Atherosclerosis & Metabolic Syndrome

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Atherosclerosis & Metabolic Syndrome
2012-10-31 07:54:35

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  1. How does atherosclerosis develop in terms of appearance and composition of the inner artery? 3
    1. Yellow streaks - yellowish raised areas containing cholesterol oleate, smooth muscle cells, foam cells, and fibrous tissue. Present in all children by age 10.

    2. Fibrous plaque - grayish raised area sandwich: central core of EC fluid and necrotic cell debris with a fibromuscular cap. Underneath = smooth muscle cells, collagen, macrophages. Cholesterol ester. 

    • 3. Complicated lesions - calcified plaques with different amounts of necrosis, thrombosis, and ulceration. Clots form at edge of lesion and platelet aggregation contributes to thrombi formation.
    • Outcome: Plaques thicken gradually and can occlude the vessel. If arterial wall is weakened, intima can rupture. Emboli can form when plaque fragments dislodge in the lumen. 
  2. Describe pathogenesis of atherosclerosis 6 steps
    • 1. Deposits:  Due to hypercholesterolemia, deposits of oxidized LDL in endothelium of artery
    • 2. Monocytes --> macrophages: In response to endothelial injury, monocytes adhere to endothelial cells and move to intima --> transformed into macrophages --> inflammation
    • 3. Macrophages --> Foam cells: Macrophages uptake oxLDL and turn into foam cells. 
    • 4. Release of growth factors and cytokines --> IL6: Foam cells accumulate, releasing growth factors and cyotkines (interferon gamma, interleukin 1, TNF)  inducing prdouction of interleukin6.  that stimulate migration of smooth muscle cells from media to intima and become zombies (proliferate, produce collagen, take up lipids and potentially become foam cells)
    • 5. Interleukin 6: stimulates production of thing like CRP6, serum amyloid A and fibrinogenin --> cytokine amplification at each step of the cascade makes downstream measurements of mediators (plasma CRP) useful for diagnosis. 
    • 6. Plaque formation: Eventually, pattern continues and atherosclerotic plaque obstructing vein.
  3. What are risk factors you can do something about? name 5. What are risk factors you'er stuck with? Name 5. 
    1. Obesity, lack of exercise, smoking, high fat diet (high trans/sat fats), diabetes, hypertension, low HDL cholesterol

    2. Male sex, age >45 or 55, family history of heart attack or stroke before 65, Ethnicity (African S. Asian American Indian), high C-reactive protein, high serum tag, high LDL cholesterol. 
  4. How does uncontrolled diabetes contribute to atherosclerosis? 5
    • 1. Dyslipidemia --> increases cholesterol and TAG in plasma
    • 2. Decreases HDL
    • 3. Increases thromboxane A2 production by platelets
    • 4. May increase smooth muscle proliferation
    • 5. Produces advanced glycosylation end products (AGE products) that denatures and modifies functional properties of differnet key EC matrix molecules like collagen, plasma proteins. 
  5. How does smoking affect atherosclerosis? 2 What are some diets that have stopped or reversed atherosclerosis? 
    • 1. Associated with increased oxidation
    • 2. Associated with peripheral vascular disease

    Low fat diet - Ornish 10% fat. 
  6. What were characteristics of HDL, atherosclerosis and longevity of those with ApoA1 mutation? 3 What was the mutation? How could you summarize these ApoAMilanos? 
    Low [HDL], low atherosclerosis and high longevity.

    Mutation: mutation that allowed disulfide-linked dimer formation of HDL

    ApoAMilanos in HDL were extremely efficient at taking up cholesterol from cells and plaque 
  7. How do hyperlipidemia and endothelial injury (at area of blood turbulence) intersect? 6 facts
  8. What are dietary interventions that you'd recommend? 4
    • 1. Decrease intake of medium-chain (12-16) saturated fatty acids - impact still debated
    • 2. Substituting MUFAs for carbs (no validation in randomized trials)
    • 3. Substituting PUFAs for saturated FAs (lower LDL and HDL cholesterol, decreased CHD mortality and stroke mortality)
    • 4. Increased w3:w6 ratio
  9. How might substituting PUFAs for staurated FAs help with LDL/HDL cholesterol and CHD/stroke mortality? 4

    Gene transcription - 5
    • 1. Alters membrane fluidity (affecting activities of proteins near membranes - receptors, transporters, enzymes)
    • 2. Prevents arrhythmias and sudden death
    • 3. Eicosanoid IC signaling: effects on clotting and formation of inflammatory mediators
    • 4. Alter gene transcription (may activae PPARalpha and PPARgamma and suppress function of ChREBP and SREBP1 activatoin of FAS, ACC and GPAT. 
  10. How do omega 6 FAs affect LDL and HDL? How do Omega 3 FAs help? (4)
    Omega6 FAs lower both HDL and LDL.

    Omega 3s block synthesis of thromboxane A2 (cause of platelet aggregation and vasoconstriction) causing decrease in thrombus formation.

    • Increases NO synthesis (vasodilation increasing blood flow)
    • Ligands for nuclear transcription factors that control lipid pathways and may decrease TAG synthesis
    • Compete with arachidonic acid for COX to decrease eicosanoid production. 
  11. What might prevent arrythmias? 2
    EPA and DHA 
  12. How does consumption of trans fatty acids affect lipid profile? (2) What can you do instead of consuming trans fatty acids - 3 and what result would you see? 1
    Increases total cholesterol and decreases HDL-C

    Can subtitute 1% energy of trans fatty acids with saturated, monounsat or polyunsat FAs which decreases total cholesterol: HDL-C ratio. 
  13. How does dietary cholesterol affect serum cholesterol levels? How does vitamin A and E affect CVD risk? What about consuming functional foods containing plant sterols and stanols?
    Dietary cholesterol has little/no effect on serum cholesterol levels

    Vitamisn A and E suggest lower CVD risk due to antioxidant properties

    At 2g/day lowered LDL-C by ~10% - no studies with clinical endpoints have been performed yet.