Ischemia and Reperfusion: Pharmacological treatment options
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1 Physiologisches Institut Ischemia and Reperfusion: Pharmacological treatment options Prof. Dr. Rainer Schulz
2 Plaque rupture and myocardial ischemia Acute plaque rupture (Stary VI) Ischemic myocardium (ACS, NSTEMI, STEMI)
3 Plaque ruptur and thrombosis Stable plaque 75 % MI-Patients Unstable plaque, plaque ruptur < > 70 Diameter stenosis (%) Falk et al., Circulation 92: , 1995
4 Aging and plaque ruptur Virmani et al., ESC Stockholm September 2010
5 Ischemic injury Myocardial damage TIME IS MUSLCE Ischemic- Injury Ischemia Time
6 Ischemia-reperfusion injury Ischemia Infarct size (% area at risk) 100 Extent of collaterals 80 Rabbit Pig Humans Rat Dog Cat 20 0 Guinea pig (min) Schaper et al., Prog Cardiovasc Dis 31: 57-77,1988
7 Terkelsen et al., JAMA 304: , 2010 Patient CHD Duration of ischemia and mortality Cumulative mortality (Kaplan-Meier) in patients with STEMI and PCI (n=6.209) Mortality (%) Log-Rank p<0,001 Duration of ischemia in minutes Follow up (years)
8 Patient Reperfusion CHD Re-opening of the vessel Reperfused myocardium
9 Ischemia-reperfusion injury Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
10 Ischemia-reperfusion injury Treatment options: Before, during, following ischemia Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
11 Ischemia-reperfusion injury Treatment options before ischemia: plaque stabilization, collateralization, preconditioning Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
12 Development of an unstable plaque Libby und Aikawa, Nature Med 8: , 2002
13 Avoiding plaque rupture: statins (1976) A. Endo, Journal of Antibiotics 29: , 1976 Akira Endo Studie 4S 1994 WOSCOP 1995 CARE 1996 AFCAPS 1998 LIPID 1998 HPS 2002 LIPS 2002 PROSPER 2002 ASCOT 2003 Kombiniert Meta-Analysis: Patients Death or myocardial infarction Jahr Statine Plazebo Cheung et al., Br J Clin Pharmacol 57: , 2004
14 Patient Collateral vessel growth CHD Catheter Catheter Coronary occlusion X Coronary occlusion X
15 Patient Collateral vessel growth CHD Ischemia Stenosis or Partial occlusion Normal blood flow Inflammation Collateral vessel growth TNFα MCP-1
16 Endogenous cardioprotection: Ischemic Preconditioning Control Pre-con (Ischemia/ Drugs) Coronary occlusion First window (<2 hrs) Second window (>24hrs) Third window (>6hrs) hrs hrs Infarct size (% Area at risk) p< Control Pre-con
17 Endogenous cardioprotection: Remote Preconditioning BRAIN SKIN FLAP UPPER LIMB LOWER LIMB LIVER LUNGS KIDNEY SKELETAL MUSCLE STOMACH SMALL INTESTINE
18 Endogenous cardioprotection: Ischemic Preconditioning Pre-infarction angina Yes No Death Heart failure/shock Death/shock CK-release (24 h) 4/155 (3%) 18/254 (6%) 1/155 (1%) 15/254 (6%) 4/155 (3%) 25/254 (10%) 115 U 151 U Collaterals 8/85 (9%) 33/146 (23%) Kloner et al., Circulation 91: 37-47, 1995
19 Endogenous cardioprotection: Ischemic Pre- and Postconditioning both phenomena work perfectly in healthy hearts, however, protection might be lost with co-morbidities!
