Diagnostic discrimination between graft-related and non-graft-related perioperative myocardial infarction with cardiac troponin I after coronary artery bypass surgery

Matthias Thielmann1,*, Parwis Massoudy1, Axel Schmermund2, Markus Neuhäuser3, Günter Marggraf1, Markus Kamler1, Ulf Herold1, Ivan Aleksic1, Klaus Mann4, Michael Haude2, Gerd Heusch5, Raimund Erbel2 and Heinz Jakob1

1Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Hospital of Essen, Hufelandstraße 55, 45122 Essen, Germany
2Department of Cardiology, West-German Heart Center Essen, University Hospital of Essen, Essen, Germany
3Institute for Medical Informatics, Biometry, and Epidemiology, University Hospital of Essen, Essen, Germany
4Department of Clinical Chemistry, University Hospital of Essen, Essen, Germany
5Institute of Pathophysiology, University Hospital of Essen, Essen, Germany

Received 21 December 2004; revised 8 June 2005; accepted 7 July 2005; online publish-ahead-of-print 8 August 2005.

* Corresponding author. Tel: +49 201 723 4901; fax: +49 201 723 5451. E-mail address: matthias.thielmann{at}uni-essen.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims The rise of markers for myocardial injury indicates early graft-related or non-graft-related perioperative myocardial infarction (PMI) after coronary artery bypass grafting (CABG). A diagnostic discrimination between these two situations may enable adequate therapeutic measures, limiting myocardial damage, and improving outcome.

Methods and results In a prospective study, 94 among 3308 consecutive CABG patients underwent acute reangiography because of evidence of PMI. Of these 94 patients, 56 had graft-related PMI (group 1), 38 patients had non-graft-related PMI (group 2), and 95 patients without evidence of PMI and angiographically patent grafts served as control (group 3). Cardiac troponin I (cTnI), creatine kinase (CK), and its MB fraction were determined. CTnI, but not CK/CK-MB levels were significantly higher in group 1 than in groups 2 and 3 at 12 and 24 h after aortic unclamping (P<0.0001). Receiver operating characteristic and multivariable logistic regression analyses indicated cTnI as the best discriminator between PMI ‘in general’ and ‘inherent’ release of cTnI after CABG with a cut-off value of 10.5 ng/mL and between graft-related and non-graft-related PMI with a cut-off value of 35.5 ng/mL.

Conclusion Perioperative cTnI elevation after CABG separates among patients with graft-related, non-graft-related, and without PMI, however, not earlier than 12 h after surgery.

Key Words: Coronary artery disease • Surgery • Myocardial infarction • Bypass graft failure


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Perioperative myocardial infarction (PMI) is one of the most serious complications after coronary artery bypass grafting (CABG) that occurs with an incidence of 5–20%13 and is associated with highly increased perioperative morbidity and mortality as well as poor long-term outcome.4,5 The pathogenesis of PMI is based on a variety of different graft-related and non-graft-related mechanisms. The most common graft-related reasons for PMI are graft occlusion, graft kinking or overstretching, subtotal anastomotic stenosis, or graft spasm.3,4,6 Non-graft-related PMI might be induced by different mechanisms during surgery, including inadequate cardioplegic perfusion and myocardial protection, incomplete revascularization, and distal coronary microembolization due to surgical manipulation.4,7

The post-operative rise of biochemical markers for myocardial damage, such as creatine kinase (CK) and cardiac troponin I (cTnI), may reflect early graft failure or non-graft-related PMI.8,9 Although, early graft failure appears to be a rare event, a tool to identify graft-related PMI from other reasons of post-operative myocardial dysfunction may help to minimize the interval between first clinical event to a possible reintervention. Thus, the early identification of patients with graft failure enables adequate early reintervention strategies such as acute percutaneous coronary intervention10 or reoperation with surgical graft revision.6,11 These measures may result in salvage of reversibly damaged ischemic myocardium, thus preserving left ventricular function, which in turn is one of the most important determinant of early and long-term outcome.5,6,12

To date, the occurrence of new Q-waves in the electrocardiogram (ECG) as well as elevated serum levels of cardiac markers for myocardial damage are used to establish the diagnosis of PMI.4,7 Cardiac isoforms of troponins are supposed to be more specific and sensitive as indicators of myocardial necrosis than CK and its MB isoform,13 particularly in the post-operative period after cardiac surgery.9,14,15 However, the identification of patients with PMI induced by early graft failure still remains difficult.

