Asian Cardiovasc Thorac Ann 2003;11:198-202
© 2003 Asia Publishing EXchange Ltd
Soluble Adhesion Molecules in Coronary Artery Bypass Surgery
Minxin Wei, MD1,
Jari Laurikka, MD,
Pekka Kuukasjärvi, MD,
Erkki Pehkonen, MD,
Matti Tarkka, MD
Division of Cardiovascular Surgery, Tampere University Hospital, Tampere, Finland
1 Division of Cardiovascular Surgery, The First Affiliated Hospital of Zhongshan University, Guangzhou, People’s Republic of China
For reprint information contact: Matti Tarkka, MD Tel: 358 3 247 6378 Fax: 358 3 247 5756 email: matti.tarkka{at}tays.fi Division of Cardiovascular Surgery, Tampere University Hospital, PO Box 2000, Fin-33521 Tampere, Finland.
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ABSTRACT
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Plasma levels of sE-selectin, sP-selectin, and sICAM-1 were measured before anesthesia and at 0.5, 4, and 20 hours after cardiopulmonary bypass in 37 men undergoing coronary artery bypass surgery. Plasma sE-selectin remained close to the preoperative levels. The levels of sP-selectin increased significantly from 46.5 ± 15.3 ng•mL-1 to 69.3 ± 39.6 ng•mL-1 at 0.5 hours, 84.1 ± 45.5 ng•mL-1 at 4 hours, and 79.6 ± 35.5 ng•mL-1 at 20 hours. Plasma sICAM-1 levels decreased 0.5 hours after cardiopulmonary bypass, recovered at 4 hours, and showed a significant increase at 20 hours. The changes in plasma levels of adhesion molecules did not correlate with the duration of bypass or aortic crossclamping, hemodynamics, or creatine kinase-MB levels. However, sE-selectin and sICAM-1 levels increased considerably more in patients who needed norepinephrine in the intensive care unit. These results indicate that the transient changes in plasma levels of soluble adhesion molecules are not associated with postoperative myocardial injury in low-risk coronary grafting, although they correlate with the need for a vasopressor.
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INTRODUCTION
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Cardiopulmonary bypass (CPB) induces a systemic inflammatory response involving secretion of various inflammatory mediators which may contribute to multiple organ dysfunction postoperatively.1,2 The activation and accumulation of polymorphonuclear neutrophils appear to play important roles in the pathogenesis of the inflammatory response and increase the risk of organ failure. The mechanism of the inflammatory process includes leukocyte rolling along the endothelium, adherence, and transendothelial migration into the tissue. These interactions are mediated by adhesion molecules on the surfaces of activated leukocytes, platelets, and the endothelium.3 In addition to membrane-bound molecules, soluble isoforms are found in the circulating blood. These are believed to be markers of the extent of the inflammatory reaction, but their function is not fully understood.4 Circulating soluble adhesion molecules probably act as competitive inhibitors of the membrane-bound forms, thereby focusing the attachment of leukocytes at inflammatory sites where there are high degrees of up-regulation of the membrane-bound forms. These molecules may also be of importance in preventing the activation of circulating leukocytes.3 The association between inflammation and myocardial ischemic injury has been recognized for over 50 years and it remains a topic of continued investigation. A better understanding of this process may lead to improved patient outcome by making possible the development of novel therapies aimed at limiting the inflammatory response. Postoperative changes in soluble adhesion molecules have been reported repeatedly, however, their relationship to myocardial injury and postoperative hemodynamics needs further investigation. The aims of this study were to investigate the time-course of changes in the levels of soluble adhesion molecules after coronary artery bypass grafting (CABG) and to establish whether the levels are linked to postoperative myocardial ischemic injury and hemodynamics.
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PATIENTS AND METHODS
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The investigation was approved by the local ethics committee, and informed written consent was obtained from all patients who entered the study. They comprised 37 men with multivessel coronary artery disease and stable angina who were admitted for first-time elective CABG (Table 1
). Patients with unstable angina, poor left ventricular function (ejection fraction < 30%), valve disease, and those on corticosteroid medication were deemed ineligible. A standardized anesthetic technique was used with sufentanil, midazolam, and pancuronium. Standard CABG operations were performed using at least one internal thoracic artery and 1–3 saphenous vein grafts. The patients were perfused at 32°C with non-pulsatile flow from a membrane oxygenator (Dideco, Mirandola, Italy). The circuit was primed with 2,000 mL of Ringer’s acetate. Cold blood antegrade-retrograde cardioplegia (6°C–8°C) was delivered through a BCD-Plus device (Dideco, Mirandola, Italy) that mixed blood with crystalline solution in a ratio of 4:1. The potassium concentration of the induction cardioplegia was 21 mmol•L-1. After each distal anastomosis, additional cardioplegic solution was delivered for 1 minute through the vein graft and a coronary sinus catheter. Proximal anastomoses were completed before declamping. Warm blood retrograde cardioplegia was given at the end of the crossclamp period.
