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Ann Thorac Surg 2006;82:2179-2186
© 2006 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, University of Heidelberg, Heidelberg
b Department of Cardiothoracic Surgery, Heart Center Wuppertal, Helios Clinics, University of Witten/Herdecke, Wuppertal
c Cardiac Research Institute, University of Witten-Herdecke, Dortmund, Germany
Accepted for publication June 27, 2006.
* Address correspondence to Dr Hoda, Department of Cardiac Surgery, University Medical School of Heidelberg, Im Neuenheimer Feld 110, Heidelberg D-69120, Germany. (Email: raschid.hoda{at}med.uni-heidelberg.de).
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Abstract |
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METHODS: Forty-nine patients were enrolled in this prospective study. Conventional coronary artery bypass grafting was performed in 19 patients (ONCABG; group I), and heart valve surgery in 15 patients (group II). Fifteen patients (group III) received off-pump coronary artery bypass grafting (OPCABG). Blood samples were collected preoperatively and for as long as 72 hours postoperatively. Plasma levels of leptin and cortisol were measured by enzyme-linked immunosorbent assay.
RESULTS: Leptin serum levels decreased during the operation, reaching 73.2% of the baseline in group I, 85.3% in group II, and 38.9% in group III (p < 0.05), 2 hours postoperatively. Thereafter, leptin levels increased gradually to 218.6% of the baseline in group I and 313.7% in group II 24 hours after the operation (p < 0.01). However, patients in the OPCABG group showed only a moderate increase in serum leptin levels. Plasma cortisol levels rose to a maximum of 532.9% of baseline in group I, 526.4% in group II, and 280% in group III 12 hours postoperatively (p < 0.01).
CONCLUSIONS: Open heart surgery is associated with acute perioperative changes in plasma levels of neurohormonal stress factors leptin and cortisol. A different pattern of leptin and cortisol release was observed in patients operated on without cardiopulmonary bypass.
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Introduction |
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Leptin, a 16 kDa, 167-aminoacid peptide, the obese gene product, is released mainly by the adipocytes. After binding to its receptors in the hypothalamus, it induces a complex cellular response, which contributes to the control of body weight and energy expenditure [5, 6]. Leptin has a structure similar to that of the family of helical cytokines, which includes interleukins. Thus, leptin shares with other cytokines quite diverse physiologic functions, such as reproduction, hematopoesis, immunity, and angiogenesis [7, 8]. More recently, several studies have indicated that leptin may be involved in the acute stress response to severe illness and surgery [9, 10]. In this context, it executes its effects through regulation of the hypothalamic-pituitary-adrenal axis, cardiovascular and sympathetic responses, and the immune response [11, 12]. However, the nature of the participation of plasma leptin and its time course in the post-CPB inflammatory response is unclear.
The purpose of the present study was to investigate perioperative changes of plasma leptin levels in patients undergoing open heart surgery with or without the use of CPB. Procedures that do not use CPB, namely, off-pump coronary artery bypass grafting (OPCABG), are likely to prevent these effects as they have been shown to be associated with significant reduction in systemic inflammation and postoperative infection [13–15]. In addition, concomitant changes in cortisol serum levels were also evaluated to detect potential links to changes in serum leptin levels.
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Patients and Methods |
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Study Protocol
Patients were recruited 1 day before surgery, and venous blood was drawn for baseline biochemical serum measurements, as well as plasma cortisol and leptin. All baseline samples were obtained in the morning between 9:00 AM and noon. On the morning of surgery, another blood sample was collected in ethylenediamine tetraacetic acid–containing tubes from the venous line of the patients after the induction of anesthesia. During the operative procedures in group I and group II, the second blood sample was obtained shortly after the CPB induction, and the third blood sample in the reperfusion period 15 minutes after the termination of CPB. In group III patients, these samples were drawn after completing all distal anastomoses and at the end of the operation, respectively. After the operation, all patients were transferred to the intensive care unit, and blood samples were collected from the venous line at 2, 4, 8, 12, 18, 24, 48, and 72 hours postoperatively. Plasma was recovered immediately from all samples, aliquoted, and frozen at –80°C until final use.
Anesthesia and Cardiopulmonary Bypass
After premedication the day before surgery, total intravenous general anesthesia was induced and maintained with sufentanil and propofol in all groups. No anesthetic gases were used. After relaxation with pancuronium bromide, the trachea was intubated, and controlled normocapnic ventilation with an air-oxygen mixture was started. No patients received corticosteroids before, during, or after the operation. Heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 350 s or above. Cardiopulmonary bypass was instituted using ascending aortic cannulation and a two-stage venous cannulation in the right atrium. The CPB circuit consisted of tubings (Medtronics, Minneapolis, Minnesota) without an arterial filter, primed with a crystalloid-colloid mixture and heparin, a membrane oxygenator, and a centrifugal pump (Jostra-HL20; Maquet Cardiopulmonary AG, Hirrlingen, Germany). During aortic cross-clamping, intermittent cold-blood cardioplegia was used for myocardial protection.
