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PATH30001 - Mechanisms of Disease > Lecture 2 - AMI & Atherosclerosis > Flashcards

Lecture 2 - AMI & Atherosclerosis Flashcards

1
Q

Why is AMI significant?

A

It is the leading cause of death in industrialised countries

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2
Q

What are the two main pathways that lead to sudden coronary death?

A
  1. Myocardial ischema

2. Plaque in coronary arteries

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3
Q

What is atherosclerosis?

A

• Fibrofatty plaques in intima of arteries
due to
• Chronic inflammatory healing response

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4
Q

What is the major underlying cause of AMI?

A

Atherosclerosis (95%)

Lifestyle dependent

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5
Q

How does age and gender affect chance of AMI?

A
  • Chance increases with age

* Men are affected for than women

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6
Q

Describe the time scale during an MI

A 
As time elapses,
very soon:
 • lactate increases
 • ATP decreases
over a matter of hours:
 • decrease in 'salvageable myocardium'
 • increase in dead myocardium
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7
Q

How long does it take for loss of contractility during an MI?

A

< 2 mins

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8
Q

Describe the pathogenesis of atherosclerosis

A
  1. Endothelial injury
  2. Accumulation of lipoproteins
  3. Monocyte adhesion to the endothelium
  4. Platelet adhesion
  5. Factor release from activated immune cells
  6. Smooth muscle cell proliferation and ECM production
  7. Lipid accumulation
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9
Q

Which lipoproteins accumulate in atherosclerosis?

A

Mainly LDL

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10
Q

What does the location of the MI depend on?

A

The coronary artery that is occluded

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11
Q

Compare transmural and non-transmural infarcts

A

Transmural: entire thickness of a portion of the wall is affected

Non-transmural: part of wall is affected

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12
Q

What changes can occur to the plaques in atherosclerosis?

A
  • rupture
  • erosion
  • ulceration
  • haemorrhage
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13
Q

Why do changes to the plaque occur?

A

The plaque is unstable and weak

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14
Q

What is an aneurysm?

A

Ballooning of a portion of an artery

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15
Q

What are the clinical complications of atherosclerosis?

A
  • Aneurysm and rupture
  • Occlusion by thrombus
  • Critical stenosis
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16
Q

In what case does critical stenosis occur?

A

Continual growth of plaque so that the artery is almost completely blocked

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17
Q

What are some risk factors for atherosclerosis?

A
  • Hyperlipidaemia
  • Hypertension
  • Smoking
  • Immune reactions
  • Toxins
  • Viruses
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18
Q

What is the normal role of monocytes?

A
  • Replenish macrophages and dendritic cells
  • When an immune response is activated, they are recruited in large numbers and differentiate into macrophages for an effective immune response
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19
Q

What is a foam cell?

When are where are they seen?

A
  • A fat laden macrophage

* Seen in atherosclerosis in the intima of vascular wall

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20
Q

What is the role of smooth muscle cells in atherosclerosis?

A
  • Recruited into the intima

* Proliferate

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21
Q

Which part of the myocardium is at risk in a given coronary artery occlusion?

A

The myocardium that derives its blood supply from the portion of coronary artery distal to the blockage

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22
Q

Which part of the wall layer undergoes necrosis first in a coronary artery occlusion?

A
  • The sub-endocardial zone (interal layers)

* The necrosis then extends outward

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23
Q

What does the size of the zone of necrosis depend on?

A
  • Duration of occlusion

* Presence of collateral circulation

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24
Q

What is subacute period of MI?

A

Days old

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25
Q

What is the role of apoptosis in MI?

A

Occurs rapidly post-ischemia

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26
Q

What happens in MI if there is no reperfusion?

A

Necrosis, which is complete after 6-12 hours

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27
Q

Compare ‘salvage’, ‘partial salvage’ and ‘complete infarct’

A

This depends on how much time passes before reperfusion

Salvage: no necrosis, slight dysfunction
Partial salvage: necrosis with haemorrhage & contraction bands
Complete infarct: necrosis

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28
Q

What happens to the infarct site over the next few days?

A
  • monocyte infiltration
  • phagocytosis of necrotic cells
  • repair; scar tissue formation
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29
Q

What are the necrotic cells replaced with after an MI?

A

Collagenous scar tissue

30
Q

What are the possible medical interventions to prevent MI?

A
  • Balloon angioplasty
  • Thrombolysis
  • Coronary artery bypass graft
31
Q

What are the markers of myocardial infarction?

A
  • Creatinine phosphokinase
  • Troponin

These are released by the now leaky membrane of the myocytes

32
Q

Which tests are done to detect MI?

A
  • Troponin assay (most specific)

* CK-MB assay

33
Q

Why does reperfusion injury occur?

A
  • The new blood flowing in is ischemic, as are the cells in the blood.
  • These cells are producing free radicals
  • Free radicals cause mitochondrial damage
  • Necrosis
34
Q

How can reperfusion injury be avoided?

A

With pharmaceuticals:
• Xanthine oxidase inhibitors
• Blood without polymorphs
• Activation of RISK pathway through ischemic post conditioning

35
Q

What is ‘preconditioning’?