The aim of the present study was to find a reliable, non-invasive diagnostic tool for the identification of patients with early graft failure after CABG. Therefore, we examined the relationship between early graft patency as verified by acute repeat angiography, the post-operative rise of CK, its MB fraction as well as cTnI and post-operative ECG changes. We sought to define threshold values of cTnI to identify patients with graft-related in contrast to non-graft-related PMI.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patient population
Between January 2001 and May 2004, a total of 94 (2.8%) out of 3308 consecutive patients scheduled for elective isolated CABG with cardiopulmonary bypass (CPB) were enrolled in the study at the Department of Thoracic and Cardiovascular Surgery, University Clinic of Essen. All 94 patients underwent acute repeat angiography when there was a suspected perioperative myocardial ischemia or infarction with a post-operative cTnI level >20 ng/mL within the first 24 h after surgery and significant ECG changes (criteria discussed subsequently) and were therefore enrolled in the present study. An additional group of 95 consecutive CABG patients, operated within the same time period, were enrolled as a control group, having had an uneventful post-operative course without evidence of PMI and with patent grafts at follow-up angiography. Emergency surgery, previous myocardial infarction (<4 weeks), reoperative procedures or concomitant open-heart surgery were exclusion criteria. Institutional approval was obtained and all patients gave their informed consent. Preliminary data of the study have already been published.16

Intraoperative management
Standard CPB technique was used with ascending aortic and two-stage venous cannulation. Heparin was administered to achieve an activated coagulation time >400 s. CPB was conducted with hemodilution, mild hypothermia (>32°C) and membrane oxygenation. Myocardial protection was achieved using antegrade cold cristalloid (Bretschneider) cardioplegia supplemented by topical cooling, and single aortic cross-clamping for all distal anastomoses. The diameter of each target vessel was routinely determined using a coronary vessel probe and coronary calcification was estimated by the surgeon at graft insertion site and stratified using a score (0: no, 1: moderate, 2: extensive, 3: severe coronary calcification). The internal left thoracic artery and saphenous veins were the preferred grafts. Mean bypass graft flow was assessed after CPB just before sternal closure by Doppler transit time flowmetry (Cardiomed, MediStim, Oslo, Norway) of each graft.

Post-operative management
Patients were hemodynamically monitored and a 12-lead ECG was recorded pre-operatively, immediately after arrival on the intensive care unit and at 12, 24, 36, and 48 h post-operatively. A medication of 500 mg acetylsalicylic acid was administered intravenously within the first 6 h after surgery in the absence of significant bleeding. Echocardiographic examinations were carried out in the post-operative course by a cardiologist specialized in echocardiography. Hospital mortality was defined as any death that occurred during the same hospital admission.

Determination of cardiac markers
Blood samples were drawn pre-operatively, and at 1, 6, 12, 24, 36, and 48 h after aortic unclamping according to previous studies17,18 and analysed separately for cTnI, CK, and CK-MB isoenzyme activity. 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. CK and CK-MB catalytic concentrations were measured at 25°C using an inhibiting immunoassay (Granutest®, Merck KG, Darmstadt, Germany).

Acute repeat angiography
An acute repeat angiography was performed, when PMI, as identified by one of the following criteria, was suspected: (1) cTnI level >20 ng/mL within the first 24 h after CABG; (2) the appearance of ST-segment deviations 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 T-wave abnormalities in two or more contiguous leads.7 Repeat angiographies were performed in standardized way by our colleague cardiologists as previously described.19 When graft failure was detected, patients subsequently underwent reintervention if possible, either by percutaneous coronary intervention or by reoperation.

Statistical analysis
Continuous variables are reported as mean±SD, and categorical variables as number (%). Comparisons of categorical variables between groups were performed by Pearson's {chi}2 test, for expected frequencies <5 by Fisher's exact test. Comparisons of continuous variables between groups were performed by one-way ANOVA and post hoc comparisons by Tukey's honest significance difference test. Perioperative time courses of cTnI, CK, and CK-MB were analysed by a 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 three groups. Receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of cTnI, CK, and CK-MB cut-off values. The area under curve ±SD, its 95% confidence interval (CI), the sensitivity and specificity were calculated. Univariable and multivariable logistic regression analyses including the following variables usually related to PMI were used to determine which variables correlated most strongly with early graft failure during the post-operative period: (1) ST-deviations, (2) new Q-waves, (3) ventilation time, (4) duration of inotropic support, (5) IABP support, (6) the presence of new regional left ventricular wall-motion abnormalities, and (7) CK-MB at 6 h, (8) CK-MB at 12 h, (9) CK-MB at 24 h, (10) cTnI at 6 h, (11) cTnI at 12 h, and (12) cTnI at 24 h (ng/mL) after aortic unclamping as continuous variables. For all statistical tests, a two-tailed P-value <0.05 was considered significant. Statistical analyses were performed with SPSS 10.0 (SPSS, Chicago, IL, USA) and SAS 8.2 (SAS Institute Inc., Cary, NC, USA). ROC curves were plotted with PlotROC (CE Metz, University of Chicago, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Out of 3308 consecutive patients, who underwent isolated CABG and were monitored as mentioned previously, 94 (2.8%) fulfilled the inclusion criteria with evidence of PMI and therefore were taken to acute repeat angiography. Early graft failure was found in 56 patients (group 1), whereas 38 patients had no graft failure and were thus identified to have non-graft-related PMI (group 2). Another 95 CABG patients without evidence of PMI and with angiographically patent grafts 4.0 (6.0–7.5) months (median and 25–75% inter-quartile range) at follow-up served as controls (group 3). Pre-operative patient characteristics and intraoperative data were not different between the groups, except for the estimated coronary calcification score, which was significantly different between the groups (Tables 1 and 2). Mean transit time graft flow of the affected graft/region was lower in group 1 (36±19 mL/min) compared with group 2 (47±21 mL/min; P=0.012) and the matched graft flow of group 3 (61±22 mL/min; P<0.0001), but did not differ between groups 2 and 3 (P=0.12). Mean transit time graft flow of the unaffected grafts, however, did not differ between the groups, but unaffected mean graft flow was higher in group 1 than affected graft flows. No significant differences occurred according to post-operative data between groups 1 and 2 except the duration of inotropic support (P=0.04), but, as expected, almost all post-operative data were significantly different compared with group 3 (Table 2). The appearance of post-operative ECG changes in the groups is presented in Figure 1. However, neither the appearance of ST-segment deviations or T-wave abnormalities, nor the appearance of new or presumed new Q-waves enabled the differentiation between patients with or without early graft failure. The presence of new regional left ventricular wall-motion abnormalities detected by echocardiography at a mean time period of 2.1±1.6 days after surgery was observed in all patients of group 1 and in 28 patients (74%) of group 2 (P<0.0001). Hospital mortality tend to increase in group 1 compared with group 2 and was significantly increased compared with group 3 (P<0.001).


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Table 1 Patient characteristics
 

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Table 2 Perioperative data
 


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Figure 1 Post-operative appearance of ST-segment deviations or T-wave abnormalities and new or presumed new Q-waves in the three groups; *:P-value vs. groups 1 and 2.

 
Pre-operative cTnI serum levels did not differ between groups. Mean cTnI level of group 1 significantly increased compared with the pre-operative value at 6 h and was significantly higher than the comparable levels in group 3 at 6 h, and in group 2 at 12 h, reaching its peak value at 36 h after aortic unclamping. Mean cTnI level of group 2 significantly increased compared with the pre-operative value after 6 h and was significantly different compared with groups 1 and 3 after 12 h, also reaching its peak value at 36 h after aortic unclamping (Figure 2).



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Figure 2 Mean serum concentrations ±SD of cTnI (A), CK (B), and CK-MB (C); group 1: early graft failure (filled square); group 2: non-graft-related PMI (open square); group 3: control (open circle); {dagger}P-values vs. group 1; *P-value vs. group 2; #P-values vs. group 3.

 
Mean CK and CK-MB levels did not differ between the groups pre-operatively and were significantly increased at 1 h after aortic unclamping in the groups compared with the pre-operative values. In contrast to cTnI, however, CK and CK-MB levels did not differ between groups 1 and 2 until 36 h after aortic unclamping.

