Eur J Cardiothorac Surg 2007;31:360-365. doi:10.1016/j.ejcts.2006.11.042
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Pretreatment with aminophylline reduces release of Troponin I and neutrophil activation in the myocardium of patients undergoing cardioplegic arrest
Wan-Jun Luo*,
Jian-Fang Qian,
Hai-He Jiang
Department of Cardiothoracic Surgery, Xiang Ya Hospital, Central South University, Changsha, Hunan, PR China
Received 17 August 2006;
received in revised form 26 November 2006;
accepted 28 November 2006.
* Corresponding author. Address: Department of Cardiothoracic Surgery, Xiang Ya Hospital, Changsha, Hunan 410008, PR China. Tel.: +86 731 4310800; fax: +86 731 4327247. (Email: luowanjun{at}yahoo.com).
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Abstract
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Objective: Cardioplegic arrest and subsequent reperfusion results in myocardial injury partly related to local inflammation in the heart. It has been proven that aminophylline has numerous anti-inflammatory effects. This study has been designed to evaluate the effects of aminophylline used as a cardioprotective agent for patients undergoing cardiopulmonary bypass (CPB) for valve replacement. Methods: Thirty patients undergoing elective valve replacement were randomized to receive either aminophylline (n
= 15), or normal saline (control n
= 15). Administration of aminophylline (5 mg/kg) was injected intravenously after induction of anesthesia. The cardiac Troponin I (cTnI), myocardial myeloperoxidase (MPO) activity, atrial cyclic AMP, and a coronary sinus neutrophil count were measured before and after cardioplegic arrest. Results: There were no differences between the two groups with regard to clinical variables. The cTnI concentration increased significantly after aortic declamping in both groups. However, it was significantly lower, 8 h after aortic declamping, in aminophylline group (1.00 ± 0.41 vs 2.37 ± 1.35 ng/ml p
= 0.038). The atrial cAMP was significantly higher before aortic cross-clamping in aminophylline group (42.5 ± 6.7 pmol/g tissue vs 30.6 ± 12.4 pmol/g tissue p
= 0.04). In addition, we found that the aminophylline group had a significantly lower MPO after reperfusion (1.50 ± 0.58 U/g tissue vs 0.86 ± 0.24 U/g tissue p
= 0.003), and a significantly lower neutrophil count 30 min after aortic declamping (0.68 ± 0.11 x 103 cell/ml vs 0.32 ± 0.16 x 103 cell/ml, p
= 0.023). Conclusions: Pretreatment with intravenous aminophylline reduces the subclinical myocardial injury and neutrophil activation in patients undergoing CPB for valve replacement.
Key Words: Aminophylline • Tropnin I • Neutrophil • Myocardium protection
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1. Introduction
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Cardioplegic arrest during cardiopulmonary bypass is essential for the majority of cardiac surgical procedures including coronary artery bypass grafting, congenital heart defect repair and valve replacement/repair. Unfortunately, cardioplegic arrest and subsequent reperfusion often results in either clinical or subclinical myocardial injury. The pathogenesis of ischemia-reperfusion injury includes the activation of neutrophils, the production of reactive oxygen species, and the release of inflammatory mediators [1].
Aminophylline (or theophylline), a xanthine derivative phosphodiesterase inhibitor, has been traditionally used for the treatment of asthma and chronic obstructive pulmonary disease. It has been demonstrated that aminophylline has numerous anti-inflammatory effects, including the inhibition of inflammatory mediators and activation of nuclear factor kappa B [2–6]. Aminophylline has also been shown to improve the functional recovery of isolated rabbit heart with cardioplegic preservation [7]. Recently, aminophylline has been shown to reduce the release of cardiac Troponin I (cTnI) and improve cardiac function in patients undergoing cardiopulmonary bypass (CPB) for coronary artery bypass grafting [8].
However, the mechanisms of action and effects of aminophylline as a cardioprotective agent used during cardiac operations has not been fully investigated. Based on the above background, we hypothesized that aminophylline may reduce neutrophil activation, limit myocardium ischemia and protect against reperfusion injury of myocardial tissue in patients undergoing cardioplegic arrest. The present prospective, randomized study was designed to evaluate the mechanisms of action and effects of aminophylline as a cardioprotective agent for patients undergoing CPB for cardiac valve replacement.
