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CARDIO & RESPIRATORY phase 1b > 1b Atherosclerosis > Flashcards

1b Atherosclerosis Flashcards

1
Q

What are the modifiable risk factors of coronary heart disease?

A

Smoking, Lipids intake, blood pressure, diabetes, obesity and sedentary lifestyle

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2
Q

What are the non-modifiable risk factors for atherosclerosis?

A

Age
Sex
genetic background

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3
Q

What are the three risk factors which contribute to the risk factor multiplication?

A

Hypertension
High Cholesterol
Smoking

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4
Q

Why has hyperlipidaemia reduced over the last decade?

A

Statin treatment

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5
Q

How has hypertension changed over the last few decades?

A

Lowered due to anti-hypertensive treatment

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6
Q

What are the function of vascular endothelial cells?

A

barrier function eg to lipoproteins
involved in leukocyte recruitment

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7
Q

What is the role of platelets in atherosclerosis?

A

Thrombus generation
Cytokine and growth factor release

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8
Q

What are monocyte-macrophages involved in?

A

Foam cell formation, and the release of cytokines and growth factors
source of free radicals
metalloproteinases

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9
Q

What are the roles of vascular smooth muscle cells?

A

Migration and proliferation
Collagen Synthesis
Remodelling and fibrous cap formation

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10
Q

Which T lymphocytes are involves in macrophage activation?

A

CD4 Th1

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11
Q

Which T lymphocytes are involved in macrophage de-activation?

A

CD4 Treg

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12
Q

Which T lymphocytes are involved in VSMC death?

A

CD8 CTL

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13
Q

Which T lymphocytes are involved in B-cell/antibody help?

A

CD4 Th2

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14
Q

What is the main basis of atherosclerosis?

A

Inflammation

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15
Q

What is the connection between lipids and inflammation in atherosclerosis?

A

Cholesterol crystal formation connects lipids and inflammation in atherosclerosis

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16
Q

What happens if white blood cells are activated excessively?

A

White blood cells can damage host tissue if they are activated

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17
Q

What are the main inflammatory cells in atherosclerosis?

A

Macrophages - derived from blood monocytes

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18
Q

What regulates macrophages?

A

Combination of transcription factors binding to regulatory sequences on DNA

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19
Q

What are the two types of macrophages?

A

Inflammatory macrophages and non-inflammatory / resident
macrophages

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20
Q

What are inflammatory macrophages adapted to do?

A

Kill micro-organisms (germs)

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21
Q

What are the functions of non-inflammatory macrophages?

A

Normally homeostatic functions
Alveolar resident macrophages = involved in surfactant lipid homeostasis
Spleen = involved in iron homeostasis

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22
Q

What is LDL?

A

Low density lipoprotein - the “bad” cholesterol which is made in the liver

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23
Q

What is the function of LDL?

A

Carries cholesterol from the liver to the rest of the body including the arteries

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24
Q

What is HDL?

A

High density lipoprotein - carries. cholesterol from the peripheral tissues including arteries back to the liver = involved in reverse cholesterol transport

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25
Q

What causes modified or oxidised LDLs to form and what are they?

A

Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
Families of highly inflammatory and toxic forms of LDL found in vessel walls.

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26
Q

What is the surrounding layer of lipoproteins like?

A

Lipid monolayer which is one molecule thick - separates fat from water

Contains cargo fat for fuel

Docking molecule ‘molecular addresses for fat delivery’
Some also interact with clotting and clot lysis

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27
Q

What is carried in the center of an LDL?

A

triglycerides

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28
Q

Why do LDLs leak through the endothelial barrier?

A

Due to endothelial activation in areas of vortex

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29
Q

What traps the LDL in the sub-endothelial layer?

A

It binds to sticky matrix carbohydrates (proteoglycans) and sticks in the sub-endothelial layer - becomes susceptible to modification

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30
Q

What type of modification might a LDL undergo?

A

oxidation - through free radical attack from activated macrophages

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31
Q

What happens to the LDL once it has been oxidatively modified?

