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Role of Adenosine in Acute Myocardial Infarction PowerPoint Presentation
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Role of Adenosine in Acute Myocardial Infarction

Role of Adenosine in Acute Myocardial Infarction

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Role of Adenosine in Acute Myocardial Infarction

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  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 synonymouswith entity of acceleration of necrosis of cells that are already irreversibly injured.

  4. Vascular Changes with Reperfusion

  5. Adenosine Receptors: SignalTransduction Mechanisms A3 A1 (Very high affinity) (Low affinity) Isoforms have distinct, but overlapping, cellular distribution and are widely expressed in most cells/tissues/organs of the body. Gi KATP PLA2 PLC Ca2+ AC Gs A2B A2A (Low affinity) (High affinity)

  6. Effects of Adenosine A1 A1

  7. Effects of Adenosine A2A/A2B A2A/A2B

  8. A3 Effects of Adenosine A3

  9. A2A/2B Angiogenesis Vasculogenesis ADENOSINE Mechanisms of Myocardial Reperfusion Injury and Effects of Adenosine Reperfusion TxA2, PAF, Ang II, NE, ET-1 Platelets Leukocytes Oxygen Calcium A3 A1 A2A A2A A2A Oxygen Free Radicals Cellular Calcium Overload MPO Proteases Platelet Aggregation Vasoconstriction Vascular Plugging No Reflow Cell Death

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

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

  12. Transverse Myocardial Slice in Adenosine and Control Animal

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

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

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

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

  17. AMISTAD II – Non MACE Adverse Events

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

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

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

  21. Complete Censored 1.00 0.95 0.90 Adenosine-anterior 0.85 0.80 Placebo-anterior 0.75 R.R. 0.64, 95% C.I. 0.37 – 1.11, p = 0.13 0.70 600 800 1000 1200 1400 0 200 400 Overall Survival Curves Cumulative Proportion Surviving Time (days) ATTACC Study. Eur J Clin Pharmacol 2003; 59:1-9

  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: