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“GUIDATI DA PARADIGMI SEMPRE NUOVI, GLI SCIENZIATI ADOTTANO NUOVI STRUMENTI E PROGETTANO NUOVI STUDI GUARDANDO VERSO NUO

Nuovi target e opportunità terapeutiche del danno da riperfusione nello STEMI. “GUIDATI DA PARADIGMI SEMPRE NUOVI, GLI SCIENZIATI ADOTTANO NUOVI STRUMENTI E PROGETTANO NUOVI STUDI GUARDANDO VERSO NUOVE DIREZIONI”. Filippo Ottani, MD. Myocardial Reperfusion Injury: Definition.

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“GUIDATI DA PARADIGMI SEMPRE NUOVI, GLI SCIENZIATI ADOTTANO NUOVI STRUMENTI E PROGETTANO NUOVI STUDI GUARDANDO VERSO NUO

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  1. Nuovi target e opportunità terapeutiche del danno da riperfusione nello STEMI “GUIDATI DA PARADIGMI SEMPRE NUOVI, GLI SCIENZIATI ADOTTANO NUOVI STRUMENTI E PROGETTANO NUOVI STUDI GUARDANDO VERSO NUOVE DIREZIONI” Filippo Ottani, MD

  2. Myocardial Reperfusion Injury: Definition Features of “Reperfusion Injury”: Myocardial Stunning (reversible) No-Reflow Phenomenon (reversible/irreversible) Reperfusion Arrhytmias Lethal Reperfusion Injury (reversible) Lethal reperfusion injury is a paradoxical type of myocardial injury caused by the restoration of coronary blood flow after an ischemic episode that might be prevented by an intervention

  3. Major Mediators of Lethal Reperfusion Injury Prasad A et al. Circualtion 2009; 120: 2105

  4. Contribution of Lethal Reperfusion Injury to Final Myocardial Infarct Size Yellon D. NEJM 2007;357:1121-1135

  5. Major Differences between Animal Models and Clinical Studies of Patients with Acute Myocardial Infarction

  6. Hypothetical Construt of the Therapeutic Window for Cardioprotection Prasad A et al. Circualtion 2009; 120: 2105

  7. Infarct Size: a Determinant of Mortality Gibbons et al. JACC 2004; 44:1533-1542

  8. New Strategies for Preventing Lethal Reperfusion Injury: An Overview on Ischemic “Conditioning” Ischemic “Conditioning” : an adaptative phenomenon which renders the myocardium more resistant to the detrimental effect of acute “ischemia-reperfusion” injury Remote & POST- Conditioning 3 to 48 hrs No “Conditioning” Reperfusion Ischemia 1st & 2° Window of protection By Ischemic PRE-Conditioning “Conditioned”

  9. Preconditioning in Humans: Prodromal angina and primary Angioplasty Angina positive Angina negative p<0.05 vs ANGINA-ve N° of Chord % N° of Chord % Ottani F, JACC 2005

  10. Sixrandomizedtrialson IPC, 244 pts: Reduced CK (p=0.005) Increased LVEF (p=0.0001) Hansen PR, Int J Cardiol 2009 Thibault H, Circulation 2008; 117 1037 1044 Ischemic postconditioning in patients: Original description: Stat et al, Circulation 2005 Long term benefit: Thibault et al, Circulation 2008

  11. Protecting the heart against reperfusion injury: endogenous protection Prehospital remote ischaemic conditioning increases myocardial salvage in acute myocardial infarction. Lancet 2010;in press. Botker HE, Kharbanda RK, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Anderson NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HF, Redington AN, Nielsen TT. Intermitent arm ischemia before reperfusion Reduced reperfusion injury at PPCI

  12. New Strategies for Preventing Lethal Reperfusion Injury Pre-, Post- RemoteConditioning Adenosine, Bradykinin, Opiods G protein- coupled Receptors RISK Akt/Erk PKG/PKCε RISK Activator (eg, ADO, EPO, Statins) PKG/PKCε Activators (eg, ANP) NO and ROS mPTP inhibitor (eg, Cyclosporin A) mKATP opener (eg, Nicorandil) Mitochondria KATP mPTP Reduction in Myocardial Infarction Yellon D. NEJM 2007;357:1121-1135

