Correlations Between Cardiac Troponin I, Cardiac Troponin T, and Creatine Phosphokinase MB Elevation Following Successful Percut

Measurement of cardiac troponins has gained a leading position in the field of biochemical diagnosis of myocardial necrosis, as compared with conventional creatine kinase-MB (CK-MB) measurement. Data reported during the past decade have indicated superior efficacy, high sensitivity and specificity for troponin I (cTn-I), and cardiac troponin T (cTn-T) in the diagnosis of myocardial damage.^1–6 After percutaneous coronary intervention (PCI), cTn-I, cTn-T and CK-MB elevation is not rare and several studies have showed an association with adverse late outcomes.^4–8 Although the underlying pathophysiologic mechanism of post-procedural increase of three markers is quite similar, there are still discussions on the value of each marker in detecting “clinically significant” myocardial damage and defining the predisposition to long-term cardiac events. Accordingly, this study is designed to determine the extent of post-procedural marker elevation, the correlation between absolute levels of these three markers, the relationship between procedural myocardial damage and long-term cardiac events, and post-procedural cut-off values of each marker predicting the risk of worse event-free survival after angiographically successful PCI. Methods Study design and patients. This prospective, single center cohort study consisted of 115 consecutive patients (98 male, 17 female) who underwent coronary balloon angioplasty with or without stent implantation. Patients with stable angina or unstable angina were enrolled in the study between June 2000 and January 2001. Patients with pre-procedural elevated CK-MB or cTn-I, or cTn-T, patients undergoing primary angioplasty, andpatients with abnormal renal function were excluded before the intervention. Patients with unsuccessful angioplasty were excluded at the end of coronary angioplasty. The primary endpoint, major adverse cardiac events, was defined as a composite of acute myocardial infarction, death, recurrent angina and revascularization. Long-term follow-up data were obtained from out-patient clinic visits and/or telephone interviews with the patients, their relatives or their physician every three months. Institutional review board approval and informed consent from the patients for participation in the study were obtained. Percutaneous coronary intervention. Coronary lesions were assessed by quantitative coronary angiography with multiple orthogonal views by using the Philips Integris H 3000 (Philips Medical Systems, The Netherlands). Target lesions were characterized according to the American Heart Association classification.9 LP stents (IVT, Breda, The Netherlands) were used if stent implantation was required. We defined a successful PCI result as that which is stated by the American Heart Association/American College of Cardiology Task Force on Angioplasty.10 Routine care before and after the procedure was undertaken for all patients, including pre-treatment aspirin 300 mg once daily, ticlopidin 500 mg/day, three days before the procedure, which was continued for at least one month if the patient had a stent implantation. Intravenous heparin (10,000 IU) was administered at the beginning of the procedure. In-patients received a glycoprotein IIb/IIIa inhibitor, weight-adjusted heparin (70 IU/kg) was given. The sheaths were removed 4 to 6 hours after the procedure. Blood sampling. Blood samples for measurement of cTn-I, cTn-T, CK-MB were taken before and immediately after the procedure, and every 6 hours for the first 24 hours. The samples were drawn into tubes without an anticoagulant agent and were kept at room temperature for 30 minutes to allow clotting, centrifuged at 3,000 g for 10 minutes, and then stored in aliquots at a minimal temperature of - 20ºC until analysis. CK-MB activity was measured immediately. Biochemical analysis was performed by biochemists unaware of the patients’ therapies. Serum cTn-I values were measured with an enzyme immunometric assay (Immulite Troponin I Assay, Diagnostic Product Corporation, Los Angeles, California). Measurement of cTn-T was obtained with a cardio-specific assay (Elecsys Troponin T STAT immunoassay, Roche Diagnostics, Meylan, France). The upper limits of normal (ULN) values for cTn-T, cTn-I, and CK-MB are 0.1 ng/ml, 0.2 ng/ml, and 25 IU/L, respectively. Values for cTn-I that were higher than 0.20 ng/ml were measured quantitatively, while values less than 0.20 ng/ml could not be measured quantitatively and were thus expressed as negative. In cases where a parametric test was performed, the value was accepted as equal to 0.20 ng/ml. Myocardial infarction was defined as a raise in CK-MB levels higher than two times the ULN, or occurrence of new Q-waves. Statistics. Continuous data were expressed as mean ± standard deviation. Median values of post-procedural cardiac marker levels also were given. Categorical data were expressed as numbers per group (%). Correlations between the absolute rise of cTn-I, cTn-T, and CK-MB were performed with the Pearson correlation