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Ann Thorac Surg 2008;85:1348-1354. doi:10.1016/j.athoracsur.2007.12.077
© 2008 The Society of Thoracic Surgeons
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Nahum Nesher
Abdullah A. Alghamdi
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Original Articles: Adult Cardiac

Troponin after Cardiac Surgery: A Predictor or a Phenomenon?

Nahum Nesher, MD*, Abdullah A. Alghamdi, MD, Steve K. Singh, MD, Jeri Y. Sever, MS, George T. Christakis, MD, Bernard S. Goldman, MD, Gideon N. Cohen, MD, PhD, Fuad Moussa, MD, Stephen E. Fremes, MD

Division of Cardiac and Vascular Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Accepted for publication December 31, 2007.

* Address correspondence to Dr Nesher, 2075 Bayview Ave, H410, Toronto, Ontario, M4N 3M5, Canada (Email: nachumnesher{at}yahoo.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Increased cardiac troponin is observed after virtually every cardiac operation, indicating perioperative myocardial injury. The clinical significance of this elevation is controversial. This study aimed to correlate postoperative troponin levels with major adverse cardiac events (MACE).

Methods: The study included 1918 consecutive patients undergoing adult cardiac operations, including 1515 isolated coronary procedures, 229 valvular operations, and 174 combined coronary/valve procedures. Peak troponin T (normal value < 0.1 µg/L) was measured at less than 24 hours postoperatively. Excluded were 506 patients with a recent myocardial infarction (< 30-days of operation). The primary outcome was a composite of death, electrocardiogram-defined infarction, and low output syndrome (MACE).

Results: Mortality rates were 1.4%, 6.1%, and 7% in the coronary bypass, valve, and combined groups, respectively (p < 0.001). The rates of MACE were 17%, 35%, and 44% (p < 0.0001), and mean troponin T levels were 0.9 ± 1.5, 1.2 ± 2.9, and 1.3 ± 1.2 µg/L (p < 0.001), in the coronary bypass, valve, and combined groups, respectively. All patients were divided into quintiles based on their peak postoperative troponin level (Q1, 0.0 to 0.39; Q2, 0.4 to 0.59; Q3, 0.6 to 0.79; Q4, 0.8 to 1.29; and Q5, > 1.3 µg/L). Adverse outcomes were similar and stable in the lower quintiles. A stepwise increase in adverse outcomes was observed in the higher quintiles. Receiver operating characteristic curve analysis revealed a troponin cutoff of 0.8 µg/L was the most discriminatory for MACE (area under the curve, 0.7). Multivariable analyses showed a troponin value of more than 0.8 µg/L was independently associated with MACE.

Conclusions: Moderate elevations in troponin are common after cardiac operations; troponin is a well-described predictor of outcomes. Troponin levels exceeding 0.8 µg/L are associated with increased MACE in patients without a history of preoperative myocardial infarction within 30 days of operation.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Cardiac troponins have improved the sensitivity and specificity for detection of myocardial injury and have become the gold standard for the diagnosis of acute myocardial infarction (MI) even when creatine kinase MB (CK-MB) levels remain within normal reference ranges [1–3]. Increased cardiac troponins have been reported to occur after virtually every open heart surgery [1]. However, release of troponin in this setting may not only reflect MI related to coronary/graft occlusion but could also result from myocardial cell injury attributable to incomplete myocardial protection, reperfusion injury, unavoidable surgical trauma, intramyocardial vessel manipulation, and direct current defibrillation [4, 5]. Nonetheless, many cardiac surgical centers routinely monitor cardiac enzymes postoperatively as a quality assurance measure.

The prognostic significance of CK-MB after cardiac operations is fairly well established. The association between increased postoperative troponin release and hard clinical postoperative outcomes is controversial [6–9]; troponin may be an overly sensitive marker of cardiac injury in this setting. The cutoff value for detection of a significant amount of myocardial damage in this setting is still unresolved. The primary objective of our study was to determine whether cardiac-specific troponin T (TnT) correlates with major adverse cardiac events (MACE) after cardiac operations. The secondary objective was to determine a threshold value of troponin associated with these outcomes.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Study Population
From 2002 to 2006, 2991 consecutive adult patients underwent cardiac operations at Sunnybrook Health Sciences Centre. Patient demographic, angiographic, intraoperative, and in-hospital postoperative outcome variables were reviewed using our institution’s prospectively collected computerized clinical database. Research ethics approval was granted from our institution’s Ethics Board, which waived the need for patient consent. Eligible patients included those undergoing isolated on-pump coronary artery bypass grafting (CABG), valvular operations, or combined CABG/valve procedures. Excluded were 506 patients who had a recent MI (<30 days preoperatively) [10]. A further 352 patients were excluded who had cardiac or vascular surgical procedures other than those described.

