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Ann Thorac Surg 1995;60:1238-1244
© 1995 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Anti-CD11b Monoclonal Antibody Improves Myocardial Function After Six Hours of Hypothermic Storage

Joseph M. Forbess, MD, Takeshi Hiramatsu, MD, Fumikazu Nomura, MD, Takuya Miura, MD, G. King Farrington, PhD, Karen Sokolowski, Mark Bree, BS, John E. Mayer, Jr, MD

Department of Cardiovascular Surgery, Children's Hospital, Boston, and Repligen Corporation, Cambridge, Massachusetts

Accepted for publication June 19, 1995.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The shortage of pediatric heart donors often necessitates considerable travel time and, as a result, prolonged donor heart ischemia. This excessive hypothermic storage may contribute markedly to myocardial dysfunction in the recipient.

Methods. We investigated the role of leukocyte-endothelial interactions in this dysfunction in an isolated, immature (mean age, 11.8 ± 1.6 days) swine heart model using a monoclonal antibody against a leukocyte adhesion molecule. We studied a total of 20 hearts subjected to 6 hours of cardioplegic arrest at 4°C. Group M1/70 (n = 6) received at reperfusion 15 µg/mL of a monoclonal antibody F(ab`)2 fragment to CD11b, the {alpha}-subunit of the leukocyte adhesion molecule Mac-1. Group MB10.6 (n = 8) received 15 µg/mL of the swine unreactive F(ab`)2 MB10.6, and the third group received saline vehicle.

Results. Administration of M1/70 resulted in improved postischemic recovery of ventricular function compared with the two control groups (p < 0.05).

Conclusions. These data implicate leukocyte-endothelial interactions mediated by the leukocyte adhesion molecule CD11b in myocardial dysfunction after long-term hypothermic ischemia. Specific antiadhesion strategies such as this may safely extend storage time for pediatric donor hearts.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Leukocyte infiltration of postischemic myocardium has long been observed, but only in recent years has the pathogenic role of these cells in myocardial ischemia plus reperfusion begun to be understood. Soon after the discovery of leukocyte ``adhesion molecules,'' which mediate both binding of these inflammatory cells to the endothelium and subsequent diapedesis, monoclonal antibodies (mAb) directed against these membrane proteins were shown to reduce infarct size in animal models of normothermic regional myocardial ischemia [1]. Subsequent studies [2–6] using specific antibodies to adhesion molecules as well as mechanical leukocyte depletion have demonstrated improved recovery of myocardial function after short-term global hypothermic ischemia. The role of leukocyte-endothelial interactions in the myocardial dysfunction seen after longer periods of hypothermic ischemia is, however, unknown. In the present study, we evaluated the effects of an mAb directed against CD11b, the {alpha}-subunit of the CD11b/CD18 leukocyte adhesion glycoprotein, on the recovery of myocardial function in the isolated, blood-perfused swine heart after 6 hours of cold cardioplegic ischemia.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Experimental Preparation
Twenty Yorkshire piglets with a mean age of 11.8 ± 1.6 days were anesthetized with intramuscular administration of ketamine hydrochloride (100 mg/kg) and pancuronium bromide (0.1 mg/kg). After endotracheal intubation, each animal was ventilated with 100% oxygen, and a median sternotomy was performed. Heparin sodium (3 mg/kg) was administered intravenously, and the brachiocephalic artery was cannulated retrograde with a 12F cannula (USCI, Billerica, MA) modified to contain a fluid-filled manometer catheter extending 1 to 2 mm beyond the cannula tip.

The animal was then connected to an extracorporeal perfusion circuit composed of a roller pump (Cardiovascular Instrument Corporation, Wakefield, MA), an infant bubble oxygenator/heat exchanger (Bio-2; American Bentley, Irvine, CA), and polyvinyl chloride tubing 0.25 inch (0.625 cm) in internal diameter. This circuit was primed with fresh heparinized Yorkshire pig blood obtained from a donor animal, and the hematocrit was adjusted to approximately 25% with an isotonic crystalloid solution (Normosol; Abbott Laboratories, North Chicago, IL). The oxygenator was ventilated with a 20% oxygen, 5% carbon dioxide, and 75% nitrogen gas mixture at a flow rate adjusted to obtain a carbon dioxide tension of 40 mm Hg. All blood gas measurements were performed on an automated analyzer (Nova Medical, Waltham, MA).

