Vascular biology of athersclerosis

Question 1

Endothelium dysfunction in athersclerosis

Answer 1

• Normally endothelium maintain vascular tone by releasing vasodilators (NO)
• If they begin to dysfunction they reduce the release of vasodilators, increase release of vasoconstrictors, increase cytokines/inflammatory molecules and pro-thombotic molecules
• Primary cause of endothelial dysfunction: diet (and lack of exercise)
• 3 things contribute to atherosclerosis: endothelium dysfunction, inflammation, and thrombosis

Question 2

NO

Answer 2

• Released by endothelial cells and cause smooth muscle relaxation
• Lead to vasodilation

Question 3

Endothelin

Answer 3

• Released from endothelial cells, has 2 effects
• Primary effect is in smooth muscle cells, it causes them to contract
• But in endothelial cells it causes the release of NO

Question 4

Oxidant stress on plaque formation

Answer 4

• Oxygen free radicals oxidize LDL to oxyLDL
• OxyLDL then inhibits synthesis of NO and inhibits NO function by oxidizing it
• Overall there is an increased chance of vasoconstriction, and this is worsened by high glc and BP
• OxyLDL also recruits cholesterol into the endothelium and forms plaque

Question 5

HDL

Answer 5

• HDL is atheroprotective: it is responsible for reverse transport of cholesterol, removing it from peripheral tissues and returning it to the liver
• HDL also delivers antioxidants that can prevent HDL oxidation

Question 6

Endothelial cell activation

Answer 6

• Get activated due to damage or oxidant stress
• Lead to expression and release of cytokines/chemokines
• Initiates inflammatory process

Question 7

Classifications of atherosclerotic lesions (!)

Answer 7

• Type 1: minor changes (thickening) of the intima
• Type 2: macrophages recruited and begin consuming LDL/cholesterol, become foam cells (fatty streak in intima, under IEL)
• Type 3: small pools of extracellular lipid (preatheroma)
• Type 4: core of extracellular lipid (atheroma)
• Type 5: fibrous cap forms and thickens (fibroatheroma)
• Type 6: fibrous cap ruptures at shoulder, blood contacts the plaque and thrombus forms

Question 8

Intraplaque hemorrhage (ruptures)

Answer 8

• Potentially clinically silent (95%), but for each silent event the artery narrows
• Progressive narrowing can lead to ACS (acute coronary syndrome) or healing w/ lumen stenosis (chronic stable angina, CSA)
• Thicker plaques will have greater capillary formation in the vasa vasorum to supply the expanded aerial wall
• These thicker plaques are also more likely to rupture
• Important to note that thicker doesn’t mean smaller lumen, since the wall of the arteries can expand so much

Question 9

Vascular remodeling

Answer 9

• Metalloproteinases (MMPs) and collagenases are abundant, and degrade collagen in plaque
• This weakens the plaque and makes it less resistant to mechanical forces
• This helps remodel the plaque to prevent stenosis
• Positive remodeling: vessel wall grows to accommodate the plaque while maintaining lumen size
• Use ratio of IEL/EEL; IEL/EEL>1.05 is + remodeling, if the ratio is <.95 its negative remodeling

Question 10

Negative and positive remodeling

Answer 10

• Positive remodeling plaques are less stable and more likely to rupture
• In this case, there is less stenosis (stenosis is <50% b/c lumen relatively intact)
• These plaques generally have thinner fibrous caps and thicker plaques
• Negative remodeled plaques are more stable and less likely to rupture
• They have a great deal of stenosis (usually 80-90%), thick fibrous walls, and thinner plaques
• Negative remodeling more likely to cause CSA, positive remodeling more likely to cause ACS

Question 11

Dangers of positive remodeling

Answer 11

• These plaques have more macrophages, more lipid-rich atheroma, and more MMPs (unstable)
• They also have less collagen, less smooth muscle and thinner cap
• Therefore majority of MIs (ACS) are caused by positive remodeling plaques, when stenosis is <50%
• If the stenosis is 70-80% it means the plaque has already ruptured and healed several times, thus is now stable and unlikely to cause ACS

Question 12

Markers of a vulnerable plaque

Answer 12

• Large lipid core w/ fat-induced inflammation
• Abundant MMPs (MMP 2, 3, and 9) therefore low collagen content
• Decreases matrix synthesis and increases matrix degradation
• Thin fibrous cap, possible mural platelet and fibrin
• Endothelial dysfunction/damage
• High SMC apoptosis

Question 13

Risk factors contributing to plaque formation

Answer 13

• Diet most important (excess lipid)
• Lack of exercise
• HTN, diabetes
• Smoking

Question 14

Rx of atherosclerosis

Answer 14

• Statins: decrease LDL
• Raise HDL: niacin, fish oil
• ACE inhibitors (HTN)
• B-blockers
• Aspirin w/ clopidogrel (antiplatelets)
• Warfarin (antithrombotics)