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Eur J Cardiothorac Surg 2004;26:102-109
© 2004 Elsevier Science NL
a Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Clinic of Essen, Essen, Germany
b Department of Cardiology, West-German Heart Center Essen, University Clinic of Essen, Hufelandstraße 55, 45122 Essen, Germany
Received 5 November 2003; received in revised form 8 March 2004; accepted 15 March 2004.
* Corresponding author. Tel.: +49-201-723-3151; fax: +49-201-723-5717
e-mail: matthias.thielmann{at}uni-essen.de
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Abstract |
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 Top Abstract 1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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Key Words: Coronary artery bypass grafting • Perioperative myocardial infarction • Early graft failure • Cardiac troponin I
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1. Introduction |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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To date, the appearance of new pathologic Q-waves on the electrocardiogram (ECG) as well as elevated serum levels of cardiac markers for myocardial damage are used to establish the diagnosis of PMI [2,8,9]. Cardiac isoforms of troponins, are supposed to be more specific and sensitive as indicators of myocardial necrosis than conventional cardiac enzymes like creatine kinase (CK) [10], particularly in the postoperative period after cardiac surgery [11–13]. However, the identification of patients with PMI induced by early graft failure still remains unclear.
The purpose of the present study was to investigate a reliable, non-invasive diagnostic tool for the detection of patients with early graft failure after CABG. We therefore examined the relationship between early graft patency obtained by acute repeat angiography and the postoperative rise of cardiac markers of myocardial damage and postoperative ECG-changes. A diagnostic discrimination limit of cTnI, myoglobin (Myo) and CK was aimed at to identify patients with graft-related PMI in contrast to other non-graft-related causes of myocardial damage.
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2. Patients and methods |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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2.2. Clinical management
Anesthesia was standardized in all patients. Internal thoracic artery and saphenous vein grafts were used as graft conduits in all patients. Proximal graft anastomoses to the aorta were performed with partial occlusion of the ascending aorta. 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. During CPB, moderate hemodilution with a hematocrit level between 20 and 25% using mild systemic hypothermia (>32 °C) was maintained. Myocardial protection was achieved using antegrade cold cristalloid (Bretschneider) cardioplegic arrest and additional topical cooling with ice slush, and single aortic cross clamping for all distal anastomosis. Intraoperative graft flow measurement (Cardiomed, MediStim, Oslo, Norway) was routinely applied after CPB just before sternal closure under stable hemodynamic conditions for each graft.
Postoperative management of patients was standardized. Patients were monitored with respect to arterial pressure, pulmonary pressure, and central venous pressure. A 12-lead ECG was obtained preoperatively, immediately after the arrival on the intensive care unit and at 12, 24, 36 and 48 h postoperatively and once a day thereafter. A medication of 500 mg acetylsalicylic acid and 200–400 I.E./h heparin was administered intravenously within the first 6 h after surgery in the absence of significant bleeding.
2.3. Biochemical analysis
Venous blood samples were drawn in EDTA-coated tubes from each patient preoperatively, at 1, 6, 12, and 24 h after aortic unclamping and were analyzed separately for cTnI, Myo, CK and CK-MB isoenzyme activity. CK-MB activity was measured just at 1 h after aortic unclamping and once a day thereafter. CTnI and Myo were measured using a specific two-side immunoassay (Dimension Flex®, Dade Behring Marburg GmbH, Marburg, Germany), respectively. The detection range for cTnI was 0.1–50 ng/ml, requiring further dilutions if necessary. A cTnI value above 0.5 ng/ml was considered as abnormal. CK and CK-MB catalytic concentrations were measured at 25 °C using a Merck test kit. CK-MB activity was measured using an inhibiting immunoassay (Granutest®, Merck KG, Darmstadt, Germany).
2.4. Indications for repeat angiography
Acute repeat angiography was performed, if one or more of the following criteria were present: (1) A postoperative cTnI level above 20 ng/ml within the first 24 h after CABG. (2) Significant ST segment deviations like elevations at the J point in two or more contiguous leads with cut-off points 
0.2 mV in leads V1, V2, or V3 and 0.1 mV in other leads or significant ST segment depressions or T wave abnormalities in two or more contiguous leads [9]. All repeat angiographies were performed by the house cardiologist. The patency of all inserted grafts and native coronary arteries was determined. During repeat angiography the cardiologist and the cardiac surgeon together decided the possibility of immediate reintervention with coronary stenting of native coronary arteries on the one hand or reoperation on the other hand.