With the heart in situ, normothermic (37°C) retrograde perfusion of the brachiocephalic artery was begun at a pressure of 60 mm Hg as the main pulmonary artery was transected and the animal exsanguinated into the reservoir of the bubble oxygenator. The distal aortic arch was ligated and divided, as were the superior and inferior venae cavae. The left ventricle was passively vented through an apical ventriculotomy.

After removal from the chest, the heart was placed in a temperature-controlled bath, and the main pulmonary artery was cannulated with a 24F venous cannula (USCI), to return the coronary venous blood to the reservoir. An in-line electromagnetic flowmeter (MFV-3100; Nihon-Kohden, Tokyo) connected to the venous return portion of the circuit provided real-time coronary blood flow measurements. A 5F polyethylene catheter was placed in the coronary sinus by way of the hemiazygos vein. A latex balloon containing a micromanometer (SPC-350; Millar Instruments, Houston, TX) was placed in the left ventricle through the apical ventriculotomy. The balloon was connected to a saline solution–filled syringe. An 8F Foley catheter was placed in the left atrium. The tip of this catheter was positioned at the mitral valve orifice and its balloon inflated with 2 mL of saline solution. A 20-gauge needle thermistor (Yellow Springs Instrument Co, Yellow Springs, OH) was placed in the right ventricular infundibulum. Electrocardiographic electrodes were placed on the right atrium and the brachiocephalic artery. With these preparations completed, the perfusion pressure was adjusted to 70 mm Hg.

All analog physiologic data were digitized in real time at a speed of 125 Hz by an analog-digital converter (DT2801; Data Translation, Marlboro, MA) and displayed graphically on a desktop computer (Gateway 2000; N Sioux City, SD) using a commercially available software package (Dataflow; Crystal Biotech, Hopkinton, MA). The completed preparation is shown in Figure 1Go. White blood cell counts were performed on an automated cell-sorting system (Technicon H-1; Miles, Tarrytown, NY).



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  		Fig 1. . Completed experimental preparation. (Amp = amplifier; A to D = analog-digital converter; EM = electromagnetic; LV = left ventricular.)

 
All animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Preparation of Antibodies
The anti-CD11b IgG1 mAb M1/70 was grown as ascites in BALB/c mice as previously described [7]. The ascites was filtered through cheesecloth and centrifuged at 10,000 g for 60 minutes. The supernatant was subsequently dialyzed overnight against 3 L of a loading buffer of 4 mol/L NaCl, and 20 mmol/L glycine, pH 8.6. The dialysate was loaded onto an IPA-400 protein A column (Repligen Corp, Cambridge, MA), and the eluent absorbance at a wavelength of 280 nm (A280) was monitored. The column was washed sequentially with five column volumes of the loading buffer, five column volumes of the loading buffer containing 0.2% Triton X-100, and then sufficient loading buffer until A280 returned to baseline. The antibody was then eluted with two column volumes of 100 mmol/L glycine, pH 5.

Fractions containing pure M1/70 by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a protein concentration of greater than 0.5 mg/mL were pooled. The antibody was then dialyzed against ten volumes, changed twice, of 25 mmol/L NaOAc at pH 4.5. The pH was lowered to 3.8 with acetic acid at 37°C for 3 hours. M1/70 was then digested for 4 hours at a 1:100 w/w ratio of pepsin. The digested protein was then loaded on an S-sepharose (Pharmacia, Piscataway, NJ) column preequilibrated with 25 mmol/L NaOAc, pH 4.5, and washed with three column volumes of the same buffer. The protein was then eluted twice with a 500 mL gradient of NaCl from 0.15 to 0.5 mmol/L in 25 mmol/L NaOAc. The pH of fractions containing protein by A280 were adjusted to between 7.0 and 8.0 using 10-fold concentrated Dulbecco's phosphate-buffered saline solution (Gibco, Gaithersburg, MD). The protein was then buffer exchanged into phosphate-buffered saline solution using a miniultrasette (Filtron Corp, Waltham, MA).

