Complete prevention of myocardial stunning, contracture, low-reflow, and edema after heart transplantation by blocking neutrophil adhesion molecules during reperfusion

J. G. Byrne, W. J. Smith, M. P. Murphy, G. S. Couper, R. F. Appleyard, L. H. Cohn, D. C. Drinkwater

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Abstract

This study tested the hypothesis that preventing neutrophil adhesion during reperfusion, by blocking either the neutrophil membrane CD18 integrin complex or its endothelial and myocyte ligand, intercellular adhesion molecule-1 (ICAM-1), would reduce myocardial inflammation and edema and improve reflow and ventricular function after heart preservation and transplantation. After cardioplegia and insertion of a left ventricular balloon, rabbit hearts were heterotopically transplanted into recipient rabbits either immediately (immediate, n = 12) or after preservation in 4° C saline (3 hours of ischemia, n = 33). Forty-five minutes before reperfusion, recipients of preserved hearts received intravenous infusions of either saline (vehicle, n = 13), anti-CD18 monoclonal antibody (Mab) R15.7 (2 mg/kg) (anti-CD18, n = 10), or anti-ICAM-1 Mab R1.1 (2 mg/kg) (anti-ICAM, n = 10). During 3 hours of reperfusion the slope of the peak-systolic pressure-volume relation and its volume-axis intercept, the exponential elastic coefficient of the end-diastolic pressure-volume relation, the unstressed ventricular volume, and the time constant of the exponential left ventricular pressure decay after dP/dt(min) were serially measured. Myocardial blood flow was measured with microspheres from which coronary vascular resistance was calculated. After explantation, the degree of myocardial inflammation, estimated by tissue neutrophil sequestration (myeloperoxidase assay) and myocardial water content were determined. Within each group no significant differences in measurements made at 1, 2, and 3 hours of reperfusion were noted. Compared with the immediate transplantation group, the vehicle group demonstrated a significant increase in myeloperoxidase activity (3380 ± 456 versus 1712 ± 552 μU/gm, p < 0.05), coronary vascular resistance (115.5 ± 13.4 versus 70.5 ± 10.6 U/gm, p < 0.05), and myocardial water content (79.8% ± 0.4% versus 75.6% ± 1.3%, p < 0.05), a significant decrease in unstressed ventricular volume (a leftward shift in the end-diastolic pressure-volume relation) (-0.49 ± 0.24 versus 0.28 ± 0.21 ml, p < 0.05), and a marked prolongation in exponential left ventricular pressure delay after dP/dt(min) (156.64 ± 3.81 versus 37.25 ± 3.34 msec, p < 0.01). The administration of either anti-CD18 or anti-ICAM-1 Mab prevented the increase in coronary vascular resistance (anti-CD18, 64.8 ± 4.5 versus 115.5 ± 13.4 U/gm, p < 0.05; anti-ICAM, 52.3 ± 7.6 versus 115.5 ± 13.4 U/gm, p < 0.05), the leftward shift in the end-diastolic pressure-volume relation (anti-CD18, 0.51 ± 0.43 versus -0.49 ± 0.24 ml, p < 0.05; anti-ICAM, 0.70 ± 0.23 versus - 0.49 ± 0.24 ml, p < 0.05), and the prolongation in exponential left ventricular pressure delay after dP/dt(min) (anti-CD18, 31.70 ± 4.36 versus 156.64 ± 3.81 msec, p < 0.01; anti-ICAM, 27.26 ± 3.55 versus 156.64 ± 3.81 msec, p < 0.01). However only anti-CD18 Mab significantly reduced myeloperoxidase activity (anti-CD18, 1100 ± 308 versus 3380 ± 456 μU/gm, p < 0.05; anti-ICAM, 4830 ± 657 versus 3380 ± 456, p > 0.05) and myocardial water content (anti-CD18, 75.2% ± 1.7% versus 79.8% ± 0.4%, p < 0.05; anti- ICAM, 78.2% ± 0.8% versus 79.8% ± 0.4%, p > 0.05). These results demonstrate the prevention of myocardial neutrophil sequestration, edema, the low-reflow phenomenon, and diastolic myocardial dysfunction by Mabs that block neutrophil adhesion. We conclude that neutrophil adhesion is an important mechanism of reperfusion-induced myocardial damage after heart transplantation and should be addressed in treatments directed at limiting reperfusion injury.

Original languageEnglish (US)
Pages (from-to)1589-1596
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume104
Issue number6
StatePublished - Jan 1 1992

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ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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