1. Role of Adenosine in Acute Myocardial Infarction Presented by: Mervyn B. Forman, MD, PhD, FACC

2. Potential Sequelae of Reperfusion on Ischemic Myocardium  Reperfusion Injury Conversion of reversibly injured endothelial and myocardial cells to irreversibly injured cells  Myocardial Stunning Prolonged left ventricular dysfunction of reversibly injured myocytes  Reperfusion Arrhythmias

3. Myocardial Reperfusion Injury  Definition: Conversion of reversibly injured endothelial and myocardial cells to irreversibly injured cells during the peri-reperfusion period. Not synonymous with entity of acceleration of necrosis of cells that are already irreversibly injured.

4. Vascular Changes with Reperfusion

5. A3A3 A 2A A 2B A1A1 (Very high affinity) (High affinity) (Low affinity) GiGi GsGs AC K ATP PLC Ca 2+ PLA 2 Isoforms have distinct, but overlapping, cellular distribution and are widely expressed in most cells/tissues/organs of the body. Adenosine Receptors: Signal Transduction Mechanisms

6. Effects of Adenosine A 1 SA NODEAV NODEVENTRICLEMYOCYTEBLOOD VESSELS ΘΘΘ  Θ CHRONOTROPIC EFFECT DROMOTROPIC EFFECT INOTROPIC EFFECT PRE- & POST- CONDITIONING NEURO- TRANSMITTER RELEASE A1A1

7. Effects of Adenosine A 2A /A 2B VESSELSPLATELETSNEUTROPHILSVSMC’S & CARDIAC FIBROBLASTS ENDOTHELIAL CELL  ΘΘΘ  DILATATIONAGGREGATION TxB 2 RELEASE ADHERANCE TO EC’s & FREE RADICAL RELEASE PROLIFERATION & MIGRATION AND ECM PRODUCTION ANGIO- & VASCULO- GENESIS A 2A /A 2B

8. Effects of Adenosine A 3 MYOCYTEENDOTHELIAL VSM CELLS  PRE-CONDITIONING, ↑ANTI-OXIDANT ENZYMES ↑ANTI-OXIDANT ENZYMES A3A3

9. Reperfusion Mechanisms of Myocardial Reperfusion Injury and Effects of Adenosine Leukocytes TxA 2, PAF, Ang II, NE, ET-1 Calcium Oxygen Platelets A 2A/2B Angiogenesis Vasculogenesis MPO Proteases Cellular Calcium Overload Platelet Aggregation Vasoconstriction Oxygen Free Radicals No Reflow Vascular Plugging Cell Death A 2A A1A1 A3A3 ADENOSINE

10. Infarct Size with Intracoronary Adenosine Olafsson et al. Circulation 1987; 76:1135-45 42% 44% 40.9% * 9.9% 18% ** 4.6% 0% 10% 20% 30% 40% 50% AR/LVAN/AR AN/LV Control Adenosine * p<0.001 **p=0.002

11. Effect of IV Adenosine Pitarys et al. Circulation 1991; 83: 237-47 30.2 * 39.1 35.3 ** 17.1 11 7 0 10 20 30 40 50 (%) AR/LVAN/AR AN/LV Control Adenosine * p<.05 **p<.01

12. Transverse Myocardial Slice in Adenosine and Control Animal

13. Regional Ventricular Function in Ischemic Zone Significant improvement noted at 3 and 72 hours after reperfusion. Pitarys et al. Circulation 1991; 83: 237-47 ** * 0 10 20  RS OCC vs 3H  RS OCC vs 72H (%) Control Adenosine *p<.03 **p <.01 * ** 21 17.3 -2.6 5.5 11 20 -5 0 5 10 15 20 25 BaseOCCRep 3HRep 72H Ischemic Zone Radial Shortening (%) ControlAdenosine* p<.03**p<.01

14. IC Adenosine with PCI in AMI Marzilli et al. Circulation 2000; 101:2154-2159 * 2% 19% * 64% 36% 0% 20% 40% 60% 80% 100% (%) Remodeling Recovery ADO Saline *p= 0.0001 27 * 19 1 *7*7 0 5 10 15 20 25 30 Number of Patients TIMI 3No-Reflow ADO Saline *p< 0.05 *0*0 5 * 16 23 *5*5 13 0 5 10 15 20 25 Number of Patients Death Q wave MI MACE Saline *p < 0.05 ADO

15. Final Infarct Size (as a Percentage of the Left Ventricle) AMISTAD TRIAL. J AM Coll Cardiol 1999; 34: 1711-20 Median values shown above horizontal lines n=101 n=96 n=39 n=38 n=62 n=58 p=0.96 p=0.014 p=0.085 % of Left Ventricle 0 20 40 60 80 Overall (33% reduction) Anterior (67% reduction) Nonanterior (0% reduction) 13 19.5 15 45.5 11.5 Adenosine Placebo

16. AMISTAD II  Anterior Wall MI (STE, LBBB)  6h  No contraindication for lysis  No hypotension  No bradycardia  No obstructive airway disease 2118 Patients ASA Placebo Adenosine 50mcg/Kg/min X 3h Adenosine 70mcg/Kg/min X 3h Fibrinolysis or PTCA Follow-up for 6 months Infarct size (  5 d) (243 patients)

17. AMISTAD II – Non MACE Adverse Events PLACEBOADENOSINE 50mcg/Kg/min ADENOSINE 70mcg/Kg/min Hypotension14%19%18% Bradycardia2%3% Tachycardia4%2%4% Nausea/Vomiting7% 8% Premature Drug Discontinuation 4%6%5% Second-degree AV Block0% Third-degree AV Block0%

18. AMISTAD II Infarct Size 57% reduction in median infarct size with 70mcg/kg/min group relative to placebo p=0.122 26% 23% 11% 10% 20% 30% 40% Placebo 50 mcg70mcg Median LV Infarct Size (%) p=0.028 0% 26% 17% 0% 10% 20% 30% 40% Median LV Infarct Size (%) p=0.078 PlaceboPooled Adenosine

19. AMISTAD II- Post Hoc Analysis Effect of early reperfusion treatment (3.1 hrs) on clinical outcomes 9.2% 5.2% 11.2% 7.3% 17.2% 12.0% 0% 5% 10% 15% 20% Death at 1 month Death at 6 months Composite 6 months Placebo Pooled Adenosine * p=0.01 **p=0.03 + p=0.02 + * **

20. Effect of Adenosine with Varying Duration of Ischemia CONTROL ADENOSINE * P<0.03 (ADO vs. CONTROL P<0.01 (ADO vs. CONTROL) ** * 40 MIN 120 MIN 180 MIN 70 40 30 20 10 AN/AR (%)

21. Overall Survival Curves ATTACC Study. Eur J Clin Pharmacol 2003; 59:1-9 Time (days) Cumulative Proportion Surviving Complete Censored

22. Key Points  Adenosine shown consistently to reduce infarct size  70mcg/kg/min infusion for 3 hours shows 57% relative reduction in infarct size  Strong trend toward less death and CHF  Significant reduction in death and composite endpoint at 6 months in Adenosine group treated early (~3.1 hrs) - post hoc analysis MI patients who undergo reperfusion therapy: