Visualisation and quantification of peri-operative myocardial infarction after coronary artery bypass surgery with contrast-enhanced magnetic resonance imaging

Johnny Steuera,*, Tomas Bjernerb, Olov Duvernoyb, Lena Jidéusa, Lars Johanssonb,d, Håkan Ahlströmb, Elisabeth Ståhlea and Bertil Lindahlc

a Department of Cardiothoracic Surgery, University Hospital, SE-751 85 Uppsala, Sweden
b Department of Diagnostic Radiology, University Hospital, Uppsala, Sweden
c Department of Cardiology, University Hospital, Uppsala, Sweden
d Amersham Health, Oslo, Norway

* Corresponding author. Tel.: +46-18-6114040; fax: +46-18-551526
E-mail address: johnny.steuer{at}surgsci.uu.se

Received 17 December 2003; revised 11 May 2004; accepted 18 May 2004 See page 1279 for the editorial comment on this article.1

Abstract

Aims To evaluate if elevated biochemical marker levels after coronary artery bypass grafting (CABG) correspond to the amount of peri-operatively infarcted myocardium, quantified by magnetic resonance imaging (MRI) post-operatively.

Methods and results A total of 23 patients without evidence of previous myocardial infarction or myocarditis and with normal pre-operative ECG and left ventricular function and who underwent elective, primary CABG, without any other concomitant cardiac surgery, were included. Plasma creatinine kinase MB (CK-MB) and troponin I and T were measured on the first, second and fourth post-operative days. Between the fourth and ninth post-operative days, cardiac MRI was carried out. Infarctions were found in 18 patients. The infarction mass at MRI was numerically largest in patients with transmural infarctions, all of whom had a CK-MB more than five times the upper normal limit. All three cardiac markers correlated to the mass of infarction.

Conclusion Elevated biochemical markers after CABG correspond to the amount of peri-operatively infarcted myocardium.

Key Words: By-pass • Creatinine kinase • Magnetic resonance imaging

Introduction

A large number of studies have shown that after coronary artery bypass grafting (CABG), a transient creatinine kinase MB (CK-MB) elevation above the upper reference limit is very common.1–4 The cause of this enzyme increase and its clinical significance have long been uncertain and controversial, but recent reports indicate that after CABG, elevated post-operative concentrations of CK-MB correlate to an increased risk of long-term mortality.1,2,5 After percutaneous coronary intervention (PCI), CK-MB elevation has been shown to correlate to a finding of myocardial necrosis.6 Such an association has to date never been proved in CABG patients. The lack of a diagnostic gold standard and absence of an established definition of peri-operative myocardial infarction after CABG have promoted the use of different diagnostic criteria, which in turn has contributed to a wide variation in the reported incidence of peri-operative myocardial infarction, ranging from 2% to 82%.7

Elevation of cardiac markers after CABG may be due to different mechanisms, such as surgical trauma, or global or localised ischaemia resulting from insufficient myocardial protection.7,8 Inadequate revascularisation9 and graft occlusion10 may further aggravate peri-operative ischaemia. The underlying cause will affect the extent and distribution of the infarction8, which may be transmural or sub-endocardial and which may be well-defined or patchy. Using a contrast-enhanced magnetic resonance imaging (MRI) technique, myocardial necrosis can be visualised and quantified with higher precision than with other non-invasive imaging techniques.11–13

Our hypothesis was that patients with elevated biochemical markers after CABG have sustained peri-operative myocardial infarctions. Our aim was to assess if there was a correlation between the biochemical marker level and the size of the infarction. Such a correlation would support our hypothesis. A further aim was to characterise any infarctions found morphologically. We chose to use MRI to visualise, characterise and quantify the infarcted regions.

