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Eur J Cardiothorac Surg 1999;15:340-345
© 1999 Elsevier Science NL

The heart produces but the lungs consume proinflammatory cytokines following cardiopulmonary bypass¹

^a Department of Cardiothoracic Surgery, University of Regensburg, Regensburg, Germany
^b Department of Anesthesiology, University of Regensburg, Regensburg, Germany

Received 26 October 1998; received in revised form 31 December 1998; accepted 13 January 1999.

Corresponding author. Tel.: +49-941-944-9801; fax: +49-941-944-9802; e-mail: andreas.liebold@klinik.uni-regensburg.de

	Abstract

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Objective: Proinflammatory cytokines, such as interleukin-6 (IL-6), and soluble adhesion molecules, such as E-selectin, may play an important role in patient response to cardiopulmonary bypass (CPB). We sought to define whether the heart and the lungs serve as important sources of these inflammatory mediators under clinical conditions of myocardial revascularization using CPB and cardioplegic arrest. Methods: Plasma levels of IL-6 and E-selectin were measured in coronary sinus (CS), arterial, pulmonary arterial (PA) and left atrial (LA) blood samples taken from 12 consecutive patients (68.3±11 years; five females) undergoing coronary artery bypass grafting (CABG). Blood samples were collected preoperatively, after reperfusion, and 1, 6, 12 and 18 h following surgery. CS and LA blood was drawn using transcutaneous catheters. PA artery blood was obtained through a Swan–Ganz catheter. Cytokine levels were determined by standard enzyme linked immunosorbent assay (ELISA) technique. Results: A mean of 3.8±1 coronary anastomoses were performed. The CPB time and aortic X-clamp time were 91±15 and 45±10 min, respectively. IL-6 levels increased significantly after CPB and peaked 6 h postoperatively. There was also a significant increase of E-selectin levels with an onset at 1 h and a peak at 12 h postoperatively. At all time points the IL-6 and E-selectin concentrations were significantly higher in the CS than in arterial blood. In contrast, the levels of both mediators measured in the LA were significantly lower than those in the PA. Conclusion: The reperfusion of ischemic myocardium during CABG results in a significant increase in plasma levels of IL-6 and E-selectin. Our data indicate that the myocardium, but not the lungs, is a predominant source of IL-6 and E-selectin release following CPB. The lungs may consume rather than release those mediators during reperfusion. Not the CPB per se, but the myocardial ischemia seems to be crucial in the pathogenesis of the inflammatory response observed following open heart surgery.

Key Words: Interleukin-6 • E-selectin • Coronary sinus • Inflammatory response • Coronary artery bypass grafting

	Introduction

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Cardiovascular surgery using extracorporeal circulation causes systemic inflammatory responses that have been implicated in postoperative organ dysfunction [1] [2] [3] [4]. This phenomenon is thought to be a result principally of inflammation, induced by blood contact activation with the non-biological surfaces of the cardiopulmonary bypass (CPB), together with the abnormal blood gas interfaces of the system [5]. These deleterious effects of CPB may cause complement activation, release of oxygen-free radicals, and other mediators such as cytokines. Attention has been focused on the role of proinflammatory cytokines such as interleukin-6 (IL-6) since they have been found to play an important role in attracting polymorphnuclear cells and T-lymphocytes in reperfused tissues and organs [6] [7] [8] [9] [10]. Essential for the genesis of tissue damage in reperfusion injury are leukocyte/endothelial cell interactions mediated by adhesion molecules. E-selectin is a soluble adhesion molecule which is expressed in a variety of acute and chronic inflammatory conditions [11] [12]. Several authors reported increased IL-6 plasma levels in response to extracorporeal circulation [4] [8] [13] [14]. This finding could be verified by a recent study of our group, where we could demonstrate an increase of IL-6 and E-selectin release within the peripheral circulation with peak values between 6 and 12 h after weaning off CPB [15]. However, the origin of those mediators remains to be defined. We therefore carried out a clinical study to examine whether the heart or the lung is a major site of IL-6 and E-selectin production, since these are the two mainly affected organs during operations using CPB.

