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Ann Thorac Surg 2000;70:890-894
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

Sialyl LewisX oligosaccharide preserves myocardial and endothelial function during cardioplegic ischemia

Marc L. Schermerhorn, MDa, David P. Nelson, MD, PhDb, Elizabeth D. Blume, MDb, Laurie Phillips, PhDc, John E. Mayer, Jr, MDa

a Department of Cardiac Surgery, The Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
b Department of Cardiology, The Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
c Cytel Corporation, San Diego, California, USA

Address reprint requests to Dr Mayer, Department of Cardiovascular Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA02115
e-mail: john.mayer{at}tch.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Neutrophil adhesion to endothelium contributes to myocardial reperfusion injury after cardiac operation. Initial neutrophil-endothelial interactions involve selectins, which bind Sialyl-LewisX on neutrophils. Blockade of selectin-mediated neutrophil-endothelial interactions with CY-1503, a synthetic analogue of Sialyl-LewisX, might reduce reperfusion injury after myocardial ischemia.

Methods. The efficacy of CY-1503 to attenuate global myocardial reperfusion injury was assessed in isolated blood-perfused neonatal lamb hearts that had 2 hours of cold cardioplegic ischemia. CY-1503 (40 mg/L) or saline vehicle was added to blood perfusate before ischemia. Contractile function (developed pressure, dP/dt) and coronary vascular endothelial function (acetylcholine response) were assessed at base line and during reperfusion. Myocardial neutrophil accumulation was assessed by myeloperoxidase quantification.

Results. Compared to controls, treatment with CY-1503 improved recovery of all indices of contractile function, preserved coronary vascular endothelial function, and reduced myocardial neutrophil accumulation.

Conclusions. In isolated neonatal lamb hearts that underwent hypothermic cardioplegic ischemia, CY-1503 administration reduced myocardial neutrophil accumulation and preserved endothelial and contractile function. Selectin blockade of leukocyte-endothelial interactions might attenuate reperfusion injury and enhance myocardial protection during cardiac surgical procedures.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Most reparative cardiac operations require a surgically induced period of myocardial ischemia followed by reperfusion, which results in alterations in myocardial contractile function and coronary vascular reactivity [1]. Myocardial ischemia-reperfusion injury is associated with neutrophil sequestration in reperfused tissue, and neutrophil adhesion to endothelium is a prerequisite to transmigration across the endothelium and accumulation in parenchymal tissues [2, 3]. The process of adhesion is a multistep process. The initial step is mediated by the binding of selectins (P, E, and L) to their oligosaccharide ligands on neutrophils, which results in tethering of neutrophils to endothelium so that they roll along the endothelial surface. P- and E-selectin are found on endothelium and bind to Sialyl LewisX (SLex) found on neutrophils. Prior studies from our laboratory have shown that therapies directed at neutrophils can improve myocardial function after myocardial ischemia-reperfusion injury. Neutrophil depletion, nonspecific selectin blockade, and administration of a blocking antibody directed against the leukocyte adhesion molecule CD18 preserve recovery of myocardial function in isolated blood-perfused hearts after cold cardioplegic ischemia [4–6].

Administration of a soluble SLex analogue, CY-1503, has been shown to be effective in reducing neutrophil accumulation and tissue injury in several models of ischemia-reperfusion injury, including acute lung injury [7], trauma [8], transplantation [9], and septic shock [10]. In addition, treatment with CY1503 in animal models of regional myocardial reperfusion injury have shown that it reduces infarct size and preserves contractile function and coronary vascular reactivity [11–13]. We reasoned that CY1503 might improve myocardial function after global ischemia-reperfusion injury. This study was undertaken to determine whether selectin blockade with a synthetic analogue of SLex (CY-1503) could improve recovery of myocardial and endothelial function after cold cardioplegic ischemia.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Isolated heart preparation
Neonatal lambs (3 to 5 days old, 4 to 7 kg) were anesthetized with intramuscular ketamine (40 mg/kg) and inhaled halothane (0.5%) and mechanically ventilated at 15 cycles per minute with a tidal volume of 20 mL/kg. Through a median sternotomy, coronary perfusion was established after heparinization (400 U/kg) through an arterial cannula placed at the aortic root using a roller pump (Olson Medical Products Inc, Ashland, MA) and bubble oxygenator (Bio-2; American Bentley, Irvine, CA). Great care was taken to assure constant perfusion pressure and no ischemia during explantation of the heart. Once perfusion was established, the heart was excised and placed on a 37°C water bath. The coronary venous return was drained through a cannula placed into the right ventricle through the pulmonary artery, and the superior and inferior vena cavae were ligated. A sampling catheter was placed into the coronary sinus through the hemiazygos vein. The isolated heart was perfused with heparinized, fresh, homologous, whole blood, bubble-oxygenated with a gas mixture of 20% oxygen, 5% carbon dioxide, and 75% nitrogen. Arterial pH was maintained at 7.4 with sodium bicarbonate. A pressure transducer (SPC-350; Millar Instruments, Inc, Houston, TX) was inserted through the left ventricular (LV) apex inside a saline-filled latex balloon that could be inflated to various volumes. A Foley balloon catheter was placed into the left atrium to prevent herniation of the LV balloon and to vent the LV.

