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Amanda Flashcards

1
Q

What is atherosclerosis?

A

Thickening of the artery wall due to the accumulation of fatty material leading to the production of an atheromatous plaque.

“chronic inflammatory process”

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2
Q

What is the anatomical distribution of clinical atherosclerosis?

A

Right internal carotid artery.
Proximal left anterior descending coronary artery.
Proximal left renal artery.

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3
Q

What are the clinical outcomes associated with atherosclerosis?

A

Coronary artery disease -> IHD, MI and cardiac death.
Cerebrovascular atherosclerotic disease -> increased risk of stroke.
Peripheral artery disease.
Renovascular disease.
Abdominal aortic aneurysm (AAA).

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4
Q

What is atherosclerosis initiated by?

A

Endothelial cell dysfunction.

Elevated levels of cholesterol circulating in the body and LDLs are risk factors.

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5
Q

Which part of the arteries does atherosclerosis involve?

A

The tunica intima: the innermost layer of the artery composed of endothelial cells and in contact with blood.

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6
Q

Atherosclerosis produces focal lesions (plaques) composed of what?

A

Lipid material and fibrous tissue.

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7
Q

Which type of lipoproteins are associated with an increased incidence of atherosclerosis?

A

LDLs.

Transport cholesterol to cells,

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8
Q

What type of lipoproteins are associated with a decreased incidence of atherosclerosis and why?

A

HDLs: high density as high protein %. Carry cholesterol away from tissues to the liver.

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9
Q

How are monocytes attracted to and encouraged to adhere to the endothelium?

A

LDL accumulates beneath endothelial cells where modification of LDL can occur. Oxidation of LDL attracts monocytes which adhere and then enter the subendothelial space.

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10
Q

What happens once monocytes have accumulated in the subendothelial space?

A

They will differentiate into macrophages (M-CSF) and are able to take up oxidised LDL particles forming foam cells.
The first atherosclerotic lesions then form: fatty streak.

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11
Q

What often occurs following foam cell formation in the subendothelial space?

A

Smooth muscle cells can migrate into the intima, secrete collagen and form the fibrous cap.

Immune cells also continue to accumulate and foam cells begin to release cholesterol from the lipid core.

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12
Q

How do vulnerable and stable plaques differ?

A

Vulnerable have a lipid rich/foam cell rich peripheral boundary and thinner fibrous cap.

Stable plaques have a smaller necrotic lipid core.

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13
Q

How is the fibrous cap formed in atherosclerosis?

A

Smooth muscle cells migrate into the intima tunica of the artery and secrete collagen to form the cap.

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14
Q

What is one of the earliest signs of endothelial cell dysfunction?

A

The decreased production or activity of nitrogen oxide (NO) is one of the earliest signs of endothelial cell dysfunction.

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15
Q

Upregulation of endothelial adhesion receptors such as [BLANK] are associated with the initiation of endothelial cell dysfunction.

A

VCAM-1.

Modified lipids alter the expression of receptors such as this and promote intimal immune cell infiltration.

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16
Q

Myeloperoxidases and lipooxygenases are involved in what?

A

The oxidative modification of LDL particles.

These enzymes are secreted by inflammatory cells.

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17
Q

What is diapedesis?

A

This is the attachment and migration of monocytes through the endothelial layer.

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18
Q

What happens upon ingestion of LDL particles by macrophages?

A

Turn into foam cells. They begin to produce pro-inflammatory mediators, reactive oxygen species, and tissue factor (TF) pro-coagulants that amplify local inflammation and promote thrombotic complications.

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19
Q

What role do scavenger receptors play in atherosclerosis?

A

CD36 and SR-A are highly expressed in atherosclerotic lesions. They can bind and internalise oxidised LDL helping in the formation of foam cells.

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20
Q

How is LDL cholesterol stored in macrophages/foam cells?

A

Converted into cholesterol ester and stored as lipid droplets. Free cholesterol is transported out of the cell via ABCA1 transporters.

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21
Q

What role do ABCA1 receptors play in the pathogenesis of atherosclerosis?

A

ABCA1 receptors present in foam cells/macrophages transport free cholesterol out of the cell.

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22
Q

How does the necrotic core form?

A

There is a gradual accumulation of apoptotic cells, debris and cholesterol crystals.

