Coronary artery bypass graft (CABG) surgery can result in severe postoperative complications, such as renal and pulmonary failure (1). In about 80% of the cases worldwide, it is currently performed with cardiopulmonary bypass (CPB) with cardiac arrest. Cardiopulmonary bypass leads to a systemic inflammatory response (2), which may be induced by the contact of circulating blood with artificial surfaces of the extracorporeal circuit (3). To reduce postoperative complications caused by systemic inflammation, off-pump CABG was reintroduced into clinical practice in the early 1990s (4). During off-pump surgery, the coronary artery grafts are placed on coronaries of a beating heart, thereby avoiding aortic cross clamping and CPB.
There is increasing evidence that the endothelium plays a crucial role in the pathophysiology of organ failure directly after CABG surgery. This role can be summarized as one of sensing danger signals and subsequently initiating the expression of adhesion molecules E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intracellular adhesion molecule 1 (ICAM-1) and the secretion of proinflammatory cytokines (5). This proinflammatory endothelial activation is considered detrimental to the patient. A simplified model of endothelial activation and the soluble factors during CABG is shown in Figure 1. Endothelial activation can be represented by elevated levels of circulating sE-selectin, sVCAM-1, and sICAM-1 in the blood of patients with sepsis (6) and after CPB (7–10). The proinflammatory endothelial activation leads to recruitment of polymorphonuclear leukocytes (PMNs) into organs (11), where they become activated and release cytotoxic enzymes, including elastase and myeloperoxidase (MPO). Elevated levels of these enzymes in the blood indicate that the use of CPB during CABG results in activation of PMNs (12).
Proinflammatory endothelial activation is controlled by the endothelial tyrosine kinase receptor system Angiopoietin (Ang)/Tie and the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system. The Ang/Tie2 system consists of the endothelial receptor Tie2 and its ligands Ang1 and Ang2. Angiopoietin 1 is constitutively produced and secreted by pericytes, and it acts as a paracrine factor on neighboring cells by binding to the Tie2 receptor to stabilize endothelial cells and inhibiting vascular leakage. Angiopoietin 2 is constitutively produced and stored in Weibel Palade bodies. It is released on proinflammatory stimulation of the endothelial cells and thereby causes vascular leakage (13). The Ang/Tie2 system is essential for vascular development and maturation during growth. After maturation, it controls endothelial inflammation and microvascular permeability (14–16). Vascular endothelial growth factor is an endothelial growth factor mostly known for its role in embryonic and tumor angiogenesis. Apart from this angiogenic role, VEGF levels are increased in critically ill patients (17), which contributes to the vascular leakage seen in septic patients (18). Vascular endothelial growth factor binds to its receptors VEGFR1 (fms-like tyrosine kinase 1 [Flt-1]) and VEGFR2 (kinase insert domain receptor [KDR]). A soluble form of Flt-1 (sFlt-1) is shed from the endothelial membrane and acts as a decoy receptor that inhibits VEGF signaling. Both Ang/Tie2 system (14, 19, 20) and the VEGF/ VEGFR system (18, 21, 22) are involved in endothelial activation in organ failure (23). Several reports have been published about angiogenic and vascular leakage–related factors and their soluble receptors in patients with chronic heart failure (22), yet comprehensive data in patients undergoing on-pump versus off-pump CABG surgery are scarce.
In the current study, we hypothesized that off-pump CABG would lead to less systemic inflammation and thereby to a decrease in proinflammatory endothelial activation compared with on-pump CABG.
MATERIALS AND METHODS
In this prospective, randomized, observational trial, 60 consecutive adult patients scheduled for elective CABG surgery were randomized to have CABG surgery performed either with (on-pump) or without (off-pump) CPB. The primary outcome (effects on cerebral tissue oxygenation) and neurological postoperative outcomes will be published elsewhere (Scheeren et al., in progress).
Patients older than 18 years with coronary artery disease who were suitable for both on- and off-pump CABG surgery were included. Patients with a history of head trauma or stroke, history of neurosurgery, severe or symptomatic carotid artery disease, requirement for valve surgery in addition to CABG, preexisting acute or chronic renal dysfunction, urgent or emergency surgery, or difficulty with testing for cognitive dysfunction were excluded. After obtaining a written informed consent, patients were randomized to either on-pump or off-pump surgery using a sealed envelope technique. The study protocol was approved by the Medical Ethical Committee of the University Medical Center Groningen, The Netherlands (METc 2011/045) and registered on ClinicalTrials.gov (NCT01347827).
