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Cardio Lecture 5
Pathophysiology of Dyslipidemia and Atherosclerosis 1/22/13
48
Pharmacology
Graduate
01/22/2013

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Term
Define hyperlipidemia
Definition
An elevation of one or more of the following: cholesterol, cholesterol esters, phospholipids, or triglycerides (TG)
Term
Define lipoproteins
Definition
Lipid and protein complexes that transport cholesterol, triglycerides, and phospholipid

We usually call them "lipids"
Term
Define chylomicrons
Definition
Large TG-rich lipoproteins which deliver TG to adipose tissue or skeletal muscle

Synthesized from fatty acids or dietary triglycerides and cholesterol and bile acid (why lipid panel needs to be fasting)
Term
How are chylomicrons broken down?
Definition
Catabolized by lipoprotein lipase (LPL) which forms chylomicron remnants

Taken up by the liver to free cholesterol intracellularly
TG converted to free fatty acids, apolipoproteins, or phospholipids
Term
List 5 types of lipoproteins
Definition
1. Chylomicrons
2. VLDL
3. LDL
4. HDL
5. Apolipoproteins
Term
Define VLDL (very low density lipoproteins)
Definition
Formed in the liver and intestine
Carries 15-20% total serum cholesterol and most of the TG
Precursor to LDL
Term
Define LDL (low density lipoprotein)
Definition
Formed from VLDL catabolism by LPL and hepatic lipase (HTGL)

Carries 60-70% total serum cholesterol
Greatest contributor to atherosclerosis
Term
How are lipoproteins identified?
Definition
By the density of the lipoprotein- protein is more dense than fat
Term
What properties are unique to LDL?
Definition
-More artherogenic
-Longer half life
-More easily oxidized
Term
What is the purpose of LDL?
Definition
To carry cholesterol from the liver to organs that need it
Term
How is LDL catabolized?
Definition
Interaction with LDL receptors in liver triggers degradation
Term
What feedback changes occur with high intracellular LDL?
Definition
1. Inhibition of HMG-CoA reductase
2. Decreased LDL receptors
3. Increased storage of intracellular cholesterol
4. Increased excretion into bile portion of stools
Term
Give the Freidwald equation to calculate LDL
Definition
LDL= TC- (HDL+TG/5)

If triglycerides >400, this equation is inaccurate
Term
What is the primary role of HDL?
Definition
Reverse cholesterol transport:

Removes excess systemic and peripheral cholesterol (coronary arteries) and delivers it to liver for uptake and excretion
Term
Define apolipoproteins
Definition
Proteins on outside of lipoprotein particles, provides structure, activates enzymes, and binds with cell receptors
Term
What is ApoA associated with?
Definition
HDL and chylomicrons

(Good ones)
Term
What is ApoB associated with?
Definition
LDL, VLDL, IDL, and chylomicrons

(Bad ones)
Term
Define LPL
Definition
Lipoprotein lipase

In fat and muscle, hydrolyzes TG, chylomicrons, and VLDL & releases free fatty acids (which are stored as fat or used for energy)
Term
Define HTGL
Definition
Hepatic lipase

Converts VLDL to LDL by removing TG from VLDL
Term
What is the role of Lecithin-cholesterol acyl transferase (LCAT)?
Definition
Allows HDL to collect cholesterol
Term
What is the role of Cholesterol ester transfer protein (CETP)?
Definition
Involved in the exchanges of cholesterol between TG and HDL
Term
What lipoproteins are elevated in type I dyslipidemia?
Definition
Chylomicrons
Term
What lipoproteins are elevated in type IIa dyslipidemia?
Definition
LDL only
Term
What lipoproteins are elevated in type IIb dyslipidemia?
Definition
LDL and VLDL
Term
What lipoproteins are elevated in type IV dyslipidemia?
Definition
VLDL
Term
What lipoproteins are elevated in type V dyslipidemia?
Definition
VLDL and chylomicrons
Term
What lipoprotein phenotypes associated if a patient has high triglycerides?
Definition
I, IV, V
Term
What lipoprotein phenotypes associated if a patient has high cholesterol?
Definition
IIa and IIb
Term
List five disease secondary causes of hypercholesterolemia
Definition
Hypothyroidism
Obstructive liver disease
Nephrotic syndrome
Anorexia nervosa
Acute intermittent porphyria
Term
What drugs can cause secondary hypercholesterolemia?
Definition
Progestins, thiazide diuretics, glucocorticoids, β-blockers, isotretinoin, protease inhibitors, cyclosporine, mirtazapine, sirolimus
Term
List disease secondary causes of hypertriglyceridemia
Definition
Obesity
Diabetes mellitus
Lipodystrophy
Glycogen storage disease

