ABSTRACT


Background: Biomarkers of myocardial injury are important tools in the diagnosis and management of patients with acute cardiovascular disease. cTnI levels measured 24 hours after cardiac surgery has been reported to be independently predictive of short and long term mortality.

Aim: To evaluate the usefulness of cTnI as a marker of myocardial injury after CABG in our laboratory, we measured cTnI level after CABG operation at Al-Salam Hospital in Aleppo, Syria and correlated it with the morbidity and mortality outcome of this operation.

Method: Troponin I (cTnI) level was measured after coronary artery bypass grafting operations (CABG) at Al-Salam Hospital in Aleppo, Syria. Consecutive measurements were obtained prospectively in 333 such patients. The patients were divided into two groups: Group I with cTnI level less than 10 ng/ml (256 patients), and Group II with cTnI level more than 10 ng/ml (77 patients). The two groups were similar in all aspects except for significantly more smoking, and more use of IMA graft in group I patients. There was a trend towards using off-pump technique (OPCAB) in Group I patients, but this difference was not statistically significant.


Results: Group II patients had significantly higher cardiac (13%) and non-cardiac (12%) complications than group I (4%, and 6.7% respectively). Group II patients also had higher 30 day mortality (6.5%) than group I (0.4%). The higher morbidity and mortality in group II was statistically significant even after adjusting for OPCAB and IMA differences. The sensitivity of cTnI test in our lab was 46%; the specificity 81%; the positive predictive value 31%; the negative predictive value 89%; and the relative risk of cTnI >10 ng/ml was 2.85 .

Conclusion: cTnI level is an important predictor of early morbidity and mortality after CABG operation.

Heart Views 2007;8(1):6-9  © Gulf Heart Association 2007.



Introduction


     
      Biomarkers of myocardial injury are important tools in the diagnosis and management of patients with acute cardiovascular disease. Transaminases were known to be increased in acute myocardial infarction, but they were not specific enough to be clinically useful. Creatine kinase (CK) and its MB isoenzyme (CK-MB) were used for many years as useful markers of myocardial injury. However, the American College of Cardiology and the European Society of Cardiology in 2000, acknowledged that elevation of cardiac troponin I (cTnI) and T (cTnT) is a “cornerstone” in the diagnosis of acute myocardial infarction, and that cTnI and cTnT had replaced CK-MB as the analysis of choice for this diagnosis1. cTnI levels measured 24 hours after cardiac surgery was reported to be independently predictive of short and long term mortality2.

     To evaluate the usefulness of cTnI as a marker of myocardial injury after CABG in our lab, we measured cTnI level after CABG operation at Al-Salam Hospital in Aleppo, Syria and correlated it with the morbidity and mortality outcome of this operation.


Method



    Serum level of cTnI was measured prospectively in 333 consecutive CABG patients. We excluded all redo CABG operations, and patients who required a combined procedure, such as valve replacement or left ventricular aneurysm repair, when performed at the same time with CABG operation.
 

Table 1: Medical characteristics of Group I and Group II patients:

The measurement of cTnI level was done only once on the next morning of the CABG operation, about 16-18 hours postoperatively. The quantitative serum level of cTnI was measured in our lab using immunometric assay of Immulite analyzer by DPC, and reported in nanograms/ml (ng/ml). The patients were followed up for a period of 30 days during their hospital stay and after being discharged. Mortality and major morbidities, such as arrhythmia, myocardial infarction, bleeding, pleural effusion, wound infection, CNS, or gastrointestinal complications were recorded.

     Statistical analysis was done using standard t-test, comparison of two proportions, and chi square. P value less than 0.05 was considered statistically significant. The sensitivity, specificity, predictive value, and relative risk were calculated for this diagnostic test results in correlation with the observed short term mortality and morbidity.

