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Y3 Diseases > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

What are some non-modifiable atherosclerosis risk factors?

A

Age
Sex
Genetics
Inflammation
Family history of CV disease

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2
Q

What are some modifiable atherosclerosis risk factors?

A

Diabetes
Hypertension
Obesity
Smoking/alcohol (nicotine damages endothelial cells)
Physical inactivity
Dyslipidaemia (elevated blood LDL). Genetic but can be controlled with drugs

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3
Q

Describe how atherosclerosis occurs

A
  1. Insult to artery wall, leading to endothelial dysfunction, reducing NO biosynthesis
  2. Inflammatory cells accumulate and migrate to the vessel wall
  3. LDL accumulates in the artery wall and is oxidised by free radicals
  4. Macrophages (activated by T-lymphocytes) engulf these, forming foam cells
  5. Foam cells secrete IL-1 and apoptose, relaseing lipid content in the intima
  6. Macrophages can no longer clear dead cells. Foam cells necrose, forming the necrotic core.
  7. Macrophages release MMPs, weakening collagen in fibrous caps to make it susceptible to rupture
  8. Necrotic core enlarges and fibrous cap thins.
  9. thrombus and myocardial infarciton. Or it can be a clinically silent
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4
Q

Where do atherosclerotic plaques normally occur?

A

In peripheral and coronary arteries
Changes in flow/turbulance, e.g junctions and bifurcation have turbulent flow
They can occlude on vessel to restrict blood flow (angina) or it can rupture

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5
Q

What is a atherosclertic core made up of

A

Lipid
Necrotic core
Connective tissue
Fibrous cap

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6
Q

What knock on effects can endothelial cells not producing NO have?

A

Synthesis of adhesion molecules (ICAM-1, VCAM-1), chemokines, IL-1, IL-6 and TNFα.
This creates a chemokine gradient, attracting T-lymphocyte infiltration and leukocytes moving from lumen to between endothelial cells. This adheres

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7
Q

What apoliproteins do all lipoproteins have?

A

Apo C and E

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8
Q

Describe the exogenous pathway

A
  1. Cholesterol enters enterocytes via NPC1L1
  2. Nascent chylomicrons containing ApoB48 form
  3. Nascent chylomicrons enter bloodstream
  4. HDL donates ApoC and E to chylomicron
  5. ApoC stimulates LPL to hydrolyse chylomicrons
  6. Cholesterol is released into tissues or enters endogenous pathway, is converted to bile or excreted
  7. Remnant chylomicrons enter liver via ApoE
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9
Q

What does the endogenous pathway transport?

A

VLDL
IDL
LDL

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10
Q

Describe endogenous pathway

A
  1. Cholesterol, triglyceride and ApoB100 combine to form VLDL
  2. VLDL enters blood stream, HDL donates ApoE and C
  3. ApoC activtaes LPL to convert VLDL to IDL and this can be further converted to LDL
    4, IDL and LDL enter liver via ApoB100 or ApoE
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11
Q

Describe the reverse cholesterol pathway

A
  1. HDL transfers cholesterol to VLDL, IDL or LDL via CETP
  2. These enter liver as LDLR receptor recognises ApoB100
  3. HDL enters liver as SRB1 recognises ApoA1
  4. The lipoproteins are moved to the intestines via ABC-G5 or secreted into bile
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12
Q

How do statins work?

A

Inhibit HMG-CoA

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13
Q

What do statins do?

A

Reduce cholesterol synthesis, mainly in liver
Decreases LDL
Impede tumour cell growth and help bone formation due to changes in Ca2+ signalling
Antiatherosclerotic effects which are independent of hypolipidemic action

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14
Q

What is dyslipidaemia?

A

Abnormal amounts of lipids in the blood (usually elevated (hyperlipidaemia))

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15
Q

How is dyslipidaemia classed?

A

Frederickson classification:
According to which lipoproteins are abnormal
Six phenotypes: higher blood LDL and lower HDL increases risk of atherosclerosis

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16
Q

What is primary dyslipidaemia?

A

Caused by diet and genetics
Polygenic or monogenic
Classified according to which lipoproteins is abnormal

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17
Q

What is secondary dyslipidaemia?

A

Concequence of diabetes, alcohol, chronic renal failure, liver disease, drugs, ect
Corrected by treating the underlying cause

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18
Q

What is familial hypercholesterolemia (FH)?

A

Genetic disorder causing high blood LDL and early cardiovascular disease
Mutations in LDLR gene
Mutations in ApoB100 (binds LDLR on liver)

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19
Q

How can high blood LDL become persistent?

A

High LDL can result in VLDL and inadequate uptake of LDL by liver (low responsiveness/abundance)

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20
Q

How is dyslipidaemia treated?

A

Dietary changes
Statins
Inhibitors of cholesterol absorption
PCSK9 inhibitor

21
Q

How is cholesterol formed?

A

3 Acetyl-CoA in cytosol interact to form HMG-CoA. HMG-CoA reductase on smooth ER converts this to Methanolate which goes through multiple intermediates to form cholesterol

22
Q

What detects changes in cholesterol?

A

Sterol regulatory element binding proteins (regulate transcription of LDL receptor gene)

23
Q

What do SREBPs do when they are active?

A

Increase HMG-CoA reductase synthesis
Reduce pools of cholesterol and slow VLDL production
Blood HDL may rise, stabilising atherosclerotic plaques and restoring NO synthesis

24
Q

What is NO function in blood vessels?

A

Vasodilator
Inhibits platelet aggregation
Vascular inflammation

25
Q

What short-lasting statins are given?

A

Simvastatin
Lovastatin
Pravastatin
These are all reversible competitive inhibitors

26
Q

How are short lasting statins given?