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2. Patients and methods
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2.1 Patients and operation
Thirty adult patients with rheumatic heart valve disease undergoing elective isolated valve replacement were randomly divided into two groups of 15 each. The patients signed a consent form approved by our hospital research committee before operation. The patients were randomized by randomized number table before anesthesia. Only the anesthesiologist and one operating room nurse were aware of the treatment groups. The hospital staffs caring for postoperative patients were blinded to grouping. Exclusion criteria for this study included: infective valve disease, valve disease with coronary artery disease, previous valve repair, and severe left ventricular enlargement (LVDED > 70 mm). None of the patients received aspirin, corticosteroids, ACE inhibitors, or statins preoperatively. In addition, none of the patients had received preoperative inotropic support.
During the surgical procedure, anesthesia was induced with midazolam and vecuronium bromide intravenously, followed by the use of intravenous fentanyl (15 µg/kg/h) and intermittent inhalation of isoflurane to maintain anesthesia. The operations were performed using standard hypothermic cardiopulmonary bypass (28–31 °C) with bicaval cannulation and left vent via right superior pulmonary vein. The myocardium was protected using intermittent perfusion of cold blood cardioplegia. The cardioplegia solution was mixed through the deliver system of the heart-lung machine with autologous blood obtained from the extracorporeal circuit in a ratio of 1:4 (crystalloid cardioplegia:autologous blood) while the patient is on bypass prior to its application. The cold blood cardioplegia at 4 °C (components: NaCl, 132 mmol/l; KCl, 16 mmol/l; CaCl2, 1.8 mmol/l; MgSO4, 15 mmol/l; Procaine, 0.05 mmol/l; NaHCO3, 19 mmol/l) was infused into the aortic root if the aortic valve was competent; otherwise, it was infused directly into the orifices of the coronary arteries. The initial dose was 20 ml/kg body weight at a flow rate of 200–250 ml/min. Thereafter, the cardioplegia was reinfused every 20 min, at a dose of 10 ml/kg, after initial infusion. The operative technique has been described previously [3].
The aminophylline group (n
= 15) received a bolus of aminophylline (5 mg/kg) intravenously immediately after induction of anesthesia and insertion of radial arterial and central venous catheters, but before skin incision was made at over 5 min period without further drug provided afterward. The dose of aminophylline used in the present study was based on the routine dose for the treatment of asthma (5–6 mg/kg IV) and the results of our pilot study.
In the control group (n
= 15), the patients received a bolus of normal saline (5 mg/kg) instead of aminophylline. The hemodynamic data including heart rate, cardiac rhythm, blood pressure (radial artery) and airway pressure were monitored continuously by the anesthesiologist during the administration of aminophylline or saline. The postoperative staff also monitored the patients for the known side effects of aminophylline, such as nausea, tremors, and seizures. The medical charts were reviewed, and the caregivers were interviewed daily for the occurrence of adverse events related to aminophylline.
2.2 Measurements of plasma cTnI
Blood samples were collected from the peripheral arterial lines immediately after anesthesia induction, and at 30 min, 8 h, and 24 h after aortic declamping. The samples were centrifuged. The plasma was transferred to a sterile polypropylene tube and stored at –20 °C until assayed. The cTnI were measured by means of commercially available enzyme-linked immunosorbent assays according to the supplier's recommendations. (Qiang Xing Biotechnology Company, Shanghai, China). The data was expressed as ng/ml. (The normal value in our hospital is <0.15 ng/ml).
2.3 Tissue cAMP contents
A myocardial tissue sample weighing approximately 150 mg, was taken from the right atrial appendage immediately after direct SVC cannulation, just before start of CPB. A purse-string suture was placed on the right atrial appendage after sampling. Thirty minutes after aortic declamping, another tissue sample was taken from the same area but below the purse-string suture placed after the first sampling. The same tissue samples were divided equally into two parts and frozen in liquid nitrogen and stored at –80 °C for determination of cAMP and myeloperoxidase (MPO).