‘modified lipids (oxidised LDL) that form a core region surrounded by a cap of smooth muscle cells and a collagen-rich matrix.’

The border regions of the NC are heavily infiltrated by T cells/ mast cells which release pro.inflam mediators and enzymes.

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23
Q

What cytokines would be expected to be secreted by monocytes and macrophages present in an atherosclerotic lesion? What does this cause?

A

Tumour necrosis factor-alpha (TNFa) and interleukin - 1Beta (IL1B).

Cause the generation of reactive oxygen species and the release of proteases such as metalloproteinases.

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24
Q

What serum parameters can be indicative of atherosclerosis?

A

CRP: acute phase reactant produced by liver in response to pro-inflamm cytokines (IL-6).

Elevated levels of homocysteine. This amino acid increases monocyte/T cell adhesion to endothelial cells.

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25
Q

Elevated levels of which amino acid are associated with atherosclerosis?

A

Homocysteine.

Causes increased monocyte/T cell adhesion to endothelial cells.

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26
Q

Why do mutations associated with cystathione-beta-synthase causes increased rates of thrombotic events?

A

CBS mutations can result in increased levels of homocysteine in the body and thus increased monocyte/T cell adhesion to endothelial cells.

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27
Q

What role do MMPs play in atherosclerosis?

A

Metal Metalloproteinases are zinc-dependent endopeptidases. They degrade components of the extracellular matrix and basement membrane.

(collagenases, gelatinases and stromeolysins)

They are secreted by macrophages and cause accumulation/breakdown of collagen etc.

Can cause thrombis.

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28
Q

How can thrombosis formation occur?

A

The underlying ECM can become exposed, including collagen fibres. This can trigger platelet aggregation and result in thrombosis.

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29
Q

What is plaque rupture?

A

This is when a structural defect present in the fibrous cap that separates the necrotic lipid core of an atherosclerotic plaque from lumen ruptures. This then exposes the necrotic core to the blood via the gap in the cap.

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30
Q

What markers identify a ‘vulnerable’ plaque?

A

A large lipid core, >50% of the overall plaque volume.
High density of macrophages and low density of smooth muscles cells in the cap.
A high tissue factor content.
A thin fibrous cap in which the collagen structure is disorganised.

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31
Q

What is the clinical outcome of an atherosclerosis induced thrombosis?

A

Death.
Plaque rupture = 80% of fatal myocardial infarctions in men.
Plaque erosion = ~50% of myocardial infarction in young women.

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32
Q

What are the modifiable risk factors for atherosclerosis?

A 
Raised LDL and lowered HDL. 
Increased Homocysteine. 
Obesity. 
Diabetes. 
Physical inactivity. 
Hypertension
Smoking.
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33
Q

What is diabetes insipidus?

A

Excretion of large amounts of dilute urine due to a failure of the kidneys to release or sense a hormone that regulates plasma osmolarity. [Anti-diuretic hormone; ADH]

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34
Q

What is the difference between type 1 and type 2 diabetes?

A

T1DM: circulating insulin is absent.
T2DM: circulating insulin is normal but cellular sensitivity is reduced. (90% of cases)

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35
Q

How do most diabetic complications arise?

A

Due to damage to blood vessels.
Can lead to accelerated atherosclerosis particularly:
- retinal, kidney and nervous system.
- microvascular

36
Q

How can a lack of circulating insulin lead to endothelial dysfunction?

A

Insulin causes Akt kinase to phosphorylate eNOS.

Unphosphorylated eNOS can cause endothelial dysfunction:

  • decreased blood flow
  • thrombosis
  • inflammation
  • neointima formation
37
Q

What is dyslipidemia?

A

Refers to abnormal levels of low density lipoproteins (raised) and high density lipoproteins (lowered) and the associated malfunctions of cholesterol delivery though the body.

38
Q

What are chylomicrons?

A

These are the form that cholesterol and triglycerides take as they are transported from the GIT in the lymph and capillaires.

39
Q

What occurs to chylomicrons when they are transported to the liver?

A

They bind the LDL receptor and endocytosed whereupon cholesterol is liberated, stored, oxidised to bile acids, secreted in the bile unaltered and enters the endogenous pathway.

40
Q

How do levels of HDL and LDL relate to atherosclerosis risk?

A

The higher the concentration of the LDL-cholesterol and the lower the concentration of the HDL-cholesterol then the greater the risk of atherosclerosis.

