wk 7- pathophysiology of ischaemia and infarction

what is ischaemia

relative lack of blood supply to tissue/organ leading to inadequate O2 supply to meet needs of tissue/organ: hypoxia

what are types of hypoxia

1. hypoxic

   • low inspired O2 level

   • normal inspired O2 but low PaO2

2. anaemic

   • normal inspired O2 but blood abnormal- as not enough haemoglobin to transport oxygen

3. stagnant

   • normal inspired O2 but abnormal delivery

   • local e.g. occlusion of vessel

   • systemic eg shock

4. cytotoxic

   • normal inspired O2 but abnormal at tissue level- tissue cannot use the oxygen being delivered to it

what are factors that affect oxygen supply

1. inspired O2

2. pulmonary function

3. blood constituents

4. blood flow

5. integrity of vasculature

6. tissue mechanisms

what are factors that affect oxygen demand

1. the tissue itself- different tissues hav edifferrnt requirements- eg. dat cells have a low energy require,emt but the brain or heart has a high high requirement

2. activity of tissue above baseline value

what are supply issues

• coronary artery atherom a

• cardiac failure

• pulmonary function

• other diseases or pulmonary oedema

what are demand issues

heart has high intrinsic demand

exertion/stress

what is atehroma/atherosclerosis

loclaised accumulation of lipid and fibrous tissue in intima of arteries

what would cause stable angina

established atherma in coronary artery

what would cause unstable angina

complicated atheroma in coronary artery

what would cause ischaemia or infarction

ulcerated/fissured plaques causing thrombosis

what would cause an aneurysm

atheroma in the aorta

what are clinical consequences of atheroma

• MI

• TIA- transient ischameic attack

• cerebral

• infarction

• abdominal aortic aneurysm

• peripheral vascular disease

• cardiac failure

what is a common scenario involving ischaemia

coronary artery disease causing MI causing cardiac failure

using equations explain how a change in vessel wall can cause thrombosis

if r=4

R=1/4⁴=1/16

Q=change in pressure/1/256= 256*chnage in pressure

in an atheromatoud vessel r=2

R=1/2⁴=1/16

Q=change in pressure/1/16= 16*change in pressure

therefore if r is decreased from 4 to 2 there is a 16 fold decrease in flow causing a decrease in oxygen causing ischaemia or infarction

what are functional effects of ischaemia

blood/O2 supply fails to meet demand due to decreased supply; increase demand; or both

related to rate of onset

what are general effects of ischaemia

can be acute- sudden

chronic- more serious

acute-on-chronic- an acute event happening on top of an already chronic ischaemic organ

what are biochemical effects of ischaemia

normal aerobic metabolism:

glucose+ 36ADP+36Pi+36H++6O2—> 6CO2+36ATP+42H2O

anaerobic metabolism:

gluocse+2Pi+2ADP—> 2lactate+2ATP+2H2O

L-lactate←—> pyruvate

pyruvate+NAD+CooA—> acetylCoA+ CO2+NADH

decrease oxygen—> anaerobic metabolism—> cell death

cellular effects of ischaemia

different tissues variable O2 requirement and are variably susceptible to ischaemia

cells with high metabolic rate (specialised cells) —> greatly and quickly affected

cells with low metabolic rate (supporting cells) —> much less affected

what are clinical effects of ischaemia

1. dysfunction

2. pain

3. physical damage

describe the time course of an infarction

within seconds- anaerobic metabolism, onset of ATP depletion

<2 minutes- loss of myocardial contractility (leading to heart failure)

a few minutes- ultrastructural changes (myofibrillar relaxation, glycogen depletion, cell and mitochondrial swelling)

20-40 minutes- myocyte necrosis (disrupting of the integrity of sarcolemmal membrane —> leakages of intracellular macromolecules: can see the results 00f this in blood tests- e.g. troponin levels)

>1hr- injury to the microvasculature

appearance of an infarct within the first 24 hours

• no change on visual inspection

• a few hours to 12 hours post insult, see swollen mitochondria on electron microscopy

appearance of infarct at 24-48 hrs

• pale infarct: e.g. myocardium, spleen, kidney

  solid tissue

• red infarct: e.g. in lung, liver

  loose tissues, previously congested tissue; second/continuing blood supply, venous occlusion

• microscopically: acute inflammation initially at edge of infarct; loss of specialised cell features

appearance of infarcts 72 hours onwards

• pale infarct: yellow/whit and red periphery

• red infarct: little change

• microscopically: chronic inflammation; macrophages remove debris; granulation tissue; fibrosis

what is the end appearance of infarcts

• scar replaces are of tissue damage

• shape depends on the territory of the occluded vessel- in the brain, you will get a cystic end result

• reperfusion injury

what is the reperfusion injury

• damage to the tissue caused when the blood supply returns to the tissue after a period of ischaemia

• the absence of nutrients and oxygen from the blood creates a condition in which the restoration of the circulation results in inflammation and oxidative damage

time course of a myocardial infarction

2-12 hours- early coagulation necrosis, oedema, haemorrhage

12-24 hours- ongoing coagulation necrosis, myocyte changes, early neutrophilic infiltrate

1-3 days- coagulation necrosis, loss of nuclei and striations, brisk neutrophilic infiltrate

3-7 days- disintegration of dead myofibers, dying neutrophils, early phagocytosis

7-10 days- well-developed phagocytosis, granulation tissue at margins

10-14 days- well-established granulation tissue with new blood vessels and collagen deposition

2-8 weeks- increased collagen deposition, decreased cellularity

>2 months- dense collagenous scar

what is a transmural infarction

ischaemic necrosis affects full thickness of the myocardium

what is a subendocardial infarction

ischaemic necrosis mostly limited to a zone of myocardium under the endocardial lining of the heart

similarities and differences of transmural and subendocardial infarctions

histological features are the same (repair time- granulation tissue stage followed by fibrosis- in subendocardial infarct possibly slightly shortened compared to transmural infarct)

how are acute infarcts classified

according to whether there is an elevation of the ST segment on the ECG

if no ST-segment elevation but a significantly elevated serum tropnonin level: non STEMI- thought to correlate with a subendocardial infarct

difficult to carry out detailed studies to show link between ECG changes seen with an infarct and exact pathological features because declining post-mortem rates

complications of MI

sudden death, arrhythmias, angina, cardiac failure, cardiac rupture- ventricular wall, septum, papillary muscle, reinfarction, pericardiditis, pulmonary embolism secondary to DVT, papillary muscle dysfunction- necrosis/rupute —> mitral incompetence, mural thrombosis, ventricular aneurysm, dresslers syndrome