       

Results


   
     We selected a cut off value of cTnI level of 10 ng/ml as the upper reference limit of “negative” value for the test. This level was selected based on studies reported in the medical literature for postoperative cTnI levels2. Accordingly, the patients were divided into two groups: Group I where cTnI level was less than 10 ng/ml and Group II where cTnI level was equal to, or more than 10 ng/ml.

     There were 256 patients in Group I, and 77 patients in Group II. The two groups were similar in all clinical aspects except for significantly more IMA graft use in Group I than in Group II (93% and 75% respectively). Smoking was also significantly more common in Group I than in Group II (50% and 31% respectively). Diabetes was more common in Group I patients, and there was a trend towards using off-pump technique (OPCAB) in Group I patients, but these differences were not statistically significant (Table 1).

       Patients with the higher cTnI levels (Group II) had significantly more major morbidity than Group I (25% and 11% respectively), (P value 0.002). Cardiac morbidity, such as arrhythmia, infarction, shock, and need for IABP, was significantly higher in Group II than in Group I (13% and 4% respectively), (P value 0.008). There was a tendency towards increased non-cardiac morbidity in Group II patients. Non-cardiac morbidity, such as bleeding, confusion, stroke, wound infection, pleural effusion, renal insufficiency, and gastrointestinal complications, were more common in Group II than in Group I (12% and 6.7% respectively) but this difference was not statistically significant. Group II patients had significantly higher 30 days mortality rate than Group I (6.5% and 0.4%), (Table 2). It was noted that cTnI level was lower when off-pump technique (OPCAB) is used. OPCAB operation was performed in 32 patients, and their average post-operative cTnI level was 4.3 ± 8.6 (0.1 – 36) ng/ml, while in 301 patients where a standard CABG operation with cardiopulmonary bypass was used, the average cTnI level was 14 ± 31 (0.2 – 180) ng/ml (P value < 0.05).
 

Table 2: Morbidity and mortality rates in Group I and Group II

      The average number of grafts/patient was also lower in OPCAB operation than in CABG (2.1 and 3.3 respectively). In urgent procedures, OPCAB operation was less likely to be done than CABG (9.4% and 29% respectively), and there was no mortality in OPCAB operations.

      Although IMA graft was more commonly used in Group I, but there was no statistically significant difference in 30 days mortality rate between patients who did not receive IMA graft in Group I and Group II (0 and 2 respectively,
P value 0.17).

      In our lab, the statistical analysis of cTnI level in detecting possible morbidity or mortality after myocardial revascularization procedures showed that sensitivity is 46%, specificity 81%, positive predictive value 31%, negative predictive value 89%, and relative risk 2.85.

 

    
Discussion


  
      Troponins and tropomyosin are protein complex that regulate the calcium-mediated interactions of actin and myosin in cardiac and skeletal muscle contraction. There are three units in the troponin complex: troponin I (inhinbitory), troponin T (Tropomyosin binding), and troponin C (Calcium binding activator of contraction), Figure 1.
 

Fig. 1: Diagram of cardiac troponin complex.

        The cardiac isoform of troponin C is present also in the slow-twitch skeletal muscles, and thus, it does not have cardiac specificity, and it is not useful as a marker of cardiac muscle injury1. Cardiac troponin I (cTnI) is not expressed in skeletal muscles or other human tissues, and there is only one cTnI isoform in myocardial tissue which made it possible to generate highly specific monoclonal antibodies for it's assay. Immunoassay of cTnI is a highly specific method in the evaluation of myocardial injury1.

       Human myocardium contains 4 isoforms of cardiac troponin T (cTnT), but only one of them is characteristic of the normal adult heart. However, fetal forms of cTnT are re-expressed in cardiac and skeletal muscle injury and regeneration. Highly specific antibodies to cTnT were developed by 1997, and the false-positive elevations from skeletal muscle were eliminated. Thus, the assay used to measure cTnT levels now has cardiac specificity equivalent to that of assays for cTnI, and can provide comparable information about myocardial injury except in patients with renal failure where cTnT levels may be elevated without other clear evidence of acute myocardial injury1.

