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Atherosclerosis & treatment of CVD Flashcards

1
Q

Risk factors for atherosclerosis

A
  1. smoking
  2. diabetes
  3. genetic (LDL receptors)
  4. endocrine (sex)
  5. hypertension
  6. hyperlipidaemia (raised LDL as opposed to HDL)
  7. oxidised LDL
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2
Q

What is LDL?

A

Sphere of phospholipids containing high concentrations of cholesterol and apo-B

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3
Q

What is the function LDL?

A

Transport of water-soluble cholesterol in the blood

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4
Q

What does PCSK9 do?

A

binding LDL receptors and promoting their intracellular degradation - could be targetted by anti-LDL antibodies

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5
Q

How may LDL cause atherosclerosis (mechanism is unknown)?

A

thought LDL particles infiltrate the intima where they undergo modification that make the immunogenic, as well as proinflammatory

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6
Q

How is HDL a risk factor? Discuss

A
  • low levels are a risk factor

- HDL is involved in transport from peripheral tissues back to the liver where it is excreted

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7
Q

How may changes to the endothelial layer lead to atherosclerosis?

A
  • plaques tend to form at points of flow disturbance and endothelial sheer stress is partially responsible for the induction of an atherogenic endothelial phenotype
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8
Q

Possible clinical manifestations of atherosclerosis

A
  • angina
  • MI
  • claudication (pain caused by too little blood flow to the legs and arms)
  • embolism
  • aneurysm
  • ischaemic stroke
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9
Q

Is atherosclerosis more common in makes or females?

A

Males

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10
Q

What stages can the pathogenesis of atherosclerosis be considered in?

A
  1. LDL oxidation (due to endothelial injury or dysfunction)
  2. monocyte/ macrophage recruitment
  3. foam cell recruitment
  4. lesion progression
  5. plaque stability
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11
Q

What do atherosclerotic lesions begin as and what is the major cellular event contributing to the formation of these structures?

A
  • They begin as fatty streaks underlying the endothelium of large arteries
  • uptake of LDL-derived cholesterol by macrophages
  • can be argued that oxidation of LDL is the main cellular event
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12
Q

Which vessels do plaques form in?

A

Absent from veins and the microvasculature

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13
Q

Why ox-LDL taken up by macrophages in particular?

A

It can no longer be recognised by LDL receptors on cells but is instead recognised by scavenger receptors found on surface of macrophages and SMCs

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14
Q

Discuss how endothelial dysfunction leads to monocyte recruitment

A
  • loss of protective effects of NO in particular
  • starts expressing a range of adhesion molecules which capture circulating monocytes
  • e.g. VCAM-1
  • E and P selectin
  • ICAM-1
  • oxLDL can also directly attract monocytes via the expression of monocyte chemotactic molecules
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15
Q

Describe platelet recruitment to endothelium

A

Endothelial erosion exposes collagen-rich prothombotic sub-endothelium, to which platelets adhere and form microthrombi

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16
Q

Aside from monocyte and platelet recruitment, what may endothelial injury cause?

A
  • generation of proatherogenic ET-1

- generation of superoxide (oxidising free radical)

17
Q

Describe the inflammation that occurs after endothelial injury

A
  • monocytes → macrophages → generate pro-oxidant species
  • platelets degranulate → release of pro-inflammatory mediators
  • SMCs begin to proliferate and for the ‘neointima’ in response to GFs and absence to anti-mitogenic NO
  • SMCs of neointima → become non-contractile and secrete ECM to stabilise developing plaque
18
Q

When do foam cells form?

A
  • caused by uptake of cholesterol by macrophages
19
Q

What is the transition from a fatty streak to a complex lesion characterised by?

A
  • Immigration of SMCs from the medial layer past the internal elastic lamina and into the sub-endothelial space
  • Intimal SMCs proliferation and take up modified lipoproteins, contributing to foam cell formation and synthesize ECM that leads to the development of the fibrous cap
20
Q

What forms the necrotic core of the apoptotic lesions?

A

SMCs and macrophages which have formed foam cells begin to apoptose and necrose

21
Q

What may happen in the plaque is unstable?

A
  • it may rupture

- can cause an ischaemic event

22
Q

What do statins do?

A

lower cholesterol by inhibiting HMG-CoA reductase and increase hepatic LDL-receptor expression
- leads to decreased plasma LDL-C and increased plasma triglycerides (and HDL)

23
Q

Aside from lowering LDL, what else may statins do?

A
  • restoration of healthy endothelium
  • anti-platelet effects
  • plaque stabilisation
24
Q

How to prevent CVD through lifestyle choices?

A
  • smoking
  • obesity
  • physical activity
  • blood pressure
  • diet
25
Q

List some anti-thombotic and thrombolytic drugs drugs

A
  • aspirin
  • GpIIb and IIIa inhibitors
  • strepokinase
  • tPA
26
Q

List some anti-coagulant drugs

A
  • heparin

- warfarin

27
Q

List some lipid lowering drugs

A

Statins

28
Q

Give examples of statins

A

simvastatin

29
Q

Describe surgical intervention in treatment of CVD

A
  • balloon angioplasty
  • stenting
  • coronary bypass
30
Q

What is coronary bypass?

A
  • surgery that redirects blood around a section of a block or partially blocked artery in your heart to improve blood flow to the heart muscle
31
Q

Mechanism of action of aspirin

A
  • inhibits COX which is required for prostagandin and thromboxane synthesis
  • prostaglandins are pro-inflammatory
  • thomboxanes promote clotting (inhibit platelet aggregation)
32
Q

Mechanism of action of GpIIb and IIIa inhibitors

A

Prevent platelet aggregation and thrombus formation by inhibiting the GpIIb/IIIa receptor on the surface of platelets
- this prevents binding of fibrinogen which blocks aggregation
(GpIIb/IIIa receptors are on the surface of platelets and bind fibrinogen)

33
Q

Mechanism of action of streptokinase

A
  • fibrinolytic
  • binds with free circulating plasminogen (or plasmin) to form a complex that can convert additional plasminogen to plasmin
  • plasmin breaks down fibrin clots created by the blood clotting cascade
34
Q

Mechanism of action of tPA

A
  • tissue plasminogen activator
    1. binds fibrin on the surface of the clot
    2. activates fibrin-bound plasminogen
    3. plasmin is cleaved from the plasminogen associated with the fibrin
    4. fibrin molecules are broken apart by the plasmin and the clot dissolves
35
Q

Example of tPA

A

Alteplase

36
Q

Mechanism of action of heparin

A

Binds to enzyme inhibitor antithrombin III → activates it

ATIII inactivated thrombin (IIa)and factor Xa

37
Q

Mechanism of action of warfarin

A
  • acts to inhibit the vitamin K post-translational modification of clotting factors II, VII and IX and X
  • inhibits vitamin K reductase
38
Q

How may action of warfarin be reversed?

A
  • oral vitamin K supplementation
39
Q

How may the action of heparin be reversed?

A
  • protamine sulphate

- binds to heparin to form a stable ion pair with no anticoagulant activity

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