Myocardial Protection Principles Myocardial Protection Principles Myocardial Protection Principles Myocardial Protection Principles David J Chambers David J Chambers David J Chambers David J Chambers Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic Surgery Surgery Surgery Surgery The Rayne Institute (King’s College London) The Rayne Institute (King’s College London) The Rayne Institute (King’s College London) The Rayne Institute (King’s College London) Guy’s & St Thomas’ NHS Foundation Trust Guy’s & St Thomas’ NHS Foundation Trust Guy’s & St Thomas’ NHS Foundation Trust Guy’s & St Thomas’ NHS Foundation Trust St Thomas’ Hospital St Thomas’ Hospital St Thomas’ Hospital St Thomas’ Hospital London London London London UK UK UK UK ScanSect, Aarhus, Denmark. 24 th August 2013
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The Rayne Institute (King’s College London)The Rayne Institute (King’s College London)The Rayne Institute (King’s College London)The Rayne Institute (King’s College London)
Guy’s & St Thomas’ NHS Foundation TrustGuy’s & St Thomas’ NHS Foundation TrustGuy’s & St Thomas’ NHS Foundation TrustGuy’s & St Thomas’ NHS Foundation Trust
St Thomas’ HospitalSt Thomas’ HospitalSt Thomas’ HospitalSt Thomas’ Hospital
LondonLondonLondonLondon
UKUKUKUK
ScanSect, Aarhus, Denmark.
24th August 2013
Optimal conditions for cardiac surgery?Optimal conditions for cardiac surgery?Optimal conditions for cardiac surgery?Optimal conditions for cardiac surgery?
The ideal conditions required by a surgeon for a successful heart operation:
These conditions can most easily be achieved by global ischemia
Onset of severe ischemiaReduced oxygen availabilityContractile failureReduced creatine phosphate
Cyanosis
Cellular potassium loss
Disturbance of transmembrane ion gradients
Depolarisation
Accumulation of Pi
Stimulation of anaerobic metabolismDepletion of intracellular GSH
Increased free radical production
Accumulation of GSSG
Accumulation of reactive oxidised lipids
ATP depletionLactate accumulation
AcidosisLeakage of metabolites
Metabolic imbalance
Glycogen utilisation
Cell swelling
Seconds
Min
ute
s
Ischemiacauses R
evers
ible
inju
ry
Onset of irreversible damage
Cell death and necrosis
Mitochondrial depolarisation
Lysosomal activation
Opening of mitochondrial PTPSevere cell swellingMembrane blebbing
Cytoskeletal disruption
Loss of membrane integrityProtein leakage
Cell autolysis
Cell swellingInhibition of anaerobic glycolysis
Opening of KATP channels
Cellular Ca accumulationStress protein translocation
Cytoskeletal reorganisation
Ultrastructural changes
Min
ute
sH
ours
?
myocardial injury
Optimal conditions for Cardiac surgery?Optimal conditions for Cardiac surgery?Optimal conditions for Cardiac surgery?Optimal conditions for Cardiac surgery?
The ideal conditions required by a surgeon for a successful heart operation:
Effect of Cardioplegic ProtectionEffect of Cardioplegic ProtectionEffect of Cardioplegic ProtectionEffect of Cardioplegic Protection
Cardiac surgery and myocardial protectionCardiac surgery and myocardial protectionCardiac surgery and myocardial protectionCardiac surgery and myocardial protection
♥ 1973-75 - revival of elevated K+-arrest [lab studies]
♥ 1975 - St Thomas’ Hospital cold crystalloid K+-cardioplegia
♥ 1979 - cold blood K+-cardioplegia
♥ 1991 - warm blood K+-cardioplegia
60
70
80
90
100
Fre
qu
en
cy (
%)
of
Su
rgeo
ns U
sin
g M
eth
od Cold crystalloid cardioplegia
Blood cardioplegia
65.9 64.8
83.5
Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)
Karthik et al, Ann Roy Coll Surg Engl 2004; 86: 413-415.
70
80
90
100F
req
uen
cy (
%)
of
Su
rgeo
ns U
sin
g M
eth
od
Cold crystalloid cardioplegia
Blood cardioplegia
83.5%
78.9%
Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)Myocardial Protection: UK Survey (2004)
♥ It is likely that inadequate myocardial protection (especially in the aged or high risk patient) is one of the factors that contribute to this increased myocardial injury!
Mechanism of KMechanism of KMechanism of KMechanism of K++++----based arrest?based arrest?based arrest?based arrest?
induces a ‘depolarisation’ of the resting membrane potential.
