Cardiac preconditioning: myths and mysteries Enjarn Lin May 2011

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

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

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

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

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

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

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

 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

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

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

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

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

‘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

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

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

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

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

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

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.

 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

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

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

 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 MAC & Sevoflurane MAC

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

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

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

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