Lipids And Cardiovascular Disease

Question 1

Structure of the arterial wall

Answer 1

• single endothelium layer
• proteoglycan rich intima (charged)
• smooth muscle below for contraction of arteries (important for blood flow)

Question 2

Risk factors for CHD

Answer 2

• behavioural: smoking, drinking, physical inactivity, unhealthy diet
• metabolic: obesity, high blood pressure/ blood glucose, dyslipidemia (>6.2 mmol/L cholesterol)
• other: inherited predisposition, gender, older age, psychological risk factors

Question 3

Process of atherosclerosis

Answer 3

1) damage to endothelium i.e high blood pressure or smoking
2) damaged endothelium expresses proteins which are recognised by monocytes which enter the intima and differentiate to macrophages
3) LDL enters the intima and becomes oxidised (many different methods and oxidants such as prostaglandins). Response to retention hypothesis: LDLs held in intima by electrostatic interactions with proteoglycan layer
4) oxidised LDL is continually engulfed by macrophages via scavenger receptors and becomes foam cells
5) activated macrophages can release inflammatory cytokines and recruit T cells which secrete additional inflammatory agents
6) inflammatory mediators cause swelling and the fibrous cap can rupture leading to exposure of intima and thrombus formation

Question 4

The protective role of HDL

Answer 4

• inhibits adhesion molecules
• decreases LDL oxidation
• anti-apoptotic
• ameliorates endothelial function
• stimulates lipid efflux from macrophages by binding ABCA1 or G1 on macrophage surface

Question 5

Mutations associated with increased circulating cholesterol

Answer 5

• familial hypercholesteraemia: autosomal dominant mutation in LDL receptor increasing circulating LDL, de novo cholesterol maintains too. Total cholesterol >7.5 mmol/litre. Leads to xanthomas and early MI
• mutations in apoB100 preventing binding to LDLR
• PCSK9: gain of function mutation where protein binding to LDLR promotes internalisation
• over 1000s of LDLR
• ARH mutations: autosomal recessive hypercholesterolaemia, binds to LDLR for internalisation

Question 6

Treatment strategies for high cholesterol

Answer 6

• statins: inhibit HMG-CoA reductase which stops de novo cholesterol synthesis, which also stops branch points too, stopping isoprenide formation which could reduce inflammation. Also stops ubiquinone formation which inhibits ETC which gives cramps/muscle pains
• antibodies against PCSK9: evolocumab and alirocumab
• ezetimibe: blocks intestinal absorption of cholesterol and lowers by ~15-20%
• LDL apheresis: analogous to renal dialysis, selectively removes apoB proteins from plasma (FHC will need regular rounds of this)

Question 7

Dietary interventions for high cholesterol

Answer 7

• in combination, could theoretically lower by 20-30%
• reduce fat intake so it is 30% of EE (saturated fat <7%, but this is debated)
• swap out saturated fats for mono and polyunsaturated fats, and use plant-sterols (these block reabsorption of bile and stop absorption of cholesterol)
• up fiber intake (inhibits intestinal absorption of cholesterol)