Anesthetic management was standardized. No premedication was given. Anesthesia was induced with a sufentanil bolus of 0.5 μg/kg and a propofol target-controlled infusion with an initial target effect size concentration of 2 μg/mL. Propofol was titrated thereafter to keep the bispectral index in the range of 30 to 50 throughout the procedure. Pancuronium (0.1 mg/kg) or rocuronium (0.6 mg/kg) was administered before tracheal intubation. During the procedure, additional sufentanil boluses of 10 μg and continuous sufentanil infusions were given at the discretion of the anesthesiologist. Corticoids were not used in any of the patients during perioperative management. A central venous oximetry catheter (PreSep; Edwards Lifesciences Corporation, Irvine, Calif) was inserted via the right internal jugular vein.
CPB and Surgical Procedure
Surgical management was standardized. After a median sternotomy and graft harvesting, the patient received heparin and protamine 1:1 (2 mg/kg in the off-pump group versus 3 mg/kg in the on-pump group). The extracorporeal system used was an open CPB system (Stöckert S5, Sorin, Italy) with a roller pump and a Terumo Rx25 oxygenator (Terumo Europe NV, Leuven, Belgium) with uncoated tubes. The system was primed with 1,500 mL of fluids, consisting of 1,000 mL crystalloid and 500 mL synthetic colloids (Voluven; Fresenius, Bad Homburg, Germany). In the on-pump CABG group, the ascending aorta and right atrium were cannulated and CPB with nonpulsatile flow was started. To induce and maintain cardiac arrest, myocardial protection was obtained using antegrade administration of cold blood cardioplegia through the aortic root and/or retrograde administration via the coronary sinus according to the patient’s anatomy. In the off-pump CABG group, cardiac stabilization and displacement were obtained using Acrobat and XPOSE 4 devices (Maquet Netherlands BV, Hilversum, The Netherlands). Anastomoses were constructed using an intracoronary shunt (Medtronic, Minneapolis, Minn) and carbon dioxide with a warm saline blower (Blower Mister, Maquet Netherlands BV). The left internal mammary artery was investigated primarily and used when quality was sufficient. Depending on the patients’ graft and target vessel characteristics, the right internal mammary artery, the left radial artery, or the saphenous vein was used as grafts in addition to or instead of the left internal mammary artery. All grafts were treated with a heparin and papaverine solution to avoid vasospasm. In the on-pump group, the distal anastomoses were constructed in a retrograde fashion and in the off-pump group in an antegrade fashion.
Blood was drawn from the arterial catheter at four time points, after the arrival of the patient in the operation room (start), after sternum closure (end), 6 h after closure (6 h post OR), and 24 h postoperatively (24 h post OR), and collected in EDTA tubes. Samples were centrifuged at 1,000 rpm for 10 min at 4°C (Thermo Fisher Scientific, Waltham, Mass). Plasma was aliquoted and stored at -80°C until further analysis.
Measurements of Plasma Cytokines and Soluble Endothelial Adhesion Molecule Levels
Plasma levels of cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-10, and MPO were measured using commercially available multiplex immunoassay kits (human CVD panel 3; EMD Millipore Corporation, Billerica, Mass). The plasma levels of soluble endothelial adhesion molecules of sE-selectin, sVCAM-1, and sICAM-1 were measured using commercially available multiplex immunoassay kits (human CVD panel 1; EMD Millipore Corporation) both according to manufacturer’s instructions.
Measurements of Plasma Levels of Soluble Factors of the Ang/Tie2 System
Levels of Ang1, Ang2, and sTie2 were measured in plasma using commercially available Quantikine ELISA kits (DANG10, DANG20, and DTE200; R&D Systems, Minneapolis, Minn), according to the manufacturer’s instructions and as previously described for Tie2 (24). Levels of VEGF were measured in plasma using commercially available multiplex immunoassay kit (human CVD panel 3; EMD Millipore Corporation), and levels of soluble VEGFR1 (sFlt-1) and VEGFR2 (KDR) were measured using commercially available Bio-Plex Pro kit (Human Cancer Biomarker Assay Panel 1; Bio-Rad Laboratories BV, Veenendaal, The Netherlands) according to the manufacturer’s instructions.
Corrections for Hemodilution
For each patient, we used the preoperative and postoperative hemoglobin levels that were measured routinely. Corrections for hemodilution were calculated as described by Schneditz et al. (25).
The patient characteristics, age, body mass index (BMI), EuroSCORE, hemoglobin levels, CPB time, aortic cross-clamp time, total operation time, and hemodilution factor were presented as mean with SD, whereas grafts, intensive care unit (ICU) length of stay, and hospital length of stay were presented as median with range. All other characteristics were presented as number of patients with percentage. Significance of differences between the groups was analyzed using the Fisher exact test comparing the categorical variables (sex, smokers, preoperative medical and surgical history, and postoperative major morbidity) and using Mann-Whitney U test comparing age, BMI, hemoglobin levels, hemodilution factor, total operation time, ICU length of stay, and hospital length of stay between the groups.
