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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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Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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Page 1: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 2: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 3: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 4: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 5: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

CardioplegiaCardioplegiaCardioplegiaCardioplegia

Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples

♥ elective, rapid and reversible

paralysis of the heart during

cardiac surgery (CPB)

Page 6: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

♥ ‘‘‘‘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])

Page 7: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 8: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 9: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 10: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 11: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 12: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 13: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 14: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

The “Blue Book”

Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples

n = 400,394 patients

Published in 2009

Page 15: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples

Page 16: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples

Page 17: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 18: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

Myocardial Protection Myocardial Protection Myocardial Protection Myocardial Protection PPPPrinciplesrinciplesrinciplesrinciples

Page 19: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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)

Page 20: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

♥ 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!

Page 21: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 22: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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+

Page 23: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

-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

Page 24: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 25: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 26: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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????

Page 27: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 28: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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+

Page 29: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 30: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 31: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

*

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

Page 32: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

**

§

*

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

Page 33: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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.

Page 34: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

Page 35: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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!

Page 36: Myocardial Protection Principles David J Chambersscansect.org/wp-content/uploads/2015/04/03-Myocardial... · 2015. 4. 4. · Myocardial Protection Myocardial Protection PPPPrinciplesrinciples

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

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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

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♥ 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

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♥ 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.

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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.

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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

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♥ 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

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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

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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 (%

)

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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

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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

?

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♥ 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.

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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.

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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?

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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)

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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

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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

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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.

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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.

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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

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