1. Myocardial preconditioning Joel Starkopf Departement of Anaesthesiology and Intensive Care University of Tartu Estonia

2. Myocardial preconditioning Content of the lecture Ischaemic preconditioning Early vs. late preconditioning Evidence, incl. humans Anaesthetics and preconditioning

3. 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

4. Murry CE, et al. Circulation 1986

5. 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

6. 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

7. Evidence in humans Angina and acute myocardial infarction Kloner et al. Circulation 1995; 91:37-47 Ottani et al. Circulation 1995; 91:291-296 Percutaneous transluminal coronary angioplasty Deutch et al. Circulation 1990; 82:2044-2051 Cribier et al. J Am Coll Card 1992; 20:578-586 Cardiac surgery Yellon et al. Lancet 1993; 342: 276-277 Isolated atrial trabeculae Walker et al. J Mol Cell Cardiol 1995; 27:1349-1357

8. Evidence in humans In vivo –Preinfarction angina –PTCA –Cardiac surgery In vitro –Isolated myocardial cells Anaesthetic preconditioning

9. EXTRACELLULAR CYTOSOL Adenosin Prostaglandins Bradykinin Opioids Noradrenalin Acetylcholine NO ROI    PLC PLD PKC ROI TyK MAPK MAPKAP Effector? Transcription mRNA HSP iNOS MnSOD COX-2 I  B  K ATP NF  B ROI AO defence

11. 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

12. 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

13. 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, K ATP channel blocker) Opioids – delayed preconditioning? Opioids Anaesthetic preconditioning

14. Volatile anaesthetics 1985 Freedman et al.: enflurane improved postischaemic functional recovery - 1997 Preservation of ATP, reduction in Ca 2+ influx to the cell, inhibition of free radical formation, activation of K ATP channels 1997 -Relation of ischaemic preconditioning and anaesthetic- induced protection, and examination of coronary system Selective adenosine A 1 receptor antagonist, G i protein inhibitor, PKC inhibitor, K ATP channel blocker, NF  B Halogenated anaesthetics provide protection via mechanism similar to that of early ischaemic preconditioning Anaesthetic preconditioning

15. 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

16. 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

17. Anaesthetic preconditioning

18. 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

19. 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

20. 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

21. 0 20 40 60 80 INFARCT SIZE 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

22. CONTROL HYPEROXIA 0 10 20 30 * Infarction (% of risk zone) Tähepõld P, et al. Acta Physiol Scan 2002, 175(4):271-277. Regional ischaemia model

23. 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