41
Q

What is lipoprotein (a)?

A

LDL-like molecule which inhibits plasminogen and is a risk factor of CVD. Prothrombotic.

42
Q

What type of obesity is particularly associated with increased atherosclerosis risk?

A

Abdominal. (Apple shaped people)

43
Q

How many genes are thought to influence predisposition to atherosclerosis?

A

Over 400. A complex multifactorial disease.

44
Q

What is Tangier disease?

A

Genetic disease of cholesterol transport.
ABCA1 gene mutation on chromosome 9q31.
Reduced ability of mutant ABCA1 transporter to transport cholesterol out of cells.

Cholesterol combines with Apolipoprotein A1 (apoA1) to form HDL, reduced levels of circulating HDL are found in Tangier’s disease.

45
Q

What are the symptoms of Tangier disease?

A

Disturbance in nerve function, enlarged orange-coloured tonsils; development of atherosclerosis; enlarged spleen, enlarged liver, clouding of the corneal.

46
Q

Why does cholesterol accumulate in cells of people with Tangiers disease?

A

Tangiers disease: mutations in the ABCA1 transporter cause reduced cholesterol efflux.

47
Q

What is familial hypercholesterolemia?

A

Cholesterol becomes deposited in various tissues, elevated plasma LDL. Nodules of cholesterol ‘xanthoma’ in skin and tendons.

48
Q

What is familial hypercholesterolemia caused by?

A

Loss of function in the LDL receptor causing decreased LDL uptake by the liver.

49
Q

How is familial hypercholesterolemia treated?

A

Lipid lowering therapies: statins.

LDL-lowering apheresis (beads which selectively bind to apoB100 in LDL)

Liver transplants.

50
Q

What causes severe hypercholesterolemia/hypocholesterolemia?

A

Mutations found in PCSK9 (proprotein convertase subtilisin/kexin type 9).

PCSK9 is a serine protease mainly expressed in the liver and the intestine.

It controls LDL receptor protein levels.

51
Q

PCSK9 mutations that increase function result in:

A

Less LDL receptor and thus hypercholesterolemia.

52
Q

PCSK9 mutations that decrease function result in:

A

More LDL receptor and this hypocholesterolemia.

53
Q

What is Evolocumab?

A

Fully human monoclonal antibody against PCSK9 to inhibit it’s activity in instances when mutations cause overexpression.

54
Q

What is Ezetimibe?

A

A cholesterol absorption inhibitor that targets absorption at the jejunal enterocyte brush border.

Targets Nieman Pick C1 like 1 protein.

55
Q

How does Ezetimibe function to inhibit cholesterol absorption?

A

Targets the cholesterol transport protein Nieman Pick C1.

56
Q

What is Alirocumab?

A

Monoclonal antibody against PCSK9.

57
Q

What type of therapy is clopidogrel?

A

Anti-thrombotic

58
Q

What type of therapy is Glybera?

A

Genetic therapy.

59
Q

What type of therapies target PCSK9?

A

Antibody based biologics.

60
Q

How do statins work?

A

Inhibitors of HMG-CoA reductase. This enzyme plays a key role in production of cholesterol.

61
Q

Why do statins improve endothelial function?

A

Lower cholesterol due to less production and increased uptake of circulating LDL.
Also statins lead to reduced protein prenylation.

62
Q

The reduced prenylation of proteins caused by statins leads to what:

A

Reduced expression of cell adhesion molecules by endothelial immune cells:

  • reduced adhesion and transendothelial migration.
  • inhibition of chemokine and MMP secretion
  • Reduced leukocyte migration
63
Q

What are fibrates?

A

Amphipathic carboxylic acids.
Activate PPAR (peroxisome proliferator-activated receptors), especially PPAR alpha.
Induces the transcription of genes that cause increased lipid metabolism.

64
Q

How do fibrates work?

A 
Activate PPAR (peroxisome proliferator-activated receptors), especially PPAR alpha. 
Induces the transcription of genes that cause increased lipid metabolism.
65
Q

What specifically are the actions of fibrates?

A

Increased expression of lipoprotein lipase, apoA1, apoA5.
Decreased VLDL secretion. Increased hepatic LDL uptake..
Reduction in CRP and fibrinogen.
Improved glucose tolerance and inhibition of vascular smooth muscle inflammation.

