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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
0
20
40
60
80
INF
AR
CT
SIZ
E
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
10
20
30
*
Infa
rcti
on
(% o
f ri
sk z
on
e)
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