Atherosclerosis Flashcards
What collects in an atherosclerotic plaque?
Inflammatory/immune cells, smooth muscle cells, lipids, connective tissue
What are the three stages of atherosclerotic plaque formation?
- Initiation and formation
- Adaptation
- Clinical
What is a genetic predisposition that can accelerate atherosclerotic plaque formation in the first decade of life?
Homozygous Familial Hypercholesterolemia
Where do atherosclerotic lesions generally form?
Where shear stress is low but fluctuates rapidly
What gene expression increases at sites prone to plaque development? What cells do these genes help recruit?
- Vascular Cell Adhesion Molecule (VCAM-1)
- Intercellular Adhesion Molecule (ICAM-1)
- Proinflammatory Genes
Monocytes/Macrophages
What factors does lipid accumulation depend on?
Disruption of the integrity of the endothelial barrier through cell loss and/or cell dysfunction
Describe the relationship betwixt LDL and atherosclerosis.
- LDL carries lipids into the intima
- Macrophages containing lipids enter intima and undergo necrosis.
- Lipids collect and contribute to plaque formation
What is the likely effect of oxidized lipoproteins in the evolution of atherogenesis?
Ox. lipos. induce tissue damage and recruit macros which can transform the normal anticoagulant vascular surface to a procoagulant one
When a thrombus forms on the early atherosclerotic plaque, what 3 things can occur?
Thrombus may
- Grow
- Lyse
- or become organized and incorporated into the plaque
What occurs when the plaque separates the intima from the nutrient-rich blood?
Intima undergoes ischemic necrosis. Macros as well as platelets release angiogenic factors causing new vaso vasorum to form
What cytokine is a key regulator of ECM deposition in atherosclerotic plaques?
TGF-Beta
Describe the adaptation stage of atherosclerosis
- Plaque protrudes into lumen and the wall of the artery remodels to maintain lumen size
- Once the plaque occupies half of the lumen, remodeling can no longer compensate and the arterial lumen becomes stenotic.
- “Clinically silent”
How can hemorrhage occur in the atherosclerotic plaque?
Fragile new vessels are formed within the plaque and can rupture
What are the two precursor lesions of atherosclerosis?
- Fatty Streaks - Intra/Extracellular lipid accumulation
- Intimal Cell Mass (“cushions” - White, thickened areas at branch points in the arterial tree, NO LIPID
What is the characteristic plaque of atherosclerosis? Characteristics?
The fibroinflammatory lipid plaque; Well defined borders, irregular shape
What is a more advanced lesion than a fibroinflammatory lipid plaque?
Fibrofatty plaques
What separates the lumen of the blood vessel from the necrotic center of the atherosclerotic plaque?
The fibrous capsule
What is an important contributor to plaque growth and subsequent complications?
Neovascularization
What are the possible states of a complicated atherosclerotic plaque?
- Calcification
- Fissure
- Hemorrhage
- Mural Thrombosis
- Erosion
- Ulceration
- Aneurysm
What causes the formation of a mural thrombus?
Abnormal blood flow around the plaque
What major cytokine within the necrotic center of the plaque is thrombogenic?
Tissue Factor
What are complications of atherosclerosis?
- Acute Occlusion
- Chronic Narrowing of the Vessel Lumen
- Aneurysm Formation
- Embolism
What is restenosis? What causes it?
Following percutaneous transluminal coronary angioplasty, stenosis again occurs; Intimal hyperplasia due to SM proliferation
What are risk factors for atherosclerosis?
- HTN
- Dyslipidemias
- Smoking
- Diabetes
- Increasing Age
- Male Sex
- Physical Inactivity
- Stress
- Homocysteine
- C-reactice protein
What are the four major components of cholesterol metabolism?
- Chylomicrons
- Very Low Density Lipoproteins
- LDLs
- High Density Lipoproteins
What are the lipoproteins in the major cholesterol metabolic pathways?
B apolipoproteins
Describe the exogenous cholesterol pathway. What apolipoprotein is used?
Fat/cholesterol is ingested and absorbed by the intestine. Chylomicrons containing apoB-48.
- Chylos acquire apoCII and apoE from HDL and transport lipid from intestine to liver
- Chylos get processed to remnants and are removed by the liver
Describe the endogenous pathway. What lipoproteins are used?
- The liver secretes lipoproteins containing apoB-100.
- Liver VLDL acquires apoCII and apoE from HDL
- LPL hydrolyzes TGs on VLDL
- VLDL -> IDL -> LDL
- LDL taken up and catabolized
What two lipoproteins are associated with HDL? What two major functions are associated with HDL?
apoAI and apoAII
- Reservoir for mainly apolipoproteins apoCII and apoE
- Reserve Cholesterol Transport - interaction with cells in the transport system to carry extrahepatic cholesterol, including that in the arterial wall, to the liver for ultimate removal from the body
What happens if there is a defect in cholesteryl ester transfer and exchange?
Dyslipoproteinemia, increaseed inctracellular cholesteryl ester concentrations and premature atherosclerosis
What is the relationship betwixt ischemic heart disease and HDL cholesterol levels?
Inverse relationship
What apolipoproteins are contained by LDL?
apoB-100
What role does oxidized LDL play in atherogenesis?
Ox LDL is atherosclerotic, toxic to vascular wall cells and are also chemotactic for macrophages
What is the genetic defect in familial hypercholesterolemia? What is the outcome of homozygotes?
LDL receptor mutation on chromosome 19; Generally death of CAD by age of 20
A patient presents with lesions on his skin and tendons as shown below. What are the lesions? What condition does he likely have? What ocular lesion might he have? Where else can lesions form?
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LDL Xanthomas; Familial Hypercholesterolemia; Arcus Lipoides; Extensor surface of elbow and knees
What is Lipoprotein (a) and what is its role in the pathogenesis of atherosclerosis?
LDL-like particle to which glycoprotein apo(a) is attached; Lp (a) is associated with increased risk of atherosclerosis of the coronary arteries and larger cerebral vessels in both men and women
What genotype of apoE is associated with type III hyperlipidemia and premature atherosclerosis?
E2/2