Measurements
LV pressure measurements, (systolic, diastolic, and the first derivative of pressure [dP/dt]) were recorded with a multichannel recorder (Honeywell Inc, Pleasantville, NY). Increments of 0.5 mL were added to the interventricular balloon until an end-diastolic pressure of 20 mm Hg was reached, with pressure recordings made at each balloon volume. Systolic function was evaluated by determining maximum values for developed pressure (DP max) and +dP/dt (+dP/dt max), and preload-standardized values for developed pressure (DP V10) and +dP/dt (+dP/dt V10) at a standardized balloon volume, V10. V10 was defined as the balloon volume corresponding to an end-diastolic pressure of 10 mm Hg during baseline measurements. Diastolic function was assessed by maximum (-dP/dt max) and preload-standardized negative dP/dt (-dP/dt V10).

Coronary blood flow was measured through an electromagnetic flow probe (MFV-33100; Nihon Kohden, Tokyo, Japan) connected to the venous cannula. Coronary endothelial function was assessed by measuring coronary vascular resistance reserve during a 30-second infusion of acetylcholine (10-7 M), an endothelial dependent vasodilator. Myocardial oxygen consumption was calculated from arterial and coronary sinus oxygen contents and coronary blood flow.

After collection of baseline hemodynamic measurements, the blood perfusate and water bath were cooled to 15°C over 10 minutes. The heart was arrested with 20 mL/kg of 4°C cardioplegia (0.45% sodium chloride, 2.5% dextrose, 20 mEq/L potassium chloride, 6 mEq/L sodium bicarbonate). A second 10 mL/kg cardioplegia dose was given 1 hour after the onset of arrest. Myocardial temperature, measured with a temperature probe placed in the right ventricular wall, was maintained below 15°C by topical cooling. After 2 hours arrest, reperfusion was reestablished with room temperature (25°C) perfusate. The gas mixture was changed to 95% oxygen and 5% carbon dioxide during cooling and during the initial 15 minutes of reperfusion. Elevated coronary perfusion pressure during initial reperfusion can result in coronary endothelial dysfunction [14], so coronary perfusion pressure during reperfusion was maintained at 20 mm Hg for the first 5 minutes, 40 mm Hg for the second 5 minutes, and 60 mm Hg for the remaining period of reperfusion. After rewarming to 37°C, functional measurements were repeated at 30 and 60 minutes of reperfusion. After 60 minutes of reperfusion, biopsy samples of left ventricle were taken for myeloperoxidase analysis.

Sialyl Lewisx analogue (CY-1503)
The SLex analogue (CY-1503) used in this study was provided by Cytel Corporation (San Diego, CA). CY-1503 (40 mg/L) was added to the pump prime of experimental isolated hearts (n = 6) before explantation of the hearts to provide a constant concentration of CY-1503 during the entire period of pump perfusion, including reperfusion. Saline was added to the pump prime of control animals (n = 6).