      In cardiac operations, some myocardial damage is inevitable due to multiple factors, such as: global myocardial ischemia during aortic cross clamp, cardiopulmonary bypass (activation of platelets, complement, and cytokines), adequacy of cardioplegia, manipulation of the heart, coronary embolism, and graft occlusion. Irrespective of the mechanism, biomarkers of myocardial injury, such as cTnI, can help in evaluating the extent of myocardial damage, and may help in detecting clinically significant degree of myocardial injury2.

      Several studies did report the usefulness of cardiac troponins in the diagnosis of myocardial infarction and the prognosis after cardiac operations2-4. Croal et al measured cTnI 2 and 24 hours postoperatively in 1365 patients. The 24 hour levels correlated significantly with 30 days, 1 year, and 3 year mortality2. In our study we elected to measure cTnI level one time postoperatively, on the morning of the first postoperative day (about 18 – 20 hours postoperatively). Based on previously published data in similar situation, we selected 10 ng/ml as the cut-off level in our lab. We only included CABG operations to evaluate this biomarker specifically in these operations. The study was done prospectively including all patients who satisfied the inclusion criteria.

       Clinical characteristics of Group I patients with cTnI <10 ng/ml were similar to those of group II except for more smokers and more diabetic patients in Group I, and IMA graft was used more in Group I. cTnI levels are not known to be affected by smoking nor by diabetes. The use of IMA graft may affect morbidity and mortality. However, there was no statistically significant difference in early postoperative morbidity and mortality in our patients between those who received IMA graft and those who did not.

      In our lab, the next morning cTnI level >10ng/ml significantly correlated with increased cardiac morbidity, and 30 days mortality after CABG operation. This finding has practical importance, because it demonstrates that one time measurement of this biomarker of myocardial injury has significant clinical prognostic value. The relative risk of this test in our hospital was 2.85 which indicates that the possibility of major cardiac morbidity or mortality is 2.85 times more likely to occur in patients with cTnI level > 10 ng/ml than in those with cTnI level < 10 ng/ml. It should be also noted that the sensitivity and the positive predictive value of this test were low (46 and 31% respectively), while the specificity and the negative predictive value were higher (81 and 89% respectively) which indicate that, after CABG operation, we should not be very alarmed if cTnI level is high
(> 10 ng/ml), and we can be more assured when TnI level is low (< 10 ng/ml). Obviously, this test can not be used as a sole prognostic marker, but it is important information that should be used wisely in conjunction with other clinical and diagnostic data.

     One major limitation of this study is that it excluded all patients who expired in the operation theater or in the intensive care unit before the first cTnI sample was obtained on the first postoperative day. However, biomarkers are usually not very useful prognostic indicators in such grave crisis situations.
 

Conclusion


    
     cTnI level < 10 ng/ml is a useful negative predictor of 30 days mortality and early cardiac morbidity after CABG operation, even when measured one time on the morning of the first postoperative day. Patients with higher levels should be observed and monitored more carefully as they may have 2.85 higher relative risk for complications than patients with lower levels.¨


References:



1. Babuin L, and Jaffe A : Troponin: the biomarker of choice for the detection of cardiac injury. CMAJ. 2005;173 (10):1191-1202.

2. Croal BL, Hillis GS, Gibson PH, Fazal MT, El-Shafei H, Gibson G, Jeffrey RR, Buchan KG, West D, and Cuthbertson BH : Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery. Circulation. 2006; 114 (14):1468-1475.

3. Carrier M, Pellerin M, Perrault LP, Solymoss BC, and Pelletier LC. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann Thorac Surg 2000; 69 (2):435-440.

4. Januzzi JL, Lewandroski K, MacGillivray TE, Newell JB, Kathiresan S, Servoss SJ, and Lee-Lewandrowski E. A comparison of cardiac troponin T and creatine kinase-MB for patients after cardiac surgery. J Am Coll Cardiol 2002; 39(9):1518-23.