Surgical Procedures
The patients were operated on through median sternotomy. All proximal anastomoses were performed by the use of a side-biting clamp. Protamine was administered at the end of the operation to fully reverse the heparin effect. Aprotinin and antifibrinolytics were not used during the study.
Group I
In all ONCABG patients, the number of distal anastomosis was as follows: 1 (4.8%), 2 (27.7%), 3 (54.5%), 4 (13.6%). The left anterior descending artery was anastomsed in 97.8% of all cases. The average time of CBP in this group was 94.5 ± 4.2 minutes; average aortic cross-clamp time was 71.6 ± 2.7 minutes.
Group II
Of 15 procedures done in group II, 10 involved aortic valve (replacement), and 5 mitral valve (3 replacements, 2 reconstructions). Average CPB time was 87.5 ± 4.9 minutes, with an average aortic cross-clamp time of 58.4 ± 3.6 minutes.
Group III
Heparin was given at a dose of 150 IU/kg and activated clotting time was kept above 300 seconds. A modified Octopus system (Medtronics, Minneapolis, MN) was used in all OPCABG cases as cardiac stabilizer. A nontraumatic, small bulldog clamp was applied to the target vessel proximal to the anastomotic site to achieve hemostasis after arteriotomy. Patients in the OPCABG group received either one (43.2%) or two (56.8%) distal anastomoses with revascularization of left anterior descending artery in all cases.
Measurements
As part of the routine clinical observance, selected clinical and biochemical data were recorded at each time point. Cortisol and leptin analyses were performed as follows. Samples were assayed in a single large batch, duplicates agreed within 15%, and quality assessment samples were within the manufacturer’s defined range. Enzyme-linked immunosorbent assay techniques were applied to determine leptin and cortisol levels in plasma (IBL, Hamburg, Germany). The intra-assay and interassay coefficients of variation were 4.1% to 5.4% and 3.6% to 7.8% for leptin, and 4.4% to 4.7% and 4.9% to 6.6% for cortisol, respectively. The plasma leptin and cortisol concentrations of CPB groups at each time-point (t) were corrected for hemodilution according to the formula: hormone level (corrected) = hormone level (measured) x hematocrit (baseline) / hematocrit (t). The mean correction factors were 1.01 ± 0.31 (±SD) for group I, and 1.32 ± 0.54 for group II.
Statistical Analysis
Data are expressed as mean ± SEM, and statistical significance was accepted at p less than 0.05. Statistical analysis was performed using SigmaPlot software version 8.0 (SPSS, Chicago, Illinois). Leptin and cortisol levels were analyzed by the repeated measures two-way analysis of variance with three groups (ONCABG, OPCABG, HVR) and 10 repeated measurements. Repeated measurement post-hoc between groups effects were tested by Tukey test. Within group effects for time were tested by post-hoc Dunnett contrasts of baseline values versus subsequent measurements. Pearson’s correlation analysis was used to determine relationships between leptin, cortisol, and other variables.
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Results |
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Comment |
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A relatively new player in the cascade of the human stress response is the hormone leptin. The recent link between this hormone and the hypothalamic-pituitary-adrenal axis has suggested its possible role as a modulator of the neuroendocrine stress response [17]. Leptin is the hormone produced by transcription of the obese gene, primarily of the human adipocyte. Its circulating level is proportional to a person’s body mass index [6]. Recent evidence supports the role of leptin in more complex physiologic systems such as angiogenesis, hematopoiesis, immunity, and inflammation. Leptin has a structure similar to that of the interleukin-6 family of cytokines [18]. Both Janus kinases and signal transducers and activators of transcription are involved as downstream components of leptin and interleukin-6 signaling, which demonstrates several similarities between leptin and the interleukin-6 family [19]. Thus, circulating leptin levels might be related to the extent of activation of the immune system and might serve as marker of the severity and outcome for patients with sepsis and systemic inflammatory response syndrome. Previous reports have found high plasma leptin concentrations in critically ill patients [20, 21].