  13. Intracoronary adenosine during PCI in STEMI Randomized, placebo controlled studies COMPLETED NOV 2011

  14. (p=0.016)

  15. A single dose of erythropoietin in ST-elevation myocardial infarction. HEBE III study Secondary endpoints. Primary endpoint LVEF by planar radionucleide VTG-500 MBq of 99mTc-pertechnetate mean left ventricular ejection fraction (± SD), 6 weeks after a successful primary coronary intervention. Voors A A et al. Eur Heart J 2010;31:2593-2600

  16. Protecting the heart against reperfusion injury: pharmacologicalprotection CK release csa NMR imagaing

  17. Studio CYCLE Efficacia della ciclosporina A nell’infarto miocardico acuto riperfuso Firenze, 12 maggio, 2011

  18. CYCLE inclusion criteria • Male and female patients with large STEMI not older than 4 hours, defined as • angina pectoris or equivalent symptoms of more than 20 minutes duration within last 4 hours, and • an ST elevation in at least 3 anterior leads and/or a deviation in at least 4 inferior leads, • TIMI flow 0 or 1 in identified culprit artery • Intended acute primary PCI • Age ≥ 18 years • Ability to understand the nature, scope, and possible consequences of the study participation / legal capacity • Written informed consent

  19. Transfer to ER • Informed consent CYCLE flow chart • If pt eligible, • Randomization • ECG (baseline), bloodsampling#1: corelab. Coronaryangiography • Start infusion of CsA (over ½ min) • Angioplasty (check for effective reperfusion!) • 60-min ECG (primary endpoint: ST resolution) Coronaryangioplasty • Transfer pt to CCU • Morning after randomization: blood sampling #2: core lab CCU-hospital • Hospital day 4: -bloodsampling#3: corelab, • -echocardiography. • Clinicalvisit • Clinicalvisit: -bloodsampling#4: corelab, • -echocardiography. Hospital discharge 4 weeks 6 months

  20. Conclusion Pre, post, and remote conditioning demonstrate that reperfusion injury is a clinically relevant fact fact Mechanistic and pre-clinical research should address many still open questions Drugs against orphan targets have to be developed Well designed and powered infarct size/area at risk proof of concept studies are still necessary Initially effective interventions need to be evaluated by clinical outcome studies Protection against reperfusion injury in STEMI is now a really promising, competitive field of translational CV research

  21. Major Mediators of Lethal Reperfusion Injury Oxygen Paradox Calcium Paradox pH Paradox Inflammation Metabolic Modulation Magnesium Therapy Therapeutic Hypothermia Mitochondrial PTP Yellon D. NEJM 2007;357:1121-1135

  22. New Cardioprotective Strategies for Reducing Lethal Reperfusion Injury Yellon D. NEJM 2007;357:1121-1135

  23. The Time Dependent Open Artery and Open Microvascular Hypothesis Plaque rupture/erosion/fissure Occlusive STEMI Non – Occlusive UA / NSTEMI Platelet thrombus Vasoconstriction Embolization TIMI 2 Flow Inflammation TIMI 0 Flow Edema Impaired tissue level perfusion Time Dependent Necrosis + Troponin / CK Arrhythmias / CHF Death

  24. Myocardial Infarction: a two-component damage Ischemia Reperfusion reperfusion injury Infarct size ischemic injury time coronary occlusion

  25. Mechanistic Pathway of Ischemic “Conditioning” Pre-, Post- RemoteConditioning Common signal transduction pathway underlying PC comprise GPCR, protein kinases, NO, ROS, mKATP, and mPTP Adenosine, Bradykinin, Opiods G protein- coupled Receptors Risk Akt/Erk PKG/PKCε NO and ROS Mitochondria KATP mPTP Reduction in Myocardial Infarction Yellon D. NEJM 2007;357:1121-1135

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