Exam 4 - Ischemia & Reperfusion Injury Flashcards
1
Q
Ischemia
A
- Inadequate tissue perfusion to sustain aerobic metabolism at a given level of cardiac performance
- Imbalance between O2 supply and demand
2
Q
Normal perfusion
A
Supply / Demand > 1
- must increase supply (flow) to increase ratio
- Ischemia occurs when ratio < 1
3
Q
Anoxia
A
- flow to tissue ok, but no O2 delivery
- O2 extraction problem
4
Q
Hypoxia
A
- Flow to tissue ok, but insufficient O2 delivery
- [O2] not high enough to meet demand
5
Q
Reperfusion
A
- Restoration of flow after period of ischemia
- Happens after x-clamp, cardioplegia, or blocked vessel
- we can control first two - Ischemic injury may be accelerated / extended by reperfusion phase
6
Q
Reperfusion injury
A
- extends / accelerates damage from ischemia
- Ischemia sets stage… reperfusion continues injury process
- Perfusionists can create optimal / protected conditions for reperfusion to minimize injury
7
Q
Why should be concerned with reperfusion injury
A
- CAD
- Treatment of MI leads to reperfusion (opens artery)
- CPB w/ x-clamp
- Off pump procedures
8
Q
Cells most affected by ischemic injury
A
- Cardiac myocyte
- no buffer periods of low flow like other cells
- high levels of aerobic metabolism (no anaerobic)
- Coronary vascular endothelium
- active tissue / release vasoactive substances (dilators/mediators)
- release NO… NO is good free radical scavenger
- free radicals hurt membranes / homeostasis of cells
9
Q
Good vasoactivators
A
- NO
- Adenosine
- Prostacyclin
10
Q
Bad vasoactivators
A
- Platelet activating factor
- Endothelin-1
- Superoxide anion
- Histamine
11
Q
What determines myocardial O2 demand
A
- Work of chambers (pressure and stroke work)
- Passive stretch (minimized by vent)
- HR (CPB stops heart…so 0)
- Basal metabolism
- Inotropic state
- Ionic homeostasis (energy needed to maintain)
12
Q
Stroke work on CPB
A
- Minimal / zero
- Stroke work is shown by area under P-V curve
13
Q
How does CPB affect O2 demand
A
- Total bypass and diastolic arrest
- drop demand 50% or more
- Myocardial cooling
- drop 50% per 10 degree C drop
- Normal drift to 34 = 25% drop in demand
- Vent decompression
- All these decrease demand AND slow ischemic injury
14
Q
Biggest factor in ischemic injury
A
- time
- 30-45 min before bad damage occurs
15
Q
Global myocardial ischemia (GMI)
A
- occurs during x-clamp or widowmaker (LAD coronary)
- no flow to entire heart
- 45 min ischemia w/ no modified reperfusion….50-60% drop in systolic function but no necrosis
16
Q
Regional myocardial ischemia (RMI)
A
- No flow to part of heart
- Off pump cases / coronary blockage
- 45 min of ischemia…subendocardial infarction / contractile dysfunction of ischemic area
17
Q
Consequences of myocardial ischemia
A
- decreased contractile function
- endothelial damage and decreased function
- decreased blood flow
- neutrophil accumulation
- Apoptosis
18
Q
Factors affecting ischemic injury
A
- duration of ischemia (biggest)
- collateral flow (more collateral…less injury)
- baseline health of tissue
- Ca influx (too much causes stone heart)
- Intracellular Na increase and K decrease (ionic homeostasis)
- stimulation of activators (cytokines, etc)
19
Q
Factors affecting time to permanent damage
A
- severity of ischemia
- heart temperature (cooler the better)
- tissue energy demand
- collateral flow
- necrosis can occur w/ 30 min of occlusion
20
Q
RPI damage
A
- extend postishchemic injury
- myocardial stunning
- no-reflow phenomenon (neutrophils stuck on vessel wall…block)
- reperfusion arrhythmia (ST changes…caused by air emboli)
- lethal perfusion injury (O2 free radicals)
21
Q
Myocardial stunning
A
- mechanical dysfunction after reperfusion
- without necrosis
- occurs even with normal coronary flow
- days/weeks to recover
- pacing after surgery helps prevent
22
Q
No-reflow phenomenon causes
A
- neutrophils plugging up caps
