Minimise the damage – Pre- and Post-conditioning Dr Derek J Hausenloy The Hatter Cardiovascular Institute, University College London, UK. Myocardial Recovery Session ADVANCED CARDIOVASCULAR INTERVENTION 2010 London, Thursday January 28 th 2010.

NO CONFLICT OF INTEREST TO DECLARE

Novel treatment strategies are required to reduce myocardial injury and improve clinical outcomes. ‘Conditioning’ the heart is an endogenous protective phenomenon. Pre- and Post- Conditioning offer novel strategies for minimising the damage. Background

What is Pre- and Post- condtioning? No ‘Conditioning’ Heart Ischaemia Reperfusion ‘Conditioned’ Ischaemic Postconditioning 2003 < 1min Ischaemic Preconditioning 1986, to 3 hrs hrs CABG surgery Cardiac Tx NSTEMI undergoing PCI Elective PCI CABG surgery Cardiac Tx Cardiac arrest STEMI CABG surgery STEMI Cardiac Tx Cardiac arrest Remote Ischaemic Preconditioning Remote Ischaemic Perconditioning Remote Ischaemic Postconditioning

RIPC in CABG surgery Hausenloy et al Lancet 2007:370;575. CK-MB/Trop release during CABG surgery. 57 adult CABG patients: RIPC- 3x5 min cuff inflation Control- 30 min deflated cuff RIPC reduced myocardial injury by 43%. Beneficial in CABG patients receiving cardioplegia alone (Venugopal et al Heart 2009). Beneficial in congenital heart disease and AAA surgery (Cheung et al JACC 2006, Ali et al Circ 2007).

200 elective PCI patients: RIPC- 3x5 min cuff inflation Control- 30 min deflated cuff RIPC reduced median trop I from 0.16 to 0.06 and increased number of trop negative patients from 24 to 42%. RIPC in elective PCI Hoole et al Circ 2009:92;1821.

RIPerC in PPCI patients Botker et al Lancet In Press Feb STEMI patients randomised in ambulance to RIPC 4x5 min cuff on arm or control. DANAMI network All comers. - Myocardial salvage index improved at 30 days (0.56 to 0.76). - Reduced myocardial infarct size at 30 days (SPECT P=0.05) - No effect on Troponin-T, TIMI flow, LVEF, MACE at 30 days. - All coronary territories, TIMI 2-3 flow and collaterals included. -LAD infarcts greater reduction in infarct size. - Future studies should focus on specific patients.

30 STEMI pts: Control- Normal PPCI IPost- 4x1 min inflations/deflations IPost reduced myocardial injury by 36%. Ischaemic Postconditioning in PPCI Staat et al Circ 2005:112;2143.

1.Improved myocardial perfusion and ST resolution 1,2 2.Reduced myocardial infarct size: 40% less CK-MB, 47% less trop I 4. 31% to 23% at 1 week (SPECT) 3. 20% to 12% at 6 mths (SPECT) 4. 63% to 51% (IS/AAR) at 3 months (N=86) 5. 3.Preserved LV ejection function by 7% (echo) at 1 year Staat et al Circ Ma et al J Interven Cardiol Yang et al J Interven Cardiol Thibault et al Circ Lonborg et al Circ Card Int 2010 Ischaemic Postconditioning in PPCI

Ischemic Postconditioning in Surgery Luo et al J Thorac Cardiovasc Surg 2007:133; children TOF surgery: Control- Normal surgery IPost- 2x30 sec aortic re- clamping. Reduced trop-I by 50% and CK-MB by 34%. Invasive treatment protocol. Other studies reporting benefit in adult valve surgery.

Pharm Postconditioning using CsA Piot et al NEJM 2008;359: STEMI patients (TIMI 0): Saline placebo or IV CsA 2.5 mg/kg prior to PPCI (<10min). Reduced Trop-I by 26% (P=NS) CK by 36%, and CMR 20% (27 patients). Most benefit for larger infarcts (>40% AAR).

Pharm Postconditioning using EPO Ludman et al Unpublished STEMI patients (TIMI 0): Saline placebo or IV EPO 50,000 IU prior to PPCI and 24 hr later. Trend to increased IS. Doubling of MVO, acute LV dilatation and increased myocardial mass. Acute Endpoints EndpointPlaceboEPOP value AUC Trop-T (µg/l)102 ± ± 78NS Infarct (% of LV)16 ± 919 ± 9NS LGE/AAR (%)61 ± 2366 ± 20NS Myocardial salvage index0.41 ± ± 0.20NS MVO (% incidence) * LVEF (%)53 ± 1051 ± 7NS LVEDVi (ml/m 2 )73 ± 1384 ± * LVESVi (ml/m 2 )34 ± 1141 ± * LVMi (g/m 2 )79 ± 1189 ± *

Conclusions Endogenous ‘conditioning’ strategies can be applied prior to or during ischaemia or at the onset of reperfusion. RIPC beneficial in cardiac surgery, AAA surgery, elective PCI, PPCI. Ischaemic and pharmacological postconditioning beneficial in PPCI patients. Large multi-centre clinical studies required to determine the effect on clinical outcomes. Potential benefit in cardiac arrest, cardiac transplantation, stroke and other surgical settings.

Professor Derek Yellon Dr Peter Mwamure Dr Vinod Venugopal Staff and patients at the Heart Hospital and Royal Free Hospital British Heart Foundation Acknowledgements