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BRS YR2 > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

what are the modifiable risk factors of artherosclerosis?

A
  • smoking
  • lipid intake
  • blood pressure
  • diabetes
  • obesity
  • sedentary lifestyle
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2
Q

what are the non-modifiable risk factors of atherosclerosis?

A
  • age
  • sex
  • genetic background
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3
Q

How much does hypertension alone increase your risk of developing atherosclerosis?

A

x 3

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4
Q

How much does high cholesterol alone increase your risk of developing atherosclerosis?

A

x 4

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5
Q

How much does smoking alone increase your risk of developing atherosclerosis?

A

x 1.6

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6
Q

How much does both hypertension and smoking increase your risk of developing atherosclerosis?

A

x 4.5

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7
Q

How much does both hypertension and high cholesterol increase your risk of developing aetherosclerosis?

A

x 9

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8
Q

How much does both smoking and high cholesterol increase your risk of developing atherosclerosis?

A

x 6

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9
Q

How much does smoking, hypertension and high cholesterol increase your risk of developing atherosclerosis?

A

x 16

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10
Q

Where does atherosclerosis tend occur?

A

at branches, bends and bifurcations

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11
Q

Why does atherosclerosis occur at branches and bends?

A

turbulent blood flow causes damage to artery and inflammation

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12
Q

What does the endothelium do?

A
  • controls contraction
  • maintain the blood pressure
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13
Q

What happens in atherosclerosis?

A

LDLs deposit in the subintimal space of artery walls and binds to matrix proteoglycans

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14
Q

What are the main cell types involved in the inflammation of the arteries and the progression of atherosclerosis?

A
  • vascular endothelial cells
  • monocyte-macrophages
  • vascular smooth muscle cells
  • T lymphocytes
  • Platelets
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15
Q

What are the roles of vascular endothelial cells?

A
  • barrier function (lipoproteins)
  • leukocyte recruitment
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16
Q

What are the roles of platelets?

A
  • thrombus generation
  • secrete cytokines and growth factor
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17
Q

What are the role of monocyte-macrophages?

A
  • foam cell formation
  • cytokine and growth factor release
  • major source of free radicals
  • metalloproteinases
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18
Q

What are the role of vascular smooth muscle cells?

A
  • Migration and proliferation
  • Collagen synthesis
  • Remodelling & fibrous cap formation
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19
Q

What are the role of T-lymphocytes?

A
  • macrophage actication - CD4 Th1
  • macrophage deactivation - CD4 Treg
  • VSMC death - CD8 CTL
  • B-cell help - CD4 Th2
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20
Q

What is the relationship between macrophages and the T lymphocytes?

A

both activate each other

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21
Q

What are the 2 main types of macrophages?

A
  • inflammatory macrophages
  • resident macrophages
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22
Q

What do inflammatory macrophages do?

A

adapted to kill microorganisms

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23
Q

What do resident macrophages do?

A
  • suppress anti-inflammatory activity for homeostasis
  • alveolar resident macrophages contribute to lipid surfactant homeostasis
  • some are osteoclasts involved in calcium and phosphate homeostasis
  • iron haemostasis in spleen
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24
Q

What characterises atherosclerosis?

A

macrophages causing inflammation in artery walls

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25
Q

What do LDLs do?

A

carries cholesterol from the liver to the rest of the body (including arteries)

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26
Q

What do HDLs do?

A

carries cholesterol from peripheral tissues (including arteries) back to the liver

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27
Q

What are oxidised/modified LDLs?

A
  • highly inflammatory and toxic forms of LDLs found in vessel walls
  • caused by the action of free radicals on LDLs
28
Q

How are LDLs modified?

A
  • LDLs leak through the endothelial barrier
  • LDLs are trapped by binding to the sticky matrix proteoglycans in the sub-endothelial layer
  • LDL becomes oxidatively modified by free radicals
29
Q

How can oxidised LDLs cause chronic inflammation?

A
  • phagocytosed by macrophages making them foam cells
  • stimulates chronic inflammation
30
Q

What is familial hyperlipidemia?

A
  • massively elevated cholesterol (>20mmol/L)
  • autosomal genetic disease (dominant)
31
Q

What causes familial hyperlipidemia?

A

failure to clear LDL from the blood

32
Q

What the effects of familial hyperlipidemia?

A
  • xanthomas
  • early atherosclerosis
  • fatal MI <20 if untreated
33
Q

What gene causes familial hyperlipidemia?

A
  • LDLR gene absent
  • causes macrophages to accumulate cholesterol
  • scavenger receptors bind to OxLDL
34
Q

What does macrophage scavenger receptor A (CD204) do?

A
  • binds to oxidised LDL
  • binds to gram positive bacteria
  • binds to dead cells
35
Q

What does macrophage scavenger receptor B (CD36) do?

