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Eur J Cardiothorac Surg 2006;30:285-293
© 2006 Elsevier Science NL
a Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Hospital of Essen, Hufelandstraße 55, 45122 Essen, Germany
b Institute for Medical Informatics, Biometry, and Epidemiology, University Hospital of Essen, Essen, Germany
Received 4 October 2005; received in revised form 8 April 2006; accepted 20 April 2006.
* Corresponding author. Tel.: +49 201 723 4928; fax: +49 201 723 5451. (Email: matthias.thielmann{at}uni-essen.de).
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Abstract |
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 Top Abstract 1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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6 h between reperfusion and symptom onset compared to group 2 at 36 h (47.9 ± 11.1 ng/ml vs 97.7 ± 17.2 ng/ml; mean ± SEM), and 48 h (33.5 ± 5.8 ng/ml vs 86.5 ± 19.2 ng/ml) after surgery, but remained unchanged between groups among patients with a treatment delay of more than 6–24 h. In-hospital adverse events and postoperative complications, ICU and hospital stay, as well as in-hospital mortality (14.3% vs 13.8%; P
= NS) were not different between groups 1 and 2. Conclusions: C1-INH administration in emergency CABG with acute STEMI is safe and effective to inhibit complement activation and may reduce myocardial ischemia–reperfusion injury as measured by cTnI.
Key Words: Coronary artery bypass grafting • ST-elevation myocardial infarction • Reperfusion injury • C1-esterase inhibitor
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1. Introduction |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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The concept that inflammatory response is an additional and aggravating mediator of myocardial cell injury following I/R has been addressed in numerous studies aiming to reduce the infarct size of the myocardium. In this context, activated complement system with cell-damaging and chemotactic properties has been demonstrated as an important mechanism of I/R injury [3]. The inhibition of the ‘classical’ complement pathway with C1-esterase inhibitor (C1-INH), a serine proteinase inhibitor, has recently been shown to have beneficial effects in myocardial I/R injury and on infarct size in a variety of experimental models [4,5] and clinical settings [6], in which such therapy was also accompanied by diminished neutrophil infiltration. The underlying mechanism has been explained primarily as a result of the inhibition of both the complement and contact systems.
Large-scale clinical trials, however, have shown that reperfusion therapy with anti-C5 complement antibodies in patients undergoing elective CABG [7], as well as in patients undergoing acute thrombolysis [8] or PCI [9] while suffering from ST-elevation myocardial infarction (STEMI) had no significant effects on infarct size, but significantly reduced markers of inflammation [10], suggesting some treatment benefits mediated through anti-inflammatory effects. In cardiac surgery, however, there seems to be some evidence that adjunctive inhibition of the complement system may attenuate myocardial cell injury [11] and restore myocardial function in patients with AMI and failed PCI undergoing rescue CABG [12].
The present study, therefore, sought to analyze the effects of adjunctive C1-INH treatment during reperfusion on complement activation, perioperative myocardial cell injury, and clinical outcome in patients undergoing emergency CABG due to acute STEMI.
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2. Patients and methods |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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0.2 mV in at least two contiguous precordial leads and/or 0.1 mV in at least two limb leads plus (3) elevated levels of serum cardiac troponin I (cTnI). Time delay between the onset of symptoms or ischemic event and reperfusion (aortic unclamping), as well as other perioperative patient data, was prospectively recorded. Patients were excluded from the study if any of the following criteria were present: (1) recent (<4 weeks) AMI, (2) new onset of left bundle branch block, (3) concomitant mechanical AMI complications, (4) reoperations, (5) concomitant heart surgery procedures besides CABG, (6) known or suspected hereditary complement deficiency, (7) known or suspected autoimmune disease such as systemic lupus erythematosus, or (8) evidence of serious infection. In case of any suspicious coagulation disorder, patients were excluded and C1-INH therapy was discontinued. Informed consent was obtained from all patients and the study protocol was approved by the review board of the institution.
2.2 Study design and protocol
The study was designed as a prospective, randomized, open-label, single-center study at the West-German Heart Center Essen. Patients were randomly assigned before surgery to receive either an intravenous bolus of C1-INH (Berinert®P, ZLB Behring, Marburg, Germany; 40 IU kg–1) starting 5 min before reperfusion (at aortic unclamping) followed by an intravenous infusion of C1-INH (20 IU kg–1) 6 h after surgery (group 1, CABG + STEMI + C1-INH) or receiving a placebo (NaCl) bolus followed by placebo infusion (group 2, CABG + STEMI). The effectiveness of C1-INH treatment was assessed by the measurement of functional C1-INH activity and complement activation measuring C3c and C4 complement fragments in the serum in a subset of the first 12 patients in group 1 and the first 17 patients in group 2. Another set of 10 elective consecutive CABG patients without STEMI and without C1-INH treatment were used as controls (group 3, CABG-STEMI).
