Inhibition of neutrophil adherence improves postischemic ventricular performance of the neonatal heart

• Published in: Circulation (New York, N.Y.) N.Y.), 1993-11, Vol.88 (5 Pt 2), p.II372-II379
• Main Authors: Wilson, I, Gillinov, A M, Curtis, W E, DiNatale, J, Burch, R M, Gardner, T J, Cameron, D E
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Cardiopulmonary Bypass; Cell Adhesion - drug effects; Leucine - analogs & derivatives; Leucine - therapeutic use; Macrophage-1 Antigen - physiology; Myocardial Reperfusion Injury - prevention & control; Neutrophils - drug effects; Neutrophils - physiology; Swine; Up-Regulation - physiology
• ISSN: 0009-7322

Reduction of the leukocyte population during postischemic coronary reperfusion results in decreased neutrophil-mediated tissue injury. However, the importance of leukocyte adhesion to coronary endothelium for postischemic ventricular dysfunction after global hypothermic myocardial ischemia is unknown. Neutrophil integrins (CD11b/CD18) upregulate in response to cardiopulmonary bypass and ischemic stress, and their role in generating postoperative ventricular dysfunction was examined in this study. An in vivo, in situ model of neonatal cardiac surgery was established in which neutrophil adherence was manipulated by administering NPC 15669 (an inhibitor of neutrophil CD11b/CD18 surface receptor upregulation). Seventeen 3- to 5-day-old piglets (8 controls and 9 NPC 15669-treated animals) were instrumented with a coronary sinus catheter, sonomicrometry crystals across the short axis of the left ventricle (LV), and a micromanometer positioned in the LV. Hearts were subjected to 90 minutes of hypothermic ischemia after a single dose of cold crystalloid cardioplegia. Myocardial granulocyte accumulation during ischemia and reperfusion was reduced in NPC animals compared with controls (myeloperoxidase activity, 43.4 +/- 2.6 and 75.8 +/- 6.3 mumol/10 mg tissue, respectively; P < or = .005). This was associated with a reduction in coronary vascular resistance in NPC animals compared with controls (P < or = .02) and decreased release of myocardial creatine phosphokinase throughout reperfusion (P < or = .05). NPC animals demonstrated an improved preservation of the end-systolic pressure-volume relation after discontinuation of cardiopulmonary bypass (71 +/- 6% and 96 +/- 6% at 60 minutes, respectively; P < or = .05). There was no difference in ventricular compliance between groups. These data demonstrate that inhibition of neutrophil CD11b/CD18 surface adherence receptor upregulation reduces granulocyte accumulation in myocardium after hypothermic global ischemia, reduces myocyte damage, and improves ventricular systolic function.