Repeat angiography was acutely performed 18.3±1.0 h after CABG. Among a total number of 340 inserted grafts, 77 were identified as failing ones. The most common cause of graft failure was graft occlusion (n=64), followed by graft kinking (n=7), and anastomotic stenosis (n=6), which was identified by angiography as a subtotal (>75%) stenosis of the graft and thus interpreted as functional occlusion. Angiographic findings of group 2 did not show any graft failure at all. Two patients were identified with a 40–50% stenosis of the native right coronary artery, which had not been grafted. One patient was identified with a significant stenosis of the LAD distal to the inserted graft. All patients of group 3 had 100% patent grafts 6.2±1.8 months after CABG.

ROC analyses of cTnI, CK, and CK-MB levels between graft-related PMI (group 1) and non-graft-related PMI (group 2) revealed cTnI as the best discriminator with an optimal cut-off value of 25.5 ng/mL at 12 h and 35.5 ng/mL at 24 h after aortic unclamping, whereas CK and CK-MB levels were not capable of discriminating groups 1 and 2. Using ROC analyses of cTnI, CK, and CK-MB levels to discriminate between PMI ‘in general’ (groups 1+2) and the ‘inherent’ release of cardiac markers after CABG (group 3), optimal cut-off values were found for cTnI with 9.0 ng/mL at 12 h and 10.5 ng/mL at 24 h and for CK-MB with 17.5 IU/L at 6 h and 26.5 IU/L at 12 h after aortic unclamping, indicating an earlier and higher discriminative power of CK-MB compared with cTnI in this situation (Tables 3 and 4 and Figures 3 and 4). CTnI, however, was the only variable, which significantly correlated with early graft failure in a univariable logistic regression model at 12 (P<0.0001) and 24 h (P=0.0001) and in a multivariable logistic regression model at 24 h (P=0.01) after aortic unclamping. All other variables were not significantly associated with early graft failure (Table 5). To check whether the linearity assumption is feasible, additional analyses were carried out using categorized variables. These additional models gave very similar conclusions.


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Table 3 Intraoperative and angiographic findings
 


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Figure 3 ROC curve analysis of cTnI levels between groups 1 and 2 at 6, 12, and 24 h after aortic unclamping.

 


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Figure 4 ROC curve analysis of cTnI levels between groups 1+2 and 3 at 6, 12, and 24 h after aortic unclamping.

 

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Table 5 Univariable and multivariable logistic regression analysis of variables associated with early graft failure
 
As a result of acute repeat angiography, 13 patients of group 1 were subsequently treated by emergent percutaneous intervention with coronary stenting, whereas 15 patients were immediately referred to an emergency reoperation 2.1±1.9 h after repeat angiography. However, clinical outcome between patients who underwent emergent reintervention and those who were treated conservatively did not differ statistically, probably reflecting the small sample size.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Myocardial cellular damage associated with cardiac surgery can be caused by different mechanisms, including direct myocardial trauma by surgical manipulations, focal damage caused by inadequate cardioplegic perfusion, and inadequate myocardial protection.7 Myocardial damage can also be induced by coronary artery microembolization20 and result in focal inflammation and regional contractile myocardial dysfunction.21 These aetiologies of myocardial damage can all result in myocardial necrosis and therefore lead to the elevations of cardiac biomarkers and enzymes.8,9,22 However, to date no cardiac marker of myocardial damage has been shown to be capable of differentiating between a myocardial damage owing to a graft-related PMI and a non-graft-related PMI in the presence of the small quantity of myocardial cellular damage associated with the CABG procedure itself.

The diagnosis of PMI is usually based on the development of new or presumably new Q-waves in the post-operative ECG besides elevation of cardiac enzymes and biomarkers.4,7,8 Major ECG changes such as the occurrence of new Q-waves have previously been reported to be strongly associated with an increased incidence of PMI after CABG.23 However, this definition of PMI is inadequate to differentiate between graft-related and non-graft-related reasons for a PMI. In the present study, post-operative ECG changes such as ST-segment deviations and T-wave abnormalities, as well as new or presumably new Q-waves were not reliable to discriminate between patients with or without graft failure.

Although the presence of new wall-motion abnormalities detected by TEE is more sensitive than the occurrence of ECG changes to identify patients with PMI,24 they were also not helpful to separate between graft-related and non-graft-related reasons of PMI in the present study.