Tissue myeloperoxidase activity
Myocardial neutrophil accumulation was quantified by neutrophil myeloperoxidase activity [15]. Using a tissue homogenizer, ventricular tissue samples were homogenized in cold extraction buffer (0.5% hexadecyltrimethylammonium bromide, 50 mmol/L potassium phosphate, pH 6.0) and centrifuged at 12,000 g for 30 minutes at 4°C. Myeloperoxidase activity in supernatants and neutrophil standards was assayed by adding 100 µL ABTS solution (containing 1 mmol/L azino-diethyl dithiazoline sulfonic acid with 10 mmol/L H2O2 in 100 mmol/L citrate buffer, pH 4.2) and measuring the change in absorbance at 405 nmol/L. Myeloperoxidase activity was estimated as neutrophil cell equivalents from a neutrophil standard curve [15] and normalized to the protein concentration of each tissue sample determined by the Bradford microassay method (Bio Rad Laboratories, Richmond, CA).

Statistical analysis
Results at 30 and 60 minutes of reperfusion are expressed as percentage recovery of baseline value (mean ± standard deviation). Comparisons were made between control and SLex groups at 30 and 60 minutes using a Student’s t test. A p value less than 0.05 was considered statistically significant.

Animals in this study received humane care in compliance with "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised, 1985).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Recovery of contractile function during reperfusion was better in isolated hearts treated with CY-1503 than in controls by all indices of myocardial systolic and diastolic function. Figure 1 shows improved recovery of developed pressure, +dP/dt and negative dP/dt in CY-1503–treated hearts compared with controls at 60 minutes of reperfusion. The improved recovery was found in both maximum and volume-standardized V10 values and was apparent at both 30 and 60 minutes of reperfusion (Table 1).



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  		Fig 1. Contractile function of control and CY-1503 groups after 2 hours of hypothermic cardioplegic arrest and 60 minutes of warm reperfusion. Data are shown as percentage recovery of baseline measurements. Recovery of contractile function during reperfusion was better in isolated hearts treated with CY-1503 than controls by all indices of myocardial systolic and diastolic function measured (p < 0.05). DP (max) indicates maximum developed pressure; +dP/dt (max) and -dP/dt (max) indicate maximum positive and negative dP/dt respectively.

 

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  		Table 1. Contractile Function in Isolated Hearts After 2 Hours of Hypothermic Cardioplegic Arrest

 
Figure 2 shows that coronary vascular resistance reserve to acetylcholine was greater in the CY-1503 group than in the control group at both 30 and 60 minutes of reperfusion. The improved coronary vasodilation in the CY-1503 group suggests that CY-1503 preserves coronary vascular endothelial function during global myocardial ischemia-reperfusion injury.



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  		Fig 2. Coronary vasodilation response to a 30-second infusion of 10-7 M acetylcholine (Ach) in CY-1503 and control hearts after 2 hours of hypothermic cardioplegic arrest at 30 and 60 minutes of warm reperfusion. The improved coronary vasodilation in the CY-1503 group indicates that CY-1503 preserved coronary endothelial function during global myocardial ischemia and reperfusion (p < 0.05).

 
Figure 3 shows that myocardial neutrophil accumulation was lower in isolated hearts treated with CY-1503 than in control hearts (p < 0.05).



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  		Fig 3. Myeloperoxidase activity (neutrophils/mg protein) in CY-1503 and control hearts after 2 hours of hypothermic cardioplegic arrest and 60 minutes of warm reperfusion. Myocardial neutrophil accumulation was lower in isolated hearts treated with CY-1503 compared with controls (p < 0.05).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Despite use of cardioplegia and hypothermia, myocardial ischemia with subsequent reperfusion initiates an inflammatory process involving neutrophils that results in myocardial and endothelial dysfunction. The adherence of activated neutrophils to endothelium is a multistep process that precedes neutrophil accumulation into reperfused tissue [3]. The initial interaction between neutrophils and endothelium is mediated by selectins and their carbohydrate ligands [16]. Although the precise mechanisms by which neutrophils mediate tissue injury are not completely understood, it is known that activated neutrophils generate several toxic substances that directly injure endothelium or myocytes. For example, neutrophil-derived proteases are believed to contribute substantially to ischemia-reperfusion damage, and neutrophils generate oxygen-derived free radicals by conversion of oxygen to superoxide anion by neutrophil NADPH oxidase. In addition to direct cytotoxic effects, superoxide anion might directly inhibit vasodilatory effects of endogenous nitric oxide, which could contribute to loss of endothelial-mediated vasodilation after ischemia-reperfusion injury [17]. Nitric oxide can inhibit neutrophil-endothelial interactions [18], and treatment with the nitric oxide precursor L-arginine improved recovery of postischemic ventricular and endothelial function [19].

