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1B Cardiorespiratory > Atherosclerosis & Peripheral Vascular disorder > Flashcards

Atherosclerosis & Peripheral Vascular disorder Flashcards

1
Q

how is the burden of IHD and CVD changing worldwide?

A

increasing

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2
Q

what are the modifiable risk factors for atherosclerosis?

A
  • Smoking
  • Lipids intake
  • Blood pressure
  • Diabetes
  • Obesity
  • Sedentary lifestyle
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3
Q

what are the non-modifiable risk factors for atherosclerosis?

A

age

sex

genetic background

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4
Q

how do different risk factors contribute to atherosclerosis risk?

A

combined risk factors in individual causes risk factor multiplication (synergistic)

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5
Q

what changes have happened in epidemiology that alter the risk of atherosclerosis?

A
  • Reduced hyperlipidaemia (statin treatment)
  • Reduced hypertension (antihypertensive treatment)
  • Increased obesity à increased diabetes
  • New improvements in diabetes treatment have doubtful effect on macrovascular disease
  • Changing pathology of coronary thrombosis possibly related to altered risk factors
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6
Q

where does atherosclerosis occur?

A

in one cell thick narrow intima within thick smooth wall

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7
Q

where does LDL deposition occur?

A

in subintimal space and bind to matrix proteoglycans

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8
Q

what are the types of initial lesions due to atherosclerosis progression and what are their features?

A
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9
Q

what is the window of opportunity for primary prevention from lesions?

A
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10
Q

what is the role of vascular endothelial cells?

A

barrier function (e.g to lipoproteins)

leukocyte recruitment

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11
Q

what is the role of monocyte-macrophages?

A

foam cell formation

cytokine and growth factor release

major source of free radicals

metalloproteineinases

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12
Q

what is the role of vascular smooth muscle cells?

A

migration and proliferation

collagen synthesis

remodelling and fibrous cap formaiton

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13
Q

what is the role of platelets?

A

thrombus generation

cytokine and growth factor release

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14
Q

what is the role of T lymphocytes

A

macrophage activation

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15
Q

what is the role of inflammation in atherosclerosis?

A

atherosclerosis has an inflammatory basis

patients at high risk atherosclerosis complications are injected with antibodies to IL-1 (have fewer major adverse CV events)

mechanisms include cholesterol crystal formation

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16
Q

what are the main inflammatory cells in atherosclerosis?

A

macrophages (derived from blood monocytes)

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17
Q

what are the classes of macrophages?

A

inflammatory

resident

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18
Q

what are inflammtory macrophages?

A

adapted to kill microorganisms (germs) at expense of some host damage

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19
Q

what are resident macrophages?

A

normally homeostasis- suppress inflammatory activity

alveolar resident macrophages- surfactant lipid homeostasis

osteoclasts- calcium and phosphate homeostasis

spleen- iron homeostasis

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20
Q

what are the types of lipoproteins?

A

LDL

HDL

oxidised LDLs, modified LDLs

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21
Q

where is LDL synthesised?

A

in liver

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22
Q

what is LDL?

A

low density lipoprotein

bad cholesterol

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23
Q

what does LDL do?

A

carries cholesterol from liver to rest of body including arteries

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24
Q

what is the composition of LDL?

A
25
Q

what is the risk from LDL?

A

high LDL= increased risk CVD and atherosclerosis

26
Q

do we need LDL?

A

yes- need some to survive

27
Q

what is HDL?

A

high density lipoprotein

good cholesterol

28
Q

what is the role of HDL?

A

carries cholesterol from peripheral tissues including arteries back to liver

(= reverse cholesterol transport)

29
Q

how are oxidised LDLs/ modified LDLs created?

A

due to the action of free radicals on LDL

not one single substance

30
Q

where are oxidised LDLs/modified LDLs found?

A

families of highly inflammatory and toxic forms of LDL found in vessel walls

31
Q

how are modified LDLs created?

A
  • LDLs leak through endothelial barrier
  • LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in sub-endothelial layer and becomes susceptible to modification
  • Best studies modification= oxidation
  • LDL becomes oxidatively modified by free radicals
  • Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation!
32
Q

what is familial hyperlipidaemia?