The endotoxin level in the F(ab`)2 was determined using the limulus assay (Cape Cod Assoc, Woods Hole, MA) to be less than 5 EU/mg of protein. M1/70 was shown to be reactive with Yorkshire pig neutrophils in preliminary experiments (Fig 2Go). MB10.6, an anti-CD11b IgG1 F(ab`)2 fragment, was similarly prepared and found to be nonreactive with Yorkshire swine neutrophils by flow cytometric analysis (see Fig 2Go). In in vitro chamber adhesion assays, M1/70 F(ab`)2 was able to inhibit CD11b/CD18–dependent adhesion of swine neutrophils to fibrinogen, though to a lesser degree than the intact mAb M1/70, or a positive control, the anti-CD18 mAb 60.4 (Fig 3Go).



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  		Fig 2. . Fluorescence histograms of Yorkshire swine neutrophils incubated with (A) M1/70 and (B) MB10.6.

 


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  		Fig 3. . Inhibition of N-formyl-met-leu-phe–stimulated porcine neutrophil adhesion to fibrinogen-coated coverslips in chamber adhesion assay. (MAb M170 = intact anti-CD11b monoclonal antibody M1/70; MAb M170 f(ab`)2 = anti-CD11b monoclonal antibody M1/70 F(ab`)2 fragment; MAb 60.4 = anti-CD18 monoclonal antibody 60.4.)

 
Experimental Design
Each heart was allowed to stabilize in the normothermic state on the perfusion circuit for 20 minutes. At that point, baseline hemodynamic data were recorded. Arterial and coronary sinus blood were sampled to determine myocardial oxygen consumption, where myocardial oxygen consumption = coronary blood flow x (arterial oxygen content - venous oxygen content). Two milliliters of perfusate was sampled to determine white blood cell count. The intraventricular latex balloon was then serially inflated in 0.5-mL increments. Peak systolic and end-diastolic left ventricular pressures as well as peak positive and negative first derivatives of left ventricular pressure (+dP/dt and -dP/dt, respectively) were recorded at each inflation. Left ventricular developed pressure was defined as peak systolic left ventricular pressure - end-diastolic left ventricular pressure at a given balloon volume. During these serial inflations, that balloon volume at which the left ventricular end-diastolic pressure was 10 mm Hg was recorded and designated as V10. The left ventricular pressure and dP/dt data were recorded at V10. Balloon inflation continued until maximum left ventricular pressure and dP/dt values were obtained.

Once baseline data acquisition was completed, the heart was perfusion-cooled to 15°C over 10 minutes. The temperature bath was similarly cooled to 15°C. To simulate clinical conditions, the gas mixture ventilating the oxygenator was changed to 95% oxygen and 5% carbon dioxide during cooling. At the completion of this cooling period, the perfusion cannula was clamped, and 20 mL/kg of 4°C cardioplegia was infused into the coronary arteries through the perfusion pressure manometer catheter in the aortic root. The cardioplegia was vented through a 3-mm right ventriculotomy placed in the infundibulum. This incision was closed primarily with 6-0 polypropylene suture. The heart was then submerged and stored in iced saline solution for 360 minutes. This storage technique consistently achieved a myocardial temperature of 4° ± 0.5°C in all hearts studied.