A

Phagocytosed by macrophages which stimulates chronic inflammation

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32
Q

What do the engulfed oxidised LDL’s become?

A

Foam cells = leads to chronic inflammation

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33
Q

What is seen in children with familial hyperlipidaemia?

A

Xanthoma - lesions containing cholesterol and fat

34
Q

What are the chemical features of patients with familial hyperlipidaemia?

A

Massively elevated cholesterol levels, resulting in xanthomas and early atherosclerosis - if untreated can lead to risk of myocardial infarction before the age of 20

35
Q

What is the problem in patients with familial hyperlipidaemia?

A

It is an autosomal genetic disease which leads to a failure to clear LDL from the blood

36
Q

How is cholesterol synthesis regulated?

A

Negatively By cellular cholesterol

37
Q

What is the general mechanism of action of statins?

A

HMG-CoA reductase inhibitors

38
Q

What happens to cholesterol in LDLR-negative patients?

A

Macrophages accumulate cholesterol

39
Q

What are the types of LDL receptors and how do they differ?

A

LDL Receptor = under negative feedback with intracellular cholesterol levels

Scavenger receptors = hoover up chemically modified LDL = accidently bind OxidisedLDL

40
Q

How does PCSK9 work?

A

LDL enters hepatocytes via LDLR
PCSK9 degrades LDLRs
PCSK9 inhibitors now used to supplement statins in severe or statin-resistant hyperlipidemia

41
Q

How does LDLR affect cholesterol synthesis?

A

Cholesterol synthesis is negatively regulated by cellular cholesterol

LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis

42
Q

What is the advantage of a PCSK9 defiency?

A

PCSK9-deficient humans are protected from cardiovascular disease

43
Q

Explain the ineteration between ABCA1 ABCG1 and ApoA and how the allow for reverse cholesterol transport?

A

ABCA1 ABCG1 are Cholesterol export pumps

Export selective to Apolipoprotein A as interactor (found on HDL)

Export to HDL is reverse cholesterol transport
Removes cholesterol from arteries and initiates return to the liver

44
Q

What is the explanation for LDLR-negative patients, where macrophages accumulate cholesterol?

A

There is a second LDL receptor (scavenger receptor) which is not under feedback control, in the atherosclerotic lesions

These receptors accidentally bind to OxLDL and so this leads to macrophages which are also in the atherosclerotic lesions to hoover up this modified LDL

45
Q

What are macrophage scavenger receptors A and B also known as?

A

Macrophage scavenger receptor A - CD204

Macrophage scavenger receptor B - CD36

46
Q

What binds to both the two macrophage scavenger receptors?

A

Oxidised LDL and dead cells

47
Q

What type of bacteria binds to macrophage scavenger receptor A?

A

gram positive bacteria = like staphlyococci and Streptococci

48
Q

What microorganism binds to macrophage scavenger receptor B?

A

Malaria parasites

49
Q

When arterial Ox-LDL is deposited, what is there a balance between when activating macrophages?

A

Inflammation (activation of bug-detector pathways) and Homeostasis (safe clearance and reverse cholesterol transport)

50
Q

What are the three oxidising enzymes that macrophages have that can modify native LDL?

A

NADPH Oxidase (superoxide O2)
Myeloperoxidase (hypochlorous acid from bleach)
Generation of H2O2

51
Q

How can myeloperoxidase release then result in damage to the artery walls?

A

If inflammatory cells are in our vessels and primed to secrete this enzyme each time we eat anything with cholesterol which is then taken by LDL and deposited into our vessels, then this triggers hypochlorite bleach release (HOCl) from ROS + Cl-

52
Q

What happens after macrophages generate free radicals to oxidise lipoproteins?

A

Phagocytose modified lipoproteins, & become foam cells

53
Q

What changes might be seen in the lumen when foam cells form?

A

cholesterol crystals, zone of sick and dying foam cells, fat globules and foam cell debris

54
Q

What is expressed by plaque macrophages which helps with monocyte recruitment?

A

inflammatory factors

55
Q

What are cytokines?

