Pathophysiology of ischemia-reperfusion injury (and how to protect against it ) Dr Derek J Hausenloy Reader in Cardiovascular Medicine BHF Senior Clinical Research Fellow Honorary Consultant Cardiologist The Hatter Cardiovascular Institute, University College London, UK. From bench to practice: STEMI ESC Munich Sunday Aug 26 th 2012.
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Background In STEMI -2 components of myocardial injuryacute ischemic injury and reperfusion injury. Early and effective reperfusion reduces acute ischemic injury and limits MI size. Despite this STEMI patients treated by PPCI still have significant morbidity and mortality. Acute myocardial reperfusion injury remains a neglected therapeutic target. Potential novel therapies for limiting MI size in STEMI patients.
Early effective reperfusion is essential Early and effective myocardial reperfusion reduces the duration of acute myocardial ischemia, limits MI size, preserves LV systolic function and reduces MACE. Strategies already in place to reduce acute ischemic injury. Chest pain Arrival at PPCI centre PPCI Effective reperfusion PPCI Anti-platelet Anti-thrombotic Distal protection Acute myocardial ischemia Reperfusion Chest pain to PPCI time
Acute myocardial ischemic injury Principal determinants: 1. Duration of myocardial ischemia. 2. Myocardium at risk of infarction (AAR). 3. Residual blood flow from collateralisation.
Wavefront of ischemic death Reimer et al Circ 1977 Transmural progression of necrosis within the ischemic bed size (myocardium at risk) Canine heart Prox Cx occlusion and 4 days reperfusion 40 min MI size 38% of LV 3 hours MI size 57% of LV 6 hours MI size 71% of LV 24 hour MI size 85% of LV
Reperfusion limits MI size Myocardial salvage dependent on ischemic time. Which STEMI patients are most likely to benefit from cardioprotective strategy? Early presenters (<3 hrs) or later presenters (>3hrs). Gersh et al JAMA 2005
The area at risk The AAR risk of myocardial infarction varies considerably, depending on which coronary artery is involved and the site of the occlusion. Normalise MI size to area at risk (myocardial salvage). Ortiz-Perez et al EHJ 2007
Collateralisation affects MI size Canine hearts have variable collateralisation leading to a variation in MI size. About 20% of all STEMI patients have significant coronary collateralisation. Are these patients amenable to cardioprotective intervention? Reimer & Jennings Lab Invest 1979
Modifying the time course of acute myocardial ischemic injury in STEMI patients Myocardium at risk of infarction (AAR), residual blood flow from collateralisation, and duration of myocardial ischemia. Pre-infarct chest pain- Ischemic preconditioning Complete occlusion vs spontaneous reperfusion (30%) Genetic susceptibility to ischemic injury. Confounding factors and concomitant medication. Animal MI models do not take into account the above factors.
What is happening in the cardiomyocyte during acute myocardial ischemia? SSM IF PN Hallmarks of acute myocardial ischemia 1. Absence of oxygen ATP depletion 2. Metabolic switch to anerobic glycolysis 3. Intracellular ph drop (6.0) 4. Na + -H + exchanger removes H + Na + 5. Na + -Ca 2+ exchanger removes Na + Ca 2+ PO 4
Myocardial reperfusion injury Myocardial reperfusion injury is essential for myocardial salvage in STEMI patients. Paradoxically, the abrupt reperfusion of previously ischemic myocardium can induce myocardial injury and cardiomyocyte death- myocardial reperfusion injury (1960s by Jennings). Double-edged sword of reperfusion (Braunwald 1985). Currently no therapy for reducing myocardial reperfusion injury- neglected therapeutic target.
What is myocardial reperfusion injury? 1. Arrhythmias 2. Stunning 3. Microvascular obstruction 4. Lethal reperfusion injury Modified from Yellon & Hausenloy, NEJM 2007
How important is reperfusion injury? Infarct size % of LV Hausenloy & Yellon, JCI 2012 In Press Myocardium salvaged by PPCI Infarction due to reperfusion Injury Expected infarct size after PPCI Actual infarct size after PPCI Ischemia Reperfusion Time Chest pain onset Primary PCI MI size measured
Conditioning the heart with ischemia Pharmacological agent Remote Ischemic Preconditioning Remote Ischemic Perconditioning Remote Ischemic Postconditioning Ischemic Preconditioning 1986 Ischemic Postconditioning 2003 No Conditioning 0 to 3 hrs < 1min Heart Ischemia Reperfusion Conditioned
Cardioprotective interventions in STEMI To limit MI size in STEMI patients, the intervention has to be applied prior to myocardial reperfusion. Opportunities to intervene in the ambulance and at the PPCI centre prior to myocardial reperfusion. Chest pain Arrival at PPCI centre PPCI Acute myocardial ischemia Reperfusion Chest pain to PPCI time
Ischemic Postconditioning in PPCI Staat et al Circ 2005:112;2143. 30 STEMI pts: Control- Normal PPCI IPost- 4x1 min inflations/deflation 40% MI size reduction confirmed using SPECT and cardiac MRI in larger studies. Multicentre clinical outcome study now underway in Denmark- DANAMI-3.
RIC in the ambulance Botker et al Lancet 2010 246 STEMI patients: RIPC 4x5 min cuff on arm or control Myocardial salvage index improved at 30 days (0.56 to 0.76).
IV Cyclosporin-A at the PPCI centre Piot et al NEJM 2008; Mewton et al JACC 2010 CsA prevents mitochondrial dysfunction at time of reperfusion. 58 STEMI patients : Saline placebo or IV CsA 2.5 mg/kg prior to PPCI. Reduced Trop-I by 26% (P=NS) CK by 36%, and CMR 20% (27 patients). CMR follow-up. MI size reduction present 6 mths later with reduced LVESV. Most benefit for larger infarcts (>40% AAR). CIRCUS study underway.
The Gila Monster and cardioprotection?
Exenatide- lizard spit! Lonborg et al Eur Heart J 2011; Lonborg et al Circ Cardiovasc Interv. 2012 Exenatide, GLP-1 analogue, is a synthetic version of exendin- 4, a hormone found in the saliva of the Gila monster. 105 STEMI patients randomized to IV exenatide vs placebo. Increased myocardial salvage (0.71 VS 0.62). Reduced IS/AAR Infarct size from 0.39 to 0.30. Most benefit in those patients presenting within 132 min. ALL PATIENTS Ant MI PATIENTS
IV GIK cocktail in the ambulance Selker et al JAMA 2012 Metabolic modulation with GIK during myocardial ischemia beneficial as it promotes glucose metabolism. CREATE-ECLA GIK at time of PPCI not beneficial (but 68% had GIK after PPCI). IMMEDIATE study randomised 871 suspected ACS patients: IV GIK 12 hrs or placebo in the ambulance. No difference in primary endpoint. However, for 357 STEMI patients less inhospital mortality and cardiac arrest (6.1% vs 14.4%) and smaller MI size (3 vs 12%).
Conclusions Despite optimal myocardial reperfusion, morbidity and mortality of STEMI patients undergoing PPCI still significant. Novel cardioprotective interventions which delay ischemic injury or reduce myocardial reperfusion injury may result in improve outcomes. Ongoing multicentre studies investigating whether these therapeutic interventions can improve clinical outcomes in STEMI patients.
Acknowledgements Professor Derek Yellon Staff and patients at the Heart Hospital and Royal Free Hospital British Heart Foundation