cardiac pre and post conditioning i Stefan De Hert Department of Anesthesiology University Hospital Ghent University of Ghent 2010 Universitair Ziekenhuis Gent Belgium
= limited exposition to a small potential noxious stimulus that protects against the effects of a greater exposition to a noxious stimulus Mythridates king of Pontus 132 63 BC
PRE conditioning limited exposition is applied BEFORE the longlasting l noxious stimulus POST conditioning limited exposition is applied AFTER the longlasting noxious stimulus
PRE conditioning ischemic pre conditioning Murry CE et al. Circulation 1986; 74: 1124 1136 a rapid adaptive response to a brief ischemic insult, which slows the rate of cell death and extent of cell dysfunction during a subsequent, prolonged period of ischemia
ischemic pre conditioning CONTROL IPC short occlusion sustained ischemia short reperfusion // reperfusion //
ischemic pre conditioning
ischemic pre conditioning windows of protection degree of protec ction early phase late phase 1 3 24 72 time elapsed from preconditioning stimulus (hours)
ischemic pre conditioning early and late preconditioning CONTROL ischemia reperfusion EARLY IPC IPC washout ischemia reperfusion LATE IPC IPC washout ischemia reperfusion
MPTP synthesis of cytoprotective proteins
mitochondrial permeability transition pore Zaugg M et al. Br J Anaesth 2003; 91: 551 576 Honda Y et al. Ann N Y Acad Sci 2005; 1047: 248 258
by courtesy of Prof Dr Colin Royse, Melbourne, Australia
mitochondrial permeability transition pore inhibition i of MPTP opening, attenuates lethal lmyocardial injury that occurs at the time of reperfusion 58 patients withacute ST elevation MI immediately before PCI study group: 2.5 mg / kg cyclosporine control group: normal saline Piot C et al. N Engl J Med 2008; 359: 473 481
ischemic pre conditioning clinical implications?
prodromal angina preinfarction angina is associated with a lower infarct size and a greater infarct size limitation after thrombolysis group A: preinfarction angina n = 12 group B: NO preinfarction angina n = 13 200 15 100 p < 0.01 p < 0.04 p < 0.05 10 100 50 5 0 group A group B 0 group A group B 0 group A group B peak CKMB # infarcted segments % salvaged myocardium Ottani F et al. Circulation 1995; 91: 291 297
ischemic preconditioning and coronary surgery IPC reduces myocardial injury after coronary surgery n = 16 serum troponin T (µg/l) at 72 hours n = 17 2 p = 0.05 1 0 control IPC Jenkins DP et al. Heart 1997; 77: 314 318
ischemic pre conditioning remote preconditioning Kharbanda RK et al. Lancet 2009; 374: 1557 1565
Hausenloy DJ et al. Cardiovasc Res 2008; 79: 377 386
elective CABG surgery with CPB study group: (n = 27) control group: (n = 30) RIPC: 3 x 5 min tourniquet inflation upper arm interspersed by 5 min release after anesthesia, before start of surgery normal saline Hausenloy DJ et al. Lancet 2007; 370: 575 579
POST conditioning Cour M et al. J Cardiovasc Pharmacol Ther 2010; in press
30 patients with acute ST elevation MI after PCI study group: control group: postconditioning protocol no intervention Staat P et al. Circulation 2005; 112: 2143 2148 Thibault H et al. Circulation 2008; 117: 1037 1044
A1 receptor agonists ischemic (pre )conditioning pharmacological modulation pharmacological (pre )conditioning hypotension, bradyarrhythmias, renal VC, pain, tachyphylaxis KATP channel openers hypotension, arrhythmias, hth renal VC, pain, protein kinase activators carcinogenic effects
pharmacological conditioning anesthetic agents
anesthetic PRE conditioning volatile anesthetics BEFORE myocardial ischemia reduce myocardial ischemic injury 60 min control 60 min LAD occlusion 3 hrs reperfusion 30 min control 30 min sevoflurane 60 min LAD occlusion 3 hrs reperfusion size k) 30 control sevoflurane dial infarct area at risk myocard (% of a 25 20 15 10 5 0 * Toller W et al. Anesthesiology 1999; 91: 1437 1441
anesthetic POST conditioning volatile anesthetics AFTER myocardial ischemia (during early reperfusion) reduce myocardial ischemic injury 30 min ischemia 120 min reperfusion 15 min volatile anesthetic control desflurane sevoflurane t size sk) dial infarct f area at ris myocard (% of 60 * * 40 * 20 0 Preckel B et al. Br J Anaesth 1998; 81: 905 912
anesthetic PRE and POST conditioning 50 farct size at risk) ardial inf of area a myoca (% o 40 30 20 10 0 control sevo PC sevo REP sevo PC + REP Obal D et al. Anesth Analg 2005; 101: 1252 1260
anesthetic PRE conditioning clinical implications?