Because all patients have the same baseline levels, the results of the analyses of the blood samples at the start of the procedure in the on-pump and off-pump CABG group were pooled. The data are presented as median. Significance of differences between the groups was analyzed using one-way analysis of variance with Bonferroni correction for multiple comparisons. All statistical analyses were performed using GraphPad Prism (GraphPad Software, San Diego, Calif). Differences were considered to be significant when P < 0.05
No differences in patient baseline characteristics were found between the on-pump CABG and off-pump CABG groups
In total, 60 patients were included in the study. One patient who was randomized for on-pump CABG surgery was excluded from the study because off-pump surgery was performed because of the presence of a “porcelain aorta.” Ninety percent of the patients in both groups were male, and the average age in both groups was 63 years (range, 47 – 77 years). More than 65% of the patients in each group were smokers. The mean CPB time in the on-pump CABG group was 82 ± 23 min, and the mean aortic cross-clamp time was 53 ± 15 min. The total procedure time in the on-pump CABG group was 188 ± 31 min and in the off-pump CABG group was 186 ± 58 min. The median number of grafts in both groups was three. Cell savers were used in the off-pump group. The blood volume processed and retransfused was 600 ± 227 mL. In the on-pump group, intraoperative blood losses were collected with the cardiotomy suction of the CPB. Total blood transfusion was not different between the groups. The median ICU length of stay was 1 day in both groups (range of 0.5 to 8 days in the off-pump group and 0.5 to 12 days in the on-pump group). No significant differences between on-pump and off-pump CABG group characteristics were found (Table 1).
Coronary artery bypass grafting leads to systemic inflammation, which is more prominent in the on-pump CABG group
At the end of the procedure, the proinflammatory cytokine TNF-α was 4.4-fold increased in on-pump CABG patients compared with the start of the procedure; whereas in off-pump CABG patients, the levels were unaltered (Fig. 2A). In both groups, TNF-α normalized after 6 h. Compared with the start of the procedure, at the early time point, there was no change in IL-6 levels; whereas 6 h after the end of the procedure, IL-6 was increased (75-fold vs. 95-fold) but without significant differences between groups. Increased IL-6 levels were still present in both groups 24 h after the end of the procedure (Fig. 2B). In the on-pump CABG group, levels of IL-10 were increased 40-fold at the end of procedure; whereas in the off-pump CABG group, the maximum increase occurred at a later time point, that is, 6 h after the end of the procedure, with a 25-fold induction (Fig. 2C). Levels of IL-10 were still increased 40-fold in the on-pump CABG group and 30-fold in the off-pump CABG group at 6 h after the end of the procedure. These levels normalized after 24 h in both groups. Myeloperoxidase levels increased to a greater extent in on-pump CABG compared to the off-pump CABG group at the end of procedure (9-fold versus 2.6-fold). Myeloperoxidase levels in the off-pump group were only increased at the end of the procedure (Fig. 2D).
Soluble endothelial adhesion molecule levels in plasma are not elevated during and after coronary artery bypass surgery
Systemic inflammation is a potent stimulus for proinflammatory endothelial activation (5), yet the same pattern of changes in all systemic soluble endothelial adhesion molecules (E-selectin, VCAM-1, and ICAM-1) was shown in both groups during and after CABG. Levels of soluble E-selectin, VCAM-1, and ICAM-1 were 1.5-fold lower in the on-pump and 1.2-fold in the off-pump CABG group at the end of the procedure compared with the start of the procedure (Fig. 3). Corrected levels for hemodilution show that there is still no increase in soluble adhesion molecules at the end of the procedure compared with the start (sE-selectin, 44 ng/mL end vs. 36 ng/mL start; sICAM-1, 65 ng/mL end vs. 68 ng/mL start; sVCAM-1, 1,030 ng/mL end vs. 870 ng/mL start). Levels of all soluble endothelial adhesion molecules normalized within 6 h after the end of the procedure to levels comparable to those at the start of the procedure. No significant differences were found between the on-pump CABG and off-pump CABG groups at any time point.