analysis, and concordances between positivity (higher than ULN) of three markers were evaluated with the kappa statistic. Logistic regression anlysis was used to determine the predictors of major cardiac events. The candidate parameters with the potential to influence the rate of major cardiac events were age, unstable angina, diabetes, AHA/ACC type C lesion, glycoprotein IIb/IIIa inhibitor administration, and post-procedural cTn-I, cTn-T, CK-MB elevation. The effects of each marker were tested by including four different categories of increase: > ULN, 4 x ULN. The Kaplan Meier method was used to construct a plot depicting time-to-clinical-events, and curves were compared using the log rank test. Survival analysis was performed for each above-mentioned subgroup. A p-value Clinical and interventional characteristics of patients. Patients with stable angina (n = 67) or unstable angina (n = 48) were included in the study. Four patients were excluded at the end of the coronary angioplasty procedure because of unsuccessful angioplasty. Consequently, the post-procedural minor myocardial damage was examined in the remaining 111 patients who had angiographically successful angioplasty. Clinical and interventional characteristics of the patients were presented in Tables 1 and 2. AHA/ACC type B lesions were the most frequent lesion type (63%), and left anterior descending artery was the most frequent target vessel (48%). Eighty-six percent of lesions were treated with stent implantation with and without predilation, and 14% of lesions were treated with balloon angioplasty alone. The indications for stent implantation were suboptimal result after balloon angioplasty in 41 lesions, non-occlusive coronary dissection in 20, and as a primary procedure (direct stenting) in 49 lesions. The percentage of diameter stenosis improved from 82 ± 10% before dilatation to 16 ± 8.0% after intervention. Side branch occlusion was observed in 5 patients (4.5%). Acute or subacute occlusion, death, and Q-wave-myocardial infarction were not observed during the in-hospital period. Six patients had a femoral hematoma that was relieved spontaneously. Myocardial injury markers. Post-procedural cTn-I elevation was observed in 45 patients (40%). The mean post-procedural maximum cTn-I values was 2.7 ± 7.6 ng/m (median 0.2 ng/ml), and the mean cTn-I value in patients with a cTn-I level higher than the ULN was 7.5 ± 11 ng/ml (median 1.9 ng/ml). Twelve patients (10.8%) had a cTn-I increase less than 2 x ULN, 9 patients (8%) 2 to 4 x ULN, and 24 patients (21%) > 4 x ULN. The mean post-procedural maximum cTn-T level was 0.23 ± 0.63 ng/ml (median 0.03 ng/ml). A total of 27 patients (24%) had post-procedural cTn-T levels above ULN, and the mean cTn-T level in those patients was 0.9 ± 1.14 ng/ml (median 0.4 ng/ml). Patients with cTn-T elevations 4 x ULN were 9 (8%), 6 (5.4%), and 12 (10.8%), respectively. A significant percentage of the patients with elevated cTn-I and cTn-T were in > 4 x group. Both cTn-I and cTn-T reached maximum levels at six and twelve hours in a significant percentage of patients (68%). Post-procedural maximum CK-MB level was measured as 22 ± 19 IU/L (median 17 IU/L). A total of 17 patients (15%) had post-procedural CK-MB levels > ULN, and the mean maximal CK-MB levels in those patients was 54 ± 35 IU/L (median 39 IU/L). Eleven patients (10%) had CK-MB elevation 4 x ULN. Accordingly, 6 patients (5.4%) experienced post-procedural non-Q-wave myocardial infarction defined by a CK-MB increase > 2 x ULN. There were strong correlations between the post-procedural absolute values of three markers (Figure 1). When the ULN was used as a reference limit, there was a significant concordance with the post-procedural cTn-I and cTn-T (kappa = 0.59). However, there was no significant association between the CK-MB level and cTn-T (kappa = 0.42) and cTn-I (kappa = 0.38). Long-term follow-up. During the follow-up period of 21 ± 8.2 months (range 1 to 31 months), the primary end point occurred in 29 patients (26%). Acute myocardial infarction occurred in 3 patients (2.7%), death in 4 patients (3%), death or myocardial infarction in 6 patients (5%), recurrent angina in 7 patients (6%), and repeat revascularization in 16 patients (14%). The Kaplan Meier survival curve revealed that patients who had an increase in cTn-I (log rank = 6.3; p = 0.012), cTn-T (log rank = 5.5, p = 0.018), or CK-MB (log rank = 5.2, p = 0.02) > ULN had significantly decreased event-free survival rates compared to those without a marker increase. Minor elevations in cTn-I and cTn-T ( 4 x in cTn-I, cTn-T, and an increase of 2 to 4 x in CK-MB proved to have a marked impact on event-free survival rates (Figures 2–4). Logistic regression analysis revelaed that elevations > ULN, 4 x ULN were not the predictors of major cardiac events for all three markers. Analysis was repeated by using the absolute values of these markers, and they were not found to be the predictors. Presentation with unstable angina showed a trend without statistical significance (p = 0.09, odds ratio = 1.1, 95% CI = 0.98–1.28). Discussion This prospective study shows that there