Myocardial Protection PrinciplesMyocardial Protection PrinciplesMyocardial Protection PrinciplesMyocardial Protection Principles
David J ChambersDavid J ChambersDavid J ChambersDavid J Chambers
Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic Cardiac Surgical Research/Cardiothoracic SurgerySurgerySurgerySurgery
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:
♥ bloodless field (good visualisation)
♥ non-beating heart (for operative ease)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
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:
♥ bloodless field (so surgeon can see)
♥ non-beating heart (for ease of operation)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Cardiac surgeons needed a means of delaying the onset of irreversible myocardial injury during the elective
ischemia that is induced to correct the lesion.
Ischemia is convenient for surgeon but damaging for heart.
Many techniques tried, but most successful has been Cardioplegia
These conditions can most easily be achieved by global ischemia
CardioplegiaCardioplegiaCardioplegiaCardioplegia
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ elective, rapid and reversible
paralysis of the heart during
cardiac surgery (CPB)
♥ ‘‘‘‘intracellularintracellularintracellularintracellular----type’type’type’type’
low Na+, low or zero Ca2+, (high K+)
Cardioplegic SolutionsCardioplegic SolutionsCardioplegic SolutionsCardioplegic Solutions
Two basic Two basic Two basic Two basic types:types:types:types:
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
low Na+, low or zero Ca2+, (high K+)
(Bretschneider HTK solution (Custodiol), UW solution)
♥ ‘extracellular‘extracellular‘extracellular‘extracellular----type’type’type’type’
moderate K+ elevation, normal Na+, normal Ca2+
(St Thomas’ Hospital solutions (STH1 and Plegisol [STH2]), Celsior solution, blood solutions [Buckberg])
St Thomas’ Hospital:St Thomas’ Hospital:St Thomas’ Hospital:St Thomas’ Hospital:
Concept forConcept forConcept forConcept for Effective Cardioplegic ProtectionEffective Cardioplegic ProtectionEffective Cardioplegic ProtectionEffective Cardioplegic Protection
3 factors of importance:3 factors of importance:3 factors of importance:3 factors of importance:
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ Induction of rapid chemical arrestconserve energy and provide a still operating field
♥ Hypothermiareduce the rate of metabolism
♥ Addition of anti-ischemic agentsenhance protection by combating specific deleterious ischemia-induced changes
CompoundCompoundCompoundCompound Concentration (Concentration (Concentration (Concentration (mmolmmolmmolmmol/l) /l) /l) /l)
Sodium chloride
Potassium chloride
144.0
20.0
110.0
16.0
STH1STH1STH1STH1 STH2 (STH2 (STH2 (STH2 (PlegisolPlegisolPlegisolPlegisol))))
St Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic Solutions
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Potassium chloride
Magnesium chloride
Calcium chloride
Sodium bicarbonate
Procaine hydrochloride
Osmolarity (mOsmol/l)
pH
20.0
16.0
2.2
----
1.0
300-320
5.5-7.0
16.0
16.0
1.2
10.0
----
285-300
7.8
80
100
120R
ec
ove
ry (
%) Cardioplegia
+ treatment
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
0
20
40
60
Duration of Ischemia (Time)
Re
co
ve
ry (
%)
Ischemia
Cardioplegia
Historical developments!Historical developments!Historical developments!Historical developments!
♥ 1952-53 - 1st open heart operation/cardiopulmonary bypass
♥ 1955-60 - concept of cardioplegia by elevated K+-arrest
♥ [1960s - concept of Na+ poor/Ca2+-depletion arrest: Bretschneider/HTK solution]
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Bretschneider/HTK solution]
♥ 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)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0
10
20
30
40
50
Fre
qu
en
cy (
%)
of
Su
rgeo
ns U
sin
g M
eth
od
1999
34.1
2002
35.2
2004
16.5
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)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0
10
20
30
40
50
60
Fre
qu
en
cy (
%)
of
Su
rgeo
ns U
sin
g M
eth
od
2004
16.5%
Cold
21.1%
Warm
Karthik et al, Ann Roy Coll Surg Engl 2004; 86: 413-415.
Historical developments!Historical developments!Historical developments!Historical developments!