	Material and methods

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Patients
Plasma concentration of the proinflammatory cytokine IL-6 and the soluble adhesion molecule E-Selectin were studied in 12 patients (five females and seven males; aged 44–84 years, mean 68.3±11 years) who underwent first-time coronary-artery bypass grafting (CABG). Patients who had repeated surgery and those with diabetes mellitus or chronic steroid medication were excluded. Exclusion criteria were also unstable angina, inotropic support or use of mechanical circulatory assistance at the time of surgery. In all cases the indication for surgery was progressive three-vessel coronary artery disease. Nine of the 12 patients had a history of myocardial infarction. Mean left ventricular ejection fraction was 47±8%, and mean left ventricular end diastolic volume index 93±29 ml/m² as measured by angiography prior to surgery. Patients who were included into the study were asked to give written informed consent. The study was approved by the Institutional Ethical Board.

Anesthesia and surgery
Anesthesia was induced intravenously with fentanyl, etomidate and pancuronium, and was maintained with isoflurane supplemented with fentanyl and pancuronium bolus doses throughout the procedure. A Swan–Ganz catheter (93A-931; Baxter Healthcare, Irvine, CA) was introduced through the jugular vein, as well as a radial arterial catheter as routinely performed before surgery. The operative procedure was carried out by the same surgeon in all patients. CPB was instituted at mild hypothermia (32–34°C) with an arterial cannula placed in the ascending aorta and a venous cannula placed through the right atrium. Cardioplegic arrest was induced with cold crystalloid cardioplegia (HTK solution) administered pressure controlled via the aortic root. CPB time ranged from 64 to 112 min (mean 91.5±15 min). Duration of aortic cross clamp time ranged from 33 to 61 min (mean 45.2±10 min). All patients received an internal mammary artery graft to the left anterior descending artery. The mean number of coronary anastomoses was 3.8±1 per patient. During reperfusion, the coronary sinus (CS) was cannulated with a 3.6 French catheter (Jostra, Hirrlingen, Germany) which is normally used for left atrial pressure measurement. The same catheter was introduced into the left atrium (LA) via the right upper pulmonary vein. The catheters were fixed at the epicardium using 6.0 prolene sutures and then brought out through the skin allowing transcutaneous retraction.

Blood sampling and measurements
CS and LA blood samples were drawn from the transcutaneous catheters in the CS and LA respectively. Systemic arterial and pulmonary artery blood samples were obtained from the patients' radial arterial line and the Swan–Ganz catheter. Systemic arterial blood samples were drawn before and immediately after CPB. Samples of all four sampling sites were collected 1, 6, 12 and 18 h after reperfusion. The samples were centrifuged immediately at 5000 min^-1 (20 min, 4°C) and the plasma was deeply frozen (-70°C) until analysis. The plasma levels of IL-6 were determined by enzyme linked immunosorbent assay (ELISA) using a commercially available kit (Immulite IL-6, Diagnostic Products, Los Angeles, CA) according to the manufacturers instructions. E-selectin was assayed using a double primary sandwich ELISA (R & D Systems, Abingdon, UK).

Statistics
The data for each parameter were checked for normal distribution using the Lillifors modification of the Kolomogorov–Smirnov test. As the data were normally distributed, they are expressed as means±standard deviation The significance of differences within the same group was tested using the Student's paired t-test. Repeated measures analysis of variance (MANOVA) was used to test the significance of differences between the groups. Values were considered to be statistically significant when the P-value was less than 0.05.

