Reperfusion Injury, Cardioprotection, and 2 Decades of Failed Studies

Transcription

1 Reperfusion Injury, Cardioprotection, and 2 Decades of Failed Studies The Dark Side of Reperfusion 2014 MFMER

2 Reduction of Infarct Size in the Experimental Animal What can be achieved? No reperfusion With standard reperfusion With standard reperfusion plus cardioprotection Infarct size 75% Infarct size reduced 40% Infarct size reduced by further 25% Heusch, Gersh et al: Lancet 383:1933, MFMER

3 Mechanisms of Myocardial Malperfusion Lysis/PPCI Microvascular obstruction/ dysfunction no-reflow phenomenon Reperfusion injury? Thrombus Obstruction Platelet microemboli Spasm Atheroemboli Free O 2 radicals Hemorrhage Neutrophil plugging Microvascular spasm Mitochondrial dysfunction and permeability Intracellular Tissue calcium edema overload Myocardial necrosis? Inflammation Inflammation? 2015 MFMER

4 Event-free survival (%) Event-free survival (%) Freedom from cardiac death (%) Cumulative (%) Indices of Microvascular Dysfunction and Prognosis Angiographic TIMI Flow Reflow group ST-Segment Recovery and Myocardial Blush Grade P=0.01 <70%, Blush 0/1 (a) 1-yr mortality 10.1% P< No-Reflow group (TIMI 2) Months Morishima et al: JACC, 2000 Myocardial Contrast Echocardiography P< No microvascular dysfunction Months Bolognese et al: Circulation, 2004 Microvascular dysfunction Months Sorajja et al: Eur Heart J, 2005 P<0.01 <70%, Blush 2/3 (b) Magnetic Resonance Imaging Months Wu et al: Circulation, 1998 <70%, Blush 0/1 (c) <70%, Blush 2/3 (d) No microvascular obstruction Microvascular obstruction 6.3% 5.1% 1.2% 2014 MFMER

5 From Reperfusion of the IRA to the Myocardium Everything Works in the Experimental Model Epicardial Flow Microcirculation Myocardial Salvage Combination pharmacotherapy Facilitated PCI PTCA/Stents- Antithrombotics Filters Thromboembolectomy IIb/IIIa inhibitors Nicorandil Adenosine Neutrophil antagonists Complement inhibitors P-selectin inhibitors Statins Hyperoxemic perfusion O2 Cold GIK Nicorandil Adenosine Na+/H+ pump inhibitors Complement inhibitors P-selectin inhibitors Intracellular Ca modulators Delta-protein kinase C inhibitors Statins Stem cells Cyclosporine FX06 (pep fibrin-derived peptide) Erythropoietin Post-conditioning 2015 MFMER

6 Modification of Reperfusion Injury Large Agenda Unimpressive Results Randomized trials Disappointing No trial achieved primary clinical endpoint Further mechanistic studies required Changes in trial design and endpoints Adenosine ANF Cyclosporine A High dose atorvastatin GIK in ambulance Therapeutic hypothermia Therapeutic hyperoxemia Intracoronary abciximab Exenatide Some Promise? Intermittent coronary sinus occlusion Thrombectomy (manual) Ischemic postconditioning Remote ischemic preconditioning 2015 MFMER

7 Experimental Models vs Clinical Studies Lost in Translation Reperfusion injury not clinically relevant Timing of drug administration (pre-occlusion vs post) Impact of pre- and post-conditioning Adjunctive drug therapy Atherosclerosis vs ligature/occluder Different time course Occlusion/ reperfusion Dynamic evolving thrombosis Comorbidities in pt vs animals Age and sex Incomplete reperfusion Distal coronary emboli Differences in microvascular function, collaterals and coronary circulation 2015 MFMER

8 Innate protection of baboon myocardium: effects of coronary artery occlusion and reperfusion YOU-TANG SHEN, JOHN T. FALLON, MITSUNORI IWASE, AND STEPHEN F., VATNER Departments of Medicine, Harvard Medical School and Brigham and Women s Hospital, Boston 02115; and New England Regional Primate Research Center, Southborough, Massachusetts Effects of 60 minutes of coronary occlusion/reperfusion on infarct size as a % of area at risk Pigs Dogs Baboons IF/AAR (%) Thus pigs and baboons were characterized by minimal coronary collateral circulation, but infarct size was significantly less in conscious baboons than in conscious pigs. Potentially, these differences could be explained, in part, by natural protective mechanisms and/or less reperfusion Potentially, these differences could be injuries in primates explained, in part, by natural protective mechanisms and/or less reperfusion injuries in primates Am J Physiol, MFMER

9 Relationship Between Mortality Reduction and Extent of Salvage Mortality reduction (%) % Modifying factors Collaterals Ischemic Treatment preconditioning objectives MVO 2 0 Hours Extent of salvage (% of area at risk) Gersh: JAMA, 2005 CP

10 Impact of D-B Time on Indices of Microvascular Dysfunction 2,065 Pts. HORIZONS Trial Stratified by Duration of Ischemia Normal Myocardial Blush * DTB 90 min DTB>90 min Complete ST-Segment Resolution % hours 2-4 hours >4 hours 2 hours 2-4 hours >4 hours Symptom onset to Balloon time Symptom onset to Balloon time * No change in ejection fraction (50% in all 3 groups) Prasad, JACC Intv

