Lipoproteins, Cardiovascular disease & drugs used to treat hyperlipidaemias Flashcards
What are lipids?
Organic compounds- poorly soluble in water but miscible in organic solvents
Why are lipids important in human physiology?
Steroids- cholesterol/ steroid hormones (testosterone) Fat-soluble vitamins- A, D, E, K Phospholipids Sphingolipids Triglycerides
How are lipids important in cardiovascular disease?
Components of lipoproteins Cholesterol (free/ esterified) Triglycerides- triacylglycerol Phospholipid monolayer apoB-100 protein
What is the purpose of lipoproteins?
Transport cholesterol and triglycerides around the body via the circulation
What are the main types of lipoprotein?
Chylomicrons Very Low Density Lipoprotein (VLDL) Intermediate Density Lipoprotein (IDL) Low Density Lipoprotein (LDL) High Density Lipoprotein (HDL)
How are lipoproteins created?
Small intestine (dietary lipids)
Liver (endogenous lipids)
To peripheral tissues
Returns to liver via reverse cholesterol transport
How can transport and metabolism of lipoproteins be divided up into three main pathways?
-Intestinal absorption (cholesterol and triglycerides)
=exogenous lipid pathways to peripheral tissues
-Hepatic synthesis (cholesterol and triglycerides)
=endogenous lipid pathways to peripheral tissues
Hepatic excretion (cholesterol and bile acids)
=from peripheral tissues via reverse cholesterol transport
Describe the exogenous lipid pathway
Triglycerides- (glycerol)+ NEFA- muscle, adipose tissue
Cholesterol- liver (chylomicron remnants)
NEFA= non-esterified fatty acids
Describe the endogenous lipid pathway
NEFA (albumin- bound)+ glucose, glycerol- liver- LDL- peripheral tissues (receptor)
VLDL- triglycerides= muscle, adipose
LDL- cholesterol= peripheral tissues
Describe the main types of lipoprotein
-Chylomicrons= biggest, mostly triglycerides
-Very Low Density Lipoprotein (VLDL)= quite big, pred. triglycerides
Intermediate Density Lipoprotein (IDL)= medium sized, very short lived
Low Density Lipoprotein (LDL)= small, cholesterol-rich, long-lived
High Density Lipoprotein (HDL)= smallest, cholesterol-rich, long-lived
What are Apolipoproteins and which types belong with each lipoprotein?
Determine lipoprotein behaviour
ApoB48= chylomicrons
ApoB100= VLDL, IDL, LDL
ApoA1= HDL
Describe triglyceride metabolism
Energy
- Chylomicrons, created in the gut, deliver triglycerides to muscle and adipose tissue (converted to NEFA)- post prandial (after eating food)
- VLDLs, synthesised in the liver, also deliver triglycerides to muscle and adipose tissue (NEFA)- fasting state
Describe cholesterol metabolism
Essential building block and precursor (for steroid hormones and Vitamin D)
- Liver is the master organ= synthesis, secretion, uptake, excretion
- Delivered to peripheral tissues via LDL
- Uptake from circulation via remnants, IDL, LDL, HDL
- Returned to liver via HDL
What is the Lipid hypothesis in lipid-driven CV disease?
Elevated non-HDL cholesterol causes atherosclerosis, in particular coronary heart disease
Ancel Keys- Seven Countries Study
What does the large prospective study show in lipid-driven CV disease?
Increased CV mortality as serum total cholesterol increases
Absolute risk varies from country to country
What is the difference between HDL and LDL in studies?
Raised HDL-cholesterol decreased rates of CV disease while LDL-C increased rates of CV disease
What is the mechanism of atherosclerosis in relation to lipoproteins?
Gut (chylomicron remnants) and liver (VLDL, LDL, IDL)- ApoB-carrying lipoproteins- if not all cleared by liver, all can be taken up into arterial walls
LDLs relatively long-lived (x9 VLDL)= cumulation within arterial wall maximised by high concentration of LDL, damage o arterial wall (mechanical= hypertension, chemical= oxidation, glycation)
Fatty streak formation
Describe fatty streak formation
LDL+ monocytes + O-free radicals
Hypertension/ glycation/ O-free radicals damage endothelium
Monocytes attracted by damaged endothelium
LDLs oxidised by O-free radicals are consumed by macrophages
Macrophages laden with LDL= foam cells
Fatty streak= collection of foam cells within arterial wall
What are oxygen free-radicals produced by?
Glycation reactions (diabetes)
Toxins from cigarette smoke
Macrophages
Describe atheromatous plaque formation
Smooth muscle cells are stimulated by macrophages to migrate, proliferate, differentiate
SMCs differentiate into fibroblasts which produce a fibrous collagen cap
Foam cells undergo necrosis or apoptosis to leave a pool of extracellular cholesterol
Cholesterol pool beneath a fibrous cap within the arterial wall= atheroma
Describe the outcomes of plaque rupture
Cholesterol-rich lesions= plaque rupture+ thrombosis= total lumen obstruction= tissue ischaemia (MI) Fibrous lesions (less cholesterol)= less liable to rupture= reduced blood flow (stable angina)
What is Familial Hypercholesterolaemia?