♥ 1952-53 - 1st open heart operation/cardiopulmonary bypass
♥ 1955-60 - concept of elevated K+-arrest
♥ [1960s - concept of Na+ poor/Ca2+-depletion arrest: Bretschneider/HTK solution]
The basic concept of K+ arrest has been universal in
cardiac surgery since mid-70’s ~ 35 years
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Bretschneider/HTK solution]
♥ 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
These trends, although important, involve
relatively minor changes.
The “Blue Book”
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
n = 400,394 patients
Published in 2009
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Current practice is to operate on patients who are:
♥ Older, sicker with more diffuse and severe ischemic heart disease.
♥ Hypertrophy and heart failure.
♥ Rapid revascularisation after ACS/NSTEMI.
Patients undergoing cardiac surgery
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ Likely to have a reduced tolerance to ischemia/reperfusion (I/R) injury, and thus require enhanced protection.
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Circulation 2006; 14: 1468
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0 - 2.2
2.2 - 4.3
4.3 - 8.5
>8.5
POD1 TnI (µg/L)
♥ These data suggest that increased myocardial injury during surgery has implications for post-operative mortality and morbidity.
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Current patients undergoing cardiac surgery
operative mortality and morbidity.
♥ 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?
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Elevated extracellular K+ concentration
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)
Threshold potential for
Ca channel activation
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
403020100-100
-90
-80
-70
-60
Extracellular Potassium Concentration (mM)
Resti
ng
mem
bra
ne p
ote
nti
al (m
V)
Threshold potential for
Na channel inactivation
STH2 = 16 mM K+
4
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
16 mM K+
-40
-50
Re
sti
ng
Me
mb
ran
e P
ote
nti
al
(mV
)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
-60
-70
-80
0 60 120 180 240 300
Ischemic Duration (min)
Re
sti
ng
Me
mb
ran
e P
ote
nti
al
(mV
)
Snabaitis et al Circulation 1997;96:3148
Ischemia and hypothermia inhibits Na/K-ATPase
Limitations of KLimitations of KLimitations of KLimitations of K++++----induced induced induced induced
depolarised membrane potentialdepolarised membrane potentialdepolarised membrane potentialdepolarised membrane potential
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Na+ window current
Na+/H+
exchangeNa+ loading
Ca2+
window current
K+>>16mM
Na/Ca exchangereverse mode
K+>>16mM
Ca2+ loading
Maintained energy (ATP) utilisation, contracture, reperfusion injury, cell death
2013201320132013
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
–––– 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????
Polarised ArrestPolarised ArrestPolarised ArrestPolarised Arrest
Myocardial cell membrane potential is maintained at or near the resting membrane potential and leads to:
• balanced ionic gradients
• few channels or pumps activated
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
• few channels or pumps activated
• little metabolic demand
♥ 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
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
TTX
-60
-70
-80
0 60 120 180 240 300
Ischemic Duration (min)
Mem
bra
ne P
ote
nti
al (m
V)
Snabaitis et al Circulation 1997;96:3148
Depolarised Depolarised Depolarised Depolarised vsvsvsvs polarised polarised polarised polarised arrest arrest arrest arrest
Isolated working rat hearts: 5h global ischemia (7.5ºC)
40
50
60
Reco
very
of
Ao
rtic
Flo
w (
%)
*
*
§§§§
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0
10
20
30
Reco
very
of
Ao
rtic
Flo
w (
%)
KH(Control)
Depolarised(K+:16 mM)
Polarised(TTX: 22µM)
Snabaitis et al Circulation 1997;96:3148
*
ATPCP
12
10
8
en
erg
y p
ho
sp
ha
ted
wt)
*
§§§§
*
High-energy phosphate content at the end of ischemia (5h; 7.5°C)
Depolarised Depolarised Depolarised Depolarised vsvsvsvs polarised polarised polarised polarised arrest arrest arrest arrest
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
KH(Control)
Depolarised(K+: 16 mM)
Polarised(TTX: 22µM)
6
4
2
0
Myo
ca
rdia
l h
igh
-en
erg
y
(µM
/g d
wt
Snabaitis et al Circulation 1997;96:3148
**
§
*
50
60
70
80
90
Reco
very
of
Ao
rtic
Flo
w (
%)
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)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
TTX +HOE694(10 µM)
STH2TTX +HOE694 +
Furosemide(1.0 µM)
TTX +HOE694 +
Furosemide +BDM
(30 mM)
0
10
20
30
40
50
TTX(22 µM)
Reco
very
of
Ao
rtic
Flo
w (
%)
Snabaitis et al JTCVS 1999;118:123
SummarySummarySummarySummary
♥ Polarised arrest can be achieved with a variety of agents that target the fast Na+-channel [and the ATP-dependent K+-channel].