Ileal bypass surgery
Sepsis
Pregnancy
Acute hepatitis
Systemic lupus erythematosus
Monoclonal gammopathy: multiple myeloma, lymphoma
Term
What drugs can cause secondary hypertriglyceridemia?
Definition
Alcohol, estrogens, isotretinoin, betablockers, glucocorticoids, bile-acid resins, thiazides; asparaginase, interferons, azole antifungals, mirtazapine, anabolic steroids, sirolimus, protease inhibitors
Term
List 6 disease causes of secondary hypocholesterolemia
Definition
Chronic liver disease
Malnutrition
Malabsorption
Myeloproliferative diseases
Chronic infectious diseases: AIDS, tuberculosis
Monoclonal gammopathy
Term
List disease causes of low HDL
Definition
Malnutrition
Obesity
Term
List drugs that can cause secondary low HDL
Definition
Non-ISA β-blockers, anabolic steroids, probucol, isotretinoin, progestins
Term
Define atherosclerosis
Definition
Plaques that form in medium and large arteries that contain lipids, inflammatory cells, smooth muscle cells, and connective tissue.

In most, the underlying cause of CAD and ACS
Term
List the five vessel wall components
Definition
1. Endothelium
2. Basement membrane
3. Elastic tissue
4. Collagen
5. Smooth muscle
Term
What is the function of the endothelium in the vessel wall?
Definition
Regulates blood flow and active transport of circulating substances throughout the cytoplasm
Term
What is the function of the basement membrane in the vessel wall?
Definition
Transport barrier and membrane support
Term
What is the function of the collagen in the vessel wall?
Definition
Prevents overstretching
Term
What is the function of the smooth muscle in the vessel wall?
Definition
Arterial metabolism and active contraction, facilitates entry of lipoproteins
Term
What are the three layers of the vascular system, from inside to outside?
Definition
1. Intima
2. Media
3. Adventita
Term
What are the effects of aging on the vascular system?
Definition
Increase in intimal thickness, rigidity

Accumulation of smooth muscle cells, connective tissue, and cholesterol

This leads to vasoconstriction, thrombosis, and inflammation- which promotes atherosclerosis
Term
Define phlebosclerosis
Definition
Systemic increase in vein thickness, primarily affects lower extremity veins that are exposed to stasis and increased luminal pressure
Term
List Risk factors for atherosclerosis
Definition
•Age
•Cigarette smoking
•Hypercholesterolemia
•Lifestyle
•Family HIstory
•Hyperhomocysteinemia
•Oxydized LDL
•Mechanical injury to the endothelium
•Immunologic attack
•Infection induced
Term
What is the response to injury hypothesis
Definition
Injury to endothelium increases LDL transport and retention in intima

LDL binding to extracellular matrix increases its "residence time"

LDL changes via oxidation to cause an inflammatory response, which increases plasminogen, coagulation, and endothelin. Foam cells form, "fatty streak"
Term
Define "fatty streak"
Definition
Develops into a lesion after repeated injury and repair within an atherosclerotic plaque

Leads to a fibrous cap protecting the underlying lipid core, collagen, and inflammatory cells

Maintenance of the fibrous cap is critical to prevent rupture and consequent thrombus
Term
What are outcomes of plaque rupture?
Definition
A clot forms on the top of the ruptured plaque
Produces either a complete or incomplete occlusion of the lumen

This can cause angina, stroke, MI, death, PAD, arrhythmias, abdominal aortic aneurism
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