Methods

Patients
Twenty-three of 60 eligible patients without evidence of previous myocardial infarction or myocarditis and with normal pre-operative ECG and left ventricular function and who underwent elective, primary on-pump CABG, without any other concomitant cardiac surgery, constituted the study population. There was not a consecutive enrolment of patients. The selection of the patients was based on the CK-MB concentration, which was measured routinely on the first post-operative morning, i.e., 12 to 18 hours after surgery. The patients were selected such as to obtain a study group with scattered CK-MB levels; after having included 15 patients with a CK-MB of 20 µg/L, we thereafter only included patients with a CK-MB of >=20 µg/L. Furthermore, patient rejection, patient withdrawal or unavailability of MRI influenced the composition of the study group. The patients were operated upon at the Department of Cardiothoracic Surgery, Uppsala University Hospital, Sweden, between May 2002 and February 2003. The study protocol was approved by the Ethics Committee of Uppsala University Hospital. All patients gave informed consent. Due to the lack of previous studies on the use of MRI to diagnose peri-operative infarctions in association with CABG, we conducted this investigation as a pilot study and, therefore, no sample size calculations were performed.

There were six women (26%) and 17 men, with an age range of 53–79 years (median 63 years). Fourteen patients (61%) had hypertension and five patients (22%) had diabetes. The number of grafted coronary arteries in each patient ranged from 2 to 5. Further clinical data are presented in Table 1.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient characteristics, surgical variables and biochemical markers

 
Biochemical markers of myocardial damage
After enrolment of the patient on the first post-operative day (=day 1), further blood samples were drawn on days 1, 2 and 4. Plasma CK-MB and plasma troponin I were measured by the Access® Immunoassay System (BeckmanCoulter). The upper reference level of CK-MB, using this assay, is 4.0 µg/L. Thus, a previously suggested definition of important peri-operative myocardial injury as five times or more above the normal limit would correspond to >=20 µg/L.4 Plasma troponin T was determined by the Elecsys® immunoassay (Roche Diagnostics).

Assessment of myocardial infarction by MRI
MRI was carried out between day four and day nine post-operatively, using a clinical 1.5T MR scanner (Gyroscan Intera; Philips Medical Systems, The Netherlands). Contrast-enhanced images were obtained after a delay of 15 min following intravenous administration of 0.2 mmol/kg gadodiamide (Omniscan®; Amersham Health, UK), using the standard phased array torso coil. A breath-hold 2D, radio frequency (RF) spoiled inversion recovery, segmented gradient-echo pulse sequence was used, with a reconstructed in-plane resolution of 1.6 mmx1.6 mm and with the inversion time (TI) set to null normal myocardium. The following parameters were used: echo time (TE)/repetition time (TR)/flip angle: 1.61 ms/4.3 ms/10°. To cover the left ventricular myocardium 8–12 slices with a slice thickness of 10 mm were acquired in a short-axis view. Myocardial infarction was defined as the finding of hyperenhancement in the myocardium on MRI.13 This phenomenon is exhibited by infarcted regions, which is thought to be due to an increased volume of distribution of the contrast agent because of rupture of myocyte membranes, and slow contrast washout.13,14

The left ventricle was divided according to a 17-segment model.15 Hyperenhancement was first scored independently by two experienced radiologists, who were blinded regarding the biochemical marker levels of the patients. The images of each patient were then evaluated jointly and consensus reached. The MRI results presented represent the consensus of the two radiologists. Evaluation of hyperenhancement was based on the spatial extent in each segment, and was categorised as transmural, endocardial or patchy (Fig. 3(a)–(c)). Transmural hyperenhancement was defined as comprising >=50% of the wall thickness; endocardial as 50% transmurality and confined to the subendocardium; and patchy referred to spots of hyperenhancement, non-classifiable as transmural or endocardial. The type of infarction that represented the largest infarction mass in each patient was defined as the predominant morphology of infarction. Any infarct and the left ventricular size were then measured by planimetric segmentation in each patient's MRI examination. Mass was obtained by multiplying the infarct volume by 1.05 (g/cm3).16



View larger version (104K):
[in this window]
[in a new window]
 
Fig. 3 (a) Illustration from a two-chamber short-axis T1-weighted inversion recovery sequence for demarcation of infarcted myocardium by hyperenhancement. White arrows indicate a transmural, antero-lateral infarction. LV, left ventricle; RV, right ventricle. (b) Illustration from a two-chamber short-axis T1-weighted inversion recovery sequence for demarcation of infarcted myocardium by hyperenhancement. White arrows indicate a sub-endocardial, infero-septal infarction. LV, left ventricle; RV, right ventricle. (c) Illustration from a two-chamber short-axis T1-weighted inversion recovery sequence for demarcation of infarcted myocardium by hyperenhancement. White arrows indicate a patchy, antero-lateral infarction. LV, left ventricle; RV, right ventricle.