Operative Management
Alpha-stat acid-base management was used during cardiopulmonary bypass (CPB). Heparin (300 U/kg) was administered to maintain an activated clotting time exceeding 480 seconds. During CPB, the body temperature was allowed to drift inferiorly (32° to 34°C). Cardiac arrest was induced and maintained with antegrade/retrograde cold/tepid blood cardioplegia. Protamine was administered to reverse heparin in the standard manner (1 mg/1 mg total heparin) Tranexamic acid or aprotinin were administered before and during the operation to minimize postoperative bleeding; aprotinin was used for patients at high risk for bleeding due to recent preoperative antiplatelet medications or the extent of the planned procedure (redo, multiple valve, or combined procedure).

Postoperative Management
Patients received aspirin (325 mg) and unfractionated heparin (5000 U) 12 hours postoperatively in the absence of significant mediastinal bleeding. Warfarin was started after chest tube removal for patients after mechanical valve replacement or any mitral valve procedure.

Serum CK level (normal range, 24 to 195 IU/L) and CK-MB level (normal range, 2 to 6 µg/L) were measured by standard methods. Measurement of TnT was within 24 hours after the operation. Troponin T was measured quantitatively by a one-step enzyme immunoassay based on electrochemiluminescence technology (Elecsys 2010; Roche, Mannheim, Germany). The lower detection limit of this assay is 0.1 µg/L (normal < 0.1 µg/L).

Primary End Point
The objective of the study was to correlate TnT with perioperative MACE, which was defined as a composite end point of all-cause in hospital death, low-output syndrome (defined as inotropic or intraaortic balloon pump support, or both, to maintain the cardiac index > 2.0 L/min/m2) or perioperative MI (defined as new, persistent Q-waves ≥ 0.04 ms or R-wave reduction ≥ 25% in at least two contiguous anterior leads, or ischemic electrocardiographic ST/T wave changes with CK-MB mass elevation > 50 µg/L, in at least two consecutive daily electrocardiograms). Troponin levels were not considered for the diagnosis of perioperative MI.

Statistical Analysis
Categoric variables were summarized as frequencies and percentages, and continuous variables as means ± standard deviations or median and interquartile ranges. Categorical variables were compared using the Pearson {chi}2 test for independent proportions, and the Student t test was used to compare continuous variables. A single troponin cutoff best associated with adverse clinical events was identified according to the maximum area under the receiver operating characteristic (AUROC) curve. The study cohort was divided into quintiles by peak postoperative TnT level, and adverse events were determined in each quintile. Stepwise logistic regression was used to evaluate the effect of peak TnT on outcomes, adjusting for preoperative and operative variables (Table 1). All statistical tests were two-tailed with p < 0.05 indicating statistical significance. Statistical software SAS 8.2 (SAS Institute, Cary, NC) was used for analyses.


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  		Table 1 Demographic Characteristics and Outcomes According to Operation
 

   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Patient Population
Of the 2133 patients found eligible to participate in the study, 215 were excluded because of missing troponin levels in the computerized database, leaving 1918 patients for analysis. The spectrum of surgical interventions included isolated CABG in 1515, single or multiple valve repair or replacement in 229 (isolated aortic valve replacement in 147, isolated mitral valve surgery in 80), and combined CABG/valve operations in 174.

Patient characteristics and outcomes according to the type of operation are reported in Table 1. Early outcomes were better in the isolated CABG cohort than the other patient groups. Patients in the combined group were older, had operations more frequently, and were predominately women compared with the CABG-only cohort. The operative times as well as lengths of stay in the intensive care unit and the hospital were significantly prolonged. All adverse cardiac events were increased in the combined group. Patients in the isolated valve group generally underwent elective operations and most were women. Outcomes were intermediate between the CABG and combined groups.

Troponin Level and Outcome
To establish a clinically important threshold value of troponin, the results were dichotomized, and the best cutoff value was determined according to the AUROC curve. Our analyses yielded a TnT cutoff of more than 0.8 µg/L as the most predictive, with the maximum discriminatory performance between those who presented with MACE and those who did not for the entire cohort of patients (Fig 1). A TnT value of 0.8 µg/L was also most discriminatory for patients specifically in the isolated CABG and isolated valve groups; a value of 1.3 µg/L was the threshold value most discriminatory for the patients who underwent a combined procedure (Fig 1).


Figure 1
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  		Fig 1. Receiver operating characteristic curves for all procedures (squares) and patients who had coronary artery bypass grafting (CABG) only (circles), valve only (triangles), and combined CABG/valve procedures (asterisk). The point of maximal inflection, where troponin is most predictive of poor major adverse cardiovascular events is indicated on each line (all, CABG-only and vValve-only is 0.8 µg/L; combined, 1.3 µg/L).

