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Ann Thorac Surg 1997;63:1701-1705
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Heparin-Bonded Circuits Decrease Myocardial Ischemic Damage: An Experimental Study

Department of Cardiothoracic Surgery, The Boston University Medical Center, Boston, Massachusetts

Accepted for publication December 23, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Background. Heparin-bonded cardiopulmonary bypass circuits reduce complement activation, but their effect on myocardial function is unknown. This study was undertaken to determine whether heparin-bonded circuits reduce myocardial damage during acute surgical revascularization.

Methods. In 16 pigs, the second and third diagonal vessels were occluded with snares for 90 minutes followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion with the snares released. During the period of coronary occlusion, all animals were placed on percutaneous bypass followed by standard cardiopulmonary bypass during the periods of cardioplegic arrest and reperfusion. In 8 pigs, heparin-bonded circuits were used, whereas 8 other pigs received nonbonded circuits.

Results. Animals treated with heparin-bonded circuits had the best preservation of wall motion scores (3.5 ± 0.3 versus 2.3 ± 0.2; 4 = normal to -1 = dyskinesis; p < 0.05), least tissue acidosis (change in pH = -0.31 ± 0.02 versus -0.64 ± 0.08; p < 0.05), smallest increase in lung H₂O (1.7% ± 0.7% versus 6.1% ± .5%; p < 0.05), and the lowest area of necrosis/area of risk (20.3% ± 2.2% versus 40.4% ± 1.6%; p < 0.05).

Conclusions. We conclude that heparin-bonded circuits significantly decrease myocardial ischemic damage during acute surgical revascularization.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Recent advances in heparin bonding and coating techniques have resulted in the development of heparin-bonded cardiopulmonary bypass (CPB) circuits [1, 2]. These biocompatible circuits have been shown to decrease the activation of leukocytes, platelets, and complement [1–11]. In several clinical studies, this has resulted in lower heparin requirements and reduced blood loss [2–5]. Although heparin-bonded circuits have been shown to improve pulmonary function after CPB [12], clinical and experimental studies have not been able to detect any improvement in either myocardial function or a decrease in infarct size using these biocompatible circuits [2–5, 8–11].

In a clinical study on patients undergoing elective coronary artery bypass grafting (CABG), Gu and co-workers [5] showed that heparin-bonded CPB circuits reduced systemic leukocyte activation as reflected by significant decreases in elastase release and tumor necrosis factor generation. Activated neutrophils have been shown to release numerous cytotoxic metabolites, including oxygen free radicals and proteolytic enzymes, that result in increased myocardial necrosis during the reperfusion of ischemic myocardium [13, 14]. Recently, we [15] showed that early depletion of leukocytes on CPB immediately after a period of coronary occlusion significantly decreased infarct size and improved regional contractility. The favorable effects of heparin-bonded circuits in reducing complement and leukocyte activation prompted us to undertake this experimental study in animals undergoing acute coronary occlusion. We sought to determine whether biocompatible bypass circuits using heparin-bonding techniques would reduce infarct size and improve regional contractile function during the surgical revascularization of acutely ischemic myocardium.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Randomization
Twenty pigs were entered into the study. Animals were randomized to receive either heparin-bonded or nonbonded circuits on an alternating basis. Four animals were excluded from the study (2 from each group) due to pericarditis and pneumonia.

	Preparation

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Sixteen adult pigs (32 to 36 kg) were premedicated with intramuscular ketamine (15 mg/kg) and ACE promazine (0.5 mg/kg), anesthetized with -chloralose (75 mg/kg) and placed on positive-pressure endotracheal ventilation. After a median sternotomy, catheters were placed into the femoral artery and vein for monitoring systemic pressure and administering fluids. The azygos vein was ligated to prevent retrograde flow from the coronary sinus during the administration of retrograde cardioplegia. After systemic heparinization (3 mg/kg), the second and third diagonal branches just distal to the takeoff of the left anterior descending artery were occluded with snares for 90 minutes. Intravenous lidocaine was used to treat ventricular arrhythmias.

Immediately after the coronary arteries were occluded, all animals were placed on percutaneous bypass by inserting perfusion cannulas into the femoral artery and vein. After 90 minutes, all pigs were placed on total CPB by inserting an additional venous cannula into the right atrium. A catheter was inserted into the left atrium to infuse volume so that left ventricular end-diastolic pressure and volume could be varied. Mean arterial blood pressure during bypass ranged from 65 to 75 mm Hg, and pump flow was kept at 80 mL•kg^-1•min^-1. The hematocrit averaged 25% ± 2%, and pH was maintained at 7.41 ± 0.05.