11 New Directions Reperfusion Injury Salvage Kinase (RISK) Pathway Ischemia/necrosis > reperfusion p13.akt Erk 1/2 Pro-survival signaling cascade Protective Mitochondrial calcium and phosphate overload ATP depletion Oxidative stress Rapid ph restoration Reperfusion injury salvage kinase (RISK pathway) *Within minutes Mitochondrial permeability transition pore (mptp) opening* Uncoupling of oxidative phosphorylation Mitochondrial swelling Cell death Hausenloy and Yellon: CV Res, MFMER

12 Factors Activating the RISK Pathway Reperfusion injury salvage kinase (RISK) pathway P13K-Akt Erk 1/2 Prosurvival kinase cascades Activation Ischemiareperfusion Cyclosporine * Pre- and postconditioning* Growth factors Adenosine agonists Atorvastatin Bendavia Insulin Bradykinin Urocortin * *Might inhibit mp-tp opening directly? Hausenloy and Yellon: CV Res, MFMER

13 These data* are clearly as solid as they are surprising and the challenge the clinical use of cyclosporine and cardioprotection Potential Mechanisms <12 hours of symptoms Cyclosporine A dissolved in intralipid Kottenberg: Acha Anaest Scand, 2012 Chung: NEJM, 2015 Administration of platelet inhibiting P2Y12 antagonists which are cardioprotective Powerful cardioprotective agent Vehicle also used for propafol 2015 MFMER

14 Trials of Ischemic Postconditioning Method PLA/PoCo Ischemic postconditioning Acronym Authors CK 15/15 Staat (2005) CK-MB 47/47 Ma (2006) SPECT 18/23 Yang (2007) CK 12/12 Laskey (2008) SPECT 21/17 Thibault (2008) Tnl 26/24 Zhao (2009) MRI 43/43 Lonborg (2010) MRI 38/38 Sorensson (2010) SPECT 20/23 Xue (2010) CK-MB 21/22 Garcia (2011) CK-MB 34/30 Liu (2011) MRI 36/34 Freixa (2012) MRI 38/37 Tarantini (2012) MRI 25/25 Thuny (2012) CK-MB 42/37 Ugata (2012) MRI 40/39 Dwyer (2013) MRI 21/18 Elzbieciak (2013) CK-MB 350/350 Hahn (2013) CK-MB 21/24 Liu (2013) MRI 25/25 Mewton (2013) CK-MB 37/35 Araszkiewicz (2014) MRI 168/181 LIPSIA CONDITIONING Eitel (2015) PLA/RIC Remote ischemic conditioning SPECT 110/109 CONDI Bøtker (2010) SPECT 110/108 Munk (2010) Tnl 30/33 Rentoukas (2010) CK-MB 45/48 Crimi (2013) CK-MB 17/18 RIPOST-MI Prunier (2014) MRI 160/158 LIPSIA CONDITIONING Eitel (2015) MRI 43/40 White (2015) CK-MB 258/261 ERIC-LYSIS Yellon (2015) % 2016 MFMER slide-

15 Conclusions Routine clinical role Unlikely Biological implications Better understanding of underlying signal transduction New pharmacologic interventions 2013 MFMER

16 Infarct size (% ventricular mass) Across Species Transfer of Protection by Remote Ischemic Preconditioning Pig model Hindlimb ischemia model Myocardial signal transduction of RISK and SAFE pathways* Pig plasma transferred to isolated rat heart Infarct Size in Isolated Rat Hearts With Infusion of Pig Plasma and Blockade of RISK and SAFE Pathways Control * * * Remote Ischemic Preconditioning * * * * Reperfusion Injury Salvage Kinase * Survival Activating Factor Enhancement 0 p PLA ppla+ RISK-BL ppla+ SAFE-BL pripc pripc+ RISK-BL pripc+ SAFE-BL Skyschally: Circ Res, MFMER

17 Final infarct size (% LV) PPCI Remote Ischemic Preconditioning in Patients with STEMI 333 pt PPCI + remote preconditioning (intermittent arm ischemia) Relation Between Final Final Infarct Infarct Size Size and and Area Area at Risk at Risk P=0.008 (slope of regression line) Area at risk (% of LV) Median Salvage Index 112 pt P= Primary PCI plus remote conditioning (n=73) Primary PCI (n=69) Bøtker: Lancet, MFMER

18 The most plausible explanation for a lack of protection is the use of propofol anaesthesia in more than 90% of patients in ERICCA and all patients per-protocol in RIPHeart Propofol specifically abrogated protection ( TnI release) by remote ischemic preconditioning in patients undergoing elective CABG Protection demonstrated during CABG with isoflurane but not with propofol anesthesia a clinical trial Kottenberg: Acha Anaest Scand, MFMER

19 Remote Ischemic Preconditioning. Hopefully better understanding of the protective transfer and of the activation of myocardial signal transduction, remote ischemic preconditioning may indeed become the future of ischemic preconditioning. Mitochondria Mitochondria are critical subcellular target organelles for myocardial protection and warrant further investigation into identifying new targets, Future and Ongoing Directions Heusch and Gersh EHJ In Press 2016 MFMER

20 Myocardial salvage (%) 100 Windows of Opportunity are Limited ANo benefit: Too early to make a difference B Potential benefit: Difficulties in demonstrating a difference C No benefit: Too late to make a difference Time from symptom onset to reperfusion therapy (hour) Gersh: JAMA, MFMER