 
The entire study cohort was then divided into quintiles according to their peak postoperative troponin level (Q1, 0.0 to 0.39; Q2, 0.4 to 0.59; Q3, 0.6 to 0.79; Q4, 0.8 to 1.29; and Q5, > 1.3 µg/L). Adverse outcomes were observed to be infrequent in the lower quintiles (Q1 to 3; Table 2). A stepwise increase in the adverse outcomes was observed in the higher quintiles (Q4 and 5). The higher quintiles tended to have more of the combined patients than the lower quintiles. For this reason, further analyses were restricted to the isolated CABG patients. Characteristics of the CABG-only study cohort categorized according to their MACE status are presented in Table 3. Isolated CABG patients who had MACE were generally a higher-risk cohort, defined by older age, smoking history, creatinine exceeding 160 µmol/L, ejection fraction of less than 0.40, and New York Heart Association (NYHA) functional class III to IV (p = 0.008, p = 0.008, p = 0.0001 and p = 0.001, respectively); and they also had longer operative times than the non-MACE CABG patients. All adverse cardiac and noncardiac perioperative outcomes were increased in the MACE patients, including increased troponin levels.


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  		Table 2 Troponin T Quintile and Outcome in Entire Study Cohort
 

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  		Table 3 Characteristics and Outcomes of Coronary Artery Bypass Grafting-Only Patients by Major Adverse Coronary Event Status
 
We next compared the baseline characteristics as well as operative and postoperative outcomes of the CABG-only patients according to the troponin value (Table 4). In the CABG-only patients, 615 had peak TnT levels that exceeded 0.8 µg/L and 900 had values of less than 0.8 µg/L. Patients from the two groups had predominantly the same demographic characteristics, defined as having the same risk factors except for age and female sex, which were predominantly higher in the higher TnT group (p = 0.002, and p = 0.02, respectively) They also had the same severity of cardiac disease. The higher troponin group had more grafts performed and had longer operative times. Most adverse events were increased in the higher troponin group.


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  		Table 4 Characteristics and Outcomes of Coronary Artery Bypass Grafting-Only Patients According to Troponin T Cutoff
 
Multivariate logistic analysis was performed in the isolated CABG group to identify the best set of variables to predict MACE (Table 5). Backward, forward, and stepwise multivariable logistic regression yielded the same results. The best set of variables to predict MACE were TnT exceeding 0.8 µg/L, poor left ventricular function, age older than 70 years, female sex, NYHA class higher than II, longer CPB time, and preoperative cerebrovascular accident. The AUROC curve was 0.75, and the Hosmer-Lemeshow goodness-of-fit p value was 0.20.


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  		Table 5 Predictors of Major Adverse Cardiac Events Using Multivariable Regression Analysis
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
This study depicts a large group of patients who have had TnT levels correlated with perioperative cardiac morbidity and mortality after adult cardiac operations. Because as many as 95% of all patients undergoing cardiac procedures have an elevated postoperative troponin level, clinical interpretation of postoperative troponin concentrations is unclear and remains a controversial yet relevant issue [1–3].

The present study demonstrated that elevated TnT levels above the normal value (0.1 µg/L) were observed in more than 90% of patients within 24 hours after cardiac operations. However, a TnT elevation exceeding eight times upper limit of normal (ie, > 0.8 µg/L) was found to be an independent predictor of increased MACE after isolated coronary operations (odds ratio, 2.7; 95% confidence interval, 2.1 to 3.5; p < 0.0001). A higher threshold value of more than 1.3 µg/L was found to predict MACE after higher-risk combined cardiac operations. Other significant independent predictors of MACE included age older than 70 years, female sex, preoperative stroke history, left ventricular dysfunction, NYHA heart failure exceeding II, and prolonged CPB times. Notably, TnT levels of more than 0.8 µg/L had the largest odds risk ratio for poor outcome compared with the other independent predictors elucidated.

Previous Studies
The controversy surrounding the clinical interpretation of troponin levels after cardiac operations also arises as studies report results using the two different troponin isoforms, troponin T and troponin I. According to a meta-analysis performed in acute coronary syndrome patients, the two biomarkers have been shown to be equally as specific and sensitive to predicting MI and cardiac death [11]. Most studies report troponin I rather than troponin T values.

Historically, troponin I assays were manufactured by several companies, and the assays could be generally be implemented in hospital laboratories using existing hardware; thus, the troponin assay was usually more affordable and became more widely adopted [11, 12]. Problematically, much wider variation has occurred in the reporting of troponin I using assays from different manufacturers; for example, other investigators have reported threshold values of troponin I for MACE after cardiac operations ranging from less than 1 ng/mL to more than 40 ng/mL [7, 13–16].