After the institution of full CPB, all hearts underwent 45 minutes of multidose antegrade/retrograde cold blood cardioplegic arrest (K = 25 mEq/L; hematocrit = 20%; pH = 7.6; temperature = 4°C) supplemented with topical hypothermia. An initial arresting dose (10 mL/kg) was followed by additional doses (5 mL/kg) every 20 minutes. Half of each dose was given antegrade through a catheter inserted into the ascending aorta and the other half through a catheter positioned into the coronary sinus via a pursestring in the right atrium. After the period of cardioplegic arrest, the cross-clamp was removed, the coronary snares were released, and all hearts were reperfused for 3 hours on CPB at 37°C.

	Experimental Groups

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
During the period of percutaneous and full CPB, the animals were divided into two groups.

HEPARIN-BONDED GROUP.
In 8 animals, a completely heparinized system using a Duraflo II heparin-coated circuit (Baxter-Bentley Laboratories, Irvine, CA) was employed. This included heparin coating of all cannulas, arterial filters, and the cardiotomy reservoir.

NONBONDED GROUP.
In 8 animals, a conventional circuit was used (Baxter-Bentley Laboratories, Irvine, CA). All groups received systemic heparin (3 mg/kg initial dose) to achieve an activated clotting time greater than 400 seconds. The activated clotting time was determined before the median sternotomy, after the initial heparin administration, before CPB, and every 20 minutes on CPB.

	Measurements and Data Analysis

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Electrocardiographic leads were placed to measure heart rate and to monitor electrical activity during arrest. Left ventricular end-diastolic pressure was recorded with a piezoelectric Mikro-Tip catheter pressure transducer (Millar Instruments, Inc, Houston, TX) inserted via a stab wound in the left ventricular apex. Systemic body temperature was measured with a rectal temperature probe (Yellow Springs Instrument Co, Yellow Springs, CO). Myocardial tissue pH was measured with a pH probe (Khuri Tissue Ischemia Monitor; Vascular Technology Inc, North Chelmsford, MA) and was standardized according to myocardial temperature, which was measured simultaneously with a temperature probe (Vascular Technology). Temperature and pH measurements were made in the center of the area at risk between the second and third diagonal vessels. All recorded pH measurements were corrected for temperature. Control pH measurements were made after a 30-minute period of equilibration and then recorded on-line. The pH values were expressed as the change in pH from preischemic values and recorded for each experiment and then averaged for all experiments in the heparin-bonded and nonbonded groups.

Two-dimensional echocardiograms were obtained with a hand-held 3.5-MHz ultrasound transducer (ATL, Tempe, AZ). Left ventricular end-diastolic volume was obtained by planimetry of a perpendicular long-axis length and a short-axis area. The same echocardiographic short-axis sections were also used to assess wall motion changes. The ventricle was divided into eight anatomic areas, and wall motion was analyzed qualitatively by a numeric score (4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, 1 = severe hypokinesis, 0 = akinesis, and -1 = dyskinesis). Echocardiographic sections for wall motion analysis were obtained as left ventricular end-diastolic pressure was varied using the right heart bypass technique at a constant afterload (mean arterial pressure = 65 mm Hg). Only sections with the same left ventricular end-diastolic volume during the preischemic, coronary occlusion, and reperfusion periods were used for analysis, thereby ensuring that preload conditions were similar. Wall motion scoring was made in a blinded fashion by an experienced echocardiographer (S.A.B.), and the scores were averaged for the periods of coronary occlusion and reperfusion for each experiment and, in turn, for the heparin-bonded and nonbonded groups.

Lung samples were excised using a stapler before percutaneous bypass and after 3 hours of reperfusion for wet-to-dry weight measurements. Lung wet-to-dry weight ratios were determined by weighing the lung samples before and after 48 hours of incubation at 100°C. They were expressed as the percentile weight gain from prebypass values for each experiment and averaged for each group.