 
The manual definition of the border was mostly evident, but in isolated cases there were difficulties. In these cases, we were aided by the planning scans, a steady-state free procession sequence obtained during the 15 min after the contrast injection, prior to the hyperenhancement sequence. The apical segment was evaluated either in a long-axis view or in the most apical short-axis slice. In four cases, however, the apical segment was not assessable in either projection.

Statistical methods
Continuous variables were summarised with medians and ranges, and categorical variables with frequencies. The Spearman rank correlation co-efficient was calculated to evaluate the association between the biochemical marker levels and the mass of left ventricular infarction; was adopted as statistically significant. The Kruskal–Wallis test was used to compare transmural, endocardial and patchy infarctions with respect to infarction mass. Only the infarction type that represented the largest mass in each patient was included in the analyses, and, therefore, each patient was only included in the analyses once. The Pearson correlation co-efficient was calculated as an assessment of intra-observer agreement regarding quantification of mass of infarction. All statistical tests were two-sided. SPSS for Windows 11.0 was used for data processing and statistical analyses.

Results

Type and localisation of infarction
There was immediate inter-observer agreement in 22 of the 23 patients regarding presence of infarction. The intra-observer agreement regarding quantification of mass of infarction was also very high (Pearson; ). Infarction was found in 18 of the 23 patients, with a median mass of 4.4 g (range 0.2–22 g), corresponding to 2.5% (range 0.2–16%) of the left ventricle. There was a difference in infarction mass between patients with predominantly transmural, endocardial and patchy infarctions (). The total infarction mass was numerically greater in patients with transmural infarctions (Fig. 1); the infarction mass among those with endocardial infarctions showed more variation, ranging from 2 to 21 g. The highest infarction mass in a patient with patchy infarction was 4.6 g. Three patients had elements of all three types of infarction, six patients had two types, and nine patients had only one type. Clinical data in relation to mass of infarction are presented in Table 1, and details of the type and localisation of the infarcted segments are shown in Table 2.



View larger version (9K):
[in this window]
[in a new window]
 
Fig. 1 Dot plots of all patients showing type of infarction in relation to mass of infarction. The median mass of infarction in each group is indicated by a horizontal line.

 

View this table:
[in this window]
[in a new window]
 
Table 2 Total number of infarcted segments of the left ventricle, divided into morphological type and coronary artery territory

 
Myocardial infarction mass in relation to biochemical markers
There was a moderate degree of correlation between CK-MB on the day of inclusion and mass of infarcted myocardium [Spearman; , Fig. 2(a)]. The rank correlation co-efficients for CK-MB on days 2 and 4, respectively, were of the same magnitude (Table 3). Likewise were the correlations between troponin I levels and infarction mass (Fig. 2(b)) of the same magnitude and statistically significant on all three sampling occasions, and a correlation was found for troponin T as well (Fig. 2(c)) (Table 3).



View larger version (15K):
[in this window]
[in a new window]
 
Fig. 2 (a) The relation between post-operative day 1 plasma creatinine kinase MB and mass of infarction. The predominant morphology of each patient's infarction is indicated by a symbol. (b) The relation between post-operative day 2 plasma troponin I and mass of infarction. The predominant morphology of each patient's infarction is indicated by a symbol. (c) The relation between post-operative day 4 plasma troponin T and mass of infarction. The predominant morphology of each patient's infarction is indicated by a symbol.

