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Putting Out the Fire

Putting Out the Fire. Shadwan Alsafwah, MD The University of Tennessee at Memphis Staff Support: Dr. Richard Davis. Introduction.

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Putting Out the Fire

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  1. Putting Out the Fire Shadwan Alsafwah, MD The University of Tennessee at Memphis Staff Support: Dr. Richard Davis

  2. Introduction • Over the past three decades, the adoption of highly effective new pharmacological and mechanical reperfusion treatments has improved survival for patients who experience acute MI • Unfortunately, reperfusion, although it relieves or reduces ischemia and necrosis, is followed by morphological and functional changes that ultimately result in tissue damage known as reperfusion injury • Myocardium that is viable at the end of the ischemic period may therefore lose viability during reperfusion

  3. Conversely, the extent of myocardial necrosis correlates with the severity and duration of myocardial ischemia • The net effects of reperfusion are usually beneficial, but strategies or interventions that could prevent its negative counterparts would optimize myocardial salvage and improve functional recovery

  4. Reperfusion Injury • Reperfusion injury, occurring with restoration of blood flow to ischemic tissue, is associated with myocardial cell death and apoptosis, microvascular injury, myocardial stunning, and arrhythmias—all of which can result in mortality and morbidity, including heart failure • Reperfusion injury can occur after percutaneous coronary intervention (PCI) or thrombolysis for acute myocardial infarction (MI) as well as after coronary blood flow is halted for 30 min or longer during coronary artery bypass graft (CABG) surgery Kloner RA, et al. Circulation 104 (2001)2981–9

  5. Reperfusion Injury During CABG • In the controlled ischemia/reperfusion setting of coronary revascularization bypass graft surgery, where the myocardium must be made ischemic, an estimated 3% to 20% of patients experience MI associated with reperfusion after bypass grafting • Up till very recently, no effective pretreatment to prevent or lessen the loss of viable myocardium has been effective Mangano, DT. West J Med 161 (1994), 87–9

  6. Approaches to Prevent from Reperfusion Injury • Numerous studies evaluating the use of pharmacologic and mechanical therapies to mitigate reperfusion injury have proven unsuccessful not only in CABG surgery but in PCI as well • These approaches have focused on oxygen free radicals, neutrophil accumulation and activation, intracellular Ca2+ overload via sodium-hydrogen exchange (NHE) inhibition, complement activation, hypothermia, hyperbaric oxygenation, and distal embolic protection devices Stone GW, et al. JAMA 293 (2005), pp. 1063–72

  7. In each of these approaches, specific mechanisms of reperfusion injury were targeted • Their disappointing results might reflect the inherent limitations of therapies that target specific mechanisms or cell types involved in the pathophysiology of reperfusion injury, perhaps because they fail to address the full spectrum of its complexity

  8. The Cellular Mechanisms of Ischemia-reperfusion Injury

  9. Cessation of oxygen supply in ischaemia leads to a loss of ATP production and an increase of reactive oxygen species (ROS) in the mitochondria Reduced activity of the ATP consuming Na+-K+-pump leads to Na+ accumulation in the myocyte and the resting membrane potential is lowered With the development of acidosis, the Na+-H+-exchanger (NHX) further increases intracellular Na+ Under these conditions the Na+-Ca2+-exchanger (NCX) operates in the reverse mode, letting Ca2+ into the cell Ca2+ also enters through the sarcolemmal L-type voltage-gated Ca2+-channel (L) as the resting membrane potential is low The increased Ca2+ is taken up into the sarcoplasmic reticulum (SR) by the SR Ca2+-pump SERCA2 (P) and released from there via two types of release channels (RYR) and the (IP3R), leading to contraction During Ischemia Zaugg M, et al. BJA 93 (2004), 21-33

