Tpoic 9 and 10: Myocardia Ischemia and Reperfusion Flashcards
Problems that lead us to Surgery and Cardioplegia? (3)
Ischemia
Injury
Infarction
Infarction (necrosis)
(necrosis):
cell death
Mycardial infarct causes what ECG waves ?
Pathologic Q waves
Permanent pathological Q waves– Troponin released
Myocardial Ischemia is caused by what things ? (5)
Not enough blood flow artherosclorosis Vasospasm Thrombis Embolism
Myocardial Ischemia has what kind of ECG wave?
depressed ST
inverted T wave
Myocardial Injury caused by what?
No blood flow
Myocardial Injury ECG waves?
elevated ST
Oxy Free Radicals-
Altered O2 molecules created when?
At XC and reperfusion
Reactions add unpaired electrons to outer orbit
Oxygen Free Radicals are what?
Reactqive Oxygen Species (ROS)
what are Constantly manufactured and removed
Oxygen Free Radicals
A missing electron can create what?
Free radical, highly reactive
How are ROS created?
Xanthine oxidase releases in endothelial cells
Enzyme important in purine breakdown path
Catalyze: hypoxanthine to xanthine to uric acid
Process generates hydrogen peroxide (H2O2)
Anoxia
Total depletion of O2
Complete lack of Oxygen
hypoxia
Lack of oxygen delivered to the tissues
Insufficient supply of O2
Ischemia
Restriction in blood supply to an organ
Results from a restriction
How can Reperfusion result in inflammation?
Results in oxidative damage through Inducing oxidative stress rather than restoration of normal function
Reperfusion
Restoration of the circulation
How does Myocyte hypercontracture cause Reperfusion Injury?
Increase intracellular Ca
Reoxygenation of myocytes
How do Oxy free Radicals cause reperfusion injury ?
Alters membrane proteins and phospholipids
Increase oxidative stress
increase inflammation
Leukocyte activation and aggregation
How does mitochondrial dysfucntion cause reperfusion injury ?
Decrease mitochondrial Ca concentration
Decrease ATP and apoptosis
How does Activation of coagulation cause Reperfusion injury ?
Platelet activation
Complement activation leading to microvascular and endothelial dysfunction
Reperfusion Injury is an independent mediator of what?
cardiomyocyte death separate from ischemic injury
Abrupt biochemical and metabolic changes
occur during reperfusion how? (5)
Mitochondrial reenergization Generation of reactive oxygen species Intracellular calcium overload Rapid restoration of physiologic pH Inflammation
Reperfusion can cause two things?
Abrupt biochemical and metabolic changes
Cell death
How is Cell death caused by reperfusion
results from opening of mitochondrial
permeability transition pore and induction of cardiac myocyte hyper-contraction
Antioxidant system (electron donators)
-Superoxide dismutase
-Catalase
-Glutathione reductase
(Protect heart from free radicals)
5’ nucleotidase system converts what?
Converts AMP-> adenosine
If adenosine nucleotide pool <50% full recovery is impossible
Mediators of Lethal Reperfusion Injury
Oxygen paradox Calcium paradox pH paradox Inflammation Myocardial edema
What is Oxygen paradox?
mediator of lethal reperfusion injury
Too much of a good thing: oxygen-derived free radical formation (reactive oxygen species (ROS))
What is Calcium paradox?
mediator of lethal perfusion
Large influx of calcium into the cell
What is pH paradox?
mediator of lethal perfusion
pH moves from acidic to normal–potentiates
many of the changes
Inflammation
mediator of lethal perfusion
Neutrophil activation
endogenous antioxidants (4)
superoxide dismutase
catalase
glutathione
glutathione peroxidase
What happens to tissue stores of endogenous antioxidants during ischemia ?
they are depleted
Greatest risk to develop Oxygen free radicals is when?
when oxygen returned to myocardium
Factors that determine the amount of Oxygen Free Radicals produced? (4)
Severity of ischemic injury
Activation and recruitment of neutrophils to myocardium
Level of O2 in CPG solution
Presence of endogenous scavengers and inhibitors
Results caused by Oxygen Free radicals? (4)
postischemic dysfunction
dysrhythmias
morphologic injury
necrosis
What changes can Oxygen Free Radicals cause?