ExcitationExcitationExcitationExcitation----Contraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for Arrest
-80
-60
-40
-20
0
+20
Action p
ote
ntial
Em
(mV
)
-50mV (depolarised arrest)
High K+e
SRL-type Ca2+ Channels
K+ Channels
Ca2+
Fast Na+
Channels
Cardiac myocyte
Na+ K+
-60
-50
-40
-30
Resti
ng
mem
bra
ne p
ote
nti
al (m
V)
Principles of KPrinciples of KPrinciples of KPrinciples of K++++ Arrest: Arrest: Arrest: Arrest: depolarisationdepolarisationdepolarisationdepolarisationCalculated resting membrane potential (Em)
Effect of elevated KEffect of elevated KEffect of elevated KEffect of elevated K++++ on membrane potentialon membrane potentialon membrane potentialon membrane potential5 h global ischemia (5 h global ischemia (5 h global ischemia (5 h global ischemia (7.57.57.57.5°°°°CCCC))))
Membrane potential measured by sharp electrode during ischemia
–––– how can protection for all patients be how can protection for all patients be how can protection for all patients be how can protection for all patients be optimisedoptimisedoptimisedoptimised????
♥ should lead to cardioprotection from cellular perspective
♥ should also attenuate adverse effects of I/R in higher risk patients
ExcitationExcitationExcitationExcitation----Contraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for Arrest
-80
-60
-40
-20
0
+20
Action p
ote
ntial
Em
(mV
)
-70mV (polarised arrest)
SRL-type Ca2+ Channels
K+ Channels
Ca2+
Fast Na+
Channels
TTXLidocaineProcaine
Cardiac myocyte
K+Na+
K+
-40
-50
Mem
bra
ne P
ote
nti
al (m
V)
Effect of elevated KEffect of elevated KEffect of elevated KEffect of elevated K++++ on membrane potentialon membrane potentialon membrane potentialon membrane potential5 h global ischemia (5 h global ischemia (5 h global ischemia (5 h global ischemia (7.57.57.57.5°°°°CCCC))))
Membrane potential measured by sharp electrode during ischemia
Depolarised vs polarised arrest:Depolarised vs polarised arrest:Depolarised vs polarised arrest:Depolarised vs polarised arrest: 8h global ischemia (7.58h global ischemia (7.58h global ischemia (7.58h global ischemia (7.5ºC)C)C)C)
♥ Compared to depolarised arrest, polarisedarrest improved protection.
ExcitationExcitationExcitationExcitation----Contraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for Arrest
♥ High-dose esmolol (1 mM) arrests the heart, and can be used as an effective cardioplegic agent with similar (at least) efficacy to St Thomas’ Hospital cardioplegia.
♥ Esmolol cardioplegia is effective when used as a blood cardioplegic solution, with improved protection
cardioplegic solution, with improved protection compared to St Thomas’ Hospital cardioplegia.
♥ Esmolol cardioplegia is effective when used during hypothermic (32ºC) ischemia. Extended infusion
durations are effective, with improved protection compared to St Thomas’ Hospital cardioplegia.
♥ Esmolol cardioplegia may be an effective alternative to hypothermic K+-based cardioplegia.
ExcitationExcitationExcitationExcitation----Contraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for Arrest
-80
-60
-40
-20
0
+20
Action p
ote
ntial
Em
(mV
)Esmolol is an effective cardioplegic agent
SRL-type Ca2+ Channels
K+ Channels
Ca2+
Fast Na+
Channels
Cardiac myocyte
Na+ K+
?Esmolol
♥ Isolated rat ventricular myocytes
♥ Voltage clamped using the ruptured patch technique
Esmolol doseEsmolol doseEsmolol doseEsmolol dose----response on Naresponse on Naresponse on Naresponse on Na----current current current current
in voltage clamped cellsin voltage clamped cellsin voltage clamped cellsin voltage clamped cells
New concepts for improving myocardial protectionNew concepts for improving myocardial protectionNew concepts for improving myocardial protectionNew concepts for improving myocardial protection
1st step
10th step
0
50
100
0.01 0.03 0.1 0.3 1 3Esmolol concentration (mM)
I Na(
%co
ntr
o
5 ms
200 pA
IC50 = 0.17±0.03 mM
ExcitationExcitationExcitationExcitation----Contraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for ArrestContraction Coupling and Targets for Arrest
-80
-60
-40
-20
0
+20
Actio
n p
ote
ntia
l
Em
(mV
)
SRL-type Ca2+ Channels
K+ Channels
Ca2+
Fast Na+
Channels
Cardiac myocyte
Na+ K+
EsmololEsmolol
?
♥ Esmolol has pronounced inhibitory effects on the L-type Ca2+-
channel and the Na+-channel. This explains its negative
inotropic and arresting effect, independent from its β-blocking
♥ The inhibitory effect of esmolol on the Na+-channel suggests
induction of polarised arrest, and hence beneficial
advantages over depolarised (high K+) cardioplegia.
Criteria for an Optimum Clinical Cardioplegic SolutionCriteria for an Optimum Clinical Cardioplegic SolutionCriteria for an Optimum Clinical Cardioplegic SolutionCriteria for an Optimum Clinical Cardioplegic Solution