In the present study, we evaluated the kinetics of plasma levels of leptin and cortisol in patients undergoing open heart surgery with or without CPB. During the postoperative course of as long as 72 hours, a biphasic kinetic of serum leptin levels could be observed in all patients. During the operation and the hours thereafter, a marked decrease in leptin levels occurred, reaching minimum levels 2 hours postoperatively in all study patients, regardless of whether CBP was used (Fig 1). We hypothesize that this could be partly due to the effects of anesthesia and related medications. Additionally, an effect of preoperative and perioperative starvation could contribute to this acute fall of leptin levels. In clinical studies, it has been shown that during starvation, the serum leptin level decreases, corresponding to the tendency of the organism to conserve energy and minimize metabolism to survive [22]. These results are consistent with reports of leptin levels in patients after surgical stress [23, 24] and in patients suffering from inflammatory bowel disease and acquired immune deficiency syndrome, conditions in which leptin is decreased while cytokine levels are elevated [25, 26]. This fall in leptin expression in response to stress may also serve other physiologic roles. First, because leptin has an inhibitory effect on cortisol secretion, it had been hypothesized that the initial stress-induced decrease in leptin levels may permit the generation of higher cortisol levels [27]. This hypothesis is supported by reports indicating that high levels of leptin inhibit both the response of the hypothalamic-pituitary-adrenal axis to acute stress and the adrenal cell response to adrenocorticotropic hormone [28]. Second, leptin may act in support of the innate inflammatory response and in opposition to the adaptive immune response [17]. Indeed, leptin has been shown to induce the production of interferon gamma and to suppress the production of antibody-inducing interleukin-4 in a dose-dependent manner [29].
In the present study, we also observed a significant inverse relationship between leptin and cortisol levels. During the early hours of the surgery, the decrease in leptin levels paralleled the increase in cortisol levels. Later, as leptin started to increase again and reached its maximum 20 to 24 hours postoperatively, cortisol levels declined gradually. The Pearson correlation between the decrease in leptin levels and the increase in cortisol levels during the early phase of postoperative course was moderate (r = 0.43, p < 0.02). Modan-Moses and colleagues [24] reported on the characteristics of leptin secretion and its relationship to cortisol in the preoperative and postoperative period in children undergoing surgery for repair of congenital heart defects. That study supports the previous work relating leptin to surgical stress by Kain and associates [23]. Both studies showed an initial decrease in serum leptin concentrations from baseline with a concomitant rise in serum cortisol levels during surgery. During the first 24 postoperative hours, leptin was slightly elevated above baseline and then returned to normal. The study by Modan-Moses and associates [24] demonstrated an even more dramatic response to the stress associated with cardiopulmonary bypass: in the group of patients who underwent open heart surgery, leptin fell initially, and then rose to 120% above baseline before returning to normal within 24 hours; cortisol levels rose early then fell by 18 to 24 hours.
There has been increasing evidence that CPB may be responsible for some of the morbidity associated with coronary artery bypass grafting surgery. After the recent development of effective devices for target vessel exposure and stabilization, beating-heart techniques—for example, OPCABG—have gained widespread diffusion as alternative techniques to conventional ONCABG. The avoidance of CPB and myocardial ischemia-reperfusion has been proposed to significantly reduce the postoperative systemic complications that negatively affect the patient’s perioperative course after surgical myocardial revascularization [30, 31].
Our prospective study showed, that the initial drop in leptin levels was followed by an increase in plasma levels of leptin reaching peaks of 218.6% of the baseline in group I (p < 0.01), and 313.7% in group II (p < 0.01) 20 to 24 hours after the operation. However, patients in the OPCABG group showed only a moderate increase in serum leptin levels 24 hours after the operation. Additionally, it is noteworthy that patients operated on in the OPCABG group had at all measurement times considerably lower leptin levels than patients in groups I (ONCABG) and II (HVR), and comparisons between ONCABG and OPCABG groups showed that the between-group differences were quite significant (p < 0.001). Also interesting is that in the OPCABG group, the maximum in cortisol levels (315.7% of the baseline; p < 0.01) occurred at an earlier time postoperatively (4 hours). And although statistically not significant, the increase in cortisol levels in OPCABG patients was less pronounced than in patients operated on with procedures requiring CPB (at 4, 12, and 18 hours). Further, the relationship between leptin and cortisol levels in the OPCABG group was not as pronounced as in the ONCABG group, and there was not a significant reciprocal relationship between cortisol and leptin over time. These data are in contrast to the study published by Velissaris and coworkers [32]. They investigated changes in plasma cortisol and vasopressin levels over a period of 24 hours after ONCABG versus OPCABG procedures and observed a similar pattern of increase in cortisol levels in the sampling period. At the current time, we are not able to explain the discrepancy between our study and the study performed by Velissaris and colleagues [32]. We believe that differences between the patient populations—namely, low risk in their study versus mixture of low and high risk in our study—might be, at least in part, responsible for the observed discrepancies.
We conclude that open heart surgery with or without CPB is associated with acute changes in circulating leptin levels. These changes parallel those in cortisol plasma levels, demonstrating an inverse relationship between these two neurohormonal stress factors in a scenario of acute systemic stress response. Taking this finding into account, patients undergoing off-pump coronary artery revascularization showed significantly less production of leptin and cortisol throughout the study period, and fewer total white blood cells, suggesting that factors other than surgical maneuvers, namely, CPB, may to a certain extent contribute to the systemic stress response with subsequent inflammatory organ dysfunction.
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  Y. J. Gu Invited commentary Ann. Thorac. Surg., December 1, 2006; 82(6): 2186 - 2186. [Full Text] [PDF]
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