The areas of risk and necrosis were determined by histochemical staining techniques. After the 3-hour reperfusion period, the second and third diagonal branches were reoccluded, the ascending aorta was cross-clamped, and the area of risk was determined by injecting 60 mL of phthalo-blue dye (Harshaw-Filtrol, Cleveland, OH) into the aortic root via a 9F catheter. The left ventricle was then excised and cut into 5- to 10-mm cross-sectional slices. The infarct area was determined by incubating the slices in triphenyltetrazolium chloride (Sigma Chemical Co, St. Louis, MO) for 30 minutes and then placing them in formaldehyde overnight. The next morning, the stained slices were placed under a glass plate and traced on clear plastic sheets. With reperfusion of ischemic myocardium, there is washout from the nonviable cells of dehydrogenases necessary to reduce nitro blue tetrazolium, and these areas remain pale. The areas of risk and infarct were then measured with a planimeter for each slice to obtain (1) the area of risk compared with the total left ventricular mass and (2) the percent area of infarct in that area of risk.

All values represent the mean ± standard error. Differences in measurements between the heparin-bonded and nonbonded groups and across time were assessed using analysis of variance techniques. In addition, a nonpaired t test was used to compare the area of necrosis with the area of risk between groups. Differences were considered significant at p less than 0.05. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication 86-23, revised 1985).

	Results

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
There was no difference in activated clotting time levels between the two groups (452 ± 22 seconds for heparin-bonded versus 440 ± 20 seconds for nonbonded; not significant [NS]). During the 90-minute period of coronary occlusion before cardioplegic arrest, mean arterial pressure (68 ± 3 mm Hg for heparin-bonded versus 70 ± 2 mm Hg for nonbonded; NS), cardiac index (2.0 ± 0.2 L•min^-1•m^-2 for heparin-bonded versus 2.1 ± 0.3 L•min^-1•m^-2 for nonbonded; NS), venous oxygen saturations (70% ± 2% for heparin-bonded versus 69% ± 3% for nonbonded; NS), and left ventricular end-diastolic pressure (1.3 ± 0.2 mm Hg for heparin-bonded versus 1.7 ± 0.3 mm Hg for nonbonded; NS) were similar in both groups. No ventricular fibrillation developed in any of the pigs.

	Changes in Myocardial pH

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Before coronary artery occlusion, myocardial pH in the area at risk was similar in both groups. (7.37 ± 0.08 for heparin-bonded versus 7.39 ± 0.07 for nonbonded; NS). The changes in pH from control values are illustrated in Figure 1. After 90 minutes of coronary occlusion, both groups showed evidence of tissue acidosis in the area at risk; however, the change in pH was significantly greater in the nonbonded hearts (-0.80 ± 0.10 for heparin-bonded versus -1.07 ± 0.06 for nonbonded; p < 0.005). Although pH values improved in both groups during reperfusion, the least tissue acidosis after 3 hours of reperfusion was seen in the heparin-bonded group (change in pH = -0.31 ± 0.02 for heparin-bonded versus -0.61 ± 0.08 for nonbonded; p < 0.002).

View larger version (18K): [in this window] [in a new window]   Fig 1. . Myocardial pH (all values represent the mean ± standard error). All hearts have significant tissue acidosis after 90 minutes of coronary occlusion; however, the change in pH (pH) values are less in the heparin-bonded group. After reperfusion, hearts treated with heparin-bonded circuits have significantly less tissue acidosis than the nonbonded group.

	Wall Motion Scores

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

View larger version (18K): [in this window] [in a new window]   Fig 2. . Wall motion scores in the area at risk (all values represent the mean ± standard error). Wall motion scores are consistently higher in hearts treated with heparin-bonded circuits.

	Lung Water Content and Histochemical Staining

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Animals treated with heparin-bonded circuits had significantly less lung water accumulation after 3 hours of reperfusion (1.7% ± 0.7% for heparin-bonded versus 6.1% ± 0.5% for nonbonded; p < 0.02).

The area of myocardium at risk was similar in both groups (18.2% ± 2.1% for heparin-bonded versus 16.8% ± 2.2% for nonbonded; NS). The lowest infarct size (area of necrosis/area at risk), however, was seen in the heparin-bonded group (20.3% ± 2.2% for heparin-bonded versus 40.4% ± 1.6% for nonbonded; p < 0.001).

	Comment

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
Cardiopulmonary bypass activates the complement cascade through the alternative pathway system, which ultimately activates terminal complement complexes, neutrophils, endotoxin, elastases, and the proinflammatory cytokines [13]. This increased inflammatory response may contribute to postoperative pulmonary dysfunction, myocardial stunning and ischemia, renal and neurologic impairment, and coagulation disorders. Heparin-bonded CPB circuits have been shown to reduce systemic inflammatory reactions by lowering complement levels, decreasing neutrophil activation, and reducing the serum levels of the inflammatory cytokines interleukin-6 and interleukin-8 [2, 5, 6, 8–10]. Heparin coating is thought to mechanically render the foreign surface of the CPB circuit inaccessible to the adsorption of complement [8]. Further support for this theory comes from Borowiec and co-workers [16], who used scanning microscopy to demonstrate that arterial surfaces of heparin-bonded circuits remained smooth with no major leukocyte or platelet adhesions, or fibrin deposits.

