Clinical Investigations

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1 Clinical Investigations Risk Factors of Cardiac Troponin T Elevation in Patients with Stable Coronary Artery Disease After Elective Coronary Drug-Eluting Stent Implantation Zhang-Wei Chen, MD; Ju-Ying Qian, MD; Jian-Ying Ma, MD; Lei Ge, MD; Jun-Bo Ge, MD Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China Address for correspondence: Junbo Ge, MD, FESC, FACC, FSCAI Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases 180 Fenglin Road Shanghai , PR China Ge.junbo@hotmail.com Background: Cardiac troponin T elevation after coronary intervention has been demonstrated to be associated with the prognosis of coronary artery disease (CAD). However, there were few studies about comprehensive risk factors analysis of troponin T elevation after elective drug-eluting stent (DES) implantation. Hypothesis: The prognosis of CAD after coronary interventions was associated with clinical and procedural risk factors of CAD, such as age, hypertension, severity extent of CAD and so on. Methods: From March to December in 2010, patients with stable CAD were admitted for elective coronary intervention in our hospital. They were divided into an elevated troponin T group and a normal troponin T group by postprocedural troponin T. Clinical factors, laboratory-test factors, and angiographic factors (such as gender, age, cholesterol, Gensini score, and others) were analyzed. Results: A total of 209 patients with an average age of 64.0 ± 9.9 years were enrolled in the study: 70 patients with elevated troponin T ( 0.03 ng/ml) after DES implantation and 139 patients with normal troponin T (<0.03 ng/ml). After univariate analysis, we found that age, hypertension, total cholesterol, low density lipoprotein-cholesterol (LDL-C), Gensini score, number of stenosed vessels, and total implanted stents were associated with postprocedural troponin T elevation. According to the results of multivariate analysis, we found that age, total cholesterol, number of stenosed vessels, and number of implanted stents were independent risk factors of postprocedural troponin T elevation. Conclusions: Age, serum total cholesterol, number of stenosed vessels, and number of implanted stents could be independent risk factors of troponin T elevation after elective DES implantation. Introduction Cardiac troponin T, which is a highly sensitive and specific biomarker for myocardial injury, 1 has been demonstrated to be associated with the prognosis of coronary artery disease (CAD). Several reports have shown that an increase in cardiac troponin T can be found in a proportion of patients after percutaneous coronary intervention (PCI), ranging from less than 10% to almost 50%. 2,3 It has also been reported that elevation of troponin T is relatively common among patients with stable coronary artery disease undergoing PCI and is an independent prognostic indicator of ischemic complications. 4,5 However, there were few studies about comprehensive risk factor analysis of troponin T elevation in patients with stable CAD after drug-eluting stent (DES) implantation. Therefore, we designed this clinical study to Z. Chen and J. Qian contributed equally to the article. This study was supported by grants from the National Natural Science Foundation of China ( and ). The authors have no funding, financial relationships, or conflicts of interest to disclose. 768 comprehensively elaborate the risk factors of troponin T elevation after DES implantation in patients with stable CAD, including clinical factors, laboratory-test factors, and angiographic factors. Methods Study Population and Measurements From March to December in 2010, a total of 209 patients referred to our hospital with stable angina pectoris for elective coronary intervention were enrolled in this study. The inclusion criteria were as follows: (1) patients 18 to 85 years old; (2) providing a complete clinical history; (3) underwent DES implantation; and (4) normal preprocedural troponin T (below the 10% coefficient of variation [CV] value, <0.03 ng/ml) 6 and creatine kinase (CK) muscle and brain subunits (MB) (<23 U/L). The exclusion criteria were as follows: (1) acute coronary syndrome; (2) elevated cardiac troponin T ( 0.03 ng/ml) and CK-MB ( 23 U/L) before coronary intervention; (3) heart failure, cardiomyopathy, congenital heart diseases, and heart valve diseases; (4) treated coronary lesion was chronic total occlusion; (5) recent surgery or trauma; (6) active Received: June 30, 2011 Accepted with revision: August 17, 2011