At 300 minutes of ischemia, fresh heparinized Yorkshire donor blood was treated according to the following protocol: In six experiments, sufficient M1/70 was added to the blood to achieve a circuit perfusate antibody concentration of 15 µg/mL. The antibody was first dissolved in 10 mL of normal saline solution. In eight experiments, the donor blood was similarly treated with MB10.6 to achieve a circuit perfusate antibody concentration of 15 µg/mL. Finally, in six experiments, 10 mL of saline vehicle alone was added to the blood. All treated donor blood was then mixed gently and incubated for 30 minutes at 4°C. The perfusion circuit was completely drained of preischemic perfusate and reprimed with blood treated with antibody or vehicle, and the hematocrit was adjusted to 25% as before. This reperfusate was circulated slowly in the circuit and warmed to a temperature of 25°C. The circuit was ventilated with 95% oxygen and 5% carbon dioxide for 10 minutes prior to reperfusion.

At 360 minutes of ischemia, the heart was removed from the iced saline solution, and the clamp was released from the arterial cannula as reperfusion was commenced at a perfusion pressure of 15 mm Hg. At 5 minutes of reperfusion, the perfusion pressure was raised to 40 mm Hg, and at 10 minutes, this was finally raised to 70 mm Hg. The heart was then electrically defibrillated in all cases. The perfusate and temperature bath were warmed to 37°C over 10 minutes. Normothermic perfusion at 70 mm Hg was then continued for a total reperfusion period of 90 minutes. Data were acquired at 30, 60, and 90 minutes of reperfusion. Ventricular function data are presented as percent recovery of preischemic baseline. Table 1Go supplies data on the three animal groups.


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  		Table 1. . Ages and Weights of Experimental Groupsa
 
Statistical Analysis
Results are expressed as the mean ± the standard deviation. Differences between experimental groups at each time point were determined by one-way analysis of variance and Student-Newman-Keuls t test when appropriate.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Recovery of both maximum and volume-normalized (V10) left ventricular developed pressures was significantly improved in group M1/70 at 30 and 60 minutes of reperfusion (p < 0.05) (Fig 4Go). At 90 minutes of reperfusion, recovery of left ventricular developed pressure at V10 was also significantly better preserved (p < 0.05). Similar results were seen for recovery of +dP/dt. Both maximum +dP/dt and +dP/dt at V10 were significantly improved in the M1/70-treated group versus both control groups at 30 and 60 minutes of reperfusion (p < 0.05) (Fig 5Go). The +dP/dt at V10 was also significantly improved at 90 minutes of reperfusion (p < 0.05). Recovery of diastolic function, as indicated by -dP/dt at V10, was significantly improved in M1/70-treated hearts at all periods of reperfusion (p < 0.05) versus the two control groups (Fig 6Go). Recovery of maximum -dP/dt of M1/70-treated hearts was better than MB10.6-treated hearts at 30 and 60 minutes of reperfusion (p < 0.05) (see Fig 6Go).



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  		Fig 4. . Percent recovery of maximum and volume-normalized (V10) left ventricular developed pressure at 30, 60, and 90 minutes of reperfusion for the three experimental groups. Data are shown as the mean ± the standard deviation. (M1/70 = hearts reperfused with 15 µg/mL of swine reactive anti–CD11b monoclonal F(ab`)2 fragment; MB10.6 = hearts reperfused with 15 µg/mL of swine nonreactive anti-CD11b F(ab`)2 fragment; Vehicle = hearts receiving saline vehicle; V10 = intraventricular balloon volume giving a left ventricular end-diastolic pressure of 10 mm Hg at preischemic baseline.)

 


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  		Fig 5. . Percent recovery of maximum and volume-normalized (V10) positive first derivative of left ventricular pressure at 30, 60, and 90 minutes of reperfusion for the three experimental groups. Data are shown as the mean ± the standard deviation. Abbreviations are the same as in Figure 4Go.

 


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  		Fig 6. . Percent recovery of maximum and volume-normalized (V10) negative first derivative of left ventricular pressure at 30, 60, and 90 minutes of reperfusion for the three experimental groups. Data are shown as the mean ± the standard deviation. Abbreviations are the same as in Figure 4Go.

 
Recovery of heart rate is shown in Figure 7Go. No significant differences were present between groups at any period during reperfusion. All hearts required defibrillation during the early reperfusion period, and postischemic heart rate was lower than preischemic heart rate in each group. All preischemic and 30-, 60-, and 90-minute reperfusion heart rate data reflect the spontaneous sinus rate of the isolated heart.



