(Circulation. 1995;92:492-499.)
© 1995 American Heart Association, Inc.
Articles |
Adjunctive Selectin Blockade Successfully Reduces Infarct Size Beyond Thrombolysis in the Electrolytic Canine Coronary Artery Model
Presented in part at the 44th Scientific Sessions of the American College of Cardiology, New Orleans, La.
From the Experimental Thrombosis Laboratory, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio; and Cytel Corporation (M.L.P.), San Diego, Calif.
Correspondence to Joseph M. Sutton, MD, Department of Cardiology F-15, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
Background An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia–reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia–reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model.
Methods and Results A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 µg/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503–treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7±8.4% versus 21.8±13.6%; P=.008) and a marked reduction in myeloperoxidase activity (0.014±0.009 versus 0.0370±0.025 U/min per gram; P=.02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias.
Conclusions Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia–reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia–reperfusion injury.
Key Words: adhesion molecules • neutrophils • thrombolysis • reperfusion • selectin
This article has been cited by other articles:
 |
|
 |
|
  C. Duilio, G. Ambrosio, P. Kuppusamy, A. DiPaula, L. C. Becker, and J. L. Zweier Neutrophils are primary source of O2 radicals during reperfusion after prolonged myocardial ischemia Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2649 - H2657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Schermerhorn, D. P. Nelson, E. D. Blume, L. Phillips, and J. E. Mayer Jr Sialyl LewisX oligosaccharide preserves myocardial and endothelial function during cardioplegic ischemia Ann. Thorac. Surg., September 1, 2000; 70(3): 890 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Schermerhorn, M. Tofukuji, P. R. Khoury, L. Phillips, P. R. Hickey, F. W. Sellke, J. E. Mayer Jr, and D. P. Nelson Sialyl LewisX oligosaccharide preserves cardiopulmonary and endothelial function after hypothermic circulatory arrest in lambs J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 230 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Jaakkola, S. Jalkanen, K. Kaunismaki, E. Vanttinen, P. Saukko, K. Alanen, M. Kallajoki, L.-M. Voipio-Pulkki, and M. Salmi Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-Selectin mediate leukocyte binding to ischemic heart in humans J. Am. Coll. Cardiol., July 1, 2000; 36(1): 122 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. KERR, W. R. AUGER, J. J. MARSH, R. M. COMITO, R. L. FEDULLO, G. J. SMITS, D. P. KAPELANSKI, P. F. FEDULLO, R. N. CHANNICK, S. W. JAMIESON, et al. The Use of Cylexin (CY-1503) in Prevention of Reperfusion Lung Injury in Patients Undergoing Pulmonary Thromboendarterectomy Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 14 - 20. [Abstract] [Full Text]
|
|
|
|
|
|
T. Shin'oka, M. Nagashima, G. Nollert, D. Shum-Tim, P. C. Laussen, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas A NOVEL SIALYL LEWIS X ANALOG ATTENUATES CEREBRAL INJURY AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1204 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Claeys, J. Bosmans, L. Veenstra, P. Jorens, Herbert De Raedt, and C. J. Vrints Determinants and Prognostic Implications of Persistent ST-Segment Elevation After Primary Angioplasty for Acute Myocardial Infarction : Importance of Microvascular Reperfusion Injury on Clinical Outcome Circulation, April 20, 1999; 99(15): 1972 - 1977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kumar, M. P. Villani, U. K. Patel, J. C. Keith Jr, and R. G. Schaub Recombinant Soluble Form of PSGL-1 Accelerates Thrombolysis and Prevents Reocclusion in a Porcine Model Circulation, March 16, 1999; 99(10): 1363 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Merhi, P. Provost, P. Chauvet, J.-F. Theoret, M. L. Phillips, and J.-G. Latour Selectin Blockade Reduces Neutrophil Interaction With Platelets at the Site of Deep Arterial Injury by Angioplasty in Pigs Arterioscler. Thromb. Vasc. Biol., February 1, 1999; 19(2): 372 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Palazzo, S. P. Jones, D. C. Anderson, D. N. Granger, and D. J. Lefer Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1865 - H1872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kumar, J. L. Hoover, C. A. Simmons, V. Lindner, and R. J. Shebuski Remodeling and Neointimal Formation in the Carotid Artery of Normal and P-Selectin–Deficient Mice Circulation, December 16, 1997; 96(12): 4333 - 4342. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Cobbaert, W. Th. Hermens, P. P. Kint, P. J. Klootwijk, F. Van de Werf, and M. L. Simoons Thrombolysis-induced coronary reperfusion causes acute and massive interstitial release of cardiac muscle cell proteins Cardiovasc Res, January 1, 1997; 33(1): 147 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miura, D. P. Nelson, M. L. Schermerhorn, T. Shin'oka, G. Zund, P. R. Hickey, E. J. Neufeld, and J. E. Mayer Jr Blockade of Selectin-Mediated Leukocyte Adhesion Improves Postischemic Function in Lamb Hearts Ann. Thorac. Surg., November 1, 1996; 62(5): 1295 - 1300. [Abstract] [Full Text]
|
|
|
|
|
|
M. C.G. Horrigan, A. I. MacIsaac, F. A. Nicolini, D. G. Vince, P. Lee, S. G. Ellis, and E. J. Topol Reduction in Myocardial Infarct Size by Basic Fibroblast Growth Factor After Temporary Coronary Occlusion in a Canine Model Circulation, October 15, 1996; 94(8): 1927 - 1933. [Abstract] [Full Text]
|
|
|
|
 |
|
 H.-P. Haring, E. L. Berg, N. Tsurushita, M. Tagaya, G. J. del Zoppo, and M. J Eppihimer E-Selectin Appears in Nonischemic Tissue During Experimental Focal Cerebral Ischemia Stroke, August 1, 1996; 27(8): 1386 - 1392. [Abstract] [Full Text]
|
|
|
|
|
|
F. M. Sheridan, P. G. Cole, and D. Ramage Leukocyte Adhesion to the Coronary Microvasculature During Ischemia and Reperfusion in an In Vivo Canine Model Circulation, May 15, 1996; 93(10): 1784 - 1787. [Abstract] [Full Text]
|
|