  10. Reoxygenation during reperfusion restores ATP production with a further boost of ROS Reactivation of the Na+-K+-pump by ATP slowly restores the sodium gradient leading to normal cation fluxes with the NCX eventually extruding the excess of cytosolic Ca2+ During the early reperfusion phase when the intracellular Ca2+ level is still high, myocardial contracture (supercontraction of myocytes) may develop When contracture affects the entire heart as it may occur after global ischaemia, it has been termed the ‘stone heart’ phenomenon During the First Minutes of Reperfusion Zaugg M, et al. BJA 93 (2004), 21-33

  11. During the Subsequent Hours of Reperfusion • With the resumption of blood flow, the endothelial lining of blood vessels subjected to ischemia-reperfusion becomes permeable, thus causing interstitial edema • Endothelial cells in reperfused myocardium assume an activated state in which they express adhesion proteins, release cytokines, and reduce production of NO • This promotes adherence, activation, and accumulation of neutrophils and monocytes in the ischemic-reperfused tissue Piper HM, et al. Ann Thorac Surg 75 (2003), 644-8

  12. The release of reactive oxygen species and proteolytic enzymes from these activated leukocytes can contribute to the damage of myocytes and vascular cells • Vascular plugging by adherent leukocytes and aggregated platelets can also promote a slow- or no-reflow phenomenon, already favored by tissue contracture and increased pressure of interstitial edema • It seems that these additional reperfusion-induced noxes contribute to infarct development predominantly during the first 2 hours of reperfusion, as myocardial necrosis almost reaches its final size during this period Piper HM, et al. Ann Thorac Surg 75 (2003), 644-8

  13. Adenosine, an endogenous purine nucleoside, is an anti-injury autocoid that targets a broad spectrum of the pathophysiology of ischemia/reperfusion injury It has been shown to improve post-ischemic ventricular function and prevent myocardial necrosis and apoptosis Adenosine Adenosine Gruber HE, et al. Circulation 80 (1989), 1400–11

  14. Adenosine Anti-inflammatory Effects • Inhibits neutrophil activation, adhesion to endothelium, and migration into the myocardium • Inhibits cytokine release from mononuclear cells • Inhibits release of oxygen radicals from granulocytes • Inhibits cardiomyocyte apoptosis • Prevents endothelial damage Gruber HE, et al. Circulation 80 (1989), 1400–11

  15. Gruber HE, et al. Circulation 80 (1989), 1400–11

  16. Other Protective Effects • Adenosine also has an anti-platelet effect that may have a role in maintaining infarct artery patency • Increases coronary collateral blood flow during ischemia • In isolated, perfused rat hearts, adenosine given at reperfusion increases glucose oxidation and inhibits glycolysis, reduces tissue lactate levels, and increases ATP levels. These effects tend to decrease cellular acidosis and Ca2+ overload and are associated with beneficial effects on mechanical function • Most importantly, adenosine has been shown to be a powerful inducer of ischemic preconditioning Gottlieb RA, et al. J Clin Invest 97 (1996), pp. 2391–8

  17. Stimulation of G-protein coupled receptors by primary messengers activates phospholipases (PL) PL in turn produce two second messengers originating from phosphatidylinositol bisphosphate (PIP2), namely inositol trisphosphate (IP3) and diacylglycerol (DAG) DAG activates different protein kinase C (PKC) isoforms PKC isoforms translocate to their appropriate target sites, activating the sarcolemmal and mitochondrial ATP-dependent potassium channels (K) and initiating distinct gene expression in the cell nucleus Adenosine Role in Ischemic Preconditioning Zaugg M, et al. BJA 93 (2004), 21-33

