Cardiac preconditioning: myths and mysteries

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 • α2-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+ & Ca2+ influx

6. Ischaemia-reperfusion injury • Rapid normalisation of pH • Ca2+/ROS • Opening of mitochondrial permeabilitytransition pore (mPTP) • Uncoupling of oxidative phosphorylation

7. Goals of myocardial protection • Limit the duration and extent of ischaemia • Ensure the adequacy of timely reperfusion • 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

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 Brief ischaemia remotely or locally PreCon Ischaemia Reperfusion Remote ischaemia Ischaemia Reperfusion PerCon Ischaemia Reperfusion PostCon

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

17. The end effectors? mitochondrial permeability transition pore: Non-specific high conductance channel Opening uncouples oxidative phosphorylation & ATP depletion Prevention of opening underpins IPC/RIPC mitochondrial KATP channel: • Implicated as critical mediator • Sulphonylureas abolish IPC • Maintains Ca2+ homeostasis • Interaction with mPTP unclear

18. Clinical trials in RIC

19. Pharmacological preconditioning

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 KATP 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 • Propofol TIVA • Sevoflurane from sternotomy to CPB • Sevoflurane after coronary anastomosis • 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