The interpretation of the post-operative rise of cardiac markers for myocardial damage seems to be more promising. Using ROC curves of cTnI, CK, and CK-MB levels between the groups, the discrimination between ‘inherent’ myocardial damage induced by the surgical procedure itself (group 3), patients with non-graft-related PMI (group 2), and patients with PMI induced by graft failure (group 1) could be achieved. Surgical trauma to the muscular wall can also induce myocardial damage, unrelated to additional myocardial ischemia. The intramural or intraseptal locations of coronary vessels mandate the creation of a muscular groove and thus induce inevitable cardiac biomarker elevations. Numerous cut-off values of cardiac biomarkers for the discrimination between the ‘normal’ and uneventful post-operative course and PMI after CABG, irrespective of the underlying mechanism, have been described so far. Recently published cut-off values of cardiac troponin T (cTnT) have been set between 1.122 and 3.4 µg/L9 at 12 h post-operatively to diagnose a transmural PMI after CABG. The cut-off values for cTnI based on the same method of measurement were set between 9.825 and 10.0 ng/mL14 at 8–12 h and 11.6 ng/mL at 24 h25 after CABG, which is in good accordance with the cTnI levels obtained in the present study.

The non-invasive detection of in-hospital graft occlusion was recently reported by Holmvang et al.11 using CK-MB and cTnT, which were found to be significantly higher in seven patients with in-hospital graft occlusion controlled by angiography 3–7 days after CABG. However, significant CK-MB and cTnT cut-off levels were not found at any time point owing to the small number of patients with graft occlusion.

In the present study, cTnI levels were significantly increased in patients with PMI induced by graft failure when compared with patients with non-graft-related PMI, suggesting that the size of PMI induced by graft failure is potentially greater than in PMI induced by non-graft-related mechanism(s). This correlation between the extent of cTnI release and the size of myocardial infarction has been previously described.26 For the first time, in the present study, patients with PMI could be discriminated into those with graft failure and those with non-graft-related problems using serum cTnI levels. However, cardiac biomarkers for myocardial damage like cTnI and CK, CK-MB in particular did not separate between graft-related and non-graft-related PMI until 12 h after CABG, and finally, an accurate discrimination between these two situations required 24 h.

Limitations of the study
The present study demonstrates the underlying mechanisms causing graft-related PMI, however, the reasons inducing non-graft-related PMI with consecutive impaired regional myocardial contractile function but unaltered graft function remains unclear. Possible explanations for this perfusion–contraction mismatch include stunned myocardium because of inadequate myocardial protection, and incomplete revascularization. However, there is also evidence for intraoperative coronary microembolization leading to patchy microinfarcts, which cause a marked inflammatory response with subsequent progressive regional contractile dysfunction in the presence of unaltered regional myocardial blood flow, as described previously.2729 From animal experiments, we know that this myocardial contractile dysfunction is reversible.30

Another limitation is that a cTnI level of 20 ng/mL had been arbitrarily set as the threshold for repeat angiography, which has been demonstrated to confirm the diagnosis of post-operative myocardial infarction with high accuracy.14 Different arbitrary cTnI levels as thresholds for repeat angiography might have resulted in different cut-off values.

Conclusions and clinical implications
For the first time, the present study demonstrates the feasibility of post-operative cTnI serum levels to discriminate between graft-related and non-graft-related perioperative myocardial damage. This may help the clinician to further decide about diagnostic and therapeutic options in these patients. However, cTnI and CK did not begin to separate until 12 h after CABG, and finally, an accurate discrimination between graft-related and non-graft-related PMI required 24 h. This detection window seems to be far too long to enable rescue or reintervention strategies, such as PCI or reoperation to prevent myocardial infarction and a loss of myocardial function. The advent of new biomarkers for myocardial ischemia such as heart type fatty acid binding proteins (hFABP)31,32 or ischemia-modified albumin3335 which have recently been reported to detect myocardial ischemia within the first 30 min, may enable early reintervention aimed at restoring myocardial perfusion.


    Acknowledgements
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors wish to express their appreciations to the cardiologists and the staff at the cardiac catheterization laboratory for performing all acute repeat angiographic studies.


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Table 4 Cut-off values and test characteristics of cTnI, CK and CK-MB
 

    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
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