20 Preconditioning: Signal transduction adenosine bradykinin opioids, UCN GPCR only adenosine p38 PI3K Akt enos NO sgc PKG ANP BNP NPR pgc H11K adenosine bradykinin opioids, UCN enos NO GPCR PI3K Akt P70S6K IGF-1 FGF-2 NPR ERK IL-6 type cytokines Heinzel et al., Circ Res 97: , 2005 gp130 JAK STAT3 NO TNFα TNF-R Boengler et al., Cardiovasc Res 67: , 2005 Rodriguez-Sinovas et al., Circ Res 99:93-101, 2006 AMPK Boengler et al., Basic Res Cardiol 104: , 2009 Rottlaender et al., J Clin Invest 120: , 2010 CB-R adiponectin NO SIRT1 inos MnSOD aldose reductase ROS MPTP PKC GSK3β MPTP Görbe et al., Am J Physiol Heart mitochondrium Circ Physiol nucleus Mar 11 K ATP mitochondrium Cx43 mitochondrium : age-dependent : species-dependent Heusch, Boengler, Schulz, Circulation 118: , 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
21 Ischemia-reperfusion injury Treatment options during ischemia: hemodynamics, per-conditioning Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
22 Patient Ischemia-reperfusion injury: ß-blockade CHD Patient Creatine kinase release Kjekshus, Am J Cardiol 57: 43F-49F (1986) Infarct size reduction [%] Propranolol Atenolol Timolol Metoprolol Metoprolol Propranolol Heart rate reduction [1/min]
23 Patient Endogenous cardioprotection: Perconditioning CHD
24 Patient Endogenous cardioprotection: Perconditioning CHD Perconditioning
25 Ischemia-reperfusion injury Treatment options following ischemia: Postconditioning, spreading of injury Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
26 Reperfusion injury 2+ Ca overload and hypercontracture Chemical interaction (GJ) Adjacent cells Physical interaction (interc. discs) BDM: Uncoupler of gap junctions (phosphatase inhibitor) Spreading of injury
27 Reperfusion injury Anesthetized pig Infarct size (% Area at risk) p< Control BDM-Treated Garcia-Dorado et al., Circulation 85: , 1992
28 Endogenous cardioprotection: Pre- and Post-conditioning Coronary occlusion Infarct size 30 (% Area at risk) Control Precon (Ischemia/ Drugs) hrs hrs p<0.05 Postcon (Ischemia/ Drugs) hrs 5 0 Control Precon Postcon
29 Endogenous cardioprotection: Ischemic Postconditioning (min) Duration of Ischemia ns Control Occluded coronary artery Reperfusion (%) Area at Risk 50 ns Direct stenting Control PostC Postcond Balloon inflations - deflations 20 Control PostC PCI CK release (AUC) Control PostC -36% (p<0.05) 4h 8h 24h 48h 72h Reperfusion (AUC x 10 4 ) Day 1 3 CK release p<0.05 Control PostC SPECT at 6 months p<0.05 Control PostC (perfusion defect index %) Staat et al., Circulation 112: , 2005 Thibault et al., Circulation 117: , 2008
30 Pre- and Post-conditioning: Signal transduction adenosine bradykinin opioids, UCN ANP BNP adenosine bradykinin opioids, UCN IGF-1 FGF-2 IL-6 type cytokines NO TNFα GPCR PI3K Akt NPR pgc GPCR NPR gp130 JAK TNF-R CB-R adiponectin only adenosine enos NO H11K PI3K Akt ERK STAT3 AMPK NO p38 sgc PKG enos NO P70S6K SIRT1 inos MnSOD aldose reductase ROS MPTP PKC MPTP GSK3β mitochondrium nucleus K ATP mitochondrium mitochondrium : age-dependent : species-dependent Heusch, Boengler, Schulz, Circulation 118: , 2008; Boengler, Schulz, Heusch, Cardiovasc Res 2009
31 Mice Ischemic Postconditioning: Signal transduction (Cyclosporine A analogue) P<0.05 Area at risk (%LV) Infarct size (%AAR) Gomez et al., Am J Physiol 293: H1654-H1661, 2007
32 Piot et al., New Engl J Med 359, , 2008 Patient Pharmacological Postconditioning CHD Cyclosporine A (or saline) (2.5 mg/kg, IV bolus) Coronary artery occlusion Direct stenting Day 1-3 CK / TnI release Infarct size CK release Control CsA TnI release (UI/L) P< P<
33 Ischemia-reperfusion injury Treatment options: Before, during, following ischemia Myocardial damage Reperfusion- Injury Ischemic- Injury Ischemia Reperfusion Time
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