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ 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
-80
-60
-40
-20
0
+20
Action p
ote
ntial
Em
(mV
)
Esmolol
SRL-type Ca2+ Channels
K+ Channels
Ca2+
Fast Na+
Channels
Cardiac myocyte
Na+ K+
Esmolol
Esmolol
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ Ultra-short-acting cardioselective β-blocker: half-life ~9 min.
♥ Rapid systemic clearance: esterase hydrolysis.
♥ High concentrations (~1mM) induce arrest!
50
75
100
baseli
ne
va
lue
Atrial rate
Ventricular rate
EsmololEsmololEsmololEsmolol as Cardioplegic Agent:as Cardioplegic Agent:as Cardioplegic Agent:as Cardioplegic Agent: DoseDoseDoseDose----responseresponseresponseresponse
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0
25% o
f b
aseli
ne
0.01 0.1 1 10
Esmolol concentration (mM)
LVDP
Bessho and Chambers JTCVS 2001;122:993
EsmololEsmololEsmololEsmolol cardioplegia cardioplegia cardioplegia cardioplegia vsvsvsvs STHSTHSTHSTH
70
80
90
100
Reco
very
of
LV
DP
(%
)
**
♥ Langendorff-perfused rat hearts♥ Global (37ºC) ischemia (40 min), multidose infusion - 2 min every 10 min
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0
10
20
30
40
50
60
Reco
very
of
LV
DP
(%
)
Control STH2 EA (1mM)
Bessho and Chambers JTCVS 2001;122:993
♥ Langendorff-perfused rat hearts♥ Global (37ºC) ischemia (60 min), multidose infusion - 3 min every 15 min
EsmololEsmololEsmololEsmolol Blood Blood Blood Blood Cardioplegia Cardioplegia Cardioplegia Cardioplegia vsvsvsvs STHSTHSTHSTH
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Fujii and Chambers JMCC 2004; 37: 210.
MultipleBlood Esmolol
MultipleBlood STH
♥ Langendorff-perfused rat hearts♥ Global (32ºC) ischemia (multidose infusion - 3 min every 30 min)
EsmololEsmololEsmololEsmolol cardioplegia cardioplegia cardioplegia cardioplegia vsvsvsvs STH:STH:STH:STH: Hypothermic (32°C) ischemia
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Nishina and Chambers JMCC 2005; 38: 1051.
Summary
♥ 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
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
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 Cardioplegia:Esmolol Cardioplegia:Esmolol Cardioplegia:Esmolol Cardioplegia: Characterisation studies
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
Calcium current (34°C) using voltage clamping on a single myocyte
0
100-60 -40 -20 0 20 40 60
mV
Inhibition of Ca2+ channels
Esmolol doseEsmolol doseEsmolol doseEsmolol dose----response on Caresponse on Caresponse on Caresponse on Ca----current current current current
in voltage clamped cellsin voltage clamped cellsin voltage clamped cellsin voltage clamped cells
-900
-800
-700
-600
-500
-400
-300
-200
-100
pA
Control
Esmolol 0.1mM
Esmolol 0.3mM
Esmolol 1mM
Esmolol 3mM
75
100
IC50 = 0.449 mMc
urr
en
t (%
)
n=5
Inhibition of L-type Ca2+ channels
Esmolol doseEsmolol doseEsmolol doseEsmolol dose----response on Caresponse on Caresponse on Caresponse on Ca----current current current current
in voltage clamped cellsin voltage clamped cellsin voltage clamped cellsin voltage clamped cells
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
0.01 0.1 1 10 1000
25
50
Log-dose esmolol (mM)
L-t
yp
e C
ac
urr
en
t (%
)
Inhibition of fast Na+ channels
150
ol)
ControlEsmolol (0.2 mM)
Washout
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
effect.
SummarySummarySummarySummary
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ 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
♥ Rapid diastolic arrest.
♥ Delay onset of irreversible ischemic injury.
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ Delay onset of irreversible ischemic injury.
♥ Rapid reversibility of arresting agent.
♥ No prolonged systemic toxic effect of arresting agent.