  18. Beneficial Effects of Intracoronary Adenosine as an Adjunct to Primary Angioplasty in Acute Myocardial Infarction

  19. Methods • 54 patients with AMI undergoing primary PTCA were randomized to either intracoronary adenosine or saline (27 patients in each) • Inclusion criteria: Patients referred for PTCA within 3 hours from the onset of AMI underwent diagnostic coronary angiography. If the culprit lesion was suitable for PTCA and presented with a TIMI flow from 0 to 2, the patient was included in the study and randomized Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  20. Exclusion criteria: -History of bronchospasm -Therapy with theophylline derivatives -Patients who had received thrombolytics in ER • The 2 groups were similar for age, sex, and infarct location Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  21. Clinical and Angiographic Characteristics Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  22. Treatment Regimen • The obstruction of the infarct-related artery was crossed with a 0.014-in guidewire • Over-the-wire balloon catheter was positioned at the level of the obstruction • The wire was pulled out, and diluted contrast was injected through the central lumen of the catheter to confirm positioning of the catheter tip and to assess patency of the distal vessel • The balloon was inflated, and either adenosine (4 mg in 2 mL saline) or saline (2 mL) was hand-injected into the distal vascular bed • The rate of injection was such as to complete treatment in 1 minute Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  23. The guidewire was then readvanced into the distal vessel, and the balloon was deflated to initiate reperfusion of the ischemic territory. The dilatation procedure was completed according to standard technique • Stenting of the dilated coronary segment was performed only for suboptimal balloon results or flow-limiting dissections • After completion of the dilation procedure, patients were observed in the catheterization room for 30 minutes. The final angiogram was then obtained, and the patient was transferred to ICU • Technically, the drug was administered distal to the coronary obstruction and before the onset of reperfusion Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  24. End Points • The primary end points of this study were feasibility and safety of intracoronary adenosine administration in the setting of primary PTCA and its effect on coronary blood flow • As secondary end points, indexes of myocardial damage, including left ventricular regional function, Q-wave MI, recurrence of angina, nonfatal MI, heart failure, and cardiac death were evaluated Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  25. Results: Feasibility and Safety • The injections of adenosine or saline in the distal coronary bed were well tolerated and free of side effects • No patients complained of worsening of chest pain • No patients suffered from hemodynamic instability • No bradyarrhythmias or tachyarrhythmias were associated with this protocol, including adenosine injection into the RCA Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  26. Results: Angiographic Results Effect of adenosine (ADO) on coronary blood flow: Intracoronary adenosine was associated with higher incidence of TIMI 3 flow and with a significant reduction in prevalence of no-reflow phenomenon Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  27. Results: The Clinical Events Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  28. Results: Clinical Course Effect of adenosine (ADO) on clinical Course: In adenosine group, a significant reduction of death, Q-wave MI, and major adverse cardiac events (MACE) was observed Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  29. Results: Left Ventricular Function Percentage of initially abnormal segments showing worsening (remodeling) or recovery at 1 week: Adenosine (ADO) adjunct to direct PTCA was associated with early recovery of wall motion Marzilli M, et al. Circulation 101 (2000), pp. 2154–9

  30. A Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial of Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction (AMISTAD-II)

  31. Design • Double-blinded, placebo-controlled, randomized study conducted in 13 countries (390 sites) and enrolled 2,118 patients between June 1999 and December 2000 • Objectives: to determine the effect of intravenous adenosine on clinical outcomes and infarct size in ST-segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  32. Methods • Enrollment required age over 18 years, reperfusion therapy (fibrinolysis or percutaneous intervention) within 6 h of onset of ischemic type pain (≥30 min), and electrocardiographic evidence of anterior STEMI • Electrocardiographic requirements were either ≥2 mm of ST-segment elevation in at least two contiguous precordial leads or new left bundle branch block Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  33. Exclusion Criteria: Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  34. Treatment Regimen • Patients selected for reperfusion therapy were randomly assigned to adenosine, 70 μg/kg/min or 50 μg/kg/min (utilized to evaluate dose-related responses), or to placebo in a 1:1:1 scheme • Study drug infusion (3 h) had to be started within 15 min either of the start of fibrinolysis or before coronary intervention Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  35. End Points • The primary end point was new congestive heart failure (CHF) beginning >24 h after randomization, or the first re-hospitalization for CHF, or death from any cause within six months • Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  36. Results: Infarct Size Infarct size measured as a percent of the LV by technetium-99m SPECT in the 243 patients in the infarct size substudy: Only the higher adenosine dose group showed a significant reduction in median infarct size relative to placebo (p = 0.023) Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  37. Infarct size measured as a percent of the LV by technetium-99m SPECT in the 28 patients in the infarct size substudy who suffered a primary end point compared with the 215 patients who did not have an end point: The group with a primary end point had larger infarcts than did those without (p < 0.001) Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  38. Results: Primary End Points • There was no difference in the primary end point between placebo (17.9%) and either the pooled adenosine dose groups (16.3%) or, separately, the 50-μg/kg/min dose and 70-μg/kg/min groups (16.5% vs. 16.1%, respectively, p = 0.43) • likely explanation for failure of the trial to demonstrate a clinical benefit was that it was underpowered: -The sample size calculation was based on a reduction of events in the pooled adenosine group by 25% compared with placebo. The reduction observed was only 11% -This result in part reflects the modest infarct size reduction in the 50% of patients receiving the lower adenosine dose Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  39. Adverse Events by Treatment Groups Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  40. AMISTAD-II Results: Conclusion • A 3-h adenosine infusion at 70 μg/kg/min (but not at the lower 50-μg/kg/min dose) reduces infarct size in anterior MI patients when given in conjunction with reperfusion therapy • The major limitation of this study was that the sample size was too small to confirm that the observed adenosine-related reduction in the combined clinical end point was statistically significant Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80