Blood samples were collected from the radial artery before induction of anesthesia (baseline) and at 0.5, 4, and 20 hours after reperfusion. All samples were anticoagulated with ethylenediaminetetraacetic acid, immediately cooled to 4°C, and centrifuged within 30 minutes (4000g for 10 minutes); plasma was transferred to polypropylene test tubes and stored at -70°C until assay. Plasma levels of sE-selectin, sP-selectin, and soluble intracellular adhesion molecule-1 (sICAM-1) were determined using a commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA). The detection levels were 0.1 ng•mL-1 for sE-selectin, 0.5 ng•mL-1 for sP-selectin, and 0.35 ng•mL-1 for sICAM-1. The values were corrected for hemodilution using the hematocrit.5 Plasma creatine kinase MB-isoenzyme (CK-MB) activity was measured 3 times in every patient: 6 hours after CPB and on the 1st and 2nd postoperative days.
Hemodynamic monitoring comprised measurements of heart rate, mean arterial pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output. Derived cardiovascular variables (cardiac index, systemic vascular resistance index, and pulmonary vascular resistance index) were calculated using standard formulae. All measurements were based on the thermodilution technique. Hemodynamic measurements and calculations were obtained at baseline before anesthetic induction and at 15 minutes, 6 hours, and 20 hours after the end of CPB. Intraoperative and postoperative occurrences of cardiac-related and noncardiac-related adverse events were recorded in all patients. After weaning from CPB, pharmacological therapy with inotropics and/or vasodilators was used to maintain a cardiac index greater than 2.0 L•min-1•m-2, and therapeutic decisions based on conventional criteria were made independently by the anesthesiologist in charge. A vasoconstrictor (norepinephrine) was used when systolic arterial pressure fell below 80 mm Hg and the systemic vascular resistance index was less than 1,000 dyne•s•cm-5•m-2 even though adequate cardiac filling pressure and cardiac index were guaranteed with volume infusions and inotropics. Norepinephrine was frequently used during and soon after CPB in the operating room, but it was only used in the intensive care unit (ICU) if hemodynamic measurements indicated vasodilation.
Statistical analyses were performed using SPSS/Win version 9.0 (SPSS, Inc., Chicago, IL, USA). Student’s t test was applied to detect demographic differences between groups, and the Pearson correlation coefficient was used to explore the relationship between adhesion-molecule levels and postoperative CK-MB values or hemodynamics. Continuous variables were analyzed by analysis of variance (ANOVA) for repeated measures. Logarithmic transformation was used as the variables were not normally distributed. The preoperative values were taken as covariates, and changes with respect to preoperative values were assessed. Statistical significance was attributed to p values lower than 0.05. All results are expressed as mean ± standard deviation.
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RESULTS
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There were no deaths or major complications in the 37 study patients. Postoperative plasma levels of sE-selectin did not change significantly at any of the time points (41.2 ± 16.3 ng•mL-1 at baseline, 34.3 ± 14.1 ng•mL-1 at 0.5 h, p = 0.09; 44.4 ± 16.4 ng•mL-1 at 4 h, p = 0.78; 46.4 ± 18.6 ng•mL-1 at 20 h, p = 0.89). The levels of sP-selectin increased significantly after CPB (46.5 ± 15.3 ng•mL-1 at baseline, 69.3 ± 39.6 ng•mL-1 at 0.5 h, p = 0.01; 84.1 ± 45.5 ng•mL-1 at 4 h, p < 0.01; 79.6 ± 35.5 ng•mL-1 at 20 h, p < 0.01). Plasma sICAM-1 levels decreased from 226.1 ± 48.8 ng•mL-1 at baseline to 187.1 ± 41.5 ng•mL-1 at 0.5 h after CPB (p < 0.01), but recovered at 4 h to 225.8 ± 53.8 ng•mL-1 (p = 0.78), and significantly increased further at 20 h to 287.9 ± 62.9 ng•mL-1 (p < 0.01) as shown in Figure 1. No correlations between the changes in plasma levels of adhesion molecules and CPB time or aortic crossclamp time were detected.
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Figure 1. Plasma levels of sE-selectin, sP-selectin, and sICAM-1 before anesthesia (Pre) and after cardiopulmonary bypass. *p < 0.05 compared to levels before anesthesia.
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None of the study patients had postoperative signs of myocardial infarction. Those with maximum CK-MB levels higher than 50 U•L-1 (9 patients) had a relatively more profound decreased of sICAM-1 at 0.5 h after CPB, however, the difference did not reach statistical significance (-51.3 ± 20.5 ng•mL-1 versus -37.7 ± 22.8 ng•mL-1, p = 0.08). No correlation was found between the other adhesion molecules and postoperative CK-MB values.