Recent studies suggest that activation of the inflammatory response by CPB may have detrimental effects and that interventions that attenuate this response may result in more favorable clinical outcomes. Steinberg and co-workers [7] demonstrated that heparin-bonded circuits resulted in lower serum levels of interleukin-6 and interleukin-8 after CPB in patients undergoing elective CABG. Elevation of interleukin-6 and interleukin-8 levels after bypass has been found to correlate with new wall motion abnormalities in patients undergoing CABG [17]. Sawa and co-workers [18] found that lowering levels of interleukin-6 and interleukin-8 using serine protease inhibitors resulted in significantly lower creatine kinase-MB levels in CABG patients. The significance of decreasing the inflammatory response in clinical outcomes was demonstrated by Jansen and co-workers [6] in a randomized trial involving patients undergoing elective CABG who received heparin-bonded circuits. Differences in patient recovery were analyzed using a score composed of fluid balance, postoperative intubation time, and the difference between rectal and skin temperature. Patients treated with heparin-bonded circuits had lower peak concentrations of terminal complement complex and elastase, and had significantly lower recovery scores. The favorable effects of attenuating the inflammatory response were also observed by Chuba and co-workers [19], who used leukocyte-depleting filters in the bypass circuits of 26 patients undergoing CABG. Leukocyte-depleted patients had significantly decreased enzyme leakage, less catecholamine use, and higher cardiac indices in the early postoperative period. Sawa and co-workers [20] added leukocyte-depleting filters to terminal blood cardioplegic solutions in a clinical study. Leukocyte depletion did not confer any added protection to hearts undergoing elective CABG. However, in patients undergoing emergent CABG, leukocyte depletion significantly lowered peak creatine kinase-MB levels and resulted in the need for less inotropic support. Our studies involving acutely ischemic porcine hearts showed that early leukocyte depletion on cardiopulmonary bypass significantly decreased infarct size and improved regional contractility [15].

Interventions that attenuate the inflammatory response may have their greatest role during the revascularization of acutely ischemic myocardium. Our porcine model sought to simulate the events that occur after a failed percutaneous transluminal coronary angioplasty that requires emergent CABG. Animals placed on heparin-bonded circuits had the best preservation of regional function, the smallest increase in lung H₂O content, the least tissue acidosis, and the lowest infarct size. These favorable effects of heparin-bonded circuits on left ventricular function and infarct size in our experimental model prompted us to perform a prospective clinical study to look at the effects of heparin-bonded circuits in 234 CABG patients [21]. Patients treated with heparin-bonded circuits and a lower anticoagulation protocol had a lower incidence of myocardial infarction (4.27% versus 0.00%; p < 0.02) and less need for inotropic support (10.3% versus 2.67%; p < 0.01). Patients on heparin-bonded circuits also had a lower incidence of prolonged (>3 days) ventilation (0.9% versus 6.8%; p < 0.01) and fewer postoperative complications (25% versus 36%; p < 0.02).

In summary, this experimental study has demonstrated that heparin-bonded circuits decrease infarct size and better preserve regional ventricular function in acutely ischemic myocardium. Our initial clinical studies using heparin-bonded circuits in patients undergoing CABG appear to support our experimental findings. Additional clinical studies are currently underway at our medical center to further delineate the role of heparin-bonded circuits in clinical practice.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Preparation Experimental Groups Measurements and Data Analysis Results Changes in Myocardial pH Wall Motion Scores Lung Water Content and... Comment Acknowledgments References

 
The secretarial support of Ms Debra Blackman and Mrs Ellie LaBombard in preparing the manuscript is greatly appreciated. We also appreciate the work of Diane Lancaster, PhD, who performed all the statistical analyses including the analysis of variance testing.

This work was supported in part by a grant from the Baxter Healthcare Corporation, Irvine, CA.

	Footnotes

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Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, The Boston University Medical Center Hospital, 88 E Newton St, Suite B-404, Boston, MA 02118.

	References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Harold L. Lazar Gabriel S. Aldea Richard J. Shemin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lazar, H. L. Articles by Shemin, R. J. Search for Related Content PubMed PubMed Citation Articles by Lazar, H. L. Articles by Shemin, R. J.