	Results

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IL-6
The mean IL-6 plasma level determined in arterial blood samples obtained preoperatively was 14.7±12 pg/ml and increased significantly at the beginning of reperfusion (169.8±100 pg/ml) and 1 h after reperfusion (858.8±700 pg/ml). IL-6 values peaked at 6 h after reperfusion (923.7±499 pg/ml). After 12 h the values started to decrease (538.8±271 pg/ml) but were still elevated after 18 h (252.8±118 pg/ml) as compared with the preoperative values (P<0.05).

In CS blood samples, mean plasma levels of IL-6 was significantly higher than in arterial blood samples at each time point during the postoperative course (1 h: 1511.9±1023 vs. 858.8±700 pg/ml; 6 h: 1070.0±535 vs. 923.7±499 pg/ml; 12 h: 595.8±287 vs. 538.8±271 pg/ml; 18 h: 311.6±212 vs. 252.8±183 pg/ml; P<0.01) ( Fig. 1 ).

View larger version (33K): [in this window] [in a new window]   Fig. 1. Interleukin-6 plasma concentrations (mean±SEM) in blood samples obtained from peripherial artery (A), coronary sinus (CS), pulmonary artery (PA) and left atrium (LA) at different time points after cardiopulmonary bypass. *P<0.01 (A vs. CS, and PA vs. LA, respectively).

E-selectin
In arterial blood samples, mean plasma levels of E-selectin obtained preoperatively, at the beginning of reperfusion and 1 h after reperfusion were similar (25.7±8, 19.7±6 and 27.1±11 ng/ml, respectively; P, not significant). The values increased significantly at 6 h (46.1±20 ng/ml), peaked at 12 h (49.4±20 ng/ml), and were still elevated at 18 h (39.2±15 ng/ml; P<0.05).

In CS blood samples, mean E-selectin levels were significantly higher than in arterial blood samples (1 h: 33.8±13 vs. 27.1±11 ng/ml; 6 h: 55.6±18 vs. 46.1±20 ng/ml; 12 h: 55.3±22 vs. 49.4±20 ng/ml; 18 h: 45.1±18 vs. 39.2±15 ng/ml; P<0.01) ( Fig. 2 ).

View larger version (36K): [in this window] [in a new window]   Fig. 2. E-selectin plasma concentrations (mean±SEM) in blood samples obtained from peripherial artery (A), coronary sinus (CS), pulmonary artery (PA) and left atrium (LA) at different time points after cardiopulmonary bypass. *P<0.01 (A vs. CS, and PA vs. LA, respectively).

	Discussion

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This report summarizes the first clinical study on the transcardiac and transpulmonary gradient of the proinflammatory cytokine IL-6 and the soluble adhesion molecule E-selectin over a time period of 18 h after CPB. Main findings are (i) a cardiac release of both mediators starting immediately after CPB and peaking 6 (IL-6) to 12 h (E-selectin) following reperfusion, and interestingly (ii) a pulmonary utilization of both mediators during reperfusion.

The relationship between inflammation and extracorporeal circulation continues to be an area of intensive investigation. Alterations to the cytokine network after exposure to the artificial surfaces of CPB are described to be part of the `postperfusion syndrome' together with the activation of complement and neutrophils, endothelial dysfunction, increased capillary permeability, accumulation of interstitial fluid and severe organ dysfunctions [2] [13]. Inflammation that follows CPB or extracorporeal membrane oxygenation always appears systemic and may be responsible for common post pump syndromes such as myocardial stunning, respiratory distress syndrome, renal failure, pancreatitis and neurologic dysfunction [2] [3] [7] [16].