Peroxidation of lipid components of myocellular membranes
(steal electrons from lipid membranes)
Impairment of vascular endothelial function
(produces vasoactive & antiinflammatory autocoids)
autocoids
act like local hormones, act near site of synthesis, short acting
Oxy Free Radicals induce opening of what?
Induce opening of mitochondrial permeability transition pore
Oxy Free Radicals chemoattract what?
Act as neutrophil chemoattractants
Oxy Free Radicals mediate what?
dysfunction of sarcoplasmic reticulum
Oxy Free Radicals overload what?
intracellular calcium overload
How do Oxy Free Radicals damage cell membrane?
Damage cell membrane by lipid peroxidation
Oxy Free Radicals induce denaturation of what?
Induce enzyme denaturation
How do Oxy Free radicals damage DNA
Cause direct oxidative damage to DNA
What is the Mitochondrial Permeability Transition Pore?
Nonselective channel (protein) of inner mitochondrial membrane
When the Mitochondrial Permeability Transition Pores open, what happens to permeability?
When open increases permeability of molecules <1500 Daltons
When are the Mitochondrial Permeability Transition Pores open? closed?
Closed during ischemia / open during
reperfusion
Why do the Mitochondrial Permeability Transition Pores open?
Opens in response to mitochondrial calcium
overload, oxidative stress, restoration of
physiologic pH, and ATP depletion
pharmacological agents that inhibit the formation of oxygen free radicals?
Anesthetic agents, Anti arrhythmics may eliminate hydroxyl radicals, Vit C->peroxides
pharmacological agents that scavenge / remove oxygen free radicals
Mannitol, N-acetylcysteine
Attack” The Oxygen Free Radical Problem
- Administer pharmacological agents that inhibit the formation of oxygen free radicals
- Admin pharmacological agents that scavenge / remove oxygen free radicals
- Administer anti-neutrophil agents
Accumulation in mitochondria kills ability to produce ATP, which affects what?
- Ability of cell to contract
- Ability of cell to move calcium out of the cell or back into the SR
Changes Are Caused By Myocyte Calcium Influx (4)
Depletion of high-energy phosphate stores
Accumulation in mitochondria kills ability to produce ATP
Activation of catalytic enzymes
Alteration of excitation-contraction coupling of actin-myosin-troponin
Activation of catalytic enzymes does what?
Increase cellular damage
Alteration of excitation-contraction coupling of actin-myosin-troponin - what happens to calcium (3)
Calcium into the cell causes the contraction
sequence
Calcium not removed (Stone heart syndrome)
Calcium can enter by multiple pathways
Stone heart syndrome?
When calcium is not removed
What starts the activation of Neutrophils
Receptor molecules will be activated / exposed
Start attachment process to the endothelium
Three types of receptor molecules
selectins (P, L, E) beta2 integrins (CD11/CD18 complex) immunoglobulin superfamily (ICAM-1)
selectins (P, L, E)
Initial binding processes with endothelial
wall of neutrophils
beta2 integrins (CD11/CD18 complex)
Mediate firmer contact with wall (of Neutrophils)
immunoglobulin superfamily (ICAM-1)
Mediates final surface adherence of neutrophils
P-selectin (endothelial cells) is triggered by what?
triggered by proinflammatory mediators
Proinflammatory mediators that can trigger P-selectin
oxygen-derived free radicals (Hydrogen Peroxide etc)
thrombin complement components
histamine
Neutrophil recruitment triggered by similar
proinflammatory mediators to what
to P-selectin inhibitors
Causes Myocardial Edema
Increased intracellular osmotic pressure
Disruption of electrical potential across cell membrane
Increased microvascular permeability
Increased interstitial osmotic pressure
High cardioplegia delivery pressure
Hypothermia induced changes to sodium-potassium pump
Increased intracellular osmotic pressure
accumulation metabolic end-products of anaerobic glycolysis, lipolysis, ATP hydrolysis
Disruption of electrical potential across cell membrane
sodium / chloride accumulate inside the cell –attract water
Increased what can cause myocardial edema? (3)
Increased microvascular permeability
Increased intracellular osmotic pressure
Increased interstitial osmotic pressure
High pressure where can cause myocardial edema?