2.5. Statistical analysis
Data are reported as mean values±standard error of the mean (SEM). Categorical variables are presented by their number and summarized as percentage. Comparisons of categorical variables between groups were performed by Fisher's exact test. Comparisons of continuous variables between groups were analyzed by unpaired t-test. The time course of cTnI, Myo, and CK levels were analyzed between groups by two-way ANOVA for repeated measurements. When a significant overall effect was detected, Tukeys honest significance difference test was performed to compare single mean values. A receiver operating characteristics (ROC) analysis was calculated to determine optimal cut-off values at different time points for cTnI, Myo, CK, respectively. Another ROC analysis of maximum CK-MB isoenzyme serum level was constructed. The area under curve and its standard deviation, the sensitivity, and the specificity was calculated to analyze the diagnostic value of all these markers. For all statistical tests, a P value less than 0.05 was taken to indicate a significant difference.
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3. Results |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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These patients were not significantly different according to all preoperative, intraoperative, and postoperative data as presented in Table 1 . Duration of ICU stay as well as hospital stay was not different between the two groups. Hospital mortality was also not significantly different, but tended to be increased in group 1 patients (Table 1). All in-hospital deaths were related to acute myocardial infarction and subsequent heart failure.
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3.2. Biochemical findings
Preoperative levels of cTnI, Myo, and CK/CK-MB were within the normal range and not different between the two groups. Maximum postoperative levels of cTnI, Myo, CK, and CK-MB showed a significant difference for cTnI, Myo but not CK and CK-MB between groups 1 and 2 (Fig. 1)
. The serum levels of cTnI, Myo, and CK levels were significantly increased at 12 and 24 h after aortic unclamping compared to their preoperative values. CTnI and Myo were significantly different between groups 1 and 2 (cTnI: 39.5±3.7 vs. 19.7±2.2 ng/ml, P<0.001; Myo: 1572±243 vs. 530±91 µg/ml, P<0.001) at 12 h after aortic unclamping and cTnI, but neither Myo nor CK were significantly different at 24 h after aortic unclamping (cTnI: 64.7±4.4 vs. 27.8±2.6 ng/ml, P<0.001; Myo: 1172±176 vs. 636±126 µg/ml, P=0.07; CK: 648±62 vs. 530±52 µg/ml, P=0.2; Figs. 2–4)
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3.4. Angiographic findings
Repeat angiography was acutely performed 22±1 h after CABG by an experienced invasive cardiologist. The most common cause of graft failure was graft occlusion (n=40), followed by graft kinking (n=4) and anastomotic stenosis (n=1), which was identified by angiography as a subtotal (>75%) stenosis of the graft and thus, interpreted as functional occlusion. Failing grafts were observed in equal number among arterial and venous grafts. The anterior ventricular wall was most often affected when arterial grafts failed (n=23, 96%) and the lateral and posterior ventricular wall was most often affected when venous grafts failed (n=22, 100%) as shown in Table 2
. Angiographic findings of group 2 did not show any graft failure at all. One patient was identified with a 40–50% stenosis of the native right coronary artery, which had not been grafted.
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4. Discussion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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In the present study, the postoperative release of cardiac biomarkers and enzymes for myocardial damage like cTnI, Myo and CK were measured in case of PMI. The postoperative rise of cardiac biomarkers and enzymes after CABG was directly related to patency of native coronary arteries and new inserted arterial and venous graft conduits obtained by acute repeat coronary angiography.
In the postoperative course of patients with suspected myocardial ischemia or infarction following CABG, the diagnostic discrimination between graft-related and non-graft-related myocardial problems enables the attending surgeon to plan early reintervention, in order to decrease or even prevent myocardial damage, thus preserving ventricular function and in turn improving patient outcome [3,6,18].