A

protein immune hormones that activate endothelial cell adhesion molecules

56
Q

What are chemokines?

A

Small protein chemoattract to monocytes

57
Q

What is the main cytokine in atherosclerosis?

A

Interleukin 1

58
Q

What does interleukin 1 do?

A

triggers eg intracellular cholesterol crystals and NFkB. Coordinates multiple processes including cell death and cell proliferation; and elevated CRP

59
Q

What is the main chemokine involved in atherosclerosis?

A

monocyte chemotactic protein-1

MCP-1

60
Q

What does MCP-1 bind to?

A

binds to a monocyte G-protein coupled receptor CCR2.

61
Q

Describe the wound healing role of macrophages?

A

Macrophages release growth factors that recruit VSMC and stimulate them to migrate, survive, proliferate and deposit extracellular matrix e.g. structurally strong collagen

62
Q

What does platelet derived growth factor do?

A

Vascular smooth muscle cell chemotaxis, survival and division

63
Q

What does TGF-beta do?

A

Increased collagen synthesis
Matrix deposition

64
Q

Describe the changes that occur in vascular smooth muscle cells to go from normal medial to atherosclerotic?

A

PDGF + TGF-b

decreased Contractile filaments
increased Matrix deposition genes

65
Q

What do macrophages do after expressing chemo-attractants and growth factors?

A

Express proteinases that degrade tissue

66
Q

What is the effect of plaque erosion/rupture?

A

Blood coagulation at the site of rupture - may lead to an occlusive thrombus and cessation of blood flow

67
Q

How do macrophages degrade collagen which leads to plaque ruptures?

A

Metalloproteinases -

68
Q

How do metalloproteins get activated?

A

Activate each other by proteolysis and degrade collagen

69
Q

What do metalloproteinases require to work?

A

Zinc

70
Q

Describe the process of macrophage apoptosis and what happens afterwards?

A

OxLDL derived metabolites are toxic eg 7-keto-cholesterol.

Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading

Once overwhelmed, macrophages die via apoptosis

Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core.

Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

71
Q

Macrophage functions in atherosclerosis pathophysiology

A

Secrete inflammatory cytokines and chemokines

Phagocytose, process and export cholesterol to reverse cholesterol transport (HDL)

Secrete oxidants that damage cells and LDL

Accumulate cholesterol and become sick and activated by cholesterol overload

Secrete matrix metalloproteinases which degrade fibrous cap collagen

Initiate death of vascular smooth muscle cells

72
Q

What are the characteristics of vulnerable and stable plaques?

A

Large, soft eccentric lipid rich necrotic core
Increased VSMC apoptosis
Reduced VSMC and Collagen content
Thin fibrous cap
Infiltrate of activated macrophage expressing MMP’s

73
Q

What is meant by a fibrous cap?

A

Layer of fibrous connective tissue which is thicker and less cellular than the normal intima, found in atherosclerotic plaques

Contains macrophages and smooth muscle cells

74
Q

A rupture of unstable plaque in what artery usually causes an anteroseptal myocardial infarction?

A

Left anterior descending coronary artery

75
Q

Describe what is seen on an ECG with a coronary artery thrombosis and myocardial infarction

A

ST-segment elevation anterior leads (T wave aversion seen later), also VE

76
Q

What is an example of an OxLDL derived metabolite?

A

7-keto-cholesterol

77
Q

What are the signs and symptoms of atherosclerosis?

A

Death of downstream tissue

Loss of function of one side of the body - major ischaemic stroke

Severe central crushing chest pain with fear, dizziness and nausea - MI

Angina

Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

78
Q

What is the master regulator of inflammation?

A

Nuclear Factor kappa B (NFkB)

79
Q

What are the three things which activate Nuclear Factor kappa B (NFkB) ?

A

Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1

80
Q

What genes does Nuclear Factor kappa B (NFkB) switch on?

A

Numerous inflammatory genes

Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1

81
Q

What regulates macrophage activation?

A

nuclear factor kappa B

CARDIO & RESPIRATORY phase 1b (14 decks)

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