2 chronic inflammation; (7) dysfunction of hematological and immunological system; or (8) carcinoma or a condition treated with immunosuppressive agents. The study was approved by the local ethics committee and informed consent was obtained from each patient. Measurements and Population Grouping The clinical characteristics of all patients including gender, age, smoking history, primary hypertension, diabetes, and hyperlipidemia were recorded before coronary angiography. Fasting blood samples before and after angiography were drawn to detect blood biochemistry and complete blood-cell counts. Cardiac troponin T was measured before and within 24 hours (from 10 to 20 hours) after coronary intervention. Serum level of troponin T was analyzed by immunoturbidimetry (Hitachi automatic biochemistry analyzer). The upper limit of normal for the assay is <0.03 ng/ml. Patients with postprocedural troponin T 0.03 ng/ml were defined as elevated troponin T group (n = 70) and others were defined as normal troponin T group (n = 139). Coronary Angiography and Intervention Coronary angiography was performed in all patients after admission. The patient was considered as having CAD once obstructive lesion of 50% reduction of lumen diameter existed in at least 1 of the coronary arteries. The severity of coronary artery disease was evaluated by: 1. Number of stenosed vessels: represented as the number of major stenosis in epicardial arteries with at least 1 obstructive lesion ( 50% reduction of lumen diameter), including left anterior descending artery (LAD), left circumflex artery (LCX), right coronary artery (RCA), and left main artery (LM). 2. Gensini score 7 for graded narrowing of the lumen: 1 for 1% to 25%, 2 for 26% to 50%, 4 for 51% to 75%, 8 for 76% to 90%, 16 for 91% to 99%, and 32 for total occlusion. This score is multiplied by a factor accounting for the importance of the lesion position in the coronary arterial tree; eg, 5 for LM, 2.5 for proximal LAD, and 1 for proximal RCA. The severity of disease was expressed as the sum of the scores for individual lesions. Gensini score, number of stenosed vessels, treated vessels, and implanted stents of each enrolled patient were recorded by observers who were blinded to the results of laboratory tests and grouping. In addition, lesion characteristics, such as diffuse lesion, bifurcation lesion and calcified lesion, were also recorded. Statistical Analysis Data were presented as the percentage or mean ± standard deviation (SD). Chi-square analysis was used to compare the frequency for categorical variables, and Student t analysis was used to compare the mean for continuous variables. Correlation analysis (Spearman test) was performed to evaluate the correlations between serum level of postprocedural troponin T and risk factors. Multivariable analysis (logistic) was performed to identify independent risk factors of elevated post-procedural troponin T. Statistical analyses were performed with SPSS software (version 18.0; SPSS Inc., Chicago, IL). All P values were 2-sided, and P < 0.05 was considered statistically significant. Results Demographic Data of Patients A total of 209 patients were enrolled in this study. There were 148 males with an average age of 62.4 ± 9.9 years and 61 females with an average of 68.1 ± 9.0 years. Their clinical characteristics and biochemical profiles were presented in Table 1. Compared with patients in normal troponin T group (n= 139), patients with elevated postprocedural troponin T (n = 70) had higher average age (68.1 vs 62.0 years; P < 0.01) and higher prevalence of hypertension (81.4% vs 61.9%; P < 0.01). In addition, plasma levels of total cholesterol and low density lipoproteincholesterol (LDL-C) were higher in patients with elevated troponin T than those with normal troponin T. Regarding the angiographic and interventional factors, we analyzed the difference concerning Gensini score, number of stenosed vessels, treated vessels, and implanted stents between the patients with and without elevated troponin T, as shown in Table 1. We found that patients with elevated postprocedural troponin T had more severe CAD and underwent more stents implantation. Association Between Postprocedural Troponin T and Risk Factors In order to identify the correlation between serum level of postprocedural troponin T and risk factors (including age, total cholesterol, LDL-C, and Gensini score), the correlation analysis (Spearman test) was performed. It was shown that there were significantly positive