A

autosomal genetic disease

characteries by massively elevated cholesteral- failure to clear LDLS from blood

xanthomas and early atherosclerosis

33
Q

what happens if Familial hyperlipidaemia is untreated?

A

fatal myocardial infarction before age 20

34
Q

what can be used to lower plasma cholesterol?

A

HMG-CoA reductase inhibitors= statins

35
Q

what are the types of LDL receptors?

A

LDL receptor

scavenger receptor

36
Q

what is the scavenger receptor

A

LDL receptor

not under feedback control

pathogen receptors that bind OxLDL

37
Q

what are the types of macrophage scavenger receptors?

A

macrophage scavenger receptor A

macrophage scavenger receptor B

38
Q

what does macrophage scavenger receptor A do?

A

known as CD204

binds oxidised LDLs

binds to gram-positive bacterial like staphylococci & streptococci

binds to dead cells

39
Q

what does macrophage scavenger receptor B do?

A

known as CD36

binds to oxidised LDL

binds to malaria parasites

binds to dead cells

40
Q

what is the role of macrophages within plaques?

A

generate free radicals that further oxides lipoproteins

phagocytose modified lipoproteins and become foam cells

express cytokine mediators that recruit monocytes

express chemo-attractant and growth factors for VSMC

express proteinases that degrade tissue

41
Q

how do macrophages generate free radicals?

A

have oxidative enzymes that can modify native LDL

NADPH oxidase- e.g superoxide O2-

myeloperoxidase- HOCL hypochlorous acid from ROS + Cl-, HONOO peroxynitrite

42
Q

how do macrophages become foam cells?

A

accumulate modified LDLs to become enlarged foam cells

43
Q

what is a cytokine?

A

protein immune hormones that activate endothelial cell adhesion molecules

44
Q

what are some examples of cytokines involved in atherosclerosis?

A

Interleukin-1 = upregulates vascular cell adhesion molecule 1 VCAM-1

VCAM-1= mediates tight monocyte binding

atherosclerosis is reduced in mice without IL-1 or VCAM-1

45
Q

what are chemokines?

A

small proteins chemoattractant to monocytes

46
Q

what are some chemokines important in atherosclerosis?

A

monocyte chemotactic protein1- (MCP-1)

MCP-1 binds to a monocyte G-protein coupled receptor CCR2

atherosclerosis is reduced in MCP-1 or CCR-2 deficient mice

47
Q

what is the role of platelet-derived growth factor?

A

VSMC chemotaxis

VSMC survival

VSMC division (Mitosis)

48
Q

what is the role of transforming GF beta?

A

increases collagen synthesis

matrix deposition

49
Q

what is the role of macrophages in expressing chemo-attractants and GF for VSMC?

A

“Wound healing” role of the macrophage in atherosclerosis -

Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix

PDGF and TGF-b causes decreased contractile filaments and increased matrix deposition geners= atherosclerosis

50
Q

what proteinases do macrophages express that degrade tissue?

A

MMPs

51
Q

what are MMPs?

A

matrix metalloproteinases

family of 28 homologous enzymes

activate each other by proteolysis

degrade collagen

catalytic mechanism based on Zn

52
Q

what are the characteristics of vulnerable plaques

A

TCFA- thin cap fibrous atheroma

  • Large soft eccentric lipid rich necrotic core
  • Increased VSMC apoptosis
  • Reduced VSMC & collagen content
  • Thin fibrous caps
  • Infiltrate of activated macrophages expressing MMPs
53
Q

how does macrophage apoptosis occur in atherosclerosis?

A
  1. OxLDL derived metabolites are toxic eg 7-keto-cholesterol
  2. Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
  3. Once overwhelmed, macrophages die via apoptosis
54
Q

what happens on foam cell apoptosis?

A
  1. Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
  2. Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood
55
Q

what is nuclear factor kappa B (NFkB)?

A

transcription factor

master regulator of inflammation

switches on numerous inflammatory genes

56
Q

what is NFkB activated by?

A
  • Scavenger receptors
  • Toll-like receptors
  • Cytokine receptors e.g. IL-1
57
Q

what doe3s NFkB activate?

A

inflammatory genes

  • Matrix metalloproteinases
  • Inducible nitric oxide synthase
  • Interleukin-1
58
Q
A

1B Cardiorespiratory (15 decks)

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