Atherosclerosis & Metabolic Syndrome

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. 

• 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.

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. 

• 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. 

• 1. Associated with increased oxidation
• 2. Associated with peripheral vascular disease

Low fat diet - Ornish 10% fat. 

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 

• 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

• 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.

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.

EPA and DHA

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.

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.