myocardial protection principles david j...

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

Ischemiacauses R

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

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)

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

♥ 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:

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:

♥ 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

STH1STH1STH1STH1 STH2 (STH2 (STH2 (STH2 (PlegisolPlegisolPlegisolPlegisol))))

St Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic SolutionsSt Thomas' Hospital Cardioplegic Solutions

Potassium chloride

Magnesium chloride

Calcium chloride

Sodium bicarbonate

Procaine hydrochloride

Osmolarity (mOsmol/l)

300-320

5.5-7.0

285-300

%) 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

Duration of Ischemia (Time)

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]

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

od Cold crystalloid cardioplegia

Blood cardioplegia

65.9 64.8

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.

Cold crystalloid cardioplegia

Blood cardioplegia

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.

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

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”

n = 400,394 patients

Published in 2009

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

♥ Likely to have a reduced tolerance to ischemia/reperfusion (I/R) injury, and thus require enhanced protection.

Circulation 2006; 14: 1468

0 - 2.2

2.2 - 4.3

4.3 - 8.5

POD1 TnI (µg/L)

♥ These data suggest that increased myocardial injury during surgery has implications for post-operative mortality and morbidity.

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?

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

Action p

-50mV (depolarised arrest)

High K+e

SRL-type Ca2+ Channels

K+ Channels

Fast Na+

Channels

Cardiac myocyte

Na+ K+

Principles of KPrinciples of KPrinciples of KPrinciples of K++++ Arrest: Arrest: Arrest: Arrest: depolarisationdepolarisationdepolarisationdepolarisationCalculated resting membrane potential (Em)

Threshold potential for

Ca channel activation

403020100-100

Extracellular Potassium Concentration (mM)

Threshold potential for

Na channel inactivation

STH2 = 16 mM K+

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+

0 60 120 180 240 300

Ischemic Duration (min)

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

Na+ window current

Na+/H+

exchangeNa+ loading

window current

K+>>16mM

Na/Ca exchangereverse mode

K+>>16mM

Ca2+ loading

Maintained energy (ATP) utilisation, contracture, reperfusion injury, cell death

2013201320132013

–––– 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

• little metabolic demand

♥ should lead to cardioprotection from cellular perspective

♥ should also attenuate adverse effects of I/R in higher risk patients

Action p

-70mV (polarised arrest)

K+ Channels

Fast Na+

Channels

TTXLidocaineProcaine

Cardiac myocyte

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

0 60 120 180 240 300

Ischemic Duration (min)

Depolarised Depolarised Depolarised Depolarised vsvsvsvs polarised polarised polarised polarised arrest arrest arrest arrest

Isolated working rat hearts: 5h global ischemia (7.5ºC)

§§§§

KH(Control)

Depolarised(K+:16 mM)

Polarised(TTX: 22µM)

§§§§

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

KH(Control)

Depolarised(K+: 16 mM)

Polarised(TTX: 22µM)

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)

TTX +HOE694(10 µM)

STH2TTX +HOE694 +

Furosemide(1.0 µM)

TTX +HOE694 +

Furosemide +BDM

(30 mM)

TTX(22 µM)

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].

♥ Compared to depolarised arrest, polarisedarrest improved protection.

Action p

Esmolol

K+ Channels

Fast Na+

Channels

Cardiac myocyte

Na+ K+

Esmolol

♥ Ultra-short-acting cardioselective β-blocker: half-life ~9 min.

♥ Rapid systemic clearance: esterase hydrolysis.

♥ High concentrations (~1mM) induce arrest!

baseli

Atrial rate

Ventricular rate

EsmololEsmololEsmololEsmolol as Cardioplegic Agent:as Cardioplegic Agent:as Cardioplegic Agent:as Cardioplegic Agent: DoseDoseDoseDose----responseresponseresponseresponse

0.01 0.1 1 10

Esmolol concentration (mM)

Bessho and Chambers JTCVS 2001;122:993

EsmololEsmololEsmololEsmolol cardioplegia cardioplegia cardioplegia cardioplegia vsvsvsvs STHSTHSTHSTH

♥ Langendorff-perfused rat hearts♥ Global (37ºC) ischemia (40 min), multidose infusion - 2 min every 10 min

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

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

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

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.

Action p

)Esmolol is an effective cardioplegic agent

K+ Channels

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

Calcium current (34°C) using voltage clamping on a single myocyte

100-60 -40 -20 0 20 40 60

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

Control

Esmolol 0.1mM

Esmolol 0.3mM

Esmolol 1mM

Esmolol 3mM

IC50 = 0.449 mMc

Inhibition of L-type Ca2+ channels

Esmolol doseEsmolol doseEsmolol doseEsmolol dose----response on Caresponse on Caresponse on Caresponse on Ca----current current current current

0.01 0.1 1 10 1000

Log-dose esmolol (mM)

Inhibition of fast Na+ channels

ControlEsmolol (0.2 mM)

Washout

Esmolol doseEsmolol doseEsmolol doseEsmolol dose----response on Naresponse on Naresponse on Naresponse on Na----current current current current

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

0.01 0.03 0.1 0.3 1 3Esmolol concentration (mM)

200 pA

IC50 = 0.17±0.03 mM

K+ Channels

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.

♥ 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.

♥ 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

♥ Rapid diastolic arrest.

♥ Delay onset of irreversible injury.

♥ Rapid reversibility.

♥ No prolonged systemic toxic effect.

EsmololEsmololEsmololEsmolol + Adenosine Cardioplegia+ Adenosine Cardioplegia+ Adenosine Cardioplegia+ Adenosine Cardioplegia

p<0.05 vs STH

♥ Langendorff-perfused rat hearts

♥ Global ischemia (4h), room temperature (23ºC), 30 min re-infusion

0 10 20 30 40 50 60

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

2 5 10 5 10 15 BDM (5)+

Mg2+ (10)BDM (mM) Mg2+ (mM)

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)

Cardiac output

External Heart Work

LVP sys

Reperfusion (min)

160* *

Reperfusion (min)

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+-

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

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

University of Vienna

Dr Bruno Podesser

Dr David Santer

Dr Dai Nishina

Dr Yuji Maruyama

Dr Hazem Fallouh

Dr Elaine Teh

myocardial protection principles david j...

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