The diagnosis of PMI is usually based upon the development of new or presumed new pathologic Q-waves on the postoperative ECG besides elevations of cardiac enzymes and biomarkers [2,19]. However, this definition of PMI is inadequate to differentiate between graft-related causes and non-graft-related causes of PMI. Thus, the identification of patients with PMI after coronary bypass surgery is still a challenging problem. The postoperative pathologic patterns such as ST segment deviations or new pathologic Q-waves on the ECG, elevations of cardiac enzymes or biomarkers, sustained arrhythmias or hemodynamic deterioration caused by acute heart failure may all be indicators of severe myocardial injury. However, it has not yet been achieved to relate such symptoms to the specific underlying pathomechanism of myocardial damage.
In the present study, the postoperative pathologic changings on the ECG like ST segment deviations, as well as new Q-waves were not reliable to separate between patients with and patients without graft failure. This is consistent with a recently published study, where ECG criteria, and the appearance of Q-waves in particular, were described as insufficient for the diagnosis of PMI after CABG [20].
The interpretation of the postoperative rise of cardiac markers for myocardial damage seems to be more promising. Numerous clinical studies could already demonstrate, that a significant rise of cardiac biomarkers like cTnI [11,12], troponin T [15,21] or Myo [21,21] as well as cardiac enzymes like CK and creatine kinase isoenzyme MB [21,22] occurs following cardiac surgery. Confirming the results of prior studies, which demonstrated cardiac troponins as more sensitive and specific markers of myocardial damage compared with Myo and CK, the present study established ROC with definite cut-off values to differentiate between early graft failure and non-graft-related PMI after CABG.
Numerous cut-off values for the differentiation between the ‘normal’ and uneventful postoperative course after CABG and PMI after CABG have been described so far. Recently published cut-off values for cTnT have been set between 1.1 [21] and 3.4 µg/l [23] at 12 h. The cut-off values for cTnI, based on the same method of cTnI measurement as used in the present study, were set between 8.3 and 13.4 ng/ml at 6 h [12], 9.8 [11] and 10.0 ng/ml [12,24] at 8–12 h and 11.6 ng/ml at 24 h [11] after CABG. However, this is the first study to find a discriminating marker for the differentiation between early graft failure and non-graft-related PMI after CABG. Non-invasive detection of in-hospital graft occlusion was performed by using optimal discrimination values of CK-MB and troponin T [15]. Peak troponin T and CK-MB values were found to be significantly higher in seven patients with in-hospital graft occlusion, as controlled by angiography 3–7 days after coronary surgery, but significant CK-MB and TnT cut-off levels could not be found at any time point. The authors concluded that the graft patency status could not be reliably predicted using these biochemical markers, but admitted that the small number of patients with graft occlusion limited the significance of their findings.
In the present study, cTnI levels were significantly increased in group 1 patients with PMI induced by graft failure as compared to group 2 patients with non-graft-related PMI, suggesting that the size of PMI induced by early graft failure was potentially greater in group 1 than PMI induced by non-graft-related mechanisms in group 2. This significant correlation between the extent of cTnI release and the size of myocardial infarction has been previously described [25]. By comparing the perioperative release of cTnI, Myo and CK in patients with graft-related and patients with non-graft-related myocardial infarction after coronary surgery, the optimal cut-off value could be determined at 24 h after aortic unclamping for cTnI. In contrast, CK and creatine kinase isoenzyme MB could not differentiate between the groups and the discriminatory power of Myo was found to be much lower. However, despite the lower discriminatory power of Myo compared to troponin I at 12 and 24 h, Myo is known as an earlier marker for myocardial ischemia than troponin I. Due to the higher difference in Myo levels for groups 1 and 2 at 12 h after aortic unclamping as compared to troponin I at the same time point and a somewhat lower sensitivity and specificity of Myo at 6 h than at 12 h, this marker of myocardial ischemia might be useful in addition to troponin I as an early warning sign of graft occlusion. If Myo would have been monitored in the present study more closely in the early postoperative course, it might have been significantly different more earlier.
A limitation of the present study is the fact that a cTnI level of 20 ng/ml had been set to be the threshold for repeat angiography. This threshold has been demonstrated to confirm the diagnosis of myocardial infarction with high accuracy [12]. However, different arbitrary cTnI levels as thresholds for repeat angiography might have resulted in different cut-off values. The most important limitation of this study is that, although we could identify troponin I to be a reliable discriminator between graft failure and PMI at 12 and 24 h after aortic unclamping, the exact time point of graft failure remains uncertain. Moreover, additional time points of blood sampling at earlier or later stages might show other ischemic markers, notably Myo and CK to be discriminators between graft failure and PMI at these specific time points.
