Lec 12- Atherosclerosis and its consequences Flashcards
1
Q
Terminology
A
- Arteriosclerosis- hardening (sclerosis) or arteries. Medial hypertrophy- age and hypertension. Symmetrical and uniform
- Atherosclerosis-related to hyperlipidaemia. Fatty fibrous plaques (atheromas) laid down on the inner surface of vessels (intima). Focal changes
- Thrombosis- consequences of atherosclerosis. thrombus (clot) formed on inner surface of the vessel. May shed of small particles- thromboemboli, can occlude vessels
2
Q
Atherosclerosis
A
- A focal disease of large arteries (may also be found in atria). High pressure
- Doesn’t occur naturally in animals
- Plaques occur at sites of haemodynamic stress- increased endothelial cells turnover e.g. carotid bifurcation, coronaries, mesenteric, renal, aorta, iliac
- Endothelial damage is initiating event
3
Q
Non-modifiable risk factor for atherosclerosis
A
- Family history of IHD or hyperlipidaemia
- Advanced age
- Male sex (and female post-menopause)
- Ethnic group
4
Q
Modifiable risk factors for atherosclerosis
A
- Hyperlipidaemia (dyslipidaemia LDL/HDL)
- Cigarette smoking
- Hypertension
- Obesity (waist to hip ratio)
- Diabetes mellitus
- Physical inactivity or sedentary lifestyle
- Stress (psychosocial factors)
- Diet poor in fruit and fresh vegetables
- Account for 80% of the elevated risk: INTERHEART 2004
5
Q
Theories of atherosclerosis
A
- Lipid Theory- High levels of blood cholesterol(LDC) injure endothelium + allow accumulation and local inflammation
- Inflammation Theory- Local inflammatory reaction possibly through local injury, through infection (chlamydial or H.pylori), attracts macrophages
- Inflammation- results from both pathways
6
Q
Initiating events in atherogenesis (adhesion of monocytes and leucocytes to endothelial cell surface)
A
- Earliest detectable evidence of pathophysiology is endothelial dysfunction Caused by:
- Hypercholesterolaemia- particularly oxidised LDL-c
- Cigarette smoking
- Hypertension
- Diabetes (partially due to lipid changes)
- Infectious organism
- Elevated level of NA and adrenaline
-Associated with reduced PgI2 and NO biosynthesis
7
Q
Lipid link to atherosclerosis
A
- Atheroma risk directly linked to total plasma ChE
- There is a link to dietary ChE but 75% of plasma from liver
- LDL and VLDL carry ChE to tissues and HDL away to liver
- LDL/HDL is diagnostic factor for risk but coronary risk correlates best with TOTL ChE/HDL ratio
- Triglycerides are not significant factor in risk
- Low intake of saturated fats and ChE reduce risk but don’t remove it
- Lipid-lowering agent reduce risk of end events and give some regression of atherosclerosis
8
Q
How does atherosclerosis develop
A
1) accumulation of modified lipid
2) endothelial cell activation
3) inflammatory cell migration
4) inflammation cell activation
5) smooth muscle cell recruitment
6) proliferation and matrix synthesis
7) fibrous cap formation
8) plaque erosion
9) platelet erosion
10) thrombosis
9
Q
Endothelial phase
A
- Lipids become oxidised (initially in the circulation later in the intima)
- Injury to endothelium causing the release of adhesion factors (VCAM-1). Attracts monocytes- activation and adherence
- Endothelial cells bind LDL with endothelial transport of lipids (LDL-c) into the intima
- Injured cells and monocytes generate free radicals and there is lipid peroxidation
- Disruption of normal LDL receptors
10
Q
Spreading damage
A
- Macrophage engulf oxidised lipids and become lipid saturated foam cells
- Macrophages move from bloodstream into the endothelial layer-large part of the atheroma mass
- Cytokines from endothelial cells, macrophages and platelets cause smooth muscle proliferation and deposition of connective material
- The fibrous material becomes a dense fibrous cap of connective materials
- Underneath there is a much looser combination of lipids and necrotic cell debris and cholesterol crystals. Ca2+ build = sclerosis
11
Q
Plaque formation- The Fibro-lipid (fibro-fatty) plaque
A
The Fibro-lipid (fibro-fatty) plaque
- An accumulation of lipid-laden cells in the tunica intima
- Typically without narrowing the lumen
- Fibrous cap covering the atheromatous core of the plaque
- A core lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, collagen, elastin, debris and proteoglycans
- In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (dead cells)
12
Q
plaque formation- fibrous plaque
A
- Is also localized within the wall of the artery resulting in thickening and expansion of the wall
- The fibrous plaque contains collagen fibres (eosinophilic), precipitates of calcium and rarely, lipid-laden cells
13
Q
Early atheroma
A
- Damage to endothelial (exacerbated by htn)
- Insudation of cholesterol
- Formation of foam cells
- Cholesterol esters deposited in intima
- Leads to fatty streaks or dots. Observed in children wide distribution- reversible
14
Q
Advanced (fibrous) plaque 20yrs old
A
- Pro-inflammatory cytokines cause VSM migration from the media to the intima. Synthesis of collagen and elastin producing fibrous cap
- Variable amounts of lipid may be present
- As the plaque enlarges, the base may start to become necrotic
- No symptoms
15
Q
Progression of atheroma: advanced to complicated 20-30 yrs
A
- The fibrous cap may slowly enlarge or may rupture
- Rupture of plaque cap leads to thrombosis: rupture is likely is the base is necrotic, if there are large deposits of cholesterol. or high numbers of inflammatory cells present)
- After fibrin clot has formed, this may be incorporated into a new (larger) plaque and a new connective tissue cap is formed: the plaque may progress suddenly in stages
- Symptoms: non or minor due to minor embolisms
