis?
1) HDL inhibits oxidation of LDL
2) HDL promotes cholesterol efflux from foam cell
3) HDL inhibits adhesion molecule expression
Give five complications with atherosclerosis
- Thrombosis
- Plaque rupture
- Hemorrhage
- Wall weakening
- Calcification
Also
- Myocardial infarct
- Central infarct (eg. brain stroke)
- Gangrene of extremities
- Abdominal aortic aneurysm
What is a type I atherosclerotic lesion?
- Isolated macrophage foam cells with modest lipid accumulation
- Present in first decade
- Clinically silent
- Possibly reversible
What is a type II atherosclerotic lesion?
Fatty streak
- Intracellular lipid accumulation
- Present in first decase
- Clinically silent
- Reversible?
What is a type III atherosclerotic lesion?
Intermediate
- Small extracellular lipid pools
- Growth of lesion through lipid accumulation
- Third decade
- Clinically silent
What is a type IV atherosclerotic lesion ?
Atheroma
- Contains core of extracellular lipid
- Growth through lipid accumulation
- Present from third decade
- Clinically silent or overt
What is a type V atherosclerotic lesion?
Fibroatheroma
- Lipid core and fibrous cap
- Proliferation of smooth muscle and extensive collagen
- Fourth decade
- Still clinically silent or overt
What is a type VI atherosclerotic lesion?
Complicated
- Defect develops in fibrous cap
- THrombus and hematoma
- Fourth decade
- Overt and acute
- Potentially fatal
Give the three major risk factor categories (and their risks) for atherosclerosis
Non-modifiable
- Increasing age
- Male gender
- Family history
- Genetic abnormalities
Potentially modifiable
- Hyperlipidemia
- Hypertension
- Smoking
- Diabetes
- Physical inactivity
Minor or uncertain factors
- Obesity
- Stress
- Homocysteine
- Post menopausal estrogen deficiency
- High carb diet
- Alcohol
- Lipoprotein
- Trans-saturated fat
- Chlamydia pneumoniae
Give four theories of atherogenesis
Lipid infiltration
- Lesion develops as result of imbalance in entry and exit of lipoprotein from intima.
Thrombogenic
- Atherosclerotic lesions develop as a result of repeated clot formation and organization eventually occluding the vessel. Problem: Lipids can accumulate by trapping in clot, but this isn’t an initiating event in atherosclerosis. It is important in lesion progression however.
Monoclonal
- Lesions develop from single cell which changes to a proliferative state at the lesion site. Eg. with viral or chemical mutagen. Supported in some lesions by isoenzyme analysis but not found in most. Probably occurs at lesion site after initiation event.
Response to injury
- Chronic endothelial injury (smoking, toxins, viruses etc.) followed by endothelial dysfunction and platelet adherence. followed by macrophage activation.
What are the two components of a fibrous plaque?
Fibrous cap (smooth muscle cells, macrophages, foam cells, lymphocytes, collage, elastin)
Necrotic centre (cholesterol crystals, foam cells, calcium)
Give two lines of evidence for the lipid infiltration theory of atherogenesis
- Atherosclerosis associated with increased LDL and decreased HDL
- Focal lesions - sites of stress or injury are sites of lipid accumulation
Atherosclerotic lesions develop as result of an imbalance in the entry and exit of lipoproteins from the intima
Eg. genetic defects of LDL-LDL receptor interaction causes atherosclerosis. Diet or drugs that modify lipoproteins favourable also reduce risk.