In the current study, administration of the SLex analogue CY-1503 resulted in preservation of both endothelial and myocardial contractile function after global myocardial ischemia-reperfusion injury. The improvement in vascular and contractile function was associated with a reduction in neutrophil accumulation in reperfused myocardium. Our findings are consistent with previous studies showing cardioprotective effects of CY-1503 [11–13]. In animal models of regional myocardial ischemia-reperfusion, CY-1503 treatment before reperfusion reduced infarct size and neutrophil accumulation while improving cardiac contractility and endothelium-dependent vasodilation [11–13]. CY-1503 has also been shown to reduce tissue injury in other animal models of inflammatory tissue injury, including acute lung injury [7], trauma [8], transplantation [9], and septic shock [10].

Preservation of endothelial function by CY-1503 is a significant finding in this study. The vascular bed seems to be a major target for neutrophil-mediated damage after ischemia and reperfusion [2]. Both regional and global myocardial ischemia-reperfusion result in loss of endothelium-dependent vasodilation and increased capillary permeability [11, 14]. Endothelial injury after ischemia-reperfusion might precede damage to myocardium [20] and interventions that improve recovery of endothelium function have been associated with improved myocardial contractile function [19, 21, 22]. Endothelial dysfunction and resultant alterations in vascular reactivity are also known to occur after cardiopulmonary bypass [1, 23]. Cardiopulmonary bypass-mediated endothelial dysfunction might result from ischemia and reperfusion or activation of blood components by the cardiopulmonary bypass circuit or a combination of both.

Our results provide further evidence to support the hypothesis that CY-1503 attenuates myocardial reperfusion injury by blocking selectin-mediated neutrophil-endothelial interactions [11–13]. Adhesion of neutrophils to the endothelium is initiated by neutrophil rolling on the endothelial surface, a process mediated by the selectins [3]. P-selectin, stored preformed in secretory granules of platelets and endothelial cells, is mobilized rapidly to the endothelial surface in response to agents such as histamine and thrombin [2]. By contrast, E-selectin is synthesized de novo in response to cytokines such as tumor necrosis factor, lipopolysaccharide, and interleukin 1 and consequently requires 4 to 6 hours for maximal endothelial surface expression. Constitutively expressed L-selectin on inactivated neutrophils is shed after neutrophil activation, and soluble/shed L-selectin might have antiinflammatory effects [24]. Monoclonal antibodies directed against both L- and P-selectin have been shown to preserve endothelial function, reduce neutrophil accumulation, and attenuate infarct size after coronary ligation in the cat [25, 26]. By contrast, a monoclonal antibody directed against L-selectin in our isolated heart ischemia model did not preserve contractility or endothelial function (unpublished data). It seems plausible that neutrophil activation occurred in this isolated heart model by exposure of perfusate blood to the extracorporeal circuit, with consequent shedding of L-selectin. The cardioprotective effects of CY-1503 in the current experiment might result from blockade of P-selectin because the limited reperfusion time would not be sufficient for substantial surface expression of E-selectin.

In summary, despite hypothermia and cardioplegia, significant contractile and endothelial dysfunction occurs after myocardial ischemia and reperfusion. This process involves neutrophil adhesion to endothelium; the initial tethering of neutrophils to endothelium is mediated by selectins. In the present study of blood-perfused neonatal lamb hearts that underwent hypothermic ischemia, selectin blockade by administration of CY-1503 before ischemia and during reperfusion decreased neutrophil accumulation in reperfused myocardium and preserved endothelial and contractile function. These results suggest that selectin-mediated neutrophil-endothelial interactions contribute to myocardial ischemia-reperfusion injury after cardiopulmonary bypass. Agents that block leukocyte-endothelial interactions might enhance myocardial protection during cardiac surgical procedures.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Supported by NIH grants SPO1 AC48675.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Sellke F.W., Shafique T., Ely D.L., Weintraub R.M. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993;88:II395-II400.
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Accepted for publication April 4, 2000.




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