Lecture 5: Ischemia and Re-perfusion Injury

Question 1

What is AMI?

Answer 1

Acute Myocardial Infarction refers to the macroscopic death of myocardium due to vascular insufficiency (VI). VI itself refers to myocardial ischaemia, which is the imbalance between the supply flow (perfusion) and demand for oxygenated blood.

Question 2

Describe the cause and consequences of ischemic heart diseases.

Answer 2

It involves an imbalance between cardiac blood supply and myocardial oxygen demand.

• Caused by:
  
  • Increased demand
  • Diminished oxygen-carrying capacity
  • Reduced coronary flow due to obstructive atherosclerosis
• Consequences:
  
  • limits tissue oxygenation (thus ATP generation)
  • reduces the availability of nutrients and the removal of metabolic wastes

Question 3

What is the major underlying cause of AMI?

Answer 3

In 95% of the case, the cause is atherosclerosis (disease caused by fibro-fatty plaques in intima of large arteries)

Question 4

Recall the various pathways in the progression of ischemic heart disease (IHD).

Answer 4

Question 5

What is Acute Coronary Syndrome? What are its outcomes?

Answer 5

Acute coronary syndrome (ACS) is a set of signs and symptoms due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies.

The common feature of ACS is downstream MI. The outcomes of ACS are:

• Stable angina
• Unstable angina
• Myocardial Infarction (heart attack)

Question 6

Recall the factors affecting the outcome of ischaemia.

Answer 6

Question 7

Recall the time of onset of key events in ischaemic cardiac myocytes.

Answer 7

Question 8

What is atherosclerosis?

Answer 8

Atherosclerosis is a chronic inflammatory and healing response of the arterial wall to endothelial injury.

Lesion progression occurs through the interaction of modified lipoproteins, macrophages, and T-lymphocytes with the normal cellular constituents of the arterial wall.

Question 9

Describe the pathogenesis of atherosclerosis.

Answer 9

Question 10

Recall the structure of an atherosclerotic plaque.

Answer 10

Question 11

Recall the pathogenesis of AMI caused by atherosclerosis

Answer 11

The possible outcomes if plaque progresses:

• Aneurysm and rupture
• Occlusion by thrombus
• Critical Stenosis

Question 12

Recall the major components of a well-developed intimal atheromatous plaque.

Answer 12

Question 13

Recall the progression of myocardial necrosis after coronary artery occlusion.

Answer 13

Necrosis begins in a small zone of myocardium beneath the endocardial surface in the centre of the ischemic zone. The area that depends on the occluded vessel for perfusion is the “at-risk” myocardium.

Question 14

Describe the pathogenesis of the AMI at the cellular level.

Answer 14

1. Cell death by necrosis and apoptosis - occurs rapidly post-ischaemia
   
   • Apoptosis inhibitors reduce infarct size
2. Reperfusion - in <20 min myocytes survive infarct event
3. No reperfusion - necrosis complete in 6-12 hour

Question 15

Recall the evolution of the infarct site in a surviving patient.

Answer 15

Question 16

Recall the role of IL-1ß in acute myocardial infarction.

Answer 16

When there is a normal regulation of IL-1ß, cardiomyopathy is still reversible. However, when there is dysregulation of IL-1ß, there is a progression to the acute phase of AMI due to inflammasome-mediated injury (headed by the IL-1ß).

Question 17

What are the inflammatory markers of AMI?

Answer 17

The release of myocyte proteins acts as inflammatory markers of AMI. Some of these proteins are:

• troponin I, C, T
• creatine phosphokinase ‘Muscle-Brain’ isoenzyme (CK-MB)

These proteins are used as diagnostic biomarkers.

Question 18

Mention the clinical features and tests for AMI.

Answer 18

Most laboratories run a troponin assay, either troponin T or I, and may also offer testing for CK-MB and/or myoglobin. Troponin demonstrates improved myocardial specificity and sensitivity over both CK-MB and myoglobin.

Question 19

What can be done to modify the infarct?

Answer 19

• Restoration of coronary blood flow (reperfusion)
• Thrombolysis
  
  • streptokinase or tissue plasminogen activator
    
    • activates fibrinolytic enzyme systems
  • dissolves thrombus
• Balloon angioplasty
  
  • procedure used to increase the flow of blood through a narrowed artery
• Coronary arterial bypass graft (CABG)

Question 20

How to achieve inhibition of myocardial death?

Answer 20

Question 21

Explain the effects of reperfusion on myocardial viability and function.

Answer 21

If flow is restored, some necrosis is prevented, the myocardium is salvaged, and some function can return. The earlier reperfusion occurs, the greater the degree of salvage.

However, the process of reperfusion itself may be damaging (reperfusion injury), and return of function of salvaged myocardium may be delayed for hours to days. (postischaemic ventricular dysfunction)

Question 22

What is the source of reperfusion injury?

Answer 22

Ischaemic myocardiocytes have a buildup of reactive oxygen species/free radicals. When blood flow returns, it spreads these ROS to surrounding tissue-damaging them. Immune cells (such as neutrophils) are also brought into the area, generating more inflammatory responses, releasing a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. Cytoplasmic xanthine oxidase is also activated - producing more ROS/FR.

Note: Blood without polymorphs (leukocytes or granulocytes) and usage of inhibitors of xanthine oxidase lead to better outcomes

Question 23

Mention the complications of AMI.

Answer 23

• contractile dysfunction
• arrhythmias
• rupture-severe effect
• pericarditis
• infarct expansion