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  		Fig 7. . Heart rate data for the three experimental groups at preischemic baseline (Pre) and during the reperfusion period. Data are shown as the mean ± the standard deviation. Abbreviations are the same as in Figure 4Go.

 
Resting coronary blood flow data for the three groups are shown in Figure 8Go. There were no significant differences in resting global coronary blood flow between groups at any time point.



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  		Fig 8. . Resting coronary blood flow data for the three experimental groups at preischemic baseline (Pre) and during the reperfusion period. Data are shown as the mean ± the standard deviation. Abbreviations are the same as in Figure 4Go.

 
Resting myocardial oxygen consumption data are shown in Figure 9Go. There were no significant differences in global myocardial oxygen consumption between the three experimental groups.



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  		Fig 9. . Resting myocardial oxygen consumption data for the three experimental groups at preischemic baseline (Pre) and during the reperfusion period. Data are shown as the mean ± the standard deviation. Abbreviations are the same as in Figure 4Go.

 
Leukocyte counts for the donor blood, experimental animal, and experimental preparation are shown in Figure 10Go. There were no intergroup differences for donor blood, experimental animal, or experimental preparation in either the preischemic or reperfusion periods.



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  		Fig 10. . Total leukocyte count data for the three experimental groups. Data are shown as the mean ± the standard deviation. (Donor = homologous Yorkshire pig blood donor; Piglet = experimental animal prior to heart extraction; Preischemia = perfusate during baseline functional measurements; Prime = extracorporeal circuit after priming and prior to perfusion of heart; other abbreviations are the same as in Figure 4Go.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Prolonged donor heart ischemic time continues to emerge as a risk factor for both morbidity and mortality for recipients after orthotopic cardiac transplantation [8–11]. This potential risk factor is encountered more frequently in the pediatric population, as the supply of pediatric donor hearts may be lower than that of adult hearts. This short supply necessitates longer distances to harvest and, subsequently, increased ischemic time for the donor heart. The role of adhesion molecule–mediated leukocyte-endothelial interactions in reperfusion injury after shorter periods of both warm and hypothermic myocardial ischemia has been previously reported [1, 4, 12–14]. This study demonstrates that these interactions continue to play a role in reperfusion injury after even longer periods of ischemia.

The extravasation of neutrophils at sites of inflammation, such as that seen in ischemia plus reperfusion, is now thought to involve at least three distinct steps [15]. Polymorphonuclear leukocytes within the flowing blood first ``roll'' on the endothelial surface, as the strength of the earliest polymorphonuclear leukocyte–endothelial interactions is not sufficient to overcome the shear forces of the bloodstream [15]. This rolling phenomenon is thought to be mediated by the group of surface adhesion molecules known as the selectins [16, 17]. After rolling, the neutrophils become much more strongly bound to the endothelium. Finally, as the third step in this paradigm, the polymorphonuclear leukocytes transmigrate through the endothelial wall. The second step is thought to be mediated by the binding of the leukocyte integrins, including Mac-1 (CD11b/CD18), to their endothelial ligands, the intercellular adhesion molecules of the immunoglobulin supergene family [16, 18]. The present study used M1/70, a monoclonal F(ab`)2 fragment, directed against the {alpha}-subunit of the ß2-integrin Mac-1.

M1/70 delivered to the immature swine heart on reperfusion improved the recovery of both systolic and diastolic function after 6 hours of global hypothermic cardioplegic ischemia. These results are in concordance with earlier studies of normothermic regional myocardial ischemia by Simpson and colleagues [1, 12], who demonstrated decreased infarct size using an anti-CD11b/CD18 mAb after 90 minutes of normothermic ischemia in a canine model. Previous studies in our laboratory [4], moreover, have demonstrated improved functional recovery in neonatal lamb hearts after 2 hours of cold cardioplegic ischemia using an anti-CD18 mAb.