 

View this table:
[in this window]
[in a new window]
 
Table 3 Correlation co-efficients () between plasma creatinine kinase MB (CK-MB), plasma troponin I and plasma troponin T concentrations, respectively, and mass of infarction on the three sampling occasions

 
Seven patients had a CK-MB on day 1 of more than five times the upper reference level (20 µg/L). One of them, with a CK-MB of 22 µg/L, had no left ventricular infarction. The mass of infarction in the other six patients ranged from 5.3 to 22 g. All the four patients with transmural infarctions had a day 1 CK-MB >=20 µg/L.

Discussion

This is one of the very first studies that has focused on the visualisation and quantification of peri-operative myocardial infarction after CABG, using contrast-enhanced MRI. Our findings strongly suggest that after CABG, elevated biochemical markers correspond to peri-operatively infarcted myocardium. Previous reports on attempts to visualise peri-operative infarctions after CABG have either been based on autopsy findings17 or on other imaging techniques, mainly scintigraphic.18

One continuously debated and predominating hypothesis on the mechanism underlying peri-operative myocardial infarction concerns inadequate myocardial protection and cardioplegia.8,19 If global ischaemia were the main cause of elevated cardiac markers, one might expect to find spread of necrosis in the myocardium. Most of the patients studied did indeed have patchy infarctions, which could neither be categorised as transmural nor endocardial. Our findings indicate, however, that high post-operative CK-MB levels, i.e., above five times the upper reference level, 20 µg/L, are not entirely due to spread of micronecrosis, but are mainly due to well-localised, identifiable infarcts. Hence, although there is no generally accepted definition of peri-operative myocardial infarction, our findings correspond well to a consensus report4, that has suggested an increase in CK-MB to a level five times or more above the upper limit as evidence of periprocedural myocardial injury.

The reported correlation co-efficients between cardiac markers and size of infarction in studies of non-CABG patients have been at the same level as in the present study, e.g., peak CK-MB in relation to mass of infarcted tissue after PCI ().6 Troponin I20 and troponin T21 have been shown to correlate to the scintigraphic estimate of the infarct size. In contrast to the cytoplasmic enzyme CK-MB, troponin I and troponin T are structural proteins of the contractile apparatus. In cases of myocardial necrosis, the troponin levels remain elevated for several days, as a result of continuous release.21,22 It has been recommended from previous studies that troponin I be measured 24 h post-operatively22,23 and troponin T 48 h23 or 4 days24 after CABG to achieve the best discrimination of patients with peri-operative myocardial infarction. We found that on all occasions the levels of CK-MB and troponin I correlated to the mass of infarcted myocardium, and the correlation co-efficients between troponin T levels and infarct size were of the same magnitude, but statistically significant only on day 4 (day 1, ; day 2, ). However, the present study did not aim to, and had not the power to, find the optimal occasion to obtain the blood samples. Nevertheless, it seems reasonable to conclude that all three cardiac markers, i.e., CK-MB, troponin I and troponin T, are adequate as markers of peri-operative myocardial infarction but, in accordance with other studies,23,24 our findings suggest that the discriminatory value of troponin T may be higher later in the post-operative course.

The inclusion and exclusion criteria were aimed at selecting patients with no previous myocardial infarctions. Similar patient selection criteria have been used in other studies of the correlation of cardiac markers to the size of the infarction, i.e., no history of myocardial infarction6,21 and no evidence of infarction on non-invasive testing.6 Still, not all patients who develop myocardial necrosis have ECG changes, and 20% of myocardial wall thickness has to be damaged to detect segmental wall motion abnormalities by echocardiography.25 Therefore, we cannot rule out with certainty that our results have been confounded by old infarctions. Another potential confounder, although not fully proved, is the possibility of slight post-operative biochemical marker elevations being a consequence of reversible ischaemia.4 Nevertheless, the finding in the present study that the higher the cardiac marker level the greater the amount of infarcted tissue, strengthens the assumption of a causal connection between peri-operative myocardial infarction and post-operative elevation of cardiac markers.