Suitability of arresting agents for clinical cardioplegia
Cardioplegia criteria
Potential cardioplegic agents
Lid
oc
ain
e
Ad
en
os
ine
Ve
rap
am
il
BD
M
Es
mo
lol
TT
X
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
♥ Rapid diastolic arrest.
♥ Delay onset of irreversible injury.
♥ Rapid reversibility.
♥ No prolonged systemic toxic effect.
Lid
oc
ain
e
Ad
en
os
ine
Ve
rap
am
il
BD
M
Es
mo
lol
TT
X?
EsmololEsmololEsmololEsmolol + Adenosine Cardioplegia+ Adenosine Cardioplegia+ Adenosine Cardioplegia+ Adenosine Cardioplegia
*
LV
DP
(%
co
ntr
ol)
100
80
* * *
p<0.05 vs STH
*
♥ Langendorff-perfused rat hearts
♥ Global ischemia (4h), room temperature (23ºC), 30 min re-infusion
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
LV
DP
(%
co
ntr
ol)
0 10 20 30 40 50 60
60
40
20
0STH2
Lidocaine (0.6mM)+Adenosine (0.25mM)
Esmolol (0.6mM)+Adenosine (0.25mM)
Reperfusion Time (min)
Esmolol + Adenosine Cardioplegia: effect of additivesEsmolol + Adenosine Cardioplegia: effect of additivesEsmolol + Adenosine Cardioplegia: effect of additivesEsmolol + Adenosine Cardioplegia: effect of additives
** *
*
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
2 5 10 5 10 15 BDM (5)+
Mg2+ (10)BDM (mM) Mg2+ (mM)
C
PigPigPigPig Study (ViennaStudy (ViennaStudy (ViennaStudy (Vienna))))
♥ STHPol (Es-Ad-Mg) versus STH2, in pigs on CPB (6/group)
♥ 60 min ischemia, 180 min reperfusion (60 min on-pump, 120 min off-pump)
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
130
140
Cardiac output
**
160
180
External Heart Work
** *
140
150
LVP sys
** *
60
70
80
90
100
110
120
130*
Re
co
ve
ry (
%)
Reperfusion (min)
Re
co
ve
ry (
%)
60
80
100
120
140
160* *
Reperfusion (min)
Re
co
ve
ry (
%)
Reperfusion (min)
60
70
80
90
100
110
120
130
140*
STH2STHPol
* p<0.05
EsmololEsmololEsmololEsmolol----based Cardioplegia:based Cardioplegia:based Cardioplegia:based Cardioplegia:
♥ was at least equal to, and probably superior to, St Thomas’
Hospital cardioplegia as crystalloid or blood-based solutions and
at normothermia or hypothermia.
♥ esmolol blocks the fast Na+- and L-type Ca2+-channels, initiating
polarised arrest; a combination of esmolol and adenosine (a K+-
SummarySummarySummarySummary
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
polarised arrest; a combination of esmolol and adenosine (a K+-
channel opener) synergistically improves function.
♥ both agents have short half-lives, metabolised independently
from the liver or kidney, improving clinical feasibility.
♥ adding anti-ischemic agents improves protection.
♥ studies evaluating efficacy of esmolol-adenosine cardioplegia in
pigs undergoing CPB suggest similar (at least) efficacy to STH2.
ConclusionConclusionConclusionConclusion
♥ Cardioplegic arrest during cardiac surgery can be induced by ‘intracellular-type’ or ‘extracellular-type’ solutions.
♥ During the past ~35 years, cardioplegia solutions have changed only minimally despite huge surgery criteria changes in patients.
♥ Current K+-based cardioplegic solutions (depolarised arrest) are probably not optimal for the current older and sicker patients
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
probably not optimal for the current older and sicker patients requiring cardiac surgery.
♥ Alternative protection concepts, such as the use of agents that induce polarised arrest, are likely to provide improved protection.
♥ Optimal protection should be the aim for all cardiac surgery patients.
♥ Esmolol-based cardioplegia may fulfill this role.
Acknowledgements
Dr Ryuzo Bessho
Dr Masahiro Fujii
Nippon Medical SchoolSt Thomas’ Hospital
Dr Andrew Snabatis
Dr Omal Walgama
Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples
University of Vienna
Dr Bruno Podesser
Dr David Santer
Dr Dai Nishina
Dr Yuji Maruyama
Dr Hazem Fallouh
Dr Elaine Teh