anesthetic PRE conditioning anesthesia and surgery CPB preconditioning ischemia reperfusion Belhomme D et al. Circulation 1999; 100 (suppl II) 340 4 Penta de Peppo A et al. Ann Thorac Surg 1999; 68: 112 8 Tomai F et al. G Ital Cardiol 1999; 29: 1007 14 Haroun Bizri S et al. J Cardiothor Vasc Anesth 2001; 15: 418 21 Pouzet B et al. Ann Thorac Surg 2002; 73: 843 8 Julier K et al. Anesthesiology 2003; 98: 1315 27 Forlani S et al. J Cardiovasc Surg (Torino) 2004; 45: 117 22 Fellahi JL et al. Eur J Anaesth 2004; 21: 688 93 Lee MC et al. Eur J Anaesth 2006; 23: 841 7 Murphy GS et al. J Cardiothor Vasc Anesth 2006; 20: 493 502 Meco M et al. Eur J Cardiothor Surg 2007; 32: 319 25 Piriou V et al. Br J Anaesth 2007; 99: 624 31 isoflurane enflurane isoflurane isoflurane sevoflurane sevoflurane isoflurane isoflurane isoflurane morphine desflurane sevoflurane
cardiac function biochemical marker Belhomme et al. not reported lower 5 nucleotidase n = 20 Penta de Peppo et al. improved function no effect n = 16 Tomai et al. improved function (subgroup) lower Tn (subgroup) n = 40 Haroun Bazri et al. improvedfunction not reported td n = 49 Pouzet et al. not reported no effect n = 20 Julier et al. not reported lowerbnp n = 72 Forlani et al. no effect lower Tn n = 40 Fellahi et al. not reported no effect n = 359 Lee et a. al. improved poedfunction cto lower Tn n = 40 Murphy et al. improved function no effect n = 46 Meco et al. improved dfunction lower Tn and BNP n = 28 Piriou V et al. no effect no effect n = 72
n = 14 n = 14 n = 14 Bein B et al. Anaesthesia 2008; 63: 1046 1055
anesthetic PRE and POST conditioning sternotomy ischemia CPB De Hert SG et al. Anesthesiology 2004; 101: 299 311
troponin I levels tropon in I (ng/m ml) tropon in I (ng/m ml) 10 10 PROPOFOL SEVO pre 8 (n = 50) 8 (n = 50) 6 6 4 4 2 2 0 0 baseline T0 T6 T12 T24 T48 baseline T0 T6 T12 T24 T48 10 8 6 4 2 SEVO all (n = 50) * * * * tropon in I (ng/m ml) tropon in I (ng/m ml) 10 8 6 4 2 SEVO post (n = 50) 0 0 baseline T0 T6 T12 T24 T48 baseline T0 T6 T12 T24 T48
stroke volume propofol p sevo PRE sevo POST sevo ALL 80 * = p < 0.001 70 60 * 50 * * * 40 base pre CPB post CPB ICU T6 ICU T12
conclusions ischemic pre and post conditioning protect the myocardium anesthetic agents confer pharmacological conditioning effects extent of protective effects of anesthetic «conditioning» in the clinical setting depends on the protocol used effects on outcome?
... other types of cardioprotection??? The role of mitochondrial and sarcolemmal K ATP channels in canine ethanol-induced preconditioning in vivo Pagel PS, et al: Anesth Analg 2002;94:841-8 76 dogs 60 min coronary occlusion, 3 h reperfusion