Fifteen patients needed norepinephrine in the ICU. The mean age of these patients was higher than the other 22 (Table 2). The CPB and aortic crossclamp times and CK-MB levels did not differ between the 2 groups. Significantly higher sE-selectin levels were found in patients requiring norepinephrine (p = 0.01, ANOVA for repeated measures). Significant changes in sE-selectin levels (compared to the baseline) were found at 20 hours after CPB in patients who had norepinephrine in the ICU, while sE-selectin levels in patients without norepinephrine remained unchanged (Figure 2A). There were no differences in sP-selectin levels between patients requiring norepinephrine and the others (p = 0.51, ANOVA for repeated measures; Figure 2B). The increase of sICAM-1 was significantly greater in patients given norepinephrine in the ICU (p = 0.02, ANOVA for repeated measures; Figure 2C). Hemodynamic parameters were similar in both groups (Table 3), and no correlation was found between hemodynamic parameters and soluble adhesion molecule levels.
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DISCUSSION
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The adhesion of leukocytes to endothelial cells requires the expression of adhesion molecules on the surface of these cells. Soluble types of some adhesion molecules have been found in peripheral blood and they may serve as markers of endothelial activation or damage.3 E-selectin is found exclusively on cytokine-activated endothelial cells and it plays a pivotal role in the interaction of endothelium and neutrophils; it appears to be a specific marker of endothelial cell activation.6 Although plasma sE-selectin levels have been reported to increase after CABG with CPB, our results showed no significant change in sE-selectin after CABG in patients who did not require norepinephrine in the ICU.7,8 A significant increase of sE-selectin was found only in patients who needed norepinephrine in the ICU, suggesting that elective low-risk CABG patients with short ischemic and CPB times may not have marked endothelial activation. Whether the use of norepinephrine might elevate plasma sE-selectin needs further investigation.
P-selectin is expressed by endothelial cells and platelets. It is mobilized to the cell membrane upon cell activation, and it mediates the adhesion of leukocytes to activated platelets and endothelial cells.9 It has been reported that high levels of sP-selectin are associated with increased morbidity and mortality in diseases in which microcirculatory disorders involving activated endothelium, platelets, and leukocytes are characteristic.10,11 Recently, sP-selectin levels were found to correlate with increased postoperative mortality risk score, hypotension, and tachycardia in children undergoing CPB.12 However, our data show no relationship between sP-selectin levels and the clinical data. The sP-selectin levels rose postoperatively and a significant increase was detected even 20 hours after CPB, but no difference was found between sP-selectin levels in patients who needed norepinephrine in the ICU and the control patients. The increased plasma levels of sP-selectin may indicate activation mainly of platelets rather than endothelial cells in low-risk patients.
The expression of ICAM-1 is increased following exposure of the endothelium to interleukin-1ß, tumor necrosis factor-
, and lipopolysaccharides. It plays an important role in the migration and extravasation of leukocytes into inflammatory sites.13 Similar to previous studies, we found sICAM-1 decreased in the early stage and then increased significantly 20 hours after reperfusion.14,15 This was evident even when the hemodilution effect of CPB was corrected by hematocrit. The decrease in systemic sICAM-1 after CABG indicates consumption of sICAM-1 somewhere during the reperfusion stage. The underlying mechanism is not yet clear, but it is probably due to adherence of sICAM-1 to the surfaces of the CPB circuit or to activated endothelial cells.16 It has been reported that the inflammatory reaction is involved in myocardial ischemia-reperfusion injury.17,18 Transcardiac sICAM-1 increases significantly after aortic declamping in CABG.8 However, our data show no correlation between sICAM-1 levels and ischemic time, CPB time, or CK-MB levels. Systemic plasma levels of soluble adhesion molecules may not properly reflect local production. This study based on arterial blood samples may not show the relationship between sICAM-1 and myocardial injury. However, a profound increase of sICAM-1 was noted in patients who needed norepinephrine in the ICU, and this was associated with higher sE-selectin levels. These findings suggest a role of ICAM-1 in the mechanism of postoperative vasodilation.
It has been established that a leukocyte-endothelial cell interaction is associated with vascular endothelial injury. Blocking monoclonal antibodies directed against ICAM-1 have been reported to preserve endothelial function and inhibit polymorphonuclear leukocyte infiltration and tissue injury.19 A correlation between sE-selectin and vascular structural changes in hypertensive patients was also defined.20 The present study showed that the need for vasoconstrictors in the ICU was associated with considerable increases of sE-selectin and sICAM-1. Although a causal relationship between soluble adhesion molecules and vasoconstrictor treatment needs further investigation, these data would support previous experimental studies showing that a leukocyte-endothelial cell interaction is associated with vascular endothelial injury. Diminishing the inflammatory response may thus be advantageous in the treatment of patients with severe comorbid conditions.
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Acknowledgments
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This study was supported by grants from the Medical Research Fund of Tampere University Hospital and the Pirkkanmaa Regional Fund of Finnish Culture Foundation.
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ABSTRACT
Introduction
