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A review of inflammatory mediators in on- versus off-pump surgery reveals that parameters of systemic inflammation differ quantitatively, not qualitatively between these approaches. Mediator system and cellular activation is observed after surgical trauma and following ischemia/reperfusion. Such activation is also modulated by genetic factors. The available literature does not permit definitive conclusions to be made on the advantages of off-pump surgery with respect to the systemic inflammatory response. The relationship between mediator systems and clinical course needs to be assessed in large patient populations to demonstrate to what extent off-pump surgery is more than just theoretically superior to on-pump surgery.

Objective and Design: Cardiopulmonary bypass (CPB) impairs monocyte and neutrophil proliferation, cytokine synthesis, and antigen presentation. This study compares in vivo data with results from an extracorporeal circulation (ECC) model, distinguishing direct effects on cytokine synthesis from regulatory mechanisms., Patients and Methods: Whole blood from 18 patients prior to, during and after CPB was stimulated with lipopolysaccharide (LPS). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels were measured. Additionally, blood from 4 volunteers was circulated in an ECC model. Cytokine levels were measured before and during mock ECC., Results: LPS-induced cytokine synthesis was reduced after CPB (TNF-alpha: 11 %; IL-6: 29 %; IL-8: 48 % of preoperative values, all p < 0.001). In mock ECC, cytokine production (except IL-8) was suppressed: TNF-alpha production was lowest 60 min after starting ECC, IL-6 synthesis was lowest at 90 min (33 % and 15 % vs. pre-ECC levels; both p < 0.001). Patient sera contained cytokine-inhibitory activity after CPB, an activity not found in mock ECC., Conclusions: (1) In patients, CPB induces early transient LPS hyporesponsiveness; (2) blood contact with foreign surfaces induces LPS hyporesponsiveness; (3) serum cytokine-inhibitory activities are released after CPB, but not in mock ECC. Impaired leukocyte function may explain increased susceptibility to infections after CPB.

Objective: Cardiopulmonary bypass is often associated with pathophysiological changes in form of systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS). In the present study, we investigated plasma levels of pro- and anti-inflammatory cytokines in survivors and non-survivors from MODS in the early postoperative course following open heart surgery., Design: Prospective clinical study., Setting: A University Cardiothoracic Intensive Care Unit., Methods: Levels of cytokines (IL-6, IL-8, IL-10, IL-18, and TGF- ) and procalcitonin (PCT) were measured at the first four postoperative days in 16 adult male patients with an Apache II-score >24 and two or more organ dysfunctions after myocardial revascularization., Main Results: All pro-inflammatory cytokines, except for IL-6, were significantly elevated in non-survivors from MODS, with peak values at the first two postoperative days. The plasma levels of immunoinhibitory cytokines showed no differences between the groups., Conclusions: The results of our study show a different expression of pro-inflammatory cytokines in survivors and non-survivors from MODS following operations with extracorporeal circulation. In addition to Apache-II score, especially IL-8, IL-18, and PCT may be used as parameters for the prognosis of patients with organ dysfunctions after cardiac surgery.