A

Orally at night to reduce cholesterol peak in early morning
Efficiently absorbed and extracted by liver
Presystemic metabolism via cyt450 and glucoronidation

27
Q

What are some pleitropic effects of statins due to them affecting lipidation?

A

Improved endothelial function
Reduced vascular inflammation
Reduced platelet aggregatobility
Increased circulation of endothelial progenitor cells
Stabilisation of atherosclerotic plaque
Enhanced fibrinolysis
Less germ cell migration during development (not good)
Immune supression

28
Q

What can create differences in haemodynamic stress?

A

Arterial junctions and bifurcations which have less stress as they experience turbulent flow, not laminar flow

29
Q

What happens before transmigration of T-lymphocytes to a lesion?

A

Endothelial cells are activated, preventing NO production due to increased oxidative stress.
Oxidative stress causes adhesion molecules (ICAM-1, VCAM-1) and cytokines (IL-1, IL-6 and TNFα) to be synthesised. The chemoattrictive gradient attracts T-lymphocytes

30
Q

How cab thrombotic lesions be stabilised?

A

Increased HDL which enhances reverse cholesterol transport

31
Q

What effect does low blood LDL have?

A

Increases NO which causes vasodilation, inhibits platelet aggregation and vascular inflammation

32
Q

How are short acting statins given?

A

Orally at night to reduce peak cholesterol synthesis in early morning
Efficiently absorbed and extracted by liver

33
Q

Statins inhibit the melvonate pathway, affecting lipidation. What does this do?

A

Improves endothelial function
Reduces vascular inflammation
Reduces platelet aggregation
Stabilises atherosclerotic plaque
Antithrombotic action
Protects against sepsin
Immune suppression
Inhibits germ cell migration during development.

34
Q

What is ezetimibe?

A

Cholesterol absorption inhibitor
Targets exogenous pathway
Blocks NPC1L1 in enterocytes (intestinal epithelial cells)
Does not affect fat-soluble vitamin, triglyceride or bile acid absorption

35
Q

What is evolacumab/raptha?

A

PCSK9 inhibitor
Targets endogenous pathway
Monoclonal antibody PCSK9, so it cannot bind LDLR. LDLR takes up LDL into liver

36
Q

Describe how PCSK9 normally functions?

A
  1. PCSK9 binds LDLR on liver and negatively regulates it
  2. LDLR internalises, ends up in lysosomes and is degraded
  3. LDL continues to circulate in blood
37
Q

What is inclisiran?

A

siRNA that targets PCSK9 mRNA for degradation, so LDLR remains on liver
Long acting, subcutaneously delivered.
siRNA-RNA binds argonaut, forming risc complex

38
Q

How do inhibitors of plant sterols work?

A

Stanols are structurally similar to cholesterol so are incorpirated into mixed micelles
May activate ABCG5/ABCG8 in enterocytes which increases cholesterol movement from enterocytes in intestinal lumen.

39
Q

How does bempedoic acid work as an atherosclerosis drug?

A

Lowers LDL levels
Used for patients that cannot tolerate strain
Prodrug that inhibits ATP citrate lyase involved in liver biosynthesis of cholesterol upstream of HMG-CoA reductase

40
Q

What is Nustendi?

A

The madness and badness combination of bemedoic acid and ezetimibe.

(Lowers plasma LDL and blocks choleserol absorption via NPC1L1 on enterocytes)

41
Q

How can PCSK9 ,mutations alter blood LDL? (Extra)

A

Changing rate of ApoB100 containing lipoproteins from liver
Increased PCSK9 activity increases VLDL productionand hypercholesterolemia

42
Q

How can lower PCSK9 reduce virus pathogenicity? (extra)

A

LDLR can shuttle viruses such as rhinovirus and hepatitis C to the liver, reducing pathogenesis to peripheral tissue

43
Q

How may fibric acid derivatives treat dyslipidaemia? (extra)

A

Lower plasma triglycerides, LDL and higher HDL
Reduces hepatic VLDL synthesis
Stimulates LPL to break down VLDL
Reduces lipoprotein A (coronary heart disease risk factor)
Stimulates apoA1 which reduces HDL conversion to LDL in plasma
Can be prothrombotic, so treated with aspirin

44
Q

How can nicotinic acid be used to treat atherosclerosis? (Extra)

A

Inhibits hepatic VLDL production
Increases plasma HDL and apoA1, so less cholesterol is transferred from HDL to VLDL
Less LDL
Constant use is associated with GI disturbances and hepatotoxicity
Nicotinic acid can affect insulin resistance, causing glucose intolerance
Reduced motality and myocardial infarction

45
Q

How does probucol act as a atherosclerosis drug? (extra)

A

Reduces LDL and HDL for patients with hypercholesterolaemia
Prevents LDL and Lp(a) oxidation
Prevents endothelial damage
May be due to lower IL-1, causing lower MMP secretion from smooth muscle, so collagen and connective tissue is not destroyed

46
Q

How can hormone replacement therapy treat atherosclerosis? (extra)

A

Oestrogen stimulates LDLR activity, lowering plasma LDL, Lp(a) and higher HDL.
Oestrogen may be cardioprotective in post-menopausal women with CHD risk factors
In trials, oestrogen HRT had conflicting results due to a lot of them not being controlled due to postmenopausal women being on various drugs

47
Q

How dies inflammation occur in atherosclerosis?

A

When leukocytes localise in lesions, adhesion molecules from SMCs bind to these, e.g VCAM-1 binds early atheroma, monocytes and T-lymphocytes
γ-interferon from T-lymphocytes in plaque halts collagen synthesis by SMCs, reducing plaque stability

48
Q

Why is HDL athero-protective?

A

It transports antioxidant enzymes that break down oxidised lipids. This prevents proinflammatory effects

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