Seppo Laine

Cytokine responses in patients undergoing coronary artery bypass surgery after ischemic preconditioning.

OBJECTIVE The release of proinflammatory cytokines has been shown to be associated with the development of complications after coronary artery bypass grafting with cardiopulmonary bypass. The purpose of the present study was to establish whether ischemic preconditioning (IP) could limit inflammatory cytokines release in patients undergoing elective coronary artery bypass surgery. METHODS Twenty-two patients with multiple-vessel coronary artery disease and stable angina admitted for first-time elective coronary artery bypass surgery were randomized into control or ischemic preconditioning groups. Patients in the IP group were exposed to two cycles of two-minute myocardial ischemia, followed by three minutes of reperfusion, at the beginning of the revascularization operation, before the cross-clamping and ischemic period used for coronary artery bypass graft anastomosis. Peripheral plasma levels of TNF-alpha, IL-6, IL-8 and IL-10 were measured perioperatively. RESULTS Significant elevation of IL-6, IL-8 and IL-10 were observed in both groups after reperfusion. Ischemic preconditioning has no effect on cytokine release in the early stage after reperfusion. Arterial blood IL-6 levels in the preconditioning group were significantly lower than in controls at 20 h after declamping (52.93 +/- 9.79 vs 96.04 +/- 17.56 pg/ml, p < 0.05). CONCLUSIONS The results indicate that ischemic preconditioning results in no effect on systemic inflammatory cytokine release in the early stage but a delayed reduction in IL-6 levels at 20 h after reperfusion.Objective - The release of proinflammatory cytokines has been shown to be associated with the development of complications after coronary artery bypass grafting with cardiopulmonary bypass. The purpose of the present study was to establish whether ischemic preconditioning (IP) could limit inflammatory cytokines release in patients undergoing elective coronary artery bypass surgery. Methods

Soluble Adhesion Molecules and Myocardial Injury during Coronary Artery Bypass Grafting

Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery. Leukocyte-endothelial binding followed by neutrophil migration appears to play a central role. These interactions are mediated by adhesion molecules on the surface of activated cells. The present study compared the perioperative levels of soluble adhesion molecules after coronary artery bypass grafting (CABG) in patients with or without cardiopulmonary bypass (CPB). Altogether, 9 patients underwent off-pump revascularization and 11 did so with CPB. Plasma levels of soluble adhesion molecules sE-selectin and sP-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) were measured before anesthesia induction and 1, 4, and 20 hours after reperfusion to the myocardium. The baseline plasma levels of the adhesion molecules were similar in the two groups. Perioperative levels of sE-selectin remained the same and did not differ between groups. Plasma sP-selectin increased in both groups, the change being significantly greater in the CPB group than that in the off-pump group (p = 0.001). Plasma sICAM-1 decreased during an early stage after CABG with CPB, recovering at 4 hours after reperfusion; and a significant increase in ICAM-1 was observed 20 hours later. In the off-pump group, sICAM-1 levels did not change at 1 and 4 hours after reperfusion but increased 20 hours later. Postoperative creatine kinase–muscle bound (CK-MB) levels were significantly higher in the CPB group than in the off-pump group (p = 0.001). The change in sP-selectin levels also showed a correlation with CK-MB values (r = 0.676, p = 0.001). The results indicated that off-pump revascularization is associated with reduced endothelial activation and myocardial injury.

Cytokine Responses in Low-Risk Coronary Artery Bypass Surgery.

Inflammatory cytokines have been implicated in myocardial function, severe congestive heart failure and sepsis. The present study tested the hypothesis that cytokine levels are elevated after low-risk coronary artery bypass surgery (CABG), and that they may be associated with postoperative cardiac dysfunction. Twenty male patients undergoing elective CABG in cardiopulmonary bypass (CPB) were studied. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-10 were measured before anesthesia induction, 5 minutes after, and 1, 4, and 20 hours after reperfusion to the myocardium. Levels of the MB isoenzyme of creatine kinase (CK-MB) were measured postoperatively. Hemodynamic data were also recorded. Myocardial ischemia was followed by an increase in the plasma levels of IL-6, IL-8, and IL-10. The duration of IL-6 response lasted throughout the postoperative period studied. Plasma cytokine levels at 1 hour after reperfusion correlated with the maximum CK-MB value (IL-6, r=0.587, p<0.01; IL-8, r=0.460, p<0.05; IL-10, r=0.570, p<0.05). Higher plasma IL-6 and IL-8 levels after reperfusion tended to be linked with lower cardiac index. The present results confirm that the levels of inflammatory cytokines IL-6, IL-8, and IL-10 are elevated after CABG. Increased systemic pro-inflammatory cytokine levels were partially associated with postoperative myocardial dysfunction.