For cAMP measurement, each sample was homogenized at 4 °C in ice-cold 6% trichloroacetic acid (ratio: 2 ml/50 mg tissue) before they were centrifuged at 3500 rpm for 15 min. The supernatant was removed, placed in a test tube, and extracted two times with water-saturated ethyl ether. The extracted supernatant was further evaporated and dried at 60 °C, and the cAMP content was determined in duplicate with a commercial radioimmunoassay kit (Sigma) [9]. Results are expressed as picomoles of cAMP per gram of wet tissue.
2.4 Tissue myeloperoxidase activity
MPO activity in myocardial tissue samples was measured as an index of neutrophil accumulation. The method and time of tissue sampling were described above. The frozen myocardial tissue samples were weighed, thawed at room temperature, and then homogenized in an ice-cold potassium phosphate buffer (pH 6). The homogenate was then centrifuged at 13,000 x
g for 20 min at 4 °C. To measure supernatant MPO activity, the supernatants were reacted with o-dianisidine dihydrochloride and 0.01% hydrogen peroxide in a 50 mM phosphate buffer (pH 6). The activity of MPO was measured spectrophotometriccally at 460 nM, and expressed as U/g tissue [10]. One unit of myeloperoxidase activity was defined as the quantity of enzyme reducing 1 µmol hydrogen peroxide per minute at 37 °C.
2.5 Transcardiac neutrophil count
Blood samples were drawn from the aorta (radial artery) and coronary sinus, to obtain the neutrophil count before cardioplegic arrest, and 30 min after aortic declamping. The white blood cell count was determined using Abbott CELL-DYN-3700. The correction of value was made for hemodilution. The difference of blood neutrophil count in the aorta and the coronary sinus was calculated (aorta-coronary sinus).
2.6 Hemodynamic measurement
Mean arterial pressure, heart rate, central venous pressure, pulmonary artery pressure and average dose of inotropes used for first 24 h postoperatively were routinely recorded during the experiment.
2.7 Statistical analysis
The sample size was calculated based on previously reported data [8] and our own pilot study on cTnI measurement. With an expected difference of 0.9 (ng/ml) between group means, 0.8 (ng/ml) SD of the means, 
= 0.05, ß
= 0.8, a sample size of 14 patients per group was necessary. If not otherwise indicated, values were expressed as a mean ± SD with range. Statistical analysis was performed with the SPSS10.0 software (SPSS Inc., Chicago, IL).
If the data is not normal distribution, a logarithmic transformation was applied to data to ensure a normal distribution before statistical analysis. The differences were assessed by unpaired Student's t-test for parametric data, Mann–Whitney test for nonparametric data. Two-factor repeated-measures analysis of variance (ANOVA) was used to evaluate differences over time between groups for plasma cTnI and hemodynamic parameters and post-hoc tests were used to compare these parameters at each time point between groups. Categorical data were analyzed using the two-tailed Fisher exact test or chi-square test as appropriate. A p-value less than 0.05 was considered significant.
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3. Results
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3.1 Clinical outcomes
There were no hospital mortalities or major complications in either group. The preoperative clinical data is shown in Table 1
. No significant differences were noted with regard to age, gender, NYHA class, ejection fraction, or liver function in either group. The operative and postoperative data are shown in Table 2
. Patients from the two study groups were similar with regard to the type of procedure, bypass time, aortic claming time, duration on ventilator, and length of stay in the intensive care unit. Repeated measures ANOVA revealed that there were no significant differences within groups or between groups for heart rate, mean arterial pressure, and central venous pressure (Table 3
). In addition, we did not observe any side effects related to aminophylline such as tachycardia, arrhythmia, and hypotension, in patients receiving aminophylline.
3.2 The levels of plasma cTnI
The levels of serum cTnI, collected at several sampling times in both groups of patients, are presented in Fig. 1
. The preoperative plasma levels of cTnI were similar in both groups. Repeated measures of ANOVA revealed significant increase at 30 min, 8 h and 24 h after aortic declamping in both group (time effect, p
= 0.017). However, the levels of plasma cTnI were significantly lower in aminophylline group than in control group (group effect, p
= 0.048; group–time interaction, p
= 0.000). The significant differences between the study groups were found at 8 h intervals after aortic declamping (p
= 0.038).