To conclude, the present study demonstrates the feasibility of using postoperative cTnI serum levels at 12 and 24 h after aortic unclamping to identify patients with early graft failure after CABG as opposed to non-graft-related myocardial infarction.
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Acknowledgments |
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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Dr Thielmann: As I said, the mean time between primary surgery and repeat angiography was about 20 hours.
Dr Mohl: So more or less you have already had the diagnostic of the troponin levels, you knew already about them?
Dr Thielmann: Yes.
Dr Mohl: And how often did you reintervene?
Dr Thielmann: We intervened directly in the cath lab. Ten patients were directly stented in the cath lab, and 12 patients were taken to redo CABG immediately, and all other patients didn't have reintervention.
Dr R. Poston (Baltimore, MD): I have difficulty knowing from your data what exactly a troponin elevation means without angiographic follow up for all patients. Most studies show that about 10% of grafts fail early and you showed <4%. So you are missing some patients there.
A Bayer sponsored study called the IMAGE trial found that about three-quarters of their patients with early graft thrombosis showed no rise in troponin, no EKG changes, no clinical problems. The only way you can find these failures is by complete follow-up angiographically.
Dr Thielmann: That's right. But we had to choose a threshold level for troponin I to say here is the threshold to do a repeat angiogram.
Jacquet and co-workers have already demonstrated that a troponin I level of 20 ng/ml 10 h after aortic unclamping confirmed the diagnosis of perioperative myocardial infarction with high accuracy.
Dr A. Moritz (Frankfurt, Germany): The most distinctive time point of your decision-making is 12 h. That is actually pretty far out in the process. So if you have myocardial infarction going on after 12 h, you won't change too much. So do you have any ideas how we could put this decision-making earlier when actually you would need to know if the patient is going into an infarct, at least, or at 6 hours? Do you have any ideas on this or can you calculate a model or something?
Dr Thielmann: This study shows that troponin I is too late to make us possible to reintervene early or not. So maybe, I don't know, we need another marker who increases earlier than troponin I.
Dr B. Walpoth (Geneva, Switzerland): Did you measure intraoperative flow in the studied grafts and, if you did so, did you see any critical low flow values correlating with your graft occlusion?
Dr Thielmann: In our institution we routinely measure intraoperatively the graft flows, and what you can see is that there is a significant difference between the control group compared with Group I and II. Group I and II, they had flows around about 30 to 40 ml/mn, and there was no difference between these two groups, between graft failure and non-graft-related PMI, but in the area at risk the flow was significantly different to group III.
Mr V. Zamvar (Edinburgh, UK): My question is related to the recruitment of patients for the control group. How did you select these patients? And in these patients who had angiography at 6 months, were there any patients who had blocked grafts at all and what were their cardiac troponin levels?
Dr Thielmann: No, we just matched this group to our study group, and the only reason for that was to have a control in the normal cTnI levels.
Mr Zamvar: Were there any patients with blocked grafts? Were any of the grafts in the control group blocked?
Mr P. Totaro (Swansea, UK): In the final slide you stated that the result of this study would be useful to modify the diagnostic or therapeutic policy. How did you actually modify your policy? I mean, did you re-angio the patient only if the troponin is above 30 after 12 h?
Dr Thielmann: That is our policy, yes.
Mr. Totaro: So if you have a problem before, you wait anyway for a 12-hour level of troponin before reangioing the patient?
Dr Thielmann: Our policy is if you have signs of perioperative myocardial infarction, as I said, with a troponin I value above 20 ng/ml after 12 hours or significant ECG changes or hemodynamic deterioration, all these patients, if they are stable enough, are taken to the cath lab, and we discuss together with the cardiologists what to do.
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References |
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TopAbstract1. Introduction2. Patients and methods3. Results4. DiscussionAppendix A. Conference...References |
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).
); group 2: non-graft-related PMI (
). P<0.05: * vs. group 2, # vs. baseline values, 
vs. preceding values (two-way ANOVA).