Vascular leakage–related endothelial factors are not different between on-pump and off-pump coronary artery bypass surgery
Systemic inflammation can cause vascular leakage, which is effective at the level of the endothelial cell (26). During the procedure, Ang1 levels dropped in both groups from 8.5 ng/mL to a minimum level of 4 ng/mL at the end of the procedure (Fig. 4A). After corrections for hemodilution at the end of the procedure, levels of Ang1 were not different from the start (9.5 ng/mL end vs. 9.7 ng/mL start). Levels normalized within 24 h after the procedure. On the other hand, Ang2 levels were stable (2 ng/mL) during the procedure but increased 2- to 2.5-fold at 24 h after the procedure in both groups (Fig. 4B). Soluble Tie2 levels dropped 1.8-fold in the on-pump CABG group and 1.4-fold in the off-pump CABG group at the end and 6 h after the end of the procedure, and these levels had normalized in both groups 24 h after the end of the procedure (Fig. 4C). After corrections for hemodilution, no change was observed in sTie2 levels at the end of the procedure compared with the start (25.2 ng/mL end vs. 24.9 ng/mL start). No significant differences in Ang1, Ang2, and sTie2 levels were found between the on-pump and off-pump groups at any time point.
Vascular endothelial growth factor levels of 3.2 pg/mL were detected in the plasma at the start of the procedure (Fig. 5A). These levels did not change in the on-pump and off-pump groups during and after the procedure. Elevated levels of sFlt-1 (5-fold in on-pump and 8.6-fold in off-pump CABG groups) were found at the end of the procedure in the plasma of patients in both groups compared with the levels at the start of the procedure (Fig. 5B). Levels of sFlt-1 were 1.7-fold higher in the off-pump CABG group compared with the on-pump CABG group. These levels normalized again in both groups by 6 and 24 h after the procedure. Levels of KDR were almost 2-fold lower 6 and 24 h after the procedure compared with the start of the procedure, but no differences were found between the on-pump and off-pump CABG groups (Fig. 5C).
This prospective randomized study showed that on-pump CABG surgery leads to a more severe systemic inflammation than off-pump CABG surgery. Yet, the difference in systemic inflammatory response however did not lead to a different pattern or level of release of soluble adhesion molecules in the blood by activated endothelial cells between the groups. In both groups, on-pump and off-pump CABG, the levels of soluble adhesion molecules decreased initially. The system involved in endothelial integrity also responded. The endothelial activation and vascular leakage–related molecule Ang2 was increased 24 h after CABG surgery in both groups, and the VEGF signaling soluble receptor sFlt-1 was more increased in the off-pump than in the on-pump CABG group. To our knowledge, this is the first randomized clinical study that describes the effects of off-pump versus on-pump CABG surgery on systemic inflammation and activation status of endothelial cells.
We found significant differences in TNF-α and IL-6 levels in the plasma between both groups, with higher levels in the on-pump CABG group. These findings are in line with the results reported by Parolari and coworkers (27). Their randomized study showed increased TNF-α production after protamine administration in on-pump CABG patients compared with that of off-pump CABG patients. Other randomized studies showed significantly lower levels of IL-10 at the end of surgery in off-pump CABG surgery compared with on-pump CABG surgery (3). The relatively low levels of proinflammatory cytokines in both on-pump and off-pump CABG patients in our study might be explained by improved anesthetic and surgical techniques. Moreover, the low EuroSCORE (<5) in both of our patient groups indicates that the study population we randomized can be regarded as a relatively low-risk population (28). Another explanation for the low cytokine levels in the off-pump group is the use of cell savers. As described by Allen et al. (29), cell salvage and washing significantly reduce the concentration of the measured cytokines in this study.
In contrary to what we expected based on the literature on CABG procedures (8, 30) and sepsis (31), we did not find any upregulation of soluble adhesion molecules in plasma. At the end of surgery, we observed a drop in the levels of soluble endothelial adhesion molecules that can be explained by the effects of hemodilution. When we use the correction for this hemodilution as described by Schneditz and coworkers (25), the levels of soluble E-selectin, sVCAM-1, sICAM-1, Ang1, and sTie2, at the end of the surgery returned to baseline levels in both on-pump and off-pump groups. The study of Wei and coworkers (8) showed that levels of sICAM-1 were elevated at 20 h after surgery, whereas levels of soluble E-selectin did not change after surgery. Similarly, Vallely and coworkers (30) found elevated sVCAM-1 and sICAM-1 24 h after surgery, whereas soluble E-selectin did not change. In both studies, these endothelial activation markers did not differ between on-pump and off-pump CABG. However, in a mouse model, protein levels of E-selectin, ICAM-1, and VCAM-1 were elevated 90 min after hemorrhagic shock induction (32). It is of note that soluble levels do not necessarily represent organ levels (33). Shapiro and coworkers (33) compared levels of soluble endothelial adhesion molecules in animal sepsis models with organ mRNA and protein levels. It appeared that levels of soluble adhesion molecules in blood did not always reflect local changes in mRNA or protein expression (33), as endothelial responses between organs differ in time and place (5). For instance, ICAM-1 protein and/or mRNA were increased in the skin, heart, lung, and brain of mice subjected to an experimental peritoneal sepsis model, whereas circulating levels of sICAM-1 levels were unaltered. Furthermore, organ-specific differences might become masked when soluble plasma levels are measured. For example, Kalawski and coworkers showed that sVCAM-1 and sICAM-1 levels in plasma samples taken from the coronary sinus increase after cardiac bypass and reperfusion, whereas the levels in arterial samples remained unchanged, indicating that the levels of sICAM-1 and sVCAM-1 might increase selectively in the microcirculation of the heart (34).