Autosomal dominant
Mutation in LDL receptor (or ApoB, PCSK9)
Common- 1:500 to 1:200 (heterozygotes)
High LDL-C levels (typically greater than 4.9 mmol/L)
Untreated leads to premature CHD onset=
50% men by 55 yr, 33% women by 60 yr
Statin treatment shown to reduce risk
What should you be suspicious of in diagnosing hypercholesterolaemia?
Family history of hyperlipidaemia/ premature CVD
Unusually high LDL-C despite very healthy lifestyle
History of hyperlipidaemia from young age
What are the stigmata (visible sign or characteristic of a disease) of hyperlipidaemia?
Tendon xanthoma= sharply demarcated yellowish collection of cholesterol underneath the skin
corneal arcus= depositing of phospholipid and cholesterol in the peripheral cornea, formation of ring
xanthelasma= yellow patches filled with cholesterol that appear on the inside of your eyelids
What is the relationship between lipoproteins and cholesterol measurement?
Specialist labs measure concentrations of lipoproteins (ultracentrifugation)/ apolipoproteins (ApoB100, ApoA1)
Routine lab measurements of lipids- total cholesterol, HDL cholesterol (HDL-C), triglycerides
LDL-C calculated not measured
How can LDL-C be calculated?
LDL-C= TC- (HDL-C +Trig/2.2 or VDLDL-C)
Freidewald equation- assumes fasting sample so no chylomicrons
How does evidence satisfy many of the Bradford-Hill criteria for lipid hypothesis?
- Strong correlation: CV risk and non-HDL-C
- Consistent relative risk across countries
- Biological gradient increases CV risk for increased non HDL-C
- Plausible mechanism (atherogenesis)
- Coherence (epidemiology consistent with animal and in-vitro models)
- Treatment to lower non-HDL-C reduces CV risk (individuals without CV disease, patients with CV disease)
How many deaths are due to CVD?
24%
Coronary heart disease 2nd common cause of death in UK
What is the treatment for MI?
Acute
Re-perfusion via primary PCI
Drug-eluting stents (anti-proliferative agent to prevent re-occlusion)
What are the types of prevention?
Primary- individuals without disease
Secondary- patients with disease
Describe secondary prevention of CVD
Greater than 20% risk of any CV -event over 10 years
Lifestyle change= smoking cessation
Drugs= ACE-inhibitor, beta blocker= reduce post MI mortality/ Aspirin, statins and clopidogrel reduce recurrence and mortality/ statins reduces CVD
Describe the mainstay of primary prevention
Lifestyles change- diet (reduce sat fat, simple carbohydrates, salt), aerobic exercise, aim for BMI 20-25 kg/m^2, reduce ethanol intake, quit smoking
How do we decide who to treat with primary prevention?
Potential benefit vs side-effect
Risk of serious side-effects must be small
Must produce reasonable reduction in risk
Treat those at highest absolute risk (CV event in next 10 years)
very high LDL-C in familial hypercholesterolaemia/ sever hypertension
How do we estimate CV risk?
Risk calculator (ASSIGN, QRISK2)
Sex, age, family history, postcode, T2DM?, RA (rheumatoid arthritis), BP, smoking status, TC:HDL (modifiable)
% risk for next 10 years
What group does CVD affect the most?
The least affluent
UK CHD mortality rate= 40 per 100,000
Scotland highest- 45% higher than SE England, 72% higher premature deaths
What is considered high-risk?
SIGN 149 (2017)- treat if greater than 20% CV risk NICE CG181 (2014)- treat if greater than 10% CV risk Treatment= lifestyle advice, statin
What are the effects and mechanism of action of statins?
Reduce LDL-C, lower risk of coronary heart disease, first choice lipid lowering drug class for CVD prevention HMG-CoA reductase inhibitors, inhibit rate-limiting step of cholesterol synthesis, intracellular cholesterol depletion= LDL uptake
What are the effects and mechanism of action of Ezetimibe?
Reduce LDL-C, lower risk of coronary heart disease, usually an adjunct
Inhibits cholesterol absorption at small intestine, binds to NPC1L1 (Nieman-Pick C1 Like 1) protein, a critical mediator of cholesterol absorption in GI epithelial cells
What are the effects and mechanism of action of Fibrates?
Reduce LDL-C and Triglycerides, increase HDL-C, only beneficial where low HDL-C and high trigs (T2DM), usually an adjunct to statin therapy Stimulate PPARa (Peroxisome Proliferator-Activator Receptor a) a nuclear transcription factor, causes increased LPL (lipoprotein lipase), hepatic fatty acid oxidation, enhanced IDL, LDL uptake, reduced VLDL synthesis
What is the next generation of lipid-lowering drugs?
PCSK9- inhibitors
Monoclonal antibodies, delivered by fortnightly s/c injection
Alirocumab, Evolocumab
Capable of 60% reduction of LDL-C (as adjunct to statin)
Reduce rate of CV events, relatively very expensive
What is the most recent PCSK9 inhibitor drug?
Inclisiran
siRNA drug suppresses PCSK9 expression
6 monthly injection
Likely significantly improved compliance relative to statins
Population-level trial planned for secondary prevention in NHS England (Jan 2020)
