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

Circulation. 1993 Nov;88(5 Pt 2):II372-9.


Background: 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.

Methods and results: 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.

Conclusions: 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.

MeSH terms

  • 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


  • Anti-Inflammatory Agents, Non-Steroidal
  • Macrophage-1 Antigen
  • N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine
  • Leucine