2.3 Perioperative management
Standard anesthetic and monitoring techniques were used in all patients. Intraaortic balloon pump (IABP) was implanted preoperatively, if ventricular function was impaired and systemic hemodynamics appeared to be inadequate. Emergency CABG was performed in a standardized way aimed at the complete revascularization using internal thoracic artery, and saphenous vein grafts as the preferred graft conduits. Heparin was administered in order to achieve an activated coagulation time above 400 s. Standard cardiopulmonary bypass (CPB) technique was used with ascending aortic and two-stage venous cannulation, moderate hemodilution, and mild hypothermia (>32 °C). Myocardial protection was achieved using antegrade and optional retrograde crystalloid cardioplegic arrest (Custodiol®, Köhler-Chemie, Alsbach-Hähnlein, Germany), additional topical cooling, and single aortic cross clamping for all distal anastomoses. Cardioplegia was additionally administered through the distal grafts until aortic unclamping. Reperfusion was applied using a modified protocol with aortic systolic blood pressure <50 mmHg during aortic unclamping and for the first 3 min of reperfusion. Proximal graft anastomoses to the aorta were performed with partial occlusion of the ascending aorta. Mean graft flow was assessed after CPB before sternal closure by Doppler transit time flowmetry (Cardiomed®, MediStim, Oslo, Norway) for each graft. Necessity for IABP support was evaluated intra- and/or postoperatively according to the coronary status and level of inotropic support. Postoperative ICU management was standardized. Patients were monitored with respect to arterial pressure, pulmonary pressure, and central venous pressure. A 12-lead ECG was obtained on admission, preoperatively, immediately after the arrival on ICU, and once a day thereafter. A medication of 500 mg acetylsalicylic acid (ASA) was administered intravenously within the first 6 h after surgery in the absence of significant bleeding followed by a daily dose of 100 mg ASA.
2.4 Clinical study endpoints
The primary endpoint of the study was myocardial infarct size or rather the extent of irreversible myocardial cell injury, as measured by the perioperative serum release of cardiac troponin I, which is known to be strongly associated with the size of myocardial infarction [13]. Secondary endpoints were in-hospital mortality, defined as death from any cause within 30 days after surgery or during the same time period of hospitalization, as well as postoperative major adverse cardiac events (MACE) during the period of hospitalization. Other postoperative complications like stroke, major bleeding, necessity for re-thoracotomy, or postoperative renal failure requiring temporary hemodialysis were also studied.
2.5 Cardiac biomarker analysis
CTnI serum levels were determined from venous blood samples obtained preoperatively and at 1, 6, 12, 24, 36, and 48 h after aortic unclamping according to previous studies [14]. A two-site immunoassay specific for cTnI was used (Dimension-Flex®, Dade Behring, Newark, DE, USA) with a detection range of 0.1–50 ng/ml, requiring further dilutions if necessary. The reference interval for serum cTnI was set at 0.00–0.05 ng/ml.
2.6 C1-INH activity
C1-INH activity (%) was determined from venous blood samples obtained preoperatively and at 1, 2, 4, 8, 16, 24, and 48 h after aortic unclamping. The functional activity of the C1-INH was measured using a functional assay (Berichrom C1-inactivator assay®, Dade Behring). Results were expressed as C1-INH activity (%) of the standard. The reference interval for serum C1-INH was >80%.
2.7 Complement activation
Complement activation was determined from venous blood samples obtained preoperatively and at 1, 2, 4, 8, 16, 24, and 48 h after aortic unclamping. Complement fragments C3c and C4 were measured in the serum using a nephelometric immunoassay method for serum C3 and C4 fragments. The assays reference intervals were 0.9–1.8 g/l for C3c and 0.1–0.4 g/l for C4 in the serum [15].
2.8 Biochemical safety monitoring
Additional biochemical parameters were routinely measured perioperatively monitoring red and white blood cell count, platelet count, potassium, sodium, magnesium, chloride, activated partial thromboplastin time (APTT), activated clotting time (ACT), prothrombin time (PT), fibrinogen, D-dimer, antithrombin III (ATIII), coagulation factor XIII, bilirubin, 
-glutamyl transferase (GT), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), c-reactive protein (CRP), and procalcitonin (PCT).