Several reports have been published about angiogenic and vascular leakage–related factors and their soluble receptors in patients with chronic heart failure (22), but comprehensive data in patients undergoing on-pump versus off-pump CABG are scarce. In our study, levels of Ang2 increased 24 h after CABG in both the on-pump and off-pump groups. These results are in line with previous results showing that Ang2 increased approximately 3-fold after CPB for CABG (14). Denizot et al. (22) showed that sFlt-1 levels in the plasma of CABG patients might play a protective role in the occurrence of postoperative CABG complications. They found lower levels of sFlt-1 in patients with cardiovascular impairments and in patients who died postoperatively (22). Animal models have shown that adenoviral delivery of sFlt-1 reduces disease severity in a chronic inflammatory disease model (35). In our study, we observed higher levels of sFlt-1 in off-pump compared with on-pump CABG patients.
Off-pump CABG was reintroduced into surgical practice to try to reduce the severity of the surgical insult, but surprisingly, studies in large groups of patients have failed to demonstrate an outcome advantage (36). Our current study adds arguments to this discussion. The inflammatory response was modest in both groups, and thus very large studies will be required to demonstrate that the lesser inflammation evoked in the off-pump group has a beneficial effect. The small beneficial effect of reduced inflammation may also be superseded by (un)recognized detrimental effects of off-pump CABG.
Our study has several limitations. First, we measured endothelial activation solely by means of circulating levels and not by gene expression or protein expression in organ biopsies because it is not possible to obtain organ biopsies from patients. Therefore, circulating soluble levels are, at best, surrogate markers of endothelial cell adhesion molecule expression in vital organs. The main reason for our experimental setup as reported is that it is not possible to obtain organ biopsies from CABG patients. Many studies have shown that circulating levels do not directly reflect endothelial activation in tissue organs. Previously, our group showed that TNF-α induced the mRNA expression of adhesion molecules E-selectin, ICAM-1, and VCAM-1 in endothelial cells and also in different mouse organs (37). In our current study, we measured a significant increase in systemic levels of TNF-α in the plasma of on-pump CABG patients compared with off-pump CABG patients. Combining this with animal studies performed by Dr J.M. Kuldo in our group, where she studied endothelial responses in organs to TNF-α, we assume that TNF-α is able to trigger the endothelium in the organs of the patients to produce and release adhesion molecules, which we measured in the plasma (http://dissertations.ub.rug.nl/faculties/medicine/2007/j.m.kuldo/). Of importance to realize here is that different organs respond differently to systemic activation, as also reported by us (13, 37) and others (33). Hence, without organ samples, we cannot say anything about the (micro)vascular origin of soluble adhesion molecules measured. Second, the sample size of our study population is relatively small. Using larger groups might lead to statistically significant differences between the groups, but we are confident that differences smaller than the observed differences in systemic endothelial responses do not have a large biological meaning. Third, we studied a low-risk surgical cohort. In high-risk patients, the circulating levels of soluble endothelial adhesion molecules may be different. Fourth, cell saver usage could have influenced the cytokine profile in off-pump patients. And fifth, in our study, on-pump and off-pump CABG patients received different dosages of heparin and protamine, and we therefore cannot rule out that the effects we found might partly be explained by the different dosages of heparin and protamine. Future studies should focus on high-risk patients and gene expression levels in organ biopsies of markers of endothelial activation and vascular leakage.
Our current study shows that the systemic inflammatory response is attenuated by off-pump compared with on-pump CABG surgery. Coronary artery bypass graft in general does not induce a greater release of soluble endothelial adhesion molecules into the systemic circulation. Finally, the systemic levels of angiogenic and vascular leakage–related molecules of the endothelial receptor systems Ang/Tie2 system and the VEGF/VEGFR system were more deranged in on-pump than in off-pump CABG surgery.
The authors thank Ans Hagenaars for collecting and providing the patient material.
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