Imbalance of pro- and anti-inflammatory cytokine responses in elderly patients after coronary artery bypass grafting

Background and aims: Increased inflammatory activity has been observed in elderly people. The aim of this study was to determine whether cytokine responses after coronary artery bypass grafting (CABG) in elderly patients are different from those in younger patients. Methods: Fifty-five male patients admitted for first-time elective coronary artery bypass surgery were divided into two age groups: group I, patients younger than 70 years (N=40); and group II, patients aged 70 years or older (N=15). Perioperative levels of cytokines and CK-MB were measured. Hemodynamic data were recorded. Results: Marginally higher IL-6 (p=0.048) and IL-8 (p=0.041) levels were observed during the intensive care unit (ICU) stay in the elderly as compared with younger patients. Lower IL-10 levels were detected in the elderly 5 minutes after reperfusion to the myocardium (p<0.05). Although the postoperative hemodynamic change was similar in both groups, the elderly needed vasopressor treatment more often during the ICU stay. This was associated with lower IL-10 levels 5 minutes after reperfusion. Conclusions: The present results show the age-related imbalance of pro- and anti-inflammatory responses after CABG, associated with hemodynamic instability in the elderly.

Pump prime aprotinin fails to limit proinflammatory cytokine release after coronary artery bypass surgery.

Background - The purpose of this study was to establish whether pump prime aprotinin could limit the cytokine responses in patients undergoing elective coronary artery bypass surgery. Methods - Twenty-one patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg aprotinin in the pump prime. Leukocyte count, creatine kinase cardiac isoenzyme (CK-MB), cytokine production and postoperative blood loss were analyzed perioperatively and compared with preoperative values. ResultsBACKGROUND The purpose of this study was to establish whether pump prime aprotinin could limit the cytokine responses in patients undergoing elective coronary artery bypass surgery. METHODS Twenty-one patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg aprotinin in the pump prime. Leukocyte count, creatine kinase cardiac isoenzyme (CK-MB), cytokine production and postoperative blood loss were analyzed perioperatively and compared with preoperative values. RESULTS The peak level of leukocyte count was lower in the aprotinin group than in controls (9.3 +/- 0.58 vs 11.2 +/- 0.68 x 10(9)/L, p = 0.01). Interleukin (IL)-6 and IL-8 did not differ significantly between the groups throughout the study period. Plasma IL-10 levels were higher in the controls than in the aprotinin group at 5 min (49.6 +/- 24.9 vs 8.13 +/- 2.8 pg/ml, p = 0.01) after reperfusion. CONCLUSION Pump prime aprotinin fails to limit proinflammatory cytokine response in circulating blood.

The human heart releases cardiotrophin-1after coronary artery bypass grafting with cardiopulmonary bypass

Abstract Objectives. Cardiotrophin-1 (CT-1) is closely linked to many cardiovascular diseases, such as myocardial infarction and heart failure, and exhibits cardioprotective effect in ischemia-reperfusion injury. The present study was designed to investigate the course of CT-1 in patients undergoing on-pump coronary artery bypass grafting (CABG), and to evaluate the relationship between plasma CT-1 levels and postoperative cardiac function. Methods. Twenty-four patients undergoing elective CABG were studied. Radial artery blood samples were collected before cardiopulmonary bypass (CPB), 5 min and 20 min after reperfusion, and 1 h, 6 h, 12 h and 24 h after CPB. Coronary sinus blood samples were collected before CPB, 5 min and 20 min after reperfusion. Plasma CT-1 levels were measured using the ELISA method. Hemodynamic data were collected. Results. Peripheral CT-1 levels did not change significantly postoperatively. Trans-myocardial CT-1 levels increased significantly 5 min and 20 minutes after reperfusion as compared to baseline. A weak positive correlation (r = 0.408, p = 0.048) was found between trans-myocardial CT-1 levels at 20 min after reperfusion and CI at 12 h after CPB. Conclusions. The heart secretes CT-1 after ischemic injury. The precise effect of CT-1 in CABG needs further investigation.