2.9 Statistical analysis
Data are reported as mean values ± standard error of the mean (SEM) and categorical variables by their number and summarized as percentage. Comparisons of categorical variables between groups were performed by Pearson's chi-square test, since expected frequencies <5 occurred; all P-values were calculated exactly. Comparisons of continuous variables between groups were analyzed by unpaired Student's t-test. Perioperative time courses of C1-INH activity, C3c, C4, and cTnI serum levels were analyzed by repeated measures ANOVA, in which the correlation between timepoints was taken into account. Post hoc comparisons were performed by Tukey's honest significance difference test (Tukey–Kramer test). This test was used to control the Type I error for the multiple comparisons between the two groups. In addition, the area under the curve (AUC) of perioperative cTnI release was determined for groups 1 and 2. A P-value less than 0.05 was considered to indicate statistical significance. All statistical analyses between groups were performed using SPSS software (Version 12.0, SPSS Inc., Chicago, IL, USA).
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3. Results |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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3.1 Baseline characteristics
All demographic and preoperative baseline characteristics of the groups are summarized in Table 1
. There were no significant differences between the groups for any of the preoperative variables, and both groups were similar with regard to the distribution of the infarct-related coronary artery vessels (Table 2
).
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3.4 C1-INH activity
There was no preoperative difference with regard to C1-INH activity between the three subset groups. C1-INH activity progressively decreased in groups 2 (CABG + STEMI) and 3 (CABG-STEMI) at 1 h and remained below the lower reference limit (<80% activity) 16 h after aortic unclamping, and returned to baseline values at 48 h after aortic unclamping, whereas in group 1 (CABG + STEMI + C1-INH) C1-INH activity remained unchanged throughout the protocol (Fig. 1a).
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3.6 Serological estimation of myocardial infarct size
Peak maximum cTnI serum levels of all STEMI patients were not significantly different between patients with or without C1-INH treatment. STEMI patients treated with C1-INH within 6 h after symptom onset had significantly lower peak maximum cTnI levels as compared to those without C1-INH treatment. Peak maximum cTnI serum levels were not significantly different between the groups in STEMI patients who were treated with a time delay of more than 6 h after symptom onset (Fig. 2
).
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6 h and 10 patients within groups 1 and 2 with a treatment delay of >6–24 h after symptom onset or ischemic event.
Again, preoperative cTnI serum levels were significantly higher in groups 1 and 2 compared with control group 3. However, there were no significant differences for preoperative cTnI levels between groups 1 and 2. CTnI serum levels in group 1 patients treated within 6 h after onset of symptoms were significantly lower at 36 and 48 h compared with the respective cTnI levels of group 2 patients treated within 6 h after onset of symptoms (Fig. 3b). Furthermore, peak maximum cTnI levels were at 24 h after aortic unclamping in group 1 and at 36 h in group 2. In patients treated within >6–24 h after onset of symptoms, there were no significant differences between the two groups throughout the observation time (Fig. 3c). The area under cTnI serum level curves confirmed these findings. There was no difference in the serological estimation of myocardial infarct size, as compared by the AUC between groups 1 and 2 (P
= 0.34), but AUC was significantly lower in group 1 patients with a treatment delay of 6 h as compared with the respective group 2 patients (P
< 0.05).
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In group 2, two patients died with multi-organ failure and low-cardiac output syndrome after emergency CABG due to multi-vessel disease and severely impaired LV function, treated 14 and 8 h after symptom onset. Another two patients died in the early postoperative period with preoperative existing LCOS caused by acute stent graft thrombosis and unsuccessful multiple PCI procedure. One of them died because of excessive bleeding after postoperative BIVAD implantation due to postoperative LCOS. A fifth patient died in the early postoperative period from therapy refractory ventricular fibrillation.
There was no significant difference between the groups according to the incidence of postoperative sustained ventricular arrhythmia and postoperative LCOS. Other postoperative complications and adverse events like major bleeding occurred in three patients in each group, with a necessity for re-exploration in two patients each, and almost the same proportion of patients with postoperative temporary hemodialysis-dependent renal failure (Table 4).