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Fig. 1. cTnI levels before cardiopulmonary bypass (CPB) and various time points after aortic declamping. Dotted line: control group; solid line: aminophylline group. Group p value: 0.048; time p-value: 0.017; time–group interaction p-value: 0.000. *
p
= 0.038. versus control.
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3.3 cAMP content of myocardium
The cAMP content in the right atrium was significantly higher in aminophylline group than that in control group before aortic cross-clamping (p
= 0.04). At the 30 min interval after aortic de-clamping, the cAMP content of the atrium was still significantly higher in patients with aminophylline, compared with control group (p
= 0.003, see Fig. 2
).
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Fig. 2. Effect of aminophylline on myocardial cyclic AMP content. A significant increase in cAMP content before ischemia and after reperfusion in aminophylline group compared with control group. (*
p
= 0.04, **
p
= 0.003, respectively).
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3.4 Tissue myeloperoxidase activity
Myocardial MPO activity in the two groups is shown in Fig. 3
. There was no significant difference between two groups before aortic cross-clamping (p
= 0.21). The myocardial MPO activity was increased significantly 30 min after aortic de-clamping in both groups. However, the MPO activity in the aminophylline group was significantly lower than that in the control group (p
= 0.004); suggesting that aminophylline reduces neutrophil sequestration in the myocardial tissue.
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Fig. 3. Effect of aminophylline on myocardial myeloperoxidase (MPO) activity after reperfusion. A significant increase after reperfusion in the MPO activity in control group compared with aminophylline group. *
p
= 0.004.
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3.5 Transcardiac neutrophil count
The blood neutrophil count difference (aorta-coronary sinus) was similar before aortic clamping in both groups (p
= 0.2). The neutrophil count difference was significantly lower in the aminophylline group than that in the control group, 30 min after aortic declamping (p
= 0.023). This demonstrates the effect of aminophylline to decrease neutrophil sequestration in the myocardium, during the period of reperfusion (Fig. 4
).
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Fig. 4. Effect of aminophylline on neutrophil sequestration in the heart 30 min after reperfusion. There is significant less neutrophil sequestration after reperfusion in aminophylline group compared with control group. *
p
= 0.023. (Neutrophil unit: 103
cell/ml).
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4. Discussion
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Although the cardiac protection is improved currently, myocardial ischemia and reperfusion injury resulting from cardioplegic arrest remains an important consideration in cardiac surgery. Reperfusion injury is clinically manifested by low cardiac output, hypotension, and the need for inotropic or even intra-aortic balloon pump support. Although myocardium damage is relatively mild or reversible in the majority of patients, subclinical injury still exists and is manifested by the elevation of markers for myocardial injury [11]. In this study, we used cTnI, known as a sensitive and specific marker for myocardial ischemia, to detect perioperative myocardial injury. Our data shows that cTnI was significantly elevated after aortic-declamping in both groups, suggesting myocardial damage occurred during the operation. This finding was consistent with previous studies from other authors [11,12].
In the present study, we evaluated the use of aminophylline as a cardioprotective agent by using cTnI for the detection of myocardial ischemia. Although there were no significant differences with regard to clinical outcomes related to myocardial protection such as hemodynamic variables, inotropic support, cTnI was significantly reduced in the aminophylline pretreatment group. A similar clinical result has been reported by Kaplan et al. [8], who found reduced postoperative cTnI and cTnT in patients treated with aminophylline for 3 days before coronary artery bypass grafting operation. Another study, using an isolated rabbit heart model [7], demonstrated that cardioplegia containing aminophylline can improve cardiac function, reduce lactate release and increase coronary blood flow. The results from our current study further provides clinical evidence of the cardioprotective effects of aminophylline.
Open-heart surgery induces an inflammatory response in the myocardial tissue in patients undergoing CPB [13]. The neutrophil infiltration of myocardial tissue is an important cause of myocardial damage in the setting of ischemia/reperfusion [14]. The activation of neutrophils initiates a cascade of cell–cell interactions leading to the adhesion of neutrophils to vascular endothelium. This in turn leads to coronary capillary plugging, and thus a reduction in coronary blood flow. Moreover, activated neutrophils promote the formation of oxygen radicals, which are capable of damaging myocardial membranes [15]. Many experimental and clinical studies have demonstrated that aminophylline (or theophylline) has anti-inflammatory and immunomodulation effects. These studies have shown that aminophylline has anti-oxidant properties, can decrease neutrophil chemotaxis and activation, and can accelerate human granulocyte apoptosis [3,5,6,16,17]. Kazuhiro et al. [18] reported that theophylline reduces the expression of transcription factor nuclear factor kappa B, which regulates inflammatory mediators. A previous study had reported that NF
B was activated during reperfusion [1]. However, the anti-inflammatory effect of aminophylline on human myocardium undergoing cardioplegic arrest in the setting of cardiac operation has not been studied.