were significant correlations between the absolute values of all three markers after angiographically successful PCI. While cTn-I and cTn-T showed a significant concordance, CK-MB level was not significantly associated with these two markers. The most sensitive marker for detecting post-PCI myocardial injury was cTn-I, because it was the most frequent post-PCI positive marker. None of the three markers were corraletes of long-term cardiac events, but all of them played a significant role in the duration of event-free survival. A > 4 x ULN increase in cTn-I and > 4 x ULN increase in cTn-T, and a 2 to 4 x ULN increase in CK-MB were the cut-off values for the occurrence of a decremental effect on event-free survival rates. Myocardial damage post-PCI has been shown to be related to the development of side branch occlusion, abrupt vessel closure, no-reflow, athero-thrombotic or platelet embolization, dissections, severe vessel spasm, and peri-procedural infarction.^7,11,12 Although cardiac marker elevation is an unexpected result after an uneventful, visually successful PCI, studies using very specific measures of myocardial necrosis show that a minor increase in cardiac markers may uncover clinically and electrocardiographically inapparent minor myocardial damage. When the extent of elevation was considered, significant correlations were detected between the three markers. There was also a significant concordance between the troponins. CK-MB showed discordance, which may possibly be due to a lower sensitivity in detecting minor necrosis, as was reported previously.¹³ Release kinetics of cTn-I and cTn-T were found to be similar; both had peak values at 6 and 12 hours post-PCI, and the extent of increase at different time points was similar. These results suggest that cTn-T can be used with comparable accruracy in detecting myocardial necrosis, although cTn-I is slightly more sensitive. Because elevated cTn-I and cTn-T after apparently successful coronary interventions is fairly common, it has been viewed as a relatively benign phenomenon. While some reports show that cardiac marker elevation is associated with a substantial increase in mortality and reduced event-free survival rates,^13,14 there are a considerable number of studies that have reported no association between peri-procedural minor myocardial injury and late outcomes.^15–18 The current study shows that a cTn-I and cTn-T increase > 4 x is associated with a significantly lower event-free survival rates. This result suggests that minor troponin elevations ( 2 x ULN, which precludes making any further conclusive comments. It is apparent that the extent of peri-procedural necrosis may not be the only predictor of a poor prognosis, because some of the patients who did not have minor necrosis experienced major cardiac events. Additionally, the frequency of adverse cardiac events was relatively higher after the first year of follow-up, resulting in a relatively sharp decline and seperation of event-free survival curves. There was a considerable time interval between the intervention and the occurrence of the majority of end points, suggesting that the causes of the end points were somewhat unrelated to the peri-procedural minor myocardial necrosis. Plaque and vessel wall constituents, including lipid, matrix, endothelial cell, and platelet thrombus can embolize following dilatation of the target lesion. Peri-procedural necrosis not only reflects the embolization plaque constituents, but may also indicate an extensive atherosclerotic burden of the entire coronary arterial tree and/or more lipid-laden plaques. This plaque burden and/or the lipid-filled vulnerable plaques in places other than the PCI target site may be responsible for the long-term cardiac events. Late separation of event-free survival curves also support this theory by suggesting that the progression and complication of existing atherosclerotic plaques and/or the development of de novo lesions, rather than early events, is due to the target lesion. Conclusion Cardiac marker elevation may frequently occur after PCI. Although the cTn-I is the most sensitive marker, cTn-T can also be used as an alternative assay with a significant correlation, concordance, and prospective value. Both troponins have predictive value for long-term event free survival, with a fourfold increase in particular associated with worse event-free survival. The marker elevation per se may not be the primary cause of death or other cardiac events, but may be a marker indicating a greater burden of vulnerable and lipid-rich plaques, and relatively widespread atherosclerosis. These findings have important implications for daily interventional cardiology practice and highlight the risks associated with the common practice of overlooking or ignoring small infarctions as a complication of PCI. Nevertheless, further prospective studies are needed to stratifify the different levels of risk and to more fully understand the mechanism of event predisposition. Such studies would advance our efforts to prevent cardiac events following PCI.

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