Myocardial preconditioning

Joel Starkopf

Departement of Anaesthesiology and Intensive Care

University of Tartu

Estonia

Myocardial preconditioning

Content of the lecture

• Ischaemic preconditioning

• Early vs. late preconditioning

• Evidence, incl. humans

• Anaesthetics and preconditioning

Murry CE, Jennings RB & Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–1136.

Brief episodes of ischaemia and reperfusion protect the heart against subsequent sustained ischaemia.

Ischaemic preconditioning

Murry CE, et al. Circulation 1986

Ischaemic preconditioning

• Reduces infarct size• Improves recovery of function at reperfusion

(reduced myocardial stunning)• Less reperfusion arrhytmias

• Strongest endogenous protective mechanism of the heart

• In all animal species tested

• Classic (early) and delayed(late) preconditioning

Ischaemic preconditioning

Early phase of protection (classic or early preconditioning):

• Begins shortly after preconditioning stimulus• Lasts for 2…3 hours

Second episode of protection (late preconditioning):

• Begins 12…24 hours after preconditioning stimulus

• Lasts for 48…72 hours

Evidence in humans

• Angina and acute myocardial infarctionKloner et al. Circulation 1995; 91:37-47Ottani et al. Circulation 1995; 91:291-296

• Percutaneous transluminal coronary angioplasty

Deutch et al. Circulation 1990; 82:2044-2051Cribier et al. J Am Coll Card 1992; 20:578-586

• Cardiac surgeryYellon et al. Lancet 1993; 342: 276-277

• Isolated atrial trabeculaeWalker et al. J Mol Cell Cardiol 1995; 27:1349-1357

Evidence in humans

• In vivo– Preinfarction angina– PTCA– Cardiac surgery

• In vitro– Isolated myocardial cells

• Anaesthetic preconditioning

EXTRACELLULAR

CYTOSOL

AdenosinProstaglandinsBradykininOpioidsNoradrenalinAcetylcholine

NO ROI

PLCPLD

PKC

ROI TyK

MAPK

MAPKAP

Effector?

Transcription

mRNA

HSPiNOSMnSODCOX-2IB

KATPNFB

ROI

AOdefence

Anaesthetic preconditioning

• Opioids• Halogenated volatile anaesthetics

Further readings:

De Hert SG. The concept of anaesthetic-induced cardioprotection: clinical relevance.Best Practice & Research Clinical Anaesthesiology, 2005 (19): 445–459.

Weber N, Schlack W. The concept of anaesthetic-induced cardioprotection: mechanisms of action. Best Practice & Research Clinical Anaesthesiology Vol. 19, No. 3, pp. 429–443, 2005

• 1995 Schultz et al. – involvement of opioid receptors incellular signalling of ischaemic preconditioning

• Exogenous opioids (morphine) protect the heart against mechanical dysfunction and infarction (Schultz et al. 1996)

• 2000 Kato et al. – fentanyl enhances postischaemic mechanical function and reduces infarct size

• Pentazocine, buprenorphine

Opioids

Anaesthetic preconditioning

• 1999 Xenopoulos et al.- intracoronary morphine (15 g/kg) mimicks ischaemic preconditioning in man (ST changes)

• 1999 Tomai et al. – naloxone blocked the adaption to ischaemia during repeated periods of PTCA

• 2000 Bell et al. - -opioid agonist protect atrial tissue against the damage from ischaemia-reperfusion (-opioid antagonist, KATP channel blocker)

• Opioids – delayed preconditioning?

Opioids

Anaesthetic preconditioning

Volatile anaesthetics

1985 Freedman et al.: enflurane improved postischaemic functional recovery

- 1997 Preservation of ATP, reduction in Ca2+ influx to the cell, inhibition of free radical formation, activation of KATP channels

1997 - Relation of ischaemic preconditioning and anaesthetic-induced protection, and examination of coronary system

Selective adenosine A1 receptor antagonist, Gi protein inhibitor, PKC inhibitor, KATP channel blocker, NFB

Halogenated anaesthetics provide protection via mechanism similar to that of early ischaemic preconditioning

Anaesthetic preconditioning

De Hert SG. Best Practice & Research Clinical Anaesthesiology, 2005 (19): 445–459.

I/v anaesthesia vs. volatile anaesthetics

Pooled data from total number of 235 patients

- sevoflurane- isoflurane

Anaesthetic preconditioning

De Hert SG. Best Practice & Research Clinical Anaesthesiology, 2005 (19): 445–459.

Pooled data from total number of 235 patients

- sevoflurane- isoflurane

Anaesthetic preconditioning

I/v anaesthesia vs. volatile anaesthetics

Anaesthetic preconditioning

Volatile anaesthetic agents

• May have a cardioprotective effect that occurs independently of their effects on myocardial oxygen balance

• The cardioprotective properties are related to a preconditioning effect and an effect on the extent of reperfusion injury

• The cardioprotective effects are most evident when the agent is administered throughout the entire procedure

Anaesthetic preconditioning

Potential harmful mechanisms

• Opening of the KATP-channels is a central mechanism in signal transduction of preconditioning

– Thiopental is safe at clinical doses

– Ketamine blocks Katp channels (R-(-)isomer; racemic mixture)

– Glibenclamide

Volatile anaesthetic agents

• Further large multicentre trials should clarify whether the choice of a volatile anaesthetic regimen might help to reduce perioperative morbidity and mortality in patients with ischaemic heart disease

• The clinical implications of the cardioprotective properties of volatile anaesthetic agents in non-cardiac surgery remain to be established

Anaesthetic preconditioning

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20

40

60

80

INF

AR

CT

SIZ

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CONTROL 95% 80% 60% 40%

(%) P=0.02

P=0.01

Tähepõld P, et al. Eur J Cardiothor Surg 2002;21:987-94 Global ischaemia model

Preconditioning with hyperoxia

CONTROL HYPEROXIA0

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20

30

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Infa

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(% o

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Tähepõld P, et al. Acta Physiol Scan 2002, 175(4):271-277.

Regional ischaemia model

• Preconditioning – strongest endogenous protective mechanism

• Early and late window of protection

• Angina and myocardial infarction

• Opioids induce preconditioning

• Volatile anaesthetics (sevoflurane) have cardioprotective properties related to a preconditioning effect

• Hyperoxia protects the rat heart from ischaemia-reperfusion injury by similar mechanisms as ischaemic preconditioning. Its effect on humans remains to be elucidated

Summary