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4. Discussion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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As shown in the present study, an adjunctive C1-INH treatment administered as a bolus (40 IU kg–1) during reperfusion and at 6 h after surgery (20 IU kg–1) did only attenuate myocardial I/R injury in those patients who had been operated within the first 6 h after symptom onset. In patients in whom surgical revascularization was performed later than 6 h after onset of symptoms, adjunctive C1-INH administration did not show any longer statistically measurable effects in terms of myocardial injury. The significant reduction of postoperative cTnI release in the subgroup of patients treated early (6 h) may indeed be attributed to adjunctive C1-INH treatment, since all baseline characteristics of the two study groups were comparable and no statistical significant difference concerning preoperative extent of myocardial ischemia or intraoperative surgical management was present.
The time-dependency of the effectiveness of complement inhibition confirms several previous studies, where complement activation was shown to be initiated either within 2–4 h after coronary occlusion in animals [19], or <12 h after AMI in human autopsies [20]. A reduction of myocardial infarct size by blocking the complement system using cobra venom was measurable within a time delay of <6 h [19], suggesting that the complement system is involved early after myocardial infarction; therefore, setting the window of therapeutic opportunity during which inhibition of complement activation can still reduce infarct size.
The underlying pathophysiologic mechanisms of myocardial I/R injury have not been fully elucidated so far. However, several mechanisms and mediators have been described including the excessive generation of oxygen-derived free radicals, changes in intracellular calcium homeostasis with intracellular calcium overload, and altered myocardial metabolism [2]. However, oxygen-derived free radicals and hypercontracture due to calcium overload are by far not the only factors inducing myocardial I/R injury. Other important factors have been described previously, including coronary endothelial and microvascular dysfunction leading to coronary vasoconstriction and reduced blood flow accompanied by activation of the contact and the complement system. The activated contact and complement system itself are leading to a subsequent local inflammatory response of the ischemic myocardium with activation and accumulation of platelets and neutrophils causing microvascular obstruction/damage and finally myocardial hemorrhage and necrosis within hours after reperfusion. The reperfusion-induced activation of the complement system generates anaphylatoxins, as well as the terminal complement complex and the membrane attack complex. The complement factors are in turn potent stimulators of neutrophil adherence and superoxide production and moreover, are directly inducing myocardial cell injury by increased cell permeability and release of histamine and platelet activating factor [21].
The complement inhibition by C1-INH application, which is an established treatment for angioedema in hereditary C1-INH deficiency, has recently been demonstrated to have beneficial anti-inflammatory and cardioprotective effects in several experimental [4,5] and clinical settings [6] following myocardial I/R injury. In vivo administration of C1-INH in a feline model significantly attenuated myocardial necrosis, preserved endothelial function, and sustained normal cardiac performance after myocardial I/R. These effects were mainly attributed to a diminished neutrophil adherence to the endothelium and a reduced myocardial neutrophil accumulation within the ischemic myocardium [4]. Some previous clinical studies have shown beneficial effects after the use of anti-C5 antibodies in patients undergoing CABG [11,22], and therefore confirmed experimental findings that complement inhibition may reduce early myocardial I/R injury [5]. Other large-scale clinical trials in patients with acute STEMI undergoing acute thrombolysis [8] or PCI [9] did not find evidence for any beneficial effects on myocardial infarct size after the use of adjunctive complement inhibition with C5a-antibodies (Pexelizumab). However, significantly reduced markers of inflammation were found [10], suggesting some benefits mediated through anti-inflammatory effects. On the contrary, in a recent clinical study, adjunctive continuous administration of C1-INH during acute thrombolysis after AMI has shown to provide a safe and effective inhibition of the complement system leading to a significant reduction in myocardial cell injury, as measured by creatine-kinase MB and cardiac troponin T [6]. Furthermore, complement inhibition using C1-INH in patients with AMI and failed PCI undergoing emergency CABG has also shown some beneficial effects in order to restore myocardial function [12]. More recent clinical trials using again Pexelizumab in patients before isolated CABG with cardiopulmonary bypass, which is known to induce strongly systemic inflammatory response, significantly reduced the incidence of postoperative myocardial infarction, non-Q-wave MI in particular [22], and reduced myocardial enzyme release compared to placebo [11].
As demonstrated in the present study, constant C1-INH activity could be maintained after CABG by bolus and additional intravenous C1-INH infusion in group 1, whereas C1-INH activity progressively decreased up to 8 h after CABG in groups 2 and 3, indicating a postoperative C1-INH consumption. Preoperative C3c and C4 complement fragment concentrations were significantly higher in STEMI groups 1 and 2 as compared with that of group 3, confirming several recent studies [4–6]. The postoperative decline of C3c and C4 serum levels in all three groups, however, is possibly caused by complement fragment consumption after CABG with CPB, slowly recovering towards 48 h after surgery.
