Atherosclerosis + Hypercholesterolaemia Flashcards
Describe cholesterol transport
Chylomicrons transport lipids from the gut to periphery
In liver bind to LDL receptors via ApoE
Endocytosed + deliver triglycerides, cholesterol + cholesterol esters
Activate LPL with their ApoCII = fatty acids released
Describe how hypercholesterolemia works
Elevated cholesterol-rich LDL in serum
Increases binding of LDL to scavenger receptor
= mediates incorporation of cholesterol in macrophages, skin + vessel walls
What is atherosclerosis?
Slowly progressing arterial disease in which intima thickened by fibrous deposits that narrow the lumen + become site of thrombus formation
What happens later on with atherosclerosis as it progresses?
Fibrous plaque forms
Describe the formation of plaque
In response to endothelial injury
Monocytes adhere to endothelial cells
Move to intima + transformed to macrophages
Macrophages consume excess modified lipoprotein = become foam cells
Release growth factors + cytokines that stimulate migration of smooth muscles
Proliferate to produce collagen
What type of plaque is most vulnerable to rupture?
Soft
When does a fibrous cap develop?
Smooth muscle migrate to intima = tough fibrous matrix that glues cells together
Describe structure of unstable plaque
Lipid-core rich + substantial inflammatory cell infiltration
Thin fibrous cap
What is unstable plaque prone to?
Plaque disruption by ulceration
= thrombus formation
Describe the structure of stable plaque
Thick fibrous cap
Describe the evolution of plaque
Initial lesion
Fatty streak
Intermediate lesion
Atheroma
Fibroatheroma
Complicated lesion
What are the causes of the atherosclerosis?
Hyperlipidaemia
Smoking
Primary inherited disorders
Secondary lipid disorders
What is hyperlipidaemia?
Serum cholesterol >6.85 mmol/L
What is an example of a primary inherited disorder?
Familial hypercholesterolaemia
What are examples of secondary lipid disorders?
Liver disease
Nephrotic syndromes
Hypothyroidism
Describe the consequences of atherosclerosis
Narrowing of lumen leads to ischaemic heart disease
Stiffening of vessel wall
Bleeding
Thrombus formation = peripheral emboli
What are the clinical options for atherosclerosis?
Dietary changes to reduce cholesterol + lipids
Cessation of smoking
Control of BP
Control of diabetes
Exercise
Drugs to reduce plasma cholesterol
What are the different strategies for lipid lowering drugs?
Inhibition of cholesterol synthesis
Prevention of cholesterol reabsorption
Reduction of VLDL secretion
Increased synthesis of lipoprotein lipase
Which drugs inhibit cholesterol synthesis?
Statins
What are examples of statins that inhibit cholesterol synthesis?
Lovastatin
Atorvastatin
What is the mechanism of action for the inhibition of cholesterol synthesis?
Inhibit HMG-CoA reductase
What are the side effects of statins?
May damage skeletal muscle or liver
Interfere with myelination in infants (contraindicated in pregnancy)
Which drugs prevent cholesterol absorption?
Resins
What are examples of resins that prevent cholesterol absorption?
Cholestyramine
Colestipol
What are the side effects of resins?
Unpleasant gritty taste
GI tract discomfort
Interference of vitamin or drug absorption
What is the mechanism of action for resins?
Non-absorbable macromolecules that bind cholesterol preventing reabsorption into cut
Which drugs reduce VLDL secretion?
Niacin
What are examples of Niacin that reduce VLDL secretion?
Nicotinic acid
Vitamin B3
What is the mechanism of action for reducing VLDL secretion?
Decrease in secretion of VLDL particles from liver
What are the side effects of Niacin?
Flush with rash BUT reduced with aspirin
Which drugs increase synthesis of lipoprotein lipase?
Fibrates
What are examples of fibrates?
Gemfibrozil
Fenofibrate
What is the mechanism of action for fibrates?
Activate peroxisome proliferation-activated receptor alpha
Increase lipoprotein lipase synthesis + beta-oxidation of lipids
What are the side effects of fibrates?
Nausea
Skin rash
Occasional risk of gallstones