- air emboli / debris
- vasoconstriction
- post ischemic edema
23
Q
Reperfusion arrhythmias treatment
A
- pace patient
- drugs
- mannitol - O2 free radical scavenger
- lidocaine
- Mg
24
Q
Lethal reperfusion injury
A
- separate from ischemic injury….2nd part
- cardiomyocyte death
- cell death results from opening of mitochondrial permeability transition pore (mPTP) and hypercontraction
25
Q
Mediators of lethal perfusion injury
A
- O2 paradox
- too much O2 leads to free radicals (most from dissolved O2)
- reactive oxygen species (ROS)
- Calcium paradox
- influx of Ca into cell
- pH paradox
- moves from acidic to normal
- Inflammation
- Neutrophil activation
- Myocardial edema (blood cpg helps reduce this)
26
Q
When are ROS generated
A
- periods of ischemia
- tissue antioxidants are depleted during ischemia
- O2 not available until reperfusion
- GREATEST production is when O2 returned to myocardium
- happens a lot during “hot shot”
27
Q
Pathway of ROS production
A
- Xanthine oxidase is enzyme for purine breakdown
- in endothelial cells
- this process makes H2O2
- H2O2 disrupts cell membranes
28
Q
Two ways H2O2 produced
A
- Re-energized ETC in mitochondria
- NADPH oxidase
29
Q
What determines amount of free radicals
A
- severity of ischemic injury
- neutrophils
- levels of O2 in cardioplegia
- status of scavengers / inhibitors
30
Q
What changes are caused by free radicals
A
- disruption of cell membrane
- poor endothelial function
- production of autocoids (like hormones/short living)
- causes:
- post-ischemic dysfunction
- dysrhythmias
- injury
- necrosis
31
Q
How do free radicals cause injury
A
- Open mPTP
- attract neutrophils
- disrupt Sarcoplasmic reticulum
- Cell Ca overload
- damage cell membrane (H2O2)
- enzyme denaturation
- damage to DNA
32
Q
mPTP
A
- nonselective
- when open…<1500 dalton molecules can enter
- when open…ATP depletion and cell death
- closed during ischemia / open during reperfusion
- opening of pore is bad
33
Q
How to treat free radical problem
A
- drugs that block free radical formation
- drugs that scavenge free radicals
- anti-neutrophil agents
34
Q
What changes caused by Ca influx
A
- depletion of energy stores
- stops ability to make aTP
- activates catalytic enzymes
- disruption of actin-myosin-troponin
- opens up mPTP
35
Q
What starts activation of neutrophils
A
- Pro-inflammatory mediators triggers P-selectin
- Pro-inflammatory mediators recruit neutrophils
- Neutrophils ultimately create free radicals
36
Q
What causes myocardial edema
A
- increased intracellular osmotic pressure
- disruption of membrane electrical potential
- Na/Cl accumulate inside cells
- increased permeability
- high cpg delivery pressure
- hypothermia changes Na/K pump
- results in no-reflow phenomenon and poor O2 delivery
37
Q
How can we target perpetrators of injury during CPB
A
- IV
- Cardioplegia
- Can alter conditions or reperfusion (route, temp, dynamics)
- Can alter composition of cpg solution
38
Q
How can we target off-pump
A
- IV administration
- No cpg
- No hypothermia
- minimal cardiac work reduction
39
Q
Clinical results of RPI
A
- Dysrhythmias (PVC, fib, etc.)
- Systolic dysfunction
- Diastolic dysfunction (impaired filling)
- Necrosis
- Endothelial dysfunction
- No-reflow phenomenon
40
Q
When can myocardial injury occur
A
- Three phases
1 - before bypass (uncontrolled)
2 - during cpg arrest (x-clamp)
3 - during reperfusion
41
Q
Phase 1 - Pre-bypass window
A
- unprotected ischemia
- coronary artery or other disease
- hypotension
- coronary spasm
- RPI possible
42
Q
Phase 2 - CPG
A
- cpg delivery / x-clamp on
- protected ischemia
- unresolved coronary stenosis
- obstruction of graft
- poor distribution of cpg / not enough delivery
- RPI possible
43
Q
Phase 3 - Peperfusion
A
- after x-clamp removal
- Ischemic injury possible
- during weaning of CPB
- dysrythmias
- vasospasm of graft
- hypotension (mannitol and K drop BP)