Studies of the correlation between biochemical markers and myocardial infarction size, including the present study, have only focused on infarctions of the left ventricle,21,26 not taking into account the plausible affection of the right ventricle. Indeed, after completion of this study, we re-examined the MRI of the only patient who had a CK-MB of 20 µg/L, but no left ventricular infarction. It was found that he had a right ventricular hypertrophy, in which there was an area of hyperenhancement, indicating that he had sustained a peri-operative right ventricular infarction. However, it is not possible to detect an infarction reliably in a non-hypertrophied right ventricle with the MRI method used, which is why we did not systematically evaluate the right ventricle.

During the study no dedicated cardiac coil was available and therefore the synergy torso coil had to be used, and for technical reasons we had to use a 2D-acquisition. Both these factors resulted in a noise level that made visualisation of small dots of infarcted myocardium difficult, which might be one possible reason for the difficulty in distinguishing patchy infarctions from no infarctions. However, smaller slice thickness and a 3D sequence would probably have improved the resolution of small infarctions. Despite these technical limitations, the inter-observer agreement between the two radiologists was very good, and the quantification of the mass of infarction was highly reproducible. It should also be emphasised that future comparison of results between studies could plausibly benefit from standardised quantitative methods.27

Since we did not enrol the patients consecutively and we selected only patients with normal left ventricular function, conclusions on the incidence of peri-operative myocardial infarctions after CABG cannot be drawn from this study.

This is one of the very first studies that has demonstrated that elevated biochemical marker levels after CABG correspond to the amount of identifiable myocardial infarction, using MRI. The findings strongly suggest that CK-MB elevation above five times the upper reference level after CABG is the consequence of peri-operative myocardial infarction.

Acknowledgments

We thank Johan Lindbäck, Uppsala Clinical Research Center, for advice regarding statistics. Professor Per Venge, Department of Clinical Chemistry, Uppsala University Hospital, for help with the biochemical analyses and interpretation of data. Financial support was provided by the Erik, Karin and Gösta Selander Foundation and the Swedish Heart Lung Foundation. Lars Johansson, BSc, is partly employed by Amersham Health.

