Lecture 2 - AMI & Atherosclerosis Flashcards
Why is AMI significant?
It is the leading cause of death in industrialised countries
What are the two main pathways that lead to sudden coronary death?
- Myocardial ischema
2. Plaque in coronary arteries
What is atherosclerosis?
• Fibrofatty plaques in intima of arteries
due to
• Chronic inflammatory healing response
What is the major underlying cause of AMI?
Atherosclerosis (95%)
Lifestyle dependent
How does age and gender affect chance of AMI?
- Chance increases with age
* Men are affected for than women
Describe the time scale during an MI
As time elapses, very soon: • lactate increases • ATP decreases over a matter of hours: • decrease in 'salvageable myocardium' • increase in dead myocardium
How long does it take for loss of contractility during an MI?
< 2 mins
Describe the pathogenesis of atherosclerosis
- Endothelial injury
- Accumulation of lipoproteins
- Monocyte adhesion to the endothelium
- Platelet adhesion
- Factor release from activated immune cells
- Smooth muscle cell proliferation and ECM production
- Lipid accumulation
Which lipoproteins accumulate in atherosclerosis?
Mainly LDL
What does the location of the MI depend on?
The coronary artery that is occluded
Compare transmural and non-transmural infarcts
Transmural: entire thickness of a portion of the wall is affected
Non-transmural: part of wall is affected
What changes can occur to the plaques in atherosclerosis?
- rupture
- erosion
- ulceration
- haemorrhage
Why do changes to the plaque occur?
The plaque is unstable and weak
What is an aneurysm?
Ballooning of a portion of an artery
What are the clinical complications of atherosclerosis?
- Aneurysm and rupture
- Occlusion by thrombus
- Critical stenosis
In what case does critical stenosis occur?
Continual growth of plaque so that the artery is almost completely blocked
What are some risk factors for atherosclerosis?
- Hyperlipidaemia
- Hypertension
- Smoking
- Immune reactions
- Toxins
- Viruses
What is the normal role of monocytes?
- 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
What is a foam cell?
When are where are they seen?
- A fat laden macrophage
* Seen in atherosclerosis in the intima of vascular wall
What is the role of smooth muscle cells in atherosclerosis?
- Recruited into the intima
* Proliferate
Which part of the myocardium is at risk in a given coronary artery occlusion?
The myocardium that derives its blood supply from the portion of coronary artery distal to the blockage
Which part of the wall layer undergoes necrosis first in a coronary artery occlusion?
- The sub-endocardial zone (interal layers)
* The necrosis then extends outward
What does the size of the zone of necrosis depend on?
- Duration of occlusion
* Presence of collateral circulation
What is subacute period of MI?
Days old
What is the role of apoptosis in MI?
Occurs rapidly post-ischemia
What happens in MI if there is no reperfusion?
Necrosis, which is complete after 6-12 hours
Compare ‘salvage’, ‘partial salvage’ and ‘complete infarct’
This depends on how much time passes before reperfusion
Salvage: no necrosis, slight dysfunction
Partial salvage: necrosis with haemorrhage & contraction bands
Complete infarct: necrosis
What happens to the infarct site over the next few days?
- monocyte infiltration
- phagocytosis of necrotic cells
- repair; scar tissue formation
What are the necrotic cells replaced with after an MI?
Collagenous scar tissue
What are the possible medical interventions to prevent MI?
- Balloon angioplasty
- Thrombolysis
- Coronary artery bypass graft
What are the markers of myocardial infarction?
- Creatinine phosphokinase
- Troponin
These are released by the now leaky membrane of the myocytes
Which tests are done to detect MI?
- Troponin assay (most specific)
* CK-MB assay
Why does reperfusion injury occur?
- 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
How can reperfusion injury be avoided?
With pharmaceuticals:
• Xanthine oxidase inhibitors
• Blood without polymorphs
• Activation of RISK pathway through ischemic post conditioning
What is ‘preconditioning’?
Repeated, short-lived ischemia
• Provides protection from later ischemia
What is mPTP?
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
What does the mPTP lead to?
Cell death (apoptosis or necrosis)
- mPTP
- Cytochrome c lost from mitochondria into cytosol
- Activation of caspases
- Activation of endonucleases & degradation of cytoskeleton
- Apoptosis
What are some complications of AMI?
- Arrythmias
- Contractile dysfunction
- Rupture
- Pericarditis
What is VI?
Vascular insufficiency
What is Acute myocardial infarction due to?
Macroscopic cell death of myocardium due to Vascular Insufficiency
Why does hypertrophy often occur in myocardial infarction?
Heart not pumping as well, so muscle hypertrophies to compensate
What is the composition of the plaque?
Cholesterol
Fibrous material
What is the initial event in AMI?
When does this occur?
Sudden change in the plaque
This can take decades to get to this point
What causes vasopasm?
Mediators released from platelets
Is necrosis of heart muscle after AMI fatal?
No
It depends on how much of the heart muscle is affected
How quickly does ATP depletion occur in AMI?
Starts after a few seconds
Most ATP is gone after about 40 mines
Once there is even a very small injury to endothelium, what starts to occur?
Accumulation of lipoproteins
Described changes to the smooth muscle layer in arteries during atherosclerosis
Smooth muscle thickens
What determines whether an infarct is transmural or non-transmural?
Transmural caused by complete blockage of coronary artery
Non-transmural caused by partial blockage
What is global hypotension?
When there is narrowing of all coronary arteries
This leads to circumferential sunendocardial infarct
What do small occlusions of coronary arteries lead to?
Microinfarcts
Compare the smooth muscle layer in arteries of infants and in aging adults
Infants: think muscle layer
Aging adult: thickened, reduced diameter of artery
What is happening when a plaque ruptures?
Plaque is normally covered by fibrotic tissue
Rupture leads to plaque spilling out through the fibrotic tissue, bringing about an acute inflammatory response
What is a thrombus?
Aggregation of platelets
i.e. a clot
Why are smooth muscle cells recruited in atherosclerosis?
Abnormal growth factor release recruits them
What do macrophages attempt to do in atherosclerosis?
They phagocytose fat in an aim to resolve the problem
This adds to the problem
Why does the inner part of the heart muscle become necrotic first?
Further away from the blood supply
How do apoptosis inhibitors affect the size of the infarct?
They reduce the size of the infarct
How quickly does reperfusion need to occur so that there is no necrosis?
20 mins
What is happening 3-4 days after an AMI?
Massive neutrophil infiltration
What is happening 7-10 days after an AMI?
Necrotic cells
What is happening 21 days after an AMI?
Collagen deposition
What is the structure of the tissue 60 days after an AMI?
Scar tissue
What clinical signs indicate AMI?
• Abnormal ECG
• Biomarkers in blood:
- Troponin
- CK
Up to half of the region of necrosis can be due to:
Reperfusion injury
What does xanthine oxidase do?
Leads to production of ROS in neutrophils
What is done before reperfusion?
Ischemic postconditioning
What is the effect of ischemic postconditioning?
Inhibit / close the mPTP (mitochondrial permeability transport pore)
Ie blocking the mechanism of apoptosis
Why are mPTPs opened after ischemia?
It is part of the apoptosis pathway
Under what conditions can complete rupture of the myocardium occur?
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
Describe the pathogenesis of atherosclerosis
(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)
Why is blood without polymorphs used to avoid reperfusion injury?
The polymorphs are producing ROS, so we want fewer of these reaching the at risk tissue
