1. Cardiac preconditioning: myths and mysteries Enjarn Lin May 2011

2. Introduction  Perioperative myocardial infarction is associated with prolonged hospital stay & increased mortality  Identify at risk patients  Institute therapeutic strategies  coronary revascularisation  β-blockade  α 2 -adrenoceptor agonists  aspirin & statins  prayer

3.  US Multicentre RCT  1802 patients undergoing CABG  Randomised to 3 groups:  Uncertain but received prayer  Uncertain & did not receive prayer  Certain & received prayer

4. Intercessory prayer  No effect on complication-free recovery from CABG  Intercessory prayer had a higher incidence of complications.

5. Ischaemia-reperfusion injury  ATP depletion  Accumulation of H +  Na + & Ca 2+ influx

6. Ischaemia-reperfusion injury  Rapid normalisation of pH  Ca 2+ /ROS  Opening of mitochondrial permeabilitytransition pore (mPTP)  Uncoupling of oxidative phosphorylation

7. Goals of myocardial protection 1. Limit the duration and extent of ischaemia 2. Ensure the adequacy of timely reperfusion 3. Modify the cellular responses to ischaemia- reperfusion injury 4. Cardiac conditioning

8. Ischaemic Preconditioning  4 cycles of 5 minute ischaemia with intermittent reperfusion prior to coronary occlusion  Subsequent infarct size 75% smaller than controls

9.  22 RCT’s 933 patients  On pump patients received cardioplegia or ICCF  Variable IPC protocols  Pooled analysis:  No difference in mortality or perioperative MI  Significant reductions in ventricular arrhythmias, inotrope use & ICU length of stay

10. Ischaemic PostConditioning  Conditioning stimulus applied after onset of myocardial ischaemia during reperfusion period  Similar ability to attenuate the detrimental effects of IRI as IPC.  Strategy to improve outcome from evolving myocardial infarction

11. Ischaemic postconditioning in cardiac surgery StudyPatient groupStimulusOutcomesNumber Luo 2007Repair Tetralogy of FallotAortic clamping (2 cycles of 5 min) Less troponin I release24 Luo 2008Valve surgery(cold-blood cardioplegia) Aortic clamping (3 cycles of 5 min) Reduced CK-MB No change to troponin I Less inotropic support 50 Luo 2008Congenital heart disease(cold-blood cardioplegia) Aortic clamping (2 cycles of 5 min) Less troponin I release Less inotropic support 40

12.  6 RCTs, 244 patients presenting with STEMI undergoing primary PCI  Significant reduction in peak CK & improved LV performance  Intervention benefit over standard care

13. Clinical Applicability  Clinical benefits limited :  Cardiology & cardiothoracic surgery  Transplantation  Inducing ischaemia in an already diseased target organ

14. ‘Preconditioning at a distance’  Brief episodes of ischaemia & reperfusion in LCx territory reduced size of a subsequent infarct due to occlusion of LAD coronary artery  Magnitude of ischaemic protection similar to direct ischaemic preconditioning  Extended to non cardiac organs: kidney, small intestine, brain & skeletal muscle  Remote ischaemic preconditioning or ischaemic preconditioning at a distance

15. Conditioning the myocardium IschaemiaReperfusion PostCon ReperfusionIschaemia PreCon Brief ischaemia remotely or locally ReperfusionIschaemia PerCon Remote ischaemia

16. Activation via G-protein couple receptor Mitogen-activated protein kinases Pro-survival protein kinases Mitochondrial K ATP channel Mitochondrial permeability Transition pore (mPTP)

17. The end effectors? mitochondrial K ATP channel:  Implicated as critical mediator  Sulphonylureas abolish IPC  Maintains Ca 2+ homeostasis  Interaction with mPTP unclear mitochondrial permeability transition pore:  Non-specific high conductance channel  Opening uncouples oxidative phosphorylation & ATP depletion  Prevention of opening underpins IPC/RIPC