In comparison, the TnT assay has a sole manufacturer. Consequentially, the TnT literature reports results that are consistent in their magnitude and range compared with TnI. Thus, it has been adopted by many larger and newer centers. Lehrke and colleagues [12] examined 204 patients undergoing isolated, elective CABG or valve operations, or both. Using ROC and multivariable analysis, they found TnT levels higher than a threshold of 0.6 µg/L to be a significant predictor of death. Baggish and colleagues [17] identified TnT levels exceeding 1.5 µg/L as the strongest predictor for longer intensive care unit stay in 222 patients analyzed [18]. These corroborate the external validity of our own results presented and support the benefits to using the T isoform assay.

Strengths and Limitations
The strength of this study is that it comprises a large contemporary cohort of patients undergoing adult cardiac procedures to answer this relevant research question. Using TnT also strengthens the clinical applicability of the thresholds and recommendations we have presented.

The study is limited by the inherent flaws of retrospective observational studies. The patient population is heterogeneous in the complexity of operations that were performed as well as the techniques that were used, such as myocardial protection, and the revascularization approach. Thus our results may not apply to other specific patient cohorts without further study into the various subgroups, including patients who had an acute MI within 30 days before operation and therefore were excluded from our study cohort.

Finally, our data provide no insights on the specific reasons for troponin elevation postoperatively. Nonetheless, the data suggest troponin should continue to be used for quality assurance as a means of detecting postoperative myocardial injury in order to rapidly intervene with early medical or repeat revascularization therapy to circumvent poor perioperative outcomes [2].

Conclusions
Cardiac troponin levels are frequently elevated after cardiac surgical procedures. We have shown in our study, that TnT concentrations were significantly different among the different patient groups, such as levels those undergoing isolated CABG or valve procedures being lower than patients undergoing combined operations.

A single measurement of TnT exceeding 0.8 µg/L in less than 24 hours after any isolated CABG procedure adds statistically significant, independent prognostic information for in-hospital outcomes, greater than any other predictor variable. Intuitively, these patients may benefit from increased monitoring and close medical care or specific interventions. A TnT level of less than 0.8 µg/L may be considered an innocuous event caused by heart manipulation and surgical trauma to cardiac tissue and thus of no prognostic significance.

For a decade, troponin levels measured in the emergency department revolutionized the management of acute coronary insufficiency. They were used as the guideline for diagnosis and directing treatment towards more invasive therapies. This study suggests that they should continue to play an important role in directing management of patients even after interventions such as cardiac procedures. Future prospective investigations of the predictive value of elevated levels of troponin isoforms after cardiac operations are certainly necessary in order to further improve patient outcomes.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Bonnefoy E, Filley S, Kirkorian G, et al. Troponin I, troponin T, or creatine kinase-MB to detect perioperative myocardial damage after coronary artery bypass surgery Chest 1998;114:482-486.[Medline]
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  3. Adams JE, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I Circulation 1993;88:101-106.[Abstract/Free Full Text]
  4. Swaanenburg JC, Loef BG, Volmer M, et al. Creatine kinase MB, troponin I, and troponin T release patterns after coronary artery bypass grafting with or without cardiopulmonary bypass and after aortic and mitral valve surgery Clin Chem 2001;47:584-587.[Free Full Text]
  5. Pichon H, Chocron S, Alwan K, et al. Crystalloid versus cold blood cardioplegia and cardiac troponin I release Circulation 1997;96:316-320.[Medline]
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  8. Koh TW, Hooper J, Kemp M, Ferdinand FD, Gibson DG, Pepper JR. Intraoperative release of troponin T in coronary venous and arterial blood and its relation to recovery of left ventricular function and oxidative metabolism following coronary artery surgery Heart 1998;80:341-348.[Abstract/Free Full Text]
  9. Fellahi JL, Gue X, Richomme X, Monier E, Guillou L, Riou B. Short-and long-term prognostic value of postoperative cardiac troponin I concentration in patients undergoing coronary artery bypass grafting Anesthesiology 2003;99:270-274.[Medline]
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  12. Lehrke S, Steen J, Sievers HH, et al. Cardiac troponin T for prediction of short- and long-term morbidity and mortality after elective open heart surgery Clin Chem 2004;50:1560-1567.[Abstract/Free Full Text]
  13. Croal BL, Hillis GS, Gibson PH, et al. Relationship between postoperative cardiac troponin I levels and outcomes of cardiac surgery Circulation 2006;114:1468-1475.[Abstract/Free Full Text]
  14. Sadony V, Korber 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]
  15. Carrier M, Pellerin M, Perrault LP, Solymoss BC, Pelletier LC. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting Ann Thorac Surg 2000;69:435-440.[Abstract/Free Full Text]
  16. Fellahi JL, Gue X, Richomme X, Monier E, Guillou L, Riou B. Short and long-term prognostic value of post-operative cardiac troponin I concentration in patients undergoing coronary artery bypass grafting Anesthesiology 2003;99:270-274.[Medline]
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