A
  • binds to oxidised LDL
  • binds to malaria parasites
  • binds to dead cells
36
Q

What oxidative enzymes activated by macrophages can modify LDL?

A 
NADPH oxidase (superoxide)
Myeloperoxidase (hypochlorous acid)
37
Q

What are the negative impacts of macrophages

A
  • generate free radicals that further oxidise lipoproteins
  • phagocytose modified lipoproteins and become foam cells
  • express cytokine mediators that recruit monocytes
  • express chemoattractants and growth factors
  • express proteinases that degrade tissue
38
Q

What are cytokines?

A

protein immune hormones that activate endothelial cell adhesion molecules

39
Q

What are chemokines?

A

small proteins chemoattractant to monocytes

40
Q

What cytokines are released by macrophages?

A
  • IL-1 stimulates intracellular cholesterol crystals and NFkB
  • coordiantes cell death and proliferation
41
Q

What happens if IL-1 isn’t present?

A

atherosclerosis is reduced (seen in mice)

42
Q

What chemokines are released by macrophages and what do they do?

A

MCP-1 binds to G protein coupled receptor CCR2

43
Q

What happens if MCP-1 or CCR2 aren’t present?

A

atherosclerosis is reduced (in mice)

44
Q

What is the wound healing role of macrophages?

A

release growth factors that recruit VSMC and stimulate them to proliferate and deposit matrix

45
Q

What is the impact of platelet derived growth factor (PDGF)?

A

Chemotaxis, survival and mitosis of VSMCs

46
Q

What is the impact of transforming growth factor beta (TGF-b)?

A
  • increased collagen synthesis
  • matrix deposition
47
Q

What are the main 2 types of growth factors released?

A
  • platelet derived growth factor
  • transforming growth factor beta
48
Q

What happens in atherosclerotic vascular smooth muscle cells?

A
  • reduced contractile filaments
  • increased matrix deposition genes
49
Q

Which proteinases are expressed by macrophages?

A

metalloproteinases (MMPs)

50
Q

What are Metalloproteinases?

A
  • family of 28 homologous enzymes
  • zinc based enzymes
51
Q

What do Metalloproteinases do?

A
  • activate eachother via proteolysis
  • degrade collagen
  • catalytic mechanism based on zinc
52
Q

What happens when MMPs breakdown collagen?

A
  • plaque erosion/rupture
    (no longer trapped in smooth muscle)
  • blood coagulation may cause an occlusive thrombus
53
Q

What are the characteristics of vulnerable and stable plaques?

A
  • lipid-rich necrotic core
  • increased VSMC apoptosis
  • reduced VSMC and collagen content
  • thin fibrous cap
  • infiltrate of activated macrophages expressing MMPs
54
Q

What happens in macrophage apoptosis?

A
  • Ox LDLs are toxic
  • Macrophage foam cells have protective systems that maintain survival when toxic lipid loading
  • when overwhelmed, apoptosis
  • then release tissue factors and toxic lipids forming a lipid necrotic core
  • thrombogenic and toxic material accumulates until plaque rupture
55
Q

What is Nuclear Factor kappa B (NFkB)?

A

transcription factor that regulates inflammation

56
Q

What activates NFkB?

A
  • scavenger receptors
  • toll-like receptors
  • cytokine receptors (IL-1)
57
Q

What does NFkB activate?

A
  • matrix metalloproteinases
  • inducible nitric oxide synthase
  • IL-1
58
Q

What happens in atherosclerotic inflammation?

A
  • LDLs are converted into OxLDLs that activate macrophages
  • activated macrophages damage artery walls
  • all regulated by NFkB
59
Q

What are statins?

A
  • HMG-CoA reductase inhibitors
  • lower plasma cholesterol
60
Q

What is PCSK9?

A

an enzyme which degrades LDLRs

61
Q

How are PCSK9 inhibitors used?

A
  • to supplement statins
  • in severe or statin-resistant hyperlipidaemia
62
Q

What are ABCA1 ABCG1 Cholesterol export pumps?

A
  • transport pumps for reverse cholesterol transport
  • export cholesterol to HDL when ApoA is found on HDL
  • removes cholesterol from arteries and initiates return to the liver
63
Q

What are the macrophage functions in atherosclerosis?

A
  • Secrete inflammatory cytokines and chemokines
  • Reverse cholesterol transport
  • Secrete oxidants that damage cells and LDL
  • Accumulate cholesterol and become activated by cholesterol overload
  • secrete matrix metalloproteinases which degrade fibrous cap collagen
  • inititate death of vascular smooth muscle cells
64
Q

What are the signs and symptoms of atherosclerosis?

A
  • death of downstream tissue (heart and brain)
  • one-sided loss of function (major ischaemic stroke)
  • severe central crushing chest pain with fear, dizziness and nausea (MI)
  • angina
  • plaque rupture
65
Q

What can a plaque rupture lead to?

A

stroke or myocardial infarction

BRS YR2 (67 decks)

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