Numerous studies have described alterations of the proinflammatory cytokines such as IL-6 and IL-8 immediately after open heart surgery. Most cytokine concentration studies report amounts measured in systemic blood [3] [4] [13] [17] [18] [19]. Kalfin et al. [17] documented an increased production of IL-8 24 h after cardiac surgery and suggested that IL-8 may play an important role in leucocyte activation after CPB. Steinberg et al. [4] reported increased IL-6 and complement plasma levels in response to extracorporeal circulation. Sablotzki et al. [13] found an increased IL-6 production after weaning off CPB with peak values 6 h after the end of the surgical procedure, coinciding with a peak in body temperature.. Menasche et al. [18] found that IL-6 levels were higher in patients having normothermic bypass and suggested that vasodilation occurring with warm heart operations is mediated by a temperature-dependent release of cytokines. Cremer et al. [3] reported on ten patients with hyperdynamic circulatory dysregulation requiring -constrictors following routine CABG. Significant higher serum levels of IL-6 were measured in those patients as compared with a group of patients with stable hemodynamic conditions.

There are few reports on the transcardiac, CS and systemic blood differences in inflammatory cytokines during CPB [7] [12] [14] [15]. Karube et al. [14] could not find a significant difference in the serum levels of IL-6, IL-8 and polymorphnuclear elastase between CS and systemic arterial blood immediately after CPB. The authors therefore concluded that the myocardium is not a predominant source of proinflammatory cytokines during CPB [14]. One limitation of the study was the short duration of CS blood sampling, since all the parameters determined are known to peak later after reperfusion.

We recently introduced CS blood sampling using a 3.6 French transcutaneous catheter as a means of monitoring cardiac metabolism during the postoperative course. The same transcutaneous catheter was used also for left atrial blood sampling. By the use of four sampling sites (arterial line–CS, PA–LA) we were able to follow the transcardiac as well as the transpulmonary differences in mediator concentrations throughout the first 18 h following surgery. We expected to find higher cytokine levels in CS blood than in systemic arterial blood, and accordingly, higher levels in the LA than in the PA. However, a sizable pulmonary release of both IL-6 and E-selectin did not occur. This observation indicates that not the lungs but the heart was a predominant source of mediator release following CPB. This finding corresponds to the results of Wan et al. [20] who measured elevated plasma levels of tumor necrosis factor-alpha and IL-6 in the CS as compared with peripherial arterial blood up to 2 h after aortic declamping, whereas the cytokine levels in the mixed venous blood showed no increase. The authors concluded from their data that the lungs may consume rather than release proinflammatory cytokines in the early phase of reperfusion [20]. The principle difference between the two organs in the setting of our clinical study was that only the heart was exposed to complete ischemia and topical cooling during CPB, whereas the lungs were nearly normothermic and partially perfused via the bronchial arteries. The relationship between ischemia and inflammation has been established in both experimental and clinical studies. In experimental models of myocardial infarction, inflammatory responses are the primary cause of microvascular incompetence in ischemia and reperfusion [21] [22] [23] [24]. Recently, Neumann et al. [6] reported on cardiac release of cytokines and inflammatory responses in acute myocardial infarction and recanalization therapy. They found differences in CS and systemic arterial blood in IL-6 before and after recanalization and in IL-8 after recanalization. The cardiac release of both cytokines significantly increased with reperfusion. The authors speculated that the vascular endothelium in the heart may be the predominant source of the cardiac release of IL-6 and IL-8 [6]. This theory may be supported by our observation that also the soluble adhesion molecule E-selectin, which is a marker for endothelial activation, is released by the reperfused myocardium.

The mechanism by which inflammatory mediators are removed from the pulmonary circulation still remains unclear. A simple effect of dilution by bronchial blood seems unlikely, since bronchial arteries contribute not more than 5% to the pulmonary venous return. A possible explanation might be that the cytokines are absorbed by chemotactic polymorphnuclear cells in the lungs during reperfusion.

	Conclusion

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There was a significant difference in the levels of IL-6 and E-selectin in CS and systemic arterial blood indicating that the myocardium is the predominant source of their release following CPB. IL-6 and E-selectin levels were significantly lower in the LA than in the PA indicating that the lungs consume rather than release those mediators during reperfusion. The mechanism by which the proinflammatory cytokines are utilized within the pulmonary circulation remains to be determined. Not the CPB per se, but the global myocardial ischemia during aortic cross-clamping seems to be one of the crucial pathogenetic factors in cardiac cytokine release. In our opinion, a better understanding of the detrimental inflammatory consequences of myocardial ischemia should force further development of beating heart coronary revascularization procedures.