Footnotes

1 doi:10.1016/j.ehj.2004.06.001. Back

References

  1. Costa MA, Carere RG, Lichtenstein SV et al. Incidence, predictors, and significance of abnormal cardiac enzyme rise in patients treated with bypass surgery in the arterial revascularization therapies study (ARTS). Circulation. 2001;104:2689–2693.[Abstract/Free Full Text]
  2. Brener SJ, Lytle BW, Schneider JP et al. Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortality. J. Am. Coll. Cardiol. 2002;40:1961–1967.[CrossRef][Medline]
  3. Januzzi JL, Lewandrowski K, MacGillivray TE et al. A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery. J. Am. Coll. Cardiol. 2002;39:1518–1523.[CrossRef][Medline]
  4. Califf RM, Abdelmeguid AE, Kuntz RE et al. Myonecrosis after revascularization procedures. J. Am. Coll. Cardiol. 1998;31:241–251.[Medline]
  5. Steuer J, Hörte LG, Lindahl B et al. Impact of perioperative myocardial injury on early and long-term outcome after coronary artery bypass grafting. Eur. Heart J. 2002;23:1219–1227.[Abstract/Free Full Text]
  6. Ricciardi MJ, Wu E, Davidson CJ et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation. Circulation. 2001;103:2780–2783.[Abstract/Free Full Text]
  7. Jain U. Myocardial infarction during coronary artery bypass surgery. J. Cardiothorac. Vasc. Anesth. 1992;6:612–623.[Medline]
  8. Harff GA, Jeurissen RW, Dijkstra JB et al. Differentiation between transmural perioperative myocardial infarction and subendocardial injury after coronary artery bypass grafting using biochemical tests, elaborated by cluster and discriminant analysis. Clin. Chim. Acta. 1998;274:29–40.[CrossRef][Medline]
  9. Greaves SC, Rutherford JD, Aranki SF et al. Current incidence and determinants of perioperative myocardial infarction in coronary artery surgery. Am. Heart J. 1996;132:572–578.[Medline]
  10. Brindis RG, Brundage BH, Ullyot DJ et al. Graft patency in patients with coronary artery bypass operation complicated by perioperative myocardial infarction. J. Am. Coll. Cardiol. 1984;3:55–62.[Medline]
  11. Mazur W, Nagueh SF. Myocardial viability: recent developments in detection and clinical significance. Curr. Opin. Cardiol. 2001;16:277–281.[CrossRef][Medline]
  12. Gunning MG, Kaprielian RR, Pepper J et al. The histology of viable and hibernating myocardium in relation to imaging characteristics. J. Am. Coll. Cardiol. 2002;39:428–435.[Medline]
  13. Kim RJ, Fieno DS et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100:1992–2002.[Abstract/Free Full Text]
  14. Kim RJ, Chen EL, Lima JAC et al. Myocardial Gd-DTPA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation. 1996;94:3318–3326.[Abstract/Free Full Text]
  15. Cerqueira, MD, Weissman, NJ, Dilsizian, V et al. American Heart Association writing group on myocardial segmentation and registration for cardiac imaging: Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the cardiac imaging committee of the council on clinical cardiology of the American Heart Association. Circulation 2002;105:539–42.
  16. Sandstede J, Lipke C, Beer M et al. Age- and gender-specific differences in left and right ventricular cardiac function and mass determined by cine magnetic resonance imaging. Eur. Radiol. 2000;10:438–442.[CrossRef][Medline]
  17. Van Lente F, Martin A, Ratliff NB et al. The predictive value of serum enzymes for perioperative myocardial infarction after cardiac operations. An autopsy study. J. Thorac. Cardiovasc. Surg. 1989;98:704–710.[Abstract]
  18. Burns RJ, Gladstone PJ, Tremblay PC et al. Myocardial infarction determined by technetium-99m pyrophosphate single-photon tomography complicating elective coronary artery bypass grafting for angina pectoris. Am. J. Cardiol. 1989;63:1429–1434.[CrossRef][Medline]
  19. Murphy CO, Pan-Chih, Gott JP et al. Microvascular reactivity after crystalloid, cold blood, and warm blood cardioplegic arrest. Ann. Thorac. Surg. 1995;60:1021–1027.[Abstract/Free Full Text]
  20. Mair J, Wagner I, Morass B et al. Cardiac troponin I release correlates with myocardial infarction size. Eur. J. Clin. Chem. Clin. Biochem. 1995;33:869–872.[Medline]
  21. Licka M, Zimmermann R, Zehelein J et al. Troponin T concentrations 72 hours after myocardial infarction as a serological estimate of infarct size. Heart. 2002;87:520–524.[Abstract/Free Full Text]
  22. Sadony V, Körber M, Albes G et al. Cardiac troponin I plasma levels for diagnosis and quantitation of perioperative myocardial damage in patients undergoing coronary artery bypass surgery. Eur. J. Cardiothorac. Surg. 1998;13:57–65.[Abstract/Free Full Text]
  23. Carrier M, Pellerin M, Perrault LP et al. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann. Thorac. Surg. 2000;69:435–440.[Abstract/Free Full Text]
  24. Eikvar L, Pillgram-Larsen J, Skjæggestad Ø et al. Serum cardio-specific troponin T after open heart surgery in patients with and without perioperative myocardial infarction. Scand. J. Clin. Lab. Invest. 1994;54:329–335.[Medline]
  25. Alpert JS, Thygesen K, Antman E et al. Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J. Am. Coll. Cardiol. 2000;36:959–969.[CrossRef][Medline]
  26. Wu E, Judd RM, Vargas JD et al. Visualisation of presence, location, and transmural extent of healed Q-wave and non-Q-wave myocardial infarction. Lancet. 2001;357:21–28.[CrossRef][Medline]
  27. Setser RM, Bexell DG, O'Donnell TP et al. Quantitative assessment of myocardial scar in delayed enhancement magnetic resonance imaging. J. Magn. Reson. Imaging. 2003;18:434–441.[CrossRef][Medline]

Related articles in EHJ:

The emerging role of delayed contrast-enhanced magnetic resonance imaging in the peri-operative evaluation of patients undergoing coronary revascularisation
Paul Schoenhagen
EHJ 2004 25: 1279-1280. [Extract] [Full Text]