Effect of 17β-Estradiol on Soluble P-Selectin in Coronary Artery Bypass Grafting

Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) initiates a systemic inflammatory response syndrome, which can result in postoperative complications after CPB [1]. This is mediated through a systemic rise of inflammatory cytokines and subsequent transendothelial leukocyte migration. The adhesion of leukocyte to endothelial cells requires the expression of the adhesion molecules on the surface of these cells. Soluble isoforms of these membrane-bound molecules may serve as markers of endothelial activation or damage. P-selectin is expressed both by endothelial cells and by platelets. It mediates the adhesion of leukocytes to activated platelets and endothelial cells [2]. It has been reported that sP-selectin increase after CABG and sP-selectin levels correlate with the postoperative risk of complications [3]. Our previous study showed that 17β-estradiol pretreatment limits leukocyte activation in male patients undergoing CABG [4]. However, the effects of 17β-estradiol on soluble adhesion molecules mediating the inflammatory response in cardiac surgery are unknown. In the present study, twenty male patients with multiple-vessel coronary artery disease and stable angina admitted for the first time for elective coronary artery bypass surgery were randomized into control or 17β-estradiol (E2) groups. No significant differences were noted between the groups in age, body surface area and disease classification (Table 1). Patients randomized into the E2 group were given 17βestradiol (Progynova©R, Schering AG, Berlin, Germany) 2 mg orally twice, at six o’clock in the evening before the operation and 1 h before transfer to the operating room. Standard CABG and CPB techniques were undertaken as previous described [4]. Blood samples were collected from the radial artery and sP-selectin levels in plasma were determined by means of a commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis MN, USA). The detection levels was 0.5 ng/ml. There were no deaths or major complications in any of the patients. Significant increases in plasma sPselectin levels were observed at 1, 4 and 20 h after reperfusion in both groups, and the change was significantly more pronounced in the controls as compared to the E2 group (1 h, 64.0 (43.2, 118.0) (mean (quartiles)) vs. 55.5 (44.5, 70.0), 4 h, 82.0 (58.0, 124.0) vs. 71.0 (56.5, 78.5), 20 h, 81.0 (70.0, 109.0) vs. 69.5 (57.3, 78.5) ng/ml, ANOVA for repeated measures, p= 0.01) (Fig. 1). Adhesion of activated platelets to endothelium with P-selectin molecules might be a crucial step for the activation of the leukocytes, and activated platelets may be involved in the inflammation. Soluble form of P-selectin may regulate the adherence of leukocytes to the P-selectin expressed on the endothelial cells, as it occupies 20–40% of the binding sites on a leukocyte in normal concentration [5]. It has been reported that high concentrations of sP-selectin were associated with increased morbidity and mortality in adults with acute lung injury [6]. Lower plasma levels of sP-selectin have been observed in women during the reproductive period than in men of the same age [7]. It was found that a single injection of 17βestradiol lowers sP-selectin in healthy male volunteers [8]. Taken together, these observation are compatible with a down-regulation of sP-selectin by female sex hormones. High levels of sP-selectin have been found in various disease states, including unstable angina pectoris, myocardial infarction, thrombotic diseases and after cardiopulmonary bypass procedures [3]. These states are associated with damage of endothelium and thrombus formation, which could be mediated by P-selectin. Release of sP-selectin into the coronary circulation has been observed after acetycholine-induced coronary spasm [9]. Though the contribution of sP-selectin to the pathogenesis of these states remains to be investigated, it would be reasonable to assume that the effect of 17β-estradiol on sP-selectin reflects either decreased

Soluble adhesion molecules in coronary surgery and cardiopulmonary bypass with pump prime aprotinin

Objective : The purpose of the present study was to establish whether pump prime aprotinin could influence soluble adhesion molecules in patients undergoing elective coronary artery bypass surgery. Design : Thirty patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg of aprotinin in the pump prime. Plasma levels of soluble adhesion molecules were analyzed perioperatively. Results : There were no significant changes in plasma sE-selectin after the operation in either group. Plasma sP-selectin increased significantly up to 20 h after reperfusion to the myocardium. Plasma sICAM-1 decreased in the early stage after cardiopulmonary bypass (CPB), then recovered at 4 h after reperfusion and a significant increase in sICAM-1 was observed 20 h later. There were no significant differences between the groups in postoperative changes in sP-selectin ( p = 0.21) and sICAM-1 ( p = 0.91). Conclusion : Pump prime aprotinin did not influence plasma levels of E-selectin, P-selectin and ICAM-1 in the present patients. The present results do not support the concept of an anti-inflammatory effect of pump prime aprotinin.

Preceding unstable angina affects inflammatory response and hemodynamics after coronary artery bypass surgery

The authors set out to investigate the inflammatory response and its impact on the hemodynamic function in stable and unstable coronary artery bypass (CABG) patients. Nineteen stable and twenty unstable patients were included in this prospective study. Serum IL-6, IL-8, TNF-α, and IL-10 were measured before, during and after cardiopulmonary bypass (CPB). Hemodynamic data was also collected. TNF-α was detected more often in unstable patients than in stable patients before (p=0.03) and after CPB (p<0.01). TNF-α response after CPB was evident (p=0.03). Serum IL-6 and IL-8 level were significantly increased after 10 minutes of CPB, reaching the peak value at 6 hours after declamping. IL-10 level reached the highest, 6.8 × the baseline at 6 hours after declamping in the unstable, but 3.3 × of baseline on the first post-operative day (POD) in the stable patients (p=0.04). CI was better preserved in unstable patients (p=0.04). Serum TNF-α was more likely to be found in patients with recent unstable episodes. CPB induces a release of serum IL-6, IL-8 and IL-10. Recent unstable angina seems to modify the cytokine response and hemodynamic outcome.