A

Repeated, short-lived ischemia

• Provides protection from later ischemia

36
Q

What is mPTP?

A

Mitochondrial permeability transition pore
• Protein pore in the inner membrane of the mitochondria, which forms under pathological conditions
• Increase in permeability of the mitochondrial membrane

37
Q

What does the mPTP lead to?

A

Cell death (apoptosis or necrosis)

  1. mPTP
  2. Cytochrome c lost from mitochondria into cytosol
  3. Activation of caspases
  4. Activation of endonucleases & degradation of cytoskeleton
  5. Apoptosis
38
Q

What are some complications of AMI?

A
  • Arrythmias
  • Contractile dysfunction
  • Rupture
  • Pericarditis
39
Q

What is VI?

A

Vascular insufficiency

40
Q

What is Acute myocardial infarction due to?

A

Macroscopic cell death of myocardium due to Vascular Insufficiency

41
Q

Why does hypertrophy often occur in myocardial infarction?

A

Heart not pumping as well, so muscle hypertrophies to compensate

42
Q

What is the composition of the plaque?

A

Cholesterol

Fibrous material

43
Q

What is the initial event in AMI?

When does this occur?

A

Sudden change in the plaque

This can take decades to get to this point

44
Q

What causes vasopasm?

A

Mediators released from platelets

45
Q

Is necrosis of heart muscle after AMI fatal?

A

No

It depends on how much of the heart muscle is affected

46
Q

How quickly does ATP depletion occur in AMI?

A

Starts after a few seconds

Most ATP is gone after about 40 mines

47
Q

Once there is even a very small injury to endothelium, what starts to occur?

A

Accumulation of lipoproteins

48
Q

Described changes to the smooth muscle layer in arteries during atherosclerosis

A

Smooth muscle thickens

49
Q

What determines whether an infarct is transmural or non-transmural?

A

Transmural caused by complete blockage of coronary artery

Non-transmural caused by partial blockage

50
Q

What is global hypotension?

A

When there is narrowing of all coronary arteries

This leads to circumferential sunendocardial infarct

51
Q

What do small occlusions of coronary arteries lead to?

A

Microinfarcts

52
Q

Compare the smooth muscle layer in arteries of infants and in aging adults

A

Infants: think muscle layer

Aging adult: thickened, reduced diameter of artery

53
Q

What is happening when a plaque ruptures?

A

Plaque is normally covered by fibrotic tissue

Rupture leads to plaque spilling out through the fibrotic tissue, bringing about an acute inflammatory response

54
Q

What is a thrombus?

A

Aggregation of platelets

i.e. a clot

55
Q

Why are smooth muscle cells recruited in atherosclerosis?

A

Abnormal growth factor release recruits them

56
Q

What do macrophages attempt to do in atherosclerosis?

A

They phagocytose fat in an aim to resolve the problem

This adds to the problem

57
Q

Why does the inner part of the heart muscle become necrotic first?

A

Further away from the blood supply

58
Q

How do apoptosis inhibitors affect the size of the infarct?

A

They reduce the size of the infarct

59
Q

How quickly does reperfusion need to occur so that there is no necrosis?

A

20 mins

60
Q

What is happening 3-4 days after an AMI?

A

Massive neutrophil infiltration

61
Q

What is happening 7-10 days after an AMI?

A

Necrotic cells

62
Q

What is happening 21 days after an AMI?

A

Collagen deposition

63
Q

What is the structure of the tissue 60 days after an AMI?

A

Scar tissue

64
Q

What clinical signs indicate AMI?

A

• Abnormal ECG
• Biomarkers in blood:
- Troponin
- CK

65
Q

Up to half of the region of necrosis can be due to:

A

Reperfusion injury

66
Q

What does xanthine oxidase do?

A

Leads to production of ROS in neutrophils

67
Q

What is done before reperfusion?

A

Ischemic postconditioning

68
Q

What is the effect of ischemic postconditioning?

A

Inhibit / close the mPTP (mitochondrial permeability transport pore)

Ie blocking the mechanism of apoptosis

69
Q

Why are mPTPs opened after ischemia?

A

It is part of the apoptosis pathway

70
Q

Under what conditions can complete rupture of the myocardium occur?

A 
When there has been a previous heart attack and there is necrotic tissue
The second (or third...) AMI then causes rupture of hge weakened tissue
71
Q

Describe the pathogenesis of atherosclerosis

A

(learn diagram)
1. Exposure
2. Epithelial injury
3. Monocyte recruitment and adhesion
4. Monocyte → macrophage
5. LDL crosses from blood stream into intima of blood vessel, then into macrophage
Macrophage → foam cell
6. Smooth muscle cell precursor recruitment
7. Hypertrophy, ECM production, necrosis (plaque formation)

72
Q

Why is blood without polymorphs used to avoid reperfusion injury?

A

The polymorphs are producing ROS, so we want fewer of these reaching the at risk tissue

PATH30001 - Mechanisms of Disease (34 decks)

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