The significant finding in our present study is that the myocardial MPO activity was significantly increased after reperfusion in both groups of patients. We used MPO activity as an indicator of the presence of neutrophil sequestration and activation [10]. In our present study, we found that MPO activity was much lower 30 min after reperfusion in aminophylline pretreatment group, suggesting that aminophylline suppresses neutrophil activation in the myocardium during reperfusion. Another similar finding, was the decrease in the transcardiac neutrophil count in the aminophylline group after reperfusion. This study provides the clinical evidence of the use of aminophylline as an anti-inflammatory agent on the human heart. However, the role of aminophylline related to its inhibition of neutrophils activation in the cardiac surgery needs further studies.
Up to now, the mechanisms of aminophylline on myocardium protection are not elucidated especially in human heart undergoing cardioplegic arrest because of multiple pharmacological aspects of aminophylline. It is well known that the primary pharmacological effects of aminophylline is to increase intracellular cyclic adenosine monophosphate concentration by nonselectively inhibiting cyclic nucleotide phosphodiesterase activity [2]. cAMP is an important second messenger in the modulation of cellular physiological functions including the inflammatory process [19,20]. The cAMP has been shown to decrease the permeability of human endothelial cell monolayers [15]. In our present study, the cAMP content in the right atrium before and after myocardium ischemia was much higher in patients following pretreatment with aminophylline. This suggests that intravenous administration of aminophylline before cardiac arrest induced by cardioplegia can increase the myocardial cAMP level. Even though we did not specifically measure the tissue activity of cyclic nucleotide phosphodiesterase, it could be speculated that elevated tissue cAMP level may be related to the inhibition of phosphodiesterase by aminophylline. In addition, the mechanism of action of aminophylline may include the release of endogenous catecholamine and acting on membranes of the sarcoplasmic reticulum [2]. However, our results indicate that the cardioprotective effect of aminophylline can be explained through its action on cAMP levels. For the ethics consideration in present study, we did not measure the cAMP levels in the ventricles. However our findings were consistent with results from Janelle and his colleagues who reported that administration of a single dose of milrinone before aortic cross-clamping resulted in a significantly larger cAMP content in the left ventricle at the end of CPB [21].
There are several limitations of our present study. Firstly, the small sample size of patients in our study is not clinically sufficient to evaluate the effects of aminophylline on the reduction of perioperative myocardial ischemia and reperfusion injury. A final determination of effect would need a larger sample size and involve a multicenter study. Secondly, patients in both groups received inotropic support postoperatively in our study. This may have confounded our measurement of myocardial cAMP levels because the many of the inotropes such as dopamine, milrinone and isoproterenol stimulate cAMP production, thereby altering the cAMP levels. However, the similar doses of inotropes used postoperatively in both groups of patients minimized this bias. Thirdly, preoperative atrial fibrillation (AF) may have influenced some of the results of our study, such as atrial MPO activity, because preoperative AF may be in part due to the consequence of local and systemic inflammation. In our present study, the majority of patients in both groups had preoperative AF, therefore it is difficult to demonstrate the effect of preoperative AF on our results. Finally, the goal of our study was to explore whether the effectiveness of aminophylline in reducing local inflammation in the myocardium caused by cardioplegic arrest. Therefore, we did not examine the optimal timing and dose of aminophylline in our present study. The optimal aminophylline concentration and dose of treatment remains to be determined.
In conclusion, our present study suggests that intraoperative administration of aminophylline reduces the release of cTnI and the activation of neutrophils in the myocardial tissue in patients undergoing cardioplegic arrest for cardiac valve replacement.
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Acknowledgments
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Special thanks to Dr Mark Davis for editing this manuscript.
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Abstract
1. Introduction
