Exam 4 - Ischemia & Reperfusion Injury Flashcards
Ischemia
- Inadequate tissue perfusion to sustain aerobic metabolism at a given level of cardiac performance
- Imbalance between O2 supply and demand
Normal perfusion
Supply / Demand > 1
- must increase supply (flow) to increase ratio
- Ischemia occurs when ratio < 1
Anoxia
- flow to tissue ok, but no O2 delivery
- O2 extraction problem
Hypoxia
- Flow to tissue ok, but insufficient O2 delivery
- [O2] not high enough to meet demand
Reperfusion
- 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
Reperfusion injury
- extends / accelerates damage from ischemia
- Ischemia sets stage… reperfusion continues injury process
- Perfusionists can create optimal / protected conditions for reperfusion to minimize injury
Why should be concerned with reperfusion injury
- CAD
- Treatment of MI leads to reperfusion (opens artery)
- CPB w/ x-clamp
- Off pump procedures
Cells most affected by ischemic injury
- 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
Good vasoactivators
- NO
- Adenosine
- Prostacyclin
Bad vasoactivators
- Platelet activating factor
- Endothelin-1
- Superoxide anion
- Histamine
What determines myocardial O2 demand
- 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)
Stroke work on CPB
- Minimal / zero
- Stroke work is shown by area under P-V curve
How does CPB affect O2 demand
- 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
Biggest factor in ischemic injury
- time
- 30-45 min before bad damage occurs
Global myocardial ischemia (GMI)
- 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
Regional myocardial ischemia (RMI)
- No flow to part of heart
- Off pump cases / coronary blockage
- 45 min of ischemia…subendocardial infarction / contractile dysfunction of ischemic area
Consequences of myocardial ischemia
- decreased contractile function
- endothelial damage and decreased function
- decreased blood flow
- neutrophil accumulation
- Apoptosis
Factors affecting ischemic injury
- 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)
Factors affecting time to permanent damage
- severity of ischemia
- heart temperature (cooler the better)
- tissue energy demand
- collateral flow
- necrosis can occur w/ 30 min of occlusion
RPI damage
- 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)
Myocardial stunning
- mechanical dysfunction after reperfusion
- without necrosis
- occurs even with normal coronary flow
- days/weeks to recover
- pacing after surgery helps prevent
No-reflow phenomenon causes
- neutrophils plugging up caps
- air emboli / debris
- vasoconstriction
- post ischemic edema
Reperfusion arrhythmias treatment
- pace patient
- drugs
- mannitol - O2 free radical scavenger
- lidocaine
- Mg
Lethal reperfusion injury
- separate from ischemic injury….2nd part
- cardiomyocyte death
- cell death results from opening of mitochondrial permeability transition pore (mPTP) and hypercontraction
Mediators of lethal perfusion injury
- 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)
When are ROS generated
- 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”
Pathway of ROS production
- Xanthine oxidase is enzyme for purine breakdown
- in endothelial cells
- this process makes H2O2
- H2O2 disrupts cell membranes
Two ways H2O2 produced
- Re-energized ETC in mitochondria
- NADPH oxidase
What determines amount of free radicals
- severity of ischemic injury
- neutrophils
- levels of O2 in cardioplegia
- status of scavengers / inhibitors
What changes are caused by free radicals
- disruption of cell membrane
- poor endothelial function
- production of autocoids (like hormones/short living)
- causes:
- post-ischemic dysfunction
- dysrhythmias
- injury
- necrosis
How do free radicals cause injury
- Open mPTP
- attract neutrophils
- disrupt Sarcoplasmic reticulum
- Cell Ca overload
- damage cell membrane (H2O2)
- enzyme denaturation
- damage to DNA
mPTP
- 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
How to treat free radical problem
- drugs that block free radical formation
- drugs that scavenge free radicals
- anti-neutrophil agents
What changes caused by Ca influx
- depletion of energy stores
- stops ability to make aTP
- activates catalytic enzymes
- disruption of actin-myosin-troponin
- opens up mPTP
What starts activation of neutrophils
- Pro-inflammatory mediators triggers P-selectin
- Pro-inflammatory mediators recruit neutrophils
- Neutrophils ultimately create free radicals
What causes myocardial edema
- 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
How can we target perpetrators of injury during CPB
- IV
- Cardioplegia
- Can alter conditions or reperfusion (route, temp, dynamics)
- Can alter composition of cpg solution
How can we target off-pump
- IV administration
- No cpg
- No hypothermia
- minimal cardiac work reduction
Clinical results of RPI
- Dysrhythmias (PVC, fib, etc.)
- Systolic dysfunction
- Diastolic dysfunction (impaired filling)
- Necrosis
- Endothelial dysfunction
- No-reflow phenomenon
When can myocardial injury occur
- Three phases
1 - before bypass (uncontrolled)
2 - during cpg arrest (x-clamp)
3 - during reperfusion
Phase 1 - Pre-bypass window
- unprotected ischemia
- coronary artery or other disease
- hypotension
- coronary spasm
- RPI possible
Phase 2 - CPG
- cpg delivery / x-clamp on
- protected ischemia
- unresolved coronary stenosis
- obstruction of graft
- poor distribution of cpg / not enough delivery
- RPI possible
Phase 3 - Peperfusion
- after x-clamp removal
- Ischemic injury possible
- during weaning of CPB
- dysrythmias
- vasospasm of graft
- hypotension (mannitol and K drop BP)