  41. Acadesine was first isolated from a culture medium of sulfonamide inhibited Eschericia coli in 1952 During studies in cultured human lymphoblasts it was found that Acadesine could augment adenosine release from cells under certain conditions Acadesine Acadesine5-Aminoimidazole-4-carboxamide-1-b-riboside

  42. Acadesine represents the prototype of a new class of Adenosine regulating agents (ARAs) that substantially increase endogenous adenosine, but importantly, only in ischemic tissue and only under conditions of adenosine triphosphate (ATP) catabolism • The exact mechanism of action for increased extracellular adenosine during ATP catabolism in the presence of Acadesine remains unknown

  43. Post-Reperfusion Myocardial Infarction Long-Term Survival Improvement Using Adenosine Regulation With Acadesine Journal of the American College of Cardiology, In Press, Corrected Proof, Available online 11 May 2006

  44. Design • Multi-institutional (54 centers), prospectively designed, randomized, placebo-controlled, and double-blinded study that assessed the effects of acadesine versus placebo on MI and secondarily on the combined outcome of cardiac death, MI, or stroke assessed at 4 days after CABG surgery • Long-term follow-up study was prospectively designed to investigate the effects of acadesine versus placebo on 2-year, all-cause mortality after perioperative MI • Hypothesized that, assessed against placebo, acadesine treatment improved 2-year survival among those patients suffering post-reperfusion MI Mangano DT, et al. JACC, in press

  45. Methods • 2,698 patients undergoing CABG surgery were randomized to receive placebo (n = 1,346) or acadesine (n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h) starting approximately 15 min before induction of anesthesia, and also in cardioplegia solution (placebo or acadesine; 5 μg/ml) • Myocardial infarction was prospectively defined as: 1) new Q-wave with CK-MB elevation (daily electrocardiography; 16 serial CK-MB measurements); or 2) autopsy evidence Mangano DT, et al. JACC, in press

  46. Baseline Characteristics for All Patients, Patients Suffering MI, and Patients Not Suffering MI

  47. Results: Post-reperfusion MI • Myocardial infarction occurred in 100 of the 2,695 patients enrolled (3.7%) • Although acadesine reduced the incidence of MI (placebo, 4.01% [54 of 1,345]; acadesine, 3.41% [46 of 1,350]), the reduction was not statistically significant (p = 0.24) • The occurrence of a perioperative MI conferred a 4.2-fold increased risk in 2-year mortality: -Among the 2,595 patients not suffering infarction, 2-year mortality was 4.28%, versus 18.0% among the 100 patients suffering infarction (p < 0.001) -The primary mortality effect appeared over the first 30 days after infarction Mangano DT, et al. JACC, in press

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