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Cardiovascular > Lipoproteins, Cardiovascular disease & drugs used to treat hyperlipidaemias > Flashcards

Lipoproteins, Cardiovascular disease & drugs used to treat hyperlipidaemias Flashcards

1
Q

What are lipids?

A

Organic compounds- poorly soluble in water but miscible in organic solvents

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2
Q

Why are lipids important in human physiology?

A 
Steroids- cholesterol/ steroid hormones (testosterone)
Fat-soluble vitamins- A, D, E, K
Phospholipids
Sphingolipids
Triglycerides
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3
Q

How are lipids important in cardiovascular disease?

A 
Components of lipoproteins
Cholesterol (free/ esterified)
Triglycerides- triacylglycerol
Phospholipid monolayer
apoB-100 protein
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4
Q

What is the purpose of lipoproteins?

A

Transport cholesterol and triglycerides around the body via the circulation

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5
Q

What are the main types of lipoprotein?

A 
Chylomicrons
Very Low Density Lipoprotein (VLDL)
Intermediate Density Lipoprotein (IDL)
Low Density Lipoprotein (LDL)
High Density Lipoprotein (HDL)
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6
Q

How are lipoproteins created?

A

Small intestine (dietary lipids)
Liver (endogenous lipids)
To peripheral tissues
Returns to liver via reverse cholesterol transport

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7
Q

How can transport and metabolism of lipoproteins be divided up into three main pathways?

A

-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

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8
Q

Describe the exogenous lipid pathway

A

Triglycerides- (glycerol)+ NEFA- muscle, adipose tissue
Cholesterol- liver (chylomicron remnants)
NEFA= non-esterified fatty acids

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9
Q

Describe the endogenous lipid pathway

A

NEFA (albumin- bound)+ glucose, glycerol- liver- LDL- peripheral tissues (receptor)
VLDL- triglycerides= muscle, adipose
LDL- cholesterol= peripheral tissues

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10
Q

Describe the main types of lipoprotein

A

-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

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11
Q

What are Apolipoproteins and which types belong with each lipoprotein?

A

Determine lipoprotein behaviour
ApoB48= chylomicrons
ApoB100= VLDL, IDL, LDL
ApoA1= HDL

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12
Q

Describe triglyceride metabolism

A

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
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13
Q

Describe cholesterol metabolism

A

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
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14
Q

What is the Lipid hypothesis in lipid-driven CV disease?

A

Elevated non-HDL cholesterol causes atherosclerosis, in particular coronary heart disease
Ancel Keys- Seven Countries Study

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15
Q

What does the large prospective study show in lipid-driven CV disease?

A

Increased CV mortality as serum total cholesterol increases

Absolute risk varies from country to country

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16
Q

What is the difference between HDL and LDL in studies?

A

Raised HDL-cholesterol decreased rates of CV disease while LDL-C increased rates of CV disease

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17
Q

What is the mechanism of atherosclerosis in relation to lipoproteins?

A

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

18
Q

Describe fatty streak formation

A

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

19
Q

What are oxygen free-radicals produced by?

A

Glycation reactions (diabetes)
Toxins from cigarette smoke
Macrophages

20
Q

Describe atheromatous plaque formation

A

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

21
Q

Describe the outcomes of plaque rupture

A 
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)
22
Q

What is Familial Hypercholesterolaemia?

A

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

23
Q

What should you be suspicious of in diagnosing hypercholesterolaemia?

A

Family history of hyperlipidaemia/ premature CVD
Unusually high LDL-C despite very healthy lifestyle
History of hyperlipidaemia from young age

24
Q

What are the stigmata (visible sign or characteristic of a disease) of hyperlipidaemia?

A

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

25
Q

What is the relationship between lipoproteins and cholesterol measurement?

A

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

26
Q

How can LDL-C be calculated?

A

LDL-C= TC- (HDL-C +Trig/2.2 or VDLDL-C)

Freidewald equation- assumes fasting sample so no chylomicrons

27
Q

How does evidence satisfy many of the Bradford-Hill criteria for lipid hypothesis?

A
  • 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)
28
Q

How many deaths are due to CVD?

A

24%

Coronary heart disease 2nd common cause of death in UK

29
Q

What is the treatment for MI?

A

Acute
Re-perfusion via primary PCI
Drug-eluting stents (anti-proliferative agent to prevent re-occlusion)

30
Q

What are the types of prevention?

A

Primary- individuals without disease

Secondary- patients with disease

31
Q

Describe secondary prevention of CVD

A

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

32
Q

Describe the mainstay of primary prevention

A

Lifestyles change- diet (reduce sat fat, simple carbohydrates, salt), aerobic exercise, aim for BMI 20-25 kg/m^2, reduce ethanol intake, quit smoking

33
Q

How do we decide who to treat with primary prevention?

A

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

34
Q

How do we estimate CV risk?

A

Risk calculator (ASSIGN, QRISK2)
Sex, age, family history, postcode, T2DM?, RA (rheumatoid arthritis), BP, smoking status, TC:HDL (modifiable)
% risk for next 10 years

35
Q

What group does CVD affect the most?

A

The least affluent
UK CHD mortality rate= 40 per 100,000
Scotland highest- 45% higher than SE England, 72% higher premature deaths

36
Q

What is considered high-risk?

A 
SIGN 149 (2017)- treat if greater than 20% CV risk
NICE CG181 (2014)- treat if greater than 10% CV risk
Treatment= lifestyle advice, statin
37
Q

What are the effects and mechanism of action of statins?

A 
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
38
Q

What are the effects and mechanism of action of Ezetimibe?

A

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

39
Q

What are the effects and mechanism of action of Fibrates?

A 
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
40
Q

What is the next generation of lipid-lowering drugs?

A

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

41
Q

What is the most recent PCSK9 inhibitor drug?

A

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)

Cardiovascular (52 decks)

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