0701- cellular reaction to ischaemia - CG

Question 1

What factors affects the supply and demand of oxygen to tissues?

Answer 1

Supply- myocardial blood delivery, myocardial blood flow, oxygen content,

Demand- work rate (intrinsic and extrinsic): cardiac contractility, HR, afterload

In ischaemia, demand > supply

Question 2

Outline the timeline of complications in myocardial tissue after ischaemia

Answer 2

cellular reactions to ischaemia is a spectrum of events that is progressive-

1. Reduced ATP = increased intracellular calcium (overload)
2. Myocardial stunning
3. Hibernation
4. Death

Calcium overload and inflammation injury most important contributor to contractile and electrophysiological abnormalities. Duration and severity of ischaemia is important

Question 3

What are the consequences of increased intracellular calcium?

Answer 3

Effect on ion channels, transporters and enzymes lead to Early or delayed afterdepolarisations (EAD, DAD) in myocardium

This causes contraction and and relaxation failure, +contracture (stiffening)

Question 4

Explain contractile failure (both diastolic failure and systolic failure)

Answer 4

Diastolic- occurs within 1st minute- associated with increased pressure during diastole

Systolic- occurs ~10min, drop in pressure and stroke volume- issues with pumping

Contracture develops long term- increased pressure due to rise in resting force (or tension) during prolonged ischemia, ie muscle don’t relax during diastole- can’t relax for blood to fill

Question 5

Describe myocardial stunning (early complication of ischaemia)

Answer 5

Myocardial stunning (short, sublethal, no irreversible damage)

2 mechanisms:

Calcium overload- uncoupling of energy generation from contraction, Caused by troponin I degradation- (cell is sick of Ca)

AND

Free radical injury- ATP into hypoxanthine, reperfusion injury- generate free radicals- tissue damage

Question 6

Describe myocardial hibernation

Answer 6

protective- prolonged contractile depression, due to abnormal regional blood flow with chronic lack of supply

Cellular integrity preserved, however loss of contractile elements and altered mitochondria Revascularisation improves contractile function

On histology, cells appear darker

Question 7

Describe cell death in response to ischaemia. What are the 2 mechanisms and how are they mediated?

Answer 7

apoptosis (controlled) or necrosis (uncontrolled) in response to severe prolonged ischaemia. Mediated by mitochondrial processes

leading to free radical damage, swelling–> membrane disruption, release or intracellular protein including cytochrome C