Week 2:Atherothrombosis Flashcards
Describe endothelial function.
produces substances that affect:
- vascular tone: NO, prostacycllin, endothelia
- inflammation: chemokines, cytokines
- thrombosis (anti thrombotic effects): tPA, PAI-1, NO (inhibits platelet adhesion)
What is the primary endothelium mediated vasodilator? Mechanism?
Nitric Oxide
-shear stress and other agonists such as AcH, serotonin, thrombin, bradykinin catalyzes formation of NO from L-arginine. NO diffuses into smooth muscle, activates guanylyl cyclase. G cyclase catalyzes GTP to cGMP, which results in SM relaxation via a mechanism that involves reduction of cytosolic Ca2+.
Describe the Endothelin Pathway
low shear stress and other agonist promotes transcription of mRNA to produce ET-1.
- has 2 receptors on SM, ETa and ETb, which causes vasoconstriction, proliferation, and migration
- also has 1 receptor ETb on endothelial wall, promotes release of NO and prostacyclin
What are risk factors of atherothrombosis caused by reduced endothelial function?
- reduced endothelial function and NO bioavailability leading to inappropriate vasoconstriction
- reduced endothelial fxn augments the recruitment of inflammatory cells into plaques
- AND promotes pro-thrombotic state
What’s relation of oxidant stress and atherothrombosis?
oxygen free radicals causes inhibition of nitric oxide synthase, decreases NO and promotes endothelial dysfunction.
-changes LDL to oxyLDL, which inhibits NOS
How is HDL atheroprotective?
- responsible for reverse cholesterol transport, removing cholesterol from peripheral tissues and delivering it to the liver via several receptors including SR-B1
- delivers antioxidants including paraoxonase that may prevent LDL oxidation
- most effective way of increasing HDL is exercise
Describe the stages of atherothrombosis.
I. lesion-pro location: adaptive thickening of smooth muscle
II. recruitment of inflammatory cells, particularly macrophages that start capturing LDL–>FOAM cells
III. Preatheroma: smal pools of extracellular lipids
IV. atheroma: organized core of extracellular lipid
V. fibroatheroma: fibrosis and calcification, fibrous thickening
VI. Complicated: can bleed from within and rupture or rupture from outside due to increased shear stress
What are the two types of vascular remodeling of atherothrombosis?
metalloproteinases and collagenases in plaque degrade collagen and weaken plaque, may be important in remodeling
1. positive remodeling: blood vessel grows by more than 5% to accommodate plaque. measured by EEMlesion/EEMnormalarea
EEM=external elastic membrane
2. Negative remodeling: there is stenosis, fibrotic and calcified lesion
Why do plaques with positive remodeling have greater vulnerability to rupture?
- more macrophages
- more lipid rich atheroma
- less collage
- less smooth muscle cells
- more metalloproteinases (2,3,9)
- more likely to cause acute coronary syndrome because of thinner cap, more blood vessels, and soft lipid. Unstable plaque.
What is the relationship between stenosis before MI and risk of MI?
- lesion that is most likely to cause MI has less than 50% stenosis of baseline
- ones that don’t have severe stenosis are more likely to cause a heart attack.
What are markers of vulnerability of a plaque?
- large lipid core size
- fat induced inflammation
- matrix metalloproteinase in cap (MMPs 2,3,9)
- plaque cap thickness thin <100u
- endothelial denudation or dysfunction
- collagen content and mechanical instability
- mural platelets and fibrin depositions post disruption
- angiogenesis, leaking vasa vasorum, intraplaque hemorrhage
- rate of apoptosis
- shear stress
- calification and its pattern
What are plaque stabilizing agents?
- statins
- raise HDL (fish oil, niacin)
- ACE inhibitors
- beta blockers
- aspirin with clopidogrel
- warfarin
-risk factors include: hypertension, diabetes, current smoking, high cholesterol.
