Cholesterol, Lipoproteins And Cardiovascular Disease Flashcards
Clinical patterns of Hyperlipidaemia - what do doctors measure?
Total cholesterol
Triglycerides
HDL
LDL
What are the biochemical markers of pure hyper cholesterolaemia?
Raised LDL cholesterol
What are the biochemical features of mixed Hyperlipidaemia?
Raised LDL cholesterol
Raised triglycerides
Low HDL cholesterol
What is mixed Hyperlipidaemia common in?
NAFLD, T2 diabetes, obesity, PCOS
Biochemical features of hypertriglyceridaemia? - what disease is this associated with?
Raised triglycerides associated with acute pancreatitis
What does pure hypercholesterolaemia and mixed Hyperlipidaemia put you more at risk of?
CVD
What are genetic causes of Hyperlipidaemia?
FH
Genetic causes of Hyperlipidaemia - What causes Hyperlipidaemia in FH?
A single gene change in:
- LDLR (LDL receptor) - makes the body less able to get rid of LDL so increased LDL in the body
- ApoB - LDL particle can’t attach to LDL receptor = increased LDL in system
- PCSK9 - destroys LDL receptors - gain of function leads to less LDL receptor and more LDL in system
What do all the genetic changes seen in FH cause?
Hypercholesterolaemia
Genetic Causes of Hyperlipidaemia - what is the genetic condition LPL deficiency? What specific illness does this lead to?
Less functional LPL leading to triglycerides not being able to be broken down and LPL hanging around in the blood.
Leads to hypertriglyceridaemia
Genetic Causes of Hyperlipidaemia - what causes the mixed Hyperlipidaemia - type 3 hyper lipoproteinaemia and what does this do?
Genetic change in ApoE causing limited uptake of chylomicrons, chylomicron remnants and IDL. This results in high cholesterol an triglycerides as these cannot be taken into hepatic cells.
Non-gentic causes of Hyperlipidaemia?
Other diseases - obesity, PCOS, obesity which all confer insulin resistance.
What does insulin resistance do to cause mixed Hyperlipidaemia?
Lowers LPL which increases VLDL which causes the overloading of HDL with triglycerides and then the HDL is targeted by LPL which lowers HDL.
How does NAFLD, ALD cause Hyperlipidaemia?
Increases hepatic triglycerides which increases VLDL
How does cholestasis lead to hyperlipidaemia?
leads to hepatic cholesterol accumulation and LDLR decrease and LDL increase.
Hormones can cause hyperlipidaemia - what disease causes this and how?
Hyperthyroidism, Cushing and exogenous glucocorticoids through decreasing LPL which increases VLDL and decreasing LDLR which increases LDL.
How does post menopausal status with reduced oestradiol cause hyperlipidaemia?
Decreases LDLR and increases LDL
Age and lifestyle including a diet high in saturated fats can cause hyperlipidaemia how does this affect biochemistry?
Food increases cholesterol which lowers LDLR and therefore increases LDL
Can all these cause CVD’s?
Yes
What type of CBVD’s can hyperlipidaemia cause?
Stroke, MI
Prevention and treatment - how do you treat an acute MI?
Re-perfusion via primary PCI, drug eluding stents (this involves putting a wire through the artery and inflating the balloon to unblock artery and leave a stent to keep artery open.
What are the two classes of CVD?
Primary (stopping healthy individuals having a CVD) and secondary (stopping someone who has already had one having further CVD’s).
Lifestyle changes to prevent a CVD?
Stopping smoking
Lose weight
excessive
What drugs do you get after having an MI?
ACE-inhibitor, beta blocker - reduces post MI mortality
Aspirin and clopidogrel
Statins
Is Statins used in primary prevention and secondary prevention?
Yes
What are the most common primary prevention?
Lifestyle change
Who would you treat with drugs in primary prevention?
Treat those at highest risk of a CVD in the next ten years and those with lowest risk of side affects.
How do you work out risk?
Use ASSIGN score which assess and gives you a percentage risk of CVD in next ten years.
Postcode - who is more likely to get CVD?
Least affluent
How do they decide who would get given the drugs - intervention in primary prevention?
Mainly due to cost of prescribing drugs
They want to give everyone over what age statins because they are cheap?
40
Why are people not wanting to take drugs in primary prevention?
They don’t think they need it as they don’t actually have any disease, lack of education
What do statins do?
Reduce LDL cholesterol and lowers CVD risk
What does Ezetimibe do?
Lowers LDL cholesterol and lowers risk or coronary heart disease
Usually adjunct to statins
What do fibrates do?
Reduce LDL cholesterol and triglycerides and increases HDL cholesterol
Only beneficial though if you ave have low HDL and high triglycerides
Usually an adjunct to statin
How do statins work?
They are HMG-CoA reductase inhibitors which inhibit the rate limiting step of cholesterol synthesis meaning there is less intracellular cholesterol and therefore higher LDL uptake.
How does ezetimibe work?
Inhibits cholesterol absorption at small intenstine and binds to NPC1L1 protein which is a critical mediator for cholesterol absorption in the GI epithelial cells
How do fibrates work?
Stimulate PPAR which is a nuclear transcription factor.
Causes increased LPL activity, hepatic fatty acid oxidation
enhanced IDL, LDL uptake and reduced VLDL synthesis
what are the two forms of PCSK9-inhibitors?
Monoclonal antibodies (allrocuamab, evolocumab) nd siRNA therapy (inclusiran)
How does the monoclonal antibodies affect PCSK9-inhibitors?
Binds PCSK9 to inhibit function
It’s a 2 week injection
Is adjunct to statin
How does the siRNA therapy affect PCSK9?
Suppresses translation of mRNA into PCSK9 protein
6 monthly injection
Is adjunct to statin
Do all these drugs reduce CVD risk?
Yes
What are some future lipid lowering drugs? (Still in trial)
Vaccine (AFFITOPE) and Crispr-cas9 (adenovirus deliver)
How would a vaccine help lower lipids with PCSK9?
Stimulate endogenous antibodies to inhibit PCSK9 and would be needed in an annual booster
How would crisper-cas9 lower lipids?
Gene editing to definitively reduce PCSK9 levels and this would be a one off life long treatment.