18. Clinical trials in RIC StudyJournalPatient groupStimulusOutcomesNumber Cheung (2006)JACCPaediatric cardiac surgery Upper-limb ischaemia (4 cycles of 5 min) Reduced troponin; reduced inotrope score; reduced airway resistance 37 Hausenloy (2007) LancetCABGUpper-limb ischaemia (3 cycles of 5 min) Reduced troponin57 Ali (2007)CirculationAAA surgeryLower-limb ischaemia (2 cycles of 10 min) Reduced troponin; reduced perioperative MI; preserved renal function 82 Hoole (2009)CirculationElective coronary angioplasty Upper-limb ischaemia (3 cycles of 5 min) Reduced troponinI ; reduced MACCE 242 Venugopal (2009) HeartCABG (cold-blood cardioplegia) Upper-limb ischaemia (3 cycles of 5 min) Reduced troponin45 Botker (2009)LancetPrimary coronary angioplasty (STEMI) Upper-limb ischaemia (3 cycles of 5 min) Increased myocardial salvage; decreased infarct size at 1 month 333

19. Pharmacological preconditioning StudyPatient groupDrugOutcomesNumber Mangano 2006CABGAcadesine (adenosine modulator) No difference in MI2698 Kitakaze 2007STEMIAtrial Natriuretic Peptide and Nicorandil ANP: decreased infarct size & improved LV function Nicorandil: No difference 1216 Mentzer 2008CABGCariporide (Na + /H + exchange inhibitor) Decreased MI Increased CVA 5761

20. Opioid preconditioning  Opioids (via δ&κ receptors) can trigger cardiac preconditioning; naloxone blocks preconditioning  Cardiomyocytes sites of endogenous opioid synthesis, storage and release  Opioids act as autocoids, released during times of stress & ischaemia  Open the K ATP channel & close the mPTP.

21.  46 patients undergoing CABG randomised to morphine or fentanyl before CPB  No difference in BNP or troponin  Morphine improved LV function  40 patients randomised to receive remifentanil bolus & infusion prior to sternotomy  Primary outcome troponin I reduced  Shorter mechanical ventilation time

22. Volatile anaesthetic preconditioning  Volatile anaesthetics can protect the myocardium  Volatile anaesthetics can similarly precondition/postcondition the myocardium  Similar mechanistic pathways as ischaemic conditioning  Evidence of volatile anaesthetic late preconditioning

23. Clinical trials with volatile anaesthetics  Randomized 200 patients undergoing CABG to 4 anaesthetic protocols 1. Propofol TIVA 2. Sevoflurane from sternotomy to CPB 3. Sevoflurane after coronary anastomosis 4. Sevoflurane from sternotomy  Compared to TIVA, continuous Sevoflurane significantly reduced troponin I leakage for the first 48 hours

24.  22 RCTs identified, 1922 patients undergoing cardiac surgery, all too small to report on mortality  Predominantly undergoing on-pump CABG, 6 RCTs of OPCAB, 1 of mitral surgery  Majority had volatile throughout; 6 had volatile only before or during expected period of ischaemia  Dosage: Desflurane 0.15-2.0 MAC & Sevoflurane 0.25-4.0 MAC

25. Landoni et al. 2007   enzyme leak   inotrope requirement   mechanical ventilation time   ICU length of stay   hospital length of stay   MI   all cause mortality

26. PostConditioning  58 patients with STEMI  IV cyclosporine (non specific mPTP blocker) prior to PCI  Reduction in enzyme leakage  Significant reduction in infarct size assessed by cardiac MRI

27. RCTs in conditioning for IRI  >50 ischaemic conditioning  Predominately RIC  >40 pharmacological preconditioning  Predominately volatile anaesthesia

28. Conclusions  Brief ischaemia is good/prolonged ischaemia is bad  Anaesthesia is good for you!  Larger trials are required  Praying for our patients doesn’t appear to improve outcomes