4.1 Selection of C1-INH dose rate
In terms of C1-INH dose selection, the C1-INH doses administered in the present study were chosen in accordance to the doses of a recent report in an experimental setting of myocardial I/R injury, where cardioprotective effects were found with intravenous doses of 40 IU kg–1 without detrimental or severe side effects [23]. It was further reported that C1-INH doses of 200 IU kg–1 can provoke procoagulatory effects without having any cardioprotective effects. These procoagulatory phenomenon has been observed and reported as possibly related to C1-INH therapy in the case of nine deaths due to thromboembolic events in 13 neonates who had received repeated intravenous doses of 300–500 IU kg–1 C1-INH following complex congenital cardiac surgery [24]. However, these high doses of C1-INH have been clinically used in patients with hereditary angioedema since three decades without any complication. Another research group could successfully demonstrate beneficial effects following the administration of 100 IU kg–1 C1-INH after complex congenital cardiac surgery without observing any unwanted side effects [25]. In the present study, constant plasma levels of C1-INH could be held by bolus and additional intravenous C1-INH infusion 6 h after surgery, and no drug-related adverse events and no procoagulatory effects were observed.
4.2 Limitations of the study
Several factors influencing the extent of myocardial infarct size following I/R injury were not completely addressed. A quantitative infarct size measurement at baseline (e.g., late-enhancement MRI) for an adequate group comparison was lacking, but baseline cTnI serum levels were used instead. Data concerning the severity of myocardial blood flow reduction (energy supply) and on heart rate and regional wall function (energy demand) are also missing. Furthermore, the present study was underpowered to detect a significant difference in the incidence of the secondary study endpoints of MACE and in-hospital mortality.
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5. Conclusion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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Constant plasma levels of C1-INH could be held by a bolus administration of 40 IU kg–1 followed by an additional intravenous C1-INH infusion of 20 IU kg–1 6 h after surgery. C1-INH treatment did not cause any unwanted side effects and allowed effective inhibition of complement activation. Myocardial infarction size as the primary endpoint of the study, as measured by the serum release of cTnI, was not significantly different between the two groups. A significant reduction of perioperative myocardial cell injury was, however, observed in a subgroup of patients with a treatment delay 6 h after symptom onset, thus confirming several recent experimental and clinical studies.
Therefore, early C1-INH administration in patients with AMI, or STEMI in particular, may constitute a novel approach in this high-risk subgroup of CABG patients.
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Appendix A |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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Dr H.-J. Schaefers (Homburg/Saar, Germany): We know from the use of C1 inhibitor in pediatric surgery that it can have a marked influence on vasopressor support. Did you see a similar difference, a similar effect? And question number two, what would be the therapeutic cost of C1 inhibitor treatment in an adult coronary patient?
Dr Thielmann: The short answer to question number one is that we don’t see the necessity of inotropic support during C1-INH administration, and answer number two, that is the main point, C1-INH treatment is quite expensive. I can’t give you an exact number, but it is expensive.
Dr Schaefers: I would estimate that the cost at 40 U kg should be a middle class car. Is that comparable or exaggerated?
Dr Thielmann: As I remember, one unit of C1-INH is about 1 euro, so I would rather estimate a ‘second-hand’ middle class car.
Dr J. Bachet (Paris, France): It is strange to me that death was a secondary endpoint. It is generally considered as a major event. I suppose that in this subset of patients the mortality is mainly due to myocardial infarction. So why did you decide not to include death as a primary endpoint?
Dr Thielmann: Because it is a very small number of patients and the incidence of mortality won’t be significant in such a small number.
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Acknowledgments |
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Footnotes |
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Presented at the joint 19th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 13th Annual Meeting of the European Society of Thoracic Surgeons, Barcelona, Spain, September 25–28, 2005. |
References |
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TopAbstract1. Introduction2. Patients and methods3. Results4. Discussion5. ConclusionAppendix AReferences |
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), and 10 CABG patients without STEMI and C1-INH treatment as controls (
). Standard serum value as indicated (
). P
< 0.005 between group 1 versus group 2, P
< 0.002 between group 1 versus group 3; two-way ANOVA for repeated measures. (b) Perioperative time course of C3c concentration (mean ± SEM) in a subset of 12 CABG patients with STEMI and C1-INH treatment (\#9632;), 17 CABG patients with STEMI without C1-INH treatment (