The mechanism by which this neutrophil-endothelial adhesion produces myocardial injury is incompletely defined, but it may involve several mechanisms. Mechanical plugging of the microvascular bed by adherent leukocytes in the microvascular bed during reperfusion is thought to contribute to the ``no-reflow phenomenon,'' where parenchymal blood flow remains insufficient despite restoration of conduit arterial inflow [19–23]. In addition, adherent neutrophils are capable of substantial vascular and parenchymal tissue injury through the generation of highly reactive oxygen free radicals and the release of proteolytic enzymes such as elastase and myeloperoxidase [24–28].

In the present study, although recovery of mechanical function was improved in the M1/70 group, resting coronary blood flow was not significantly different from that seen in the two control groups. These data differ from those noted in neonatal lamb hearts using an anti-CD18 mAb after 2 hours of global hypothermic ischemia but are in agreement with studies of warm regional ischemia in dogs, where the use of an anti-CD11b mAb decreased infarct size after 90 minutes of regional ischemia without demonstrable differences in myocardial blood flow during the reperfusion period [4, 12]. This finding suggests that anti-CD11b mAbs may act primarily through modulation of the injurious oxidative burst of the neutrophil rather than by preventing microvascular plugging by neutrophils adhering to the endothelial surface.

M1/70 offers a more specific intervention than a CD18 mAb, as activated neutrophils may still bind to the endothelium by way of CD11a/CD18– and CD11c/CD18–mediated interactions. The blockade of ß2-integrin–mediated interactions, although reducing surgically induced myocardial reperfusion injury, might substantially alter wound-healing capabilities and the ability to ward off perioperative infection. More specific antiadhesion strategies using agents such as M1/70 may be more desirable than the use of anti-CD18 mAbs, which neutralize all ß2-integrin–mediated neutrophil adhesion. Additional studies in intact animals will be necessary to confirm such speculation.

The isolated, blood-perfused heart model used in the present study is not without limitations, and these have been previously discussed [29]. It does, however, offer the advantage of being free from noncardiac influences on cardiac performance such as level of anesthesia and sympathetic tone and other neurohumoral factors. In addition, the heart is reperfused on an extracorporeal circuit in a fashion similar to that seen clinically, where the recipient is necessarily maintained on cardiopulmonary bypass during the transplantation procedure and early reperfusion period. Extracorporeal circulation has been shown to activate leukocytes, and this activation appears to include the upregulation of CD11b/CD18 [30–32]. Indeed, in several pilot experiments with the perfusion circuit used in this study, swine CD11b/CD18 was maximally upregulated within 15 minutes of priming the circuit (unpublished data). Heterotopic transplant models lack this potentially important ``recipient'' feature.

In conclusion, M1/70 decreased the postischemic myocardial dysfunction seen after 6 hours of hypothermic cardioplegic arrest in this immature swine model. CD11b-dependent neutrophil-endothelial adhesion contributes to myocardial dysfunction after prolonged periods of hypothermic ischemia. Specific antiadhesion strategies such as this may be useful adjuncts to current techniques of myocardial preservation and may decrease postischemic myocardial dysfunction.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank Mark A. Cioffi, MAT, for his expert technical assistance.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Presented in part at the Forty-third Annual Meeting of the American College of Cardiology, Atlanta, GA, March 13–17, 1994.

Address reprint requests to Dr Mayer, Department of Cardiovascular Surgery, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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R. Kalawski, E. Deskur, P. Bugajski, H. Wysocki, and T. Siminiak
STIMULATION OF NEUTROPHIL INTEGRIN EXPRESSION DURING CORONARY ARTERY BYPASS GRAFTING: COMPARISON OF CRYSTALLOID AND BLOOD CARDIOPLEGIC SOLUTIONS
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G. Zund, A. L. Dzus, R. Pretre, U. Niederhauser, P. Vogt, and M. Turina
Endothelial cell injury in cardiac surgery: salicylate may be protective by reducing expression of endothelial adhesion molecules
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P. Menasche
Blood Cardioplegia: Do We Still Need to Dilute?
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