	Footnotes

 
Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998.

	Appendix A. Conference discussion

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Dr B. Walpoth (Bern, Switzerland): You know there is a lot of argument in the literature that cytokine or mediator release could have a negative effect on the outcome. If I understand right, it would mean that you should operate on patients without cardiopulmonary bypass. But you bypass the lung while you are on cardiopulmonary bypass. Could you please comment on that point?

Dr Liebold: The reason for this phenomenon is completely unknown. We assume that not cardiopulmonary bypass per se is the reason for that. We had a strong correlation between cytokine release of the heart and ischemic markers measured in the coronary sinus, that means troponin levels were also higher in the coronary sinus than in the aorta. So we think a possible explanation for this phenomenon could be that the cytokines are released by the vascular endothelium and this is exposed to ischemia during aortic cross-clamping, whereas the endothelium in the lungs is not exposed to ischemia. We are now planning further steps in this study. We want to look at the question whether this phenomenon is also seen in patients who undergo coronary operation on the beating heart but on cardiopulmonary bypass.

Mr A. El Gamel (Manchester, UK): Just a comment on the situation that bypass is the one that released the cytokines, the question that was asked early on. In the postgraduate course there was a very good review from Paul Wilson, who just enlightened us that congestive heart failure is associated with increased inflammatory mediator, particularly cytokines. So there are a lot of other conditions that lead to the release of cytokines. Bypass is an inflammatory stimulus. Any other condition, common cold or bacterial infection or chronic bronchitis or dental abscess, will lead to the release of systemic cytokines.

My only question to you really, and I am not trying to be critical, you made a statement saying cytokines get released from the heart and absorbed by the lung. I think you only showed that interleukin-6 gets released by the heart and absorbed in the lung and E-selectin gets released by the heart and absorbed by the lung. But the rest of the cytokines could have a different metabolism and a different pathway, and, for example, interleukin-10 is absorbed by the liver and gets released by the liver. So I think just a little correction, you shouldn't have made a generalized statement. I think this is a complex subject with a lot of cytokines and each of them has a different pathway and different interaction.

Dr Liebold: I agree with you in terms of being correct with our general statement. The headline of our paper should be a little bit provocative. Of course, there is a network of cytokins which is altered during cardiopulmonary bypass and cardiac ischemia. It was not the aim of our study to show the complexity of alterations to the humoral and cellular immunity. This was already done by others. We believe we could demonstrate that there are certain differences of mediator release between the heart and the lungs, which not only could be explained by the use of cardiopulmonary bypass.

Dr J. Gurevitch (Tel Aviv, Israel): In our laboratory, we have shown that the isolated heart releases significant amounts of tumor necrosis factor following 1 h of global ischemia, so the reason you got your marvelous results is the cross-clamp, or ischemia attained on the hearts.

Regarding the questions that were asked here, whether tumor necrosis factor or other cytokines will be released in lower quantities following no-pump procedures, we have heard this morning that in no-pump operations there was lower incidence of pulmonary complications.

I definitely agree with your conclusion that the heart is the source of cytokines. In fact, we have stained ischemic hearts with specific immunoantibodies directed against tumor necrosis factor, and found tumor necrosis factor immunostaining not only in the endothelium, but also in cardiac myocytes. Hence, your conclusions that the heart is the source of cytokine release following ischemia and that the lung is their absorption site were absolutely correct.

Mr G. Angelini (Bristol, UK): We have just concluded a randomized study looking at lung function, on beating heart versus conventional surgery with cardiopulmonary bypass. I can tell you that in this particular instance the cardiopulmonary bypass has got nothing to do with damage to the lung. It is exactly the same story as if you do the operation on a beating heart with no heart-lung machine.

	References

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