hyperlipidaemia and angina

what is angina caused by

ischaemia of cardiac muscle

ApoB-100

main apolipoprotein in LDL

apolipoprotein

proteins present in lipoproteins that help the body to identify the type of lipoprotein

atheroma

fatty plaque in artery

CABG coronary artery bypass graft

• non-vital blood vessel is transplanted taken from one part of the body and is used to generate an alternative blood supply for ischaemic tissue

• bypasses blocked vessel

• It can be used to treat angina.

claudication

pain caused by ischaemia of muscles in the leg

• due to atherosclerosis of arteries supplying the leg

ezetimibe

• drug that blocks dietary uptake of cholesterol

fibrates

• drugs such as gemfibrozil and fenofibrate that act on nuclear receptors to modulate genes involved in lipid metabolism

what is a foam cell

• cell that forms part of an atheroma

• formed from macrophages

how is atheroma plaque formed

1. excess ldl in circulation enters intima of the blood vessel

2. free radicals and enzymes oxidise the unsaturated fatty acids, cholesterol esters and apob-100 in ldl

3. monocytes migrate to intima and transform to macrophages

4. macrophages take up oxidised ldl and transform to foam cells

5. smooth muscle cells recruits and attach to endothelium to create stable plaque

NPC1L1

cholesterol transporter in GI tract which absorbs dietary cholesterol

prodrug

drug that must be metabolised to active form before therapeutically possible

synthesis of cholesterol

• acetylCoA

• HMG CoA → mevalonate using HMG CoA reductase

• cholesterol

absorption of dietary cholesterol

• enterocytes have cholesterol transporter NPC1L1 on lumenal side

• absorbed cholesterol esterified in ER

• lipides and proteins added in golgi to form chylomicrons

• secreted to lymphatic system

which lipoprotein has the lowest density

chylomicrons

structure of lipoprotein

• phospholipid monolayer

• cholesterol

• carbohydrate

• ApoB-100

• lipid core - triglycerides and cholesterol esters

chylomicrons, place of synthesis and role

• synthesised in small intestine

• deliver triglycerides to periphe4ral tissues where they are hydrolysed by lipoprotein lipases

VLDL

• synthesised in the liver and released into circulation

• creates IDL

IDL

• taken up by liver

• either catbolised or hepatic lipases remove trigylcerides

• creates LDL

LDL

• carries cholesterol to tissues and maintains levels in liver

• taken up by specific receptors that recognise ApoB-100

high plasma concentration of which lipoprotein is associated with inc risk of cardiovascular disease

LDL

HDL

• produced in liver and intestine

• transfers phospholipids and apolipoproteins from chylomicrons and VLDL

• can remove cholesterol ester for excretion

high plasma conc of which lipoprotein is associated with lower cardiovascular risk

HDL

is low HDL or high LDL more harmful

low HDL

expression of which receptors increases when cholesterol levels are low

PCSK9 and LDL

LDL receptor transmembrane domain

only one

what does LDL receptor bind to

ApoB-100

• becomes endocytosed in a clathrin coated vesicle

PCSK9

• then cannot be recycled

risk factors for hypercholesterolaemia

• smoking

• obesity

• physical inactivity

• medication - thiazide diuretics

• diet

• diabetes

• genetics

• NAFLD - liver disease

familial hypercholesterolaemia

• common

• inc risk of cardiovascular diseases

• mutations of LDL receptor, ApoB-100 or PCSK9

effect of LDL receptor mutation

• stops recognition of ApoB-100

• prevents uptake of LDL by liver

effect of ApoB-100 mutation

• prevent efficient binding to LDL receptors

• reduces clearing ability of LDL from circulation

effect of gain in function of PCSK9

• inc LDL conc

• reduced LDL receptors available

  • degraded by lysosomes

risk factors of atherosclerosis

• hypercholesterolaemia

• hypertension

• smoking

• diabetes

acute coronary syndromes

• occur when blood clot forms on an atherosclerotic plaque

• unstable angina

• non ST elevated and ST elevated myocardial infarction

unstable angina compared to angina

• acute coronary syndrome

• rare and more serious

• less predictable

• not relieved by GTN spray