High Cardioplegia delivery pressure
Hypothermia induced changes to sodium-potassium pump can cause what?
cause myocardial edema
Disruption of electrical potential across cell membrane can cause what?
cause myocardial edema
Myocardial Edema results in what two things?
increased microvasculature resistance
increased diffusion distance to myofibril
What conditions can we modify of cardioplegia during bypass?
hydrodynamics
temperature
route
What elements of the composition of cardioplegia can we modify ?
pH metabolic substrate hypocalcemia oxygen pharmaceuticals
Off-Pump cases how do we minimize effects of ischmia?
IV administration of drugs?
Dysrhythmias we see as a result of RPI
PVC’s, fibrillation, non-spontaneous return of sinus rhythm, dysrhythmia persistence
Systolic dysfunction caused by the result of RPI are what?
contractile function / stroke volume
View by TEE or measure a Cardiac Output
Result of RPI (3)?
Dysrhythmias
Systolic dysfunction
Diastolic dysfunction (compliance /
relaxation)
What is the Diastolic dysfunction (compliance /
relaxation) that is the result of RPI
impaired filling
Clinical results we see as a result of RPI? (3)
Myocardial necrosis
Endothelial dysfunction
No reflow phenomenon
No reflow phenomenon (5)
Post ischemic tissue edema
Interstitial hemorrhage
Active vasoconstriction from loss of endothelium derived vasodilators
Release of neutrophil derived vasoconstrictors
Capillary plugging by adhering neutrophils
Active vasoconstriction from loss of endothelium derived vasodilators caused by what?
No reflow phenomenon
Release of neutrophil derived vasoconstrictors caused by what result of RPI?
No reflow phenomenon
Capillary plugging by adhering neutrophils caused by what result of RPI?
No reflow phenomenon
Post ischemic tissue edema caused by what result of RPI?
No reflow phenomenon
When can Myocardial Injury occur during bypass? (3)
Before bypass (think “lines”) During cardioplegic arrest (think XC ON) During reperfusion (think XC off)
“prebypass window” is what?
Pre-bypass / before delivery of cardioplegia
Period of unprotected ischemia
During Phase one “prebypass window” when Period of unprotected ischemia, what cause myocardial injury? (3)
- coronary artery or other disease process
- hypotension due to dysrhythmia and/or cardiogenic shock
- coronary spasm
Myocardial Injury, Phase 2, During cardioplegic arrest (think XC ON)
Cross-clamp applied / cardioplegia delivered
What can cause ischemia during period of protected ischemia, during phase 2 of possible myocardial injury (7)
- unresolved coronary stenosis
- obstruction within vascular graft (kink, tight anastomosis, emboli)
- maldistribution of cardioplegia
- inadequate cardioplegia delivery (inadequate -pressure or volume, inappropriate composition)
- between infusions of intermittent cardioplegia
- unintentional interruption of continuous cardioplegia
During phase 3, reperfusion, time of possible myocadial injury
Ischemic injury also possible due to what? (5)
- Ischemic injury also possible
- hypotension post clamp release (think “neo”)
- during weaning/termination CPB (do not distend)
- vascular graft thrombosis or mechanical obstruction
- Dysrhythmias(watch EKG)
- vasospasm of grafted vessel
After cross-clamp removed, when can myocardial injury can occur when/how?
Phase 3 of time of possible myocardial injury
- early phase: <4 hours
- late phase: 4 to 6 hours
- resolution of hypotension /dysrhythmia restores blood flow
- cardioplegia infused at high pressures or with improper composition
- coronary blood flow restored with unmodified blood after clamp removal
Goal of Myocardial Protection
Initiate rapid myocardial arrest
Keep the heart quiet, no electrochemical activity
Minimize ischemia
Control Reperfusion
4 main objectives of hypothermic cardioplegia
Immediate/Sustained electromechanical arrest
Rapid Sustained homogenous cooling
Maintenance of therapeutic additives in effective concentrations
Periodic washouts of metabolic inhibitors
Goals of Myocardial Protection (4)
Control Reperfusion
Initiate rapid myocardial arrest
Minimize ischemia
Keep the heart quiet, no electrochemical activity
4 main objectives of hypothermic cardioplegia
Immediate/Sustained electromechanical arrest
Rapid Sustained homogenous cooling
Maintenance of therapeutic additives in effective concentrations
Periodic washouts of metabolic inhibitors