Objectives: Cardiopulmonary bypass is associated with the release of proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 8) and anti-inflammatory cytokines (interleukin 10 and transforming growth factor beta(1)). On the one hand this cytokine release is related to the postoperative systemic inflammatory response syndrome, and on the other hand it is related to deterioration of the immune system, for example in monocyte or polymorphonuclear neutrophil function, leading to an increased susceptibility to infections. To gain further insight into the alterations of immune cell reactivity and possible regulatory mechanisms, we studied lipopolysaccharide-induced tumor necrosis factor alpha synthesis in whole blood from cardiac surgical patients., Methods: Fifteen patients undergoing elective heart surgery with cardiopulmonary bypass were included in the study. Ex vivo lipopolysaccharide-induced tumor necrosis factor alpha synthesis was measured in a whole blood assay before, during, and after bypass. Corresponding tumor necrosis factor alpha messenger RNA levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction. In addition, the influence of patient serum on whole blood responsiveness and its relationship to anti-inflammatory cytokines were evaluated in vitro., Results: Tumor necrosis factor alpha synthesis was significantly reduced after 30 minutes of cardiopulmonary bypass and showed the lowest values at the end of bypass (mean +/- SD 0.109 +/- 0.105 ng/10(6) white blood cells after 30 minutes of bypass and 0.050 +/- 0.065 ng/10(6) white blood cells at the end of bypass, vs 0.450 +/- 0.159 ng/10(6) white blood cells preoperatively, P <.001). As a further indication of reduced cytokine biosynthesis, diminished messenger RNA levels for tumor necrosis factor alpha were detected. Serum withdrawn from patients at the end of cardiopulmonary bypass reduced tumor necrosis factor alpha synthesis in heterologous blood from healthy volunteers highly significantly to 39.93% +/- 23.18% relative to control serum (P =.005) and preoperatively drawn serum (P =.024). This effect was dose dependent and was not specific for lipopolysaccharide-induced tumor necrosis factor alpha synthesis. Anesthesia and heparin administration did not influence tumor necrosis factor alpha production significantly. Ex vivo tumor necrosis factor alpha synthesis was negatively related to interleukin 10 serum levels, positively but weakly related to interleukin 4, and was not related to transforming growth factor beta(1) (Spearman correlation coefficients -0.565, P <.001, 0.362, P <.001, and -0.062, P =.460, respectively). However, interleukin 10 levels in patient serum after cardiopulmonary bypass were 300-fold below the quantities needed for half-maximal inhibition of tumor necrosis factor alpha synthesis in vitro. Moreover, the inhibitory activity could not be removed by immune absorption of interleukin 10., Conclusions: These results suggest that during cardiac operations cytokine-inhibitory serum activities are released or newly formed. These activities could not be explained by the actions of interleukins 4 and 10 or transforming growth factor beta(1). Although their exact nature remains undetermined, these substances may contribute to the diminished immune cell functions after cardiopulmonary bypass and thus need further characterization.

Cardiac impairment is a major complication in immunotherapy. In order to investigate whether the cardiac complications are due to directly cardiodepressant cytokine effects, the contractility of heart cells in culture under immune mediator exposition was studied. The beat frequency and inotropy of spontaneously contracting cultured cardiac myocytes was determined in a microscope perfusion system equipped with computer image analysis devices. Under control conditions, the perfused cardiac myocytes were rhythmically and synchronously beating for many hours. Perfusion with the cytokines (IL-1, IL-2, IL-3, TNF) induced arrhythmias resulting in a complete cessation of spontaneous contractions and a severe loss of myocyte inotropy. The effects were concentration-dependent and reversible. Our results indicate a direct toxic interference of the interleukins and TNF with the contractile function of cultured cardiac myocytes.

Diseases accompanied by severe cardiac impairment like sepsis and chronic uremia are frequently linked to an increase in cytokine release. In order to investigate possible toxic effects of the immune mediators on myocardial cells, we studied the contractility of cardiac myocytes and the de novo formation of stress proteins in cultured heart cells under cytokine exposition. All cytokines investigated induce, concentration-dependently, arrhythmias and cessation of spontaneous contractions. Interleukin(IL)-2, IL-3, IL-6, and tumor necrosis factor (TNF) stimulate the synthesis of a 30 kD stress protein in heart cells, whereas IL-1 additionally evokes two proteins of the 70 kD family. These findings confirm a direct interference of the interleukins and TNF with myocytes and, especially, myocardial protein formation. As the induction of stress proteins makes cells more resistant towards a subsequent challenge, the cytokines are possibly involved in the activation of cell protecting mechanisms in cardiac myocytes.

Background: Advanced glycation end products (AGEs) are formed by the reaction of sugars and NH2 groups of lysine and arginine residues and have been shown to accumulate in tissues, including the heart, with normal ageing. The interaction of AGEs with their receptors is known to cause changes in cell function, leading, for example, to the production of pro-inflammatory cytokines and free radicals. Objective: This study investigated the gene expression of the five known AGE receptors: AGE-R1, AGE-R2, AGE-R3, the scavenger receptor II, and the receptor for AGEs (RAGE) in human heart tissue. Methods: Tissue samples were taken from the right cardiac auricles from three patient groups: children (2.4 ± 1.1 years), adults (45.3 ± 0.8 years) and elderly subjects (76.4 ± 0.4 years). Analysis of gene expression of the five AGE receptors was performed using the reverse transcription-polymerase chain reaction (RT-PCR) and 18S mRNA levels as loading controls. Results: Our results show an age-dependent upregulation of the genes for AGE-R3 and the scavenger receptor II, but a downregulation for RAGE and no significant differences for AGE-R1 and AGE-R2. Conclusion: This study supports a pathophysiological function for AGE receptors such as AGE-R3 and RAGE in the ageing heart. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]