66
Q

How do bile acid resins work?

A

Sequester bile acids and decrease the reabsorption of bile acids. As bile acids are synthesised from cholesterol this leads to increased use of cholesterol.
Increased production of bile acids leads to an increased expression of LDL receptors and increased clearance of LDL-cholesterol from the circulation.

67
Q

What type of agents are cholestyramine, colestipol and colesevalam?

A

Bile acid binding agents.

Cause diarrhea, unpalatable, can bind other lipid soluble factors such as vitamins and some drugs (warfarin, thyroxine)

68
Q

What type of agent is aspirin?

A

Anti-thrombotic. Irrerversible COX inhibitor.
Decreases thomboxane (Tx)A2 production. (pro-platelet)
Increases PGI2 production. (antithrombotic)

69
Q

What is the mechanism of action of clopidgrel?

A

Inhibits ADP induced platelet aggregation by blocking P2Y12 receptors.
Additive effect with aspirin.

70
Q

What role do P2Y12 receptors play in atherosclerosis?

A

Activation of P2Y12 receptorcs leads to fibrinogen receptor activation and increased occurrence of thrombotic events. Clopidgrel inhibits this.

71
Q

What is clopidgrel?

A

Prodrug activated by P450 isoforms. Orally active. Inhibits ADP induced platelet aggregation by blocking P2Y12 receptors. Additive actions with aspirin.

72
Q

What are the difference between viral and liposome vectors for gene delivery?

A

Liposomes: short term gene expression, potentially cytotoxic, range of expression efficiencies.
Viral: moderate to long term gene expression, potentially cytotoxic, high levels of gene expression. Some trigger a host immune response.

73
Q

What is glybera?

A

Gene therapy to restore LPL enzyme activity.
Corrects expression of defective Lipoprotein Lipase.
Used to treat familial LPL deficiency.
Delivered via adeno-viral means.

74
Q

What is familial LPL deficiency?

A

Very severe hypertriglyceridemia. Expression of Lipoprotein Lipase is defective. The clearance of chylomicrons from the plasma is impaired and triglycerides accumulate in plasma, making it milky in appearance.

75
Q

How is glybera delivered?

A

Adenovirus

76
Q

What does glybera treat?

A

Familial LPL deficiency, defective expression of lipoprotein lipase causes accumulation of triglycerides in plasma.

77
Q

How is familial LPL deficiency treated?

A

Glybera:
Gene therapy to restore LPL enzyme activity.
Corrects expression of defective Lipoprotein Lipase.
Used to treat familial LPL deficiency.
Delivered via adeno-viral means.

78
Q

Fibrates increase the expression of what? [3]

A

They activate PPAR so increase transcription and expression of:

  1. Lipoprotein Lipase
  2. ApoA1
  3. ApoA5
79
Q

What are the beneficial effects of fibrates? [5]

A
  1. Increased expression of lipoprotein lipase, apoa1, apoa5 via activation of PPAR.
  2. Decreased VLDL secretion and increased hepatic uptake of LDL.
  3. Reduced levels of CRP + Fibrinogen.
  4. Improved glucose tolerance.
  5. Inhibition of vascular smooth muscle inflammation.
80
Q

What scavenger receptors are highly expressed in athersclerotic lesions? [2]

A

CD36 + SR-A bind to and internalise LDL, helping in the formation of foam cells.

81
Q

What do foam cells produce?

A
  1. Pro-inflammatory mediators.
  2. Reactive oxygen species.
  3. Tissue Factor pro-coagulants.
82
Q

What are MMPs secreted by and what do they cause?

A

Macrophages. Cause breakdown of collagen, thrombosis. Exposure of basement membrane. Zinc-dependent enzymes.

83
Q

What can cause unphosphorylated eNOS to accumulate and how does this cause endothelial cell dysfunction?

A

Low levels of insulin as insulin normally causes Akt kinase to phosphorylate eNOS.
Causes endothelial cell dysfunction because of:
-decreased blood flow, neointima formation, inflammation, thrombosis.

84
Q

What effect do fibrates have on CRP + fibrinogen levels?

A

They lower them.

85
Q

What effect do fibrates have on glucose tolerance?

A

They improve glucose tolerance and inhibit vascular smooth muscle inflammation.

86
Q

Homocysteine is formed by

A

S-adenosylhomocysteine hydrolase

III (24 decks)

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