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J Thorac Cardiovasc Surg 2000;120:230-237
© 2000 The American Association for Thoracic Surgery

Surgery for congenital heart disease

Sialyl LewisX oligosaccharide preserves cardiopulmonary and endothelial function after hypothermic circulatory arrest in lambs

Marc L. Schermerhorn, MDa, Motohisa Tofukuji, MD, PhDd, Philip R. Khoury, MSc, Laurie Phillips, PhDe, Paul R. Hickey, MDb, Frank W. Sellke, MDd, John E. Mayer, Jr , MDa, David P. Nelson, MD, PhDc

From the Departments of Cardiovascular Surgerya and Anesthesia,b The Children’s Hospital, Harvard Medical School, Boston, Mass; Division of Pediatric Cardiology, Department of Pediatrics, Children’s Hospital Medical Center, University of Cincinnati School of Medicine,c Cincinnati, Ohio; Division of Cardiothoracic Surgery, Beth Israel Deaconess Hospital, Harvard Medical School,d Boston, Mass; and Cytel Corporation,e San Diego, Calif.

Supported by National Institutes of Health grants RO1 HL46716 and SPO1 HL48675.

Address for reprints: David P. Nelson, MD, PhD, Division of Pediatric Cardiology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229 (E-mail:Davenelson @chmcc.org ).

Objective: Neutrophil adhesion to endothelium contributes to cardiopulmonary dysfunction after cardiac surgical procedures. Initial neutrophil-endothelial interactions involve selectins, which bind carbohydrate ligands, such as sialyl-LewisX. Blockade of selectin-mediated neutrophil interactions with CY1503, a synthetic oligosaccharide analog of sialyl-LewisX, could limit neutrophil-mediated injury after cardiopulmonary bypass.
Methods: The efficacy of CY1503 treatment was tested in a lamb model of cardiopulmonary bypass with hypothermic circulatory arrest. Neonatal lambs received CY1503 (n = 6, CPB-CY1503) or saline solution vehicle (n = 7, CPB-saline) into the pump prime before bypass and as a continuous infusion throughout reperfusion. Five lambs served as control animals for in vitro microvessel studies. Indexes of myocardial function (preload recruitable stroke work index, and rate of pressure rise) and pulmonary function (compliance, airway resistance, and arterial PO 2) were measured before bypass and during reperfusion. The effect of CY1503 on endothelium-dependent vascular reactivity was assessed by means of in vitro pulmonary and coronary microvessel studies.
Results: Myocardial function was depressed after circulatory arrest, but CY1503 preserved function near baseline (36% ± 25% vs 99% ± 19% of baseline at 3 hours of reperfusion). CY1503-treated animals also demonstrated improved pulmonary function during reperfusion. In vitro microvessel analysis of vascular reactivity revealed endothelial dysfunction after circulatory arrest compared with control lambs. CY1503-treated lambs (CPB-CY1503) had intact endothelial function, as demonstrated by normal vasodilatory responses to endothelium-dependent vasodilators.
Conclusions: CY1503 preserves cardiopulmonary and endothelial function after cardiopulmonary bypass and hypothermic circulatory arrest in neonatal lambs. This suggests a role for selectin-mediated, neutrophil-endothelial interactions in the inflammatory response after cardiac operations.




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