correlations between postprocedural troponin T and age (r = 0.336; P < 0.01) and Gensini score (r = 0.368; P < 0.01), shown in Figure 1. However, there were no significant correlations between troponin T and cholesterol. The patients were further classified into 4 subgroups by serum level of postprocedural troponin T: group A, 0.09 ng/ml (triple upper limit of normal troponin T); group B, ng/ml (lower than triple upper limit and higher than normal upper limit); group C, 0.01 to 0.03 ng/ml; and group D, <0.01 ng/ml. We found that there was a significantly higher Gensini score in patients with higher postprocedural troponin T, as shown in Figure 2A. In addition, the number of stenosed vessels was 2.1, 2.3, 1.7, and 1.4 in these 4 groups, respectively. Numbers of treated vessels (1.4 vs 1.3 vs 1.0 vs 1.0) and implanted stents (2.0 vs 1.7 vs 1.4 vs 1.2) in patients with higher troponin T were higher than those with lower level, as shown in Figure 2B. Association Between Postprocedural Troponin T and Angiographic Characteristics Characteristics of angiographic lesion, including diffuse lesion, thrombus present, bifurcation lesion, and calcified lesion, were recorded in our study. According to the results 769

3 Table 1. Comparison of Demographic Data Between Patients with and Without Troponin T Elevation After Elective PCI Clinical factors Elevated Troponin T Group (n = 70) Normal Troponin T Group (n = 139) P Male (%) 47 (67.1%) 101 (72.3%) Age (y) 68.1 ± ± 9.7 <0.01. Hypertension (%) 57 (81.4%) 86 (61.9%) <0.01 Hyperlipidemia (%) 44 (62.9%) 70 (50.4%) Diabetes (%) 20 (28.6%) 27 (19.4%) Smoking (%) 24 (34.3%) 67 (48.2%) Laboratory-test factors Serum creatinine (μmol/l) 76.7 ± ± Serum uric acid (mmol/l) ± ± Fibrinogen (g/l) ± ± Total cholesterol (mmol/l) 4.41 ± ± 0.88 <0.01 Triglyceride (mmol/l) 2.07 ± ± LDL-C (mmol/l) 2.44 ± ± HDL-C (mmol/l) 1.11 ± ± Lipoprotein-a (mmol/l) ± ± Preprocedural CK-MB (U/L) 13.6 ± ± Postprocedural CK-MB (U/L) 17.4 ± ± Preprocedural ctnt (ng/ml) <0.03 ng/ml <0.03 ng/ml Postprocedural ctnt (ng/ml) ± ± <0.01 Angiographic factors Gensini score 37.9 ± ± 15.7 <0.01 Number of stenosed vessels 2.3 ± ± 0.7 <0.01 Number of treated vessels 1.3 ± ± 0.2 <0.01 Number of stent implantation 1.8 ± ± 0.5 <0.01 Abbreviations: CK-MB, creatine kinase-mb; ctnt, cardiac troponin T; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoproteincholesterol; PCI, percutaneous coronary intervention. Bold indicates P is less than of chi-square analysis, we found there was higher prevalence of diffuse lesion (55.7% vs 28.8%; P < 0.01) and bifurcation lesion (20% vs 9.4%; P = 0.028) in patients with elevated postprocedural troponin T than those with normal level, shown in Figure 3. There was no significant difference of prevalence of thrombus present and calcified lesion between 2groups. Multivariate Logistic Regression Analysis for Elevated Postprocedural Troponin T Logistic analysis was used to evaluate the association between postprocedural troponin T and risk factors. In this analysis, postprocedural troponin T elevation was employed as a dependent variable, while age, hypertension, total cholesterol, LDL-C, Gensini score, number of stenosed vessels, and total stents implanted were set as independent variables (Table 2). After adjustment by other associated factors, the risk of postprocedural troponin T elevation was increased 177% and 105% by number of implanted stents and stenosed vessels, respectively. Age (odds ratio [OR] = 1.050; 95% confidence interval [CI], ; P = 0.014) and higher total cholesterol (OR = 2.979; 95% CI, ; P = 0.016) also increased the risk of postprocedural troponin T elevation. Discussion Cardiac troponin T is highly sensitive and specific biomarkers for myocardial injury. 1 In the setting of unstable angina or non-st-segment elevation myocardial infarction (MI), their elevation is associated with more complex coronary 770

4 (A) (B) Figure1. Correlations between postprocedural troponin T level and (A) age and (B) Gensini score. Figure 2. The difference of (A) Gensini score and (B) number of stenosed vessels, treated vessels, and implanted stents in 4 different groups classified by postprocedural troponin T (Group A, 0.09 ng/ml; group B, ng/ml; group C, ng/mL; andgroup D, <0.01 ng/ml). artery stenosis, visible thrombus, plaque rupture, and multivessel CAD. 8,9 Moreover, in the setting of acute coronary syndrome, patients with baseline elevations of troponin T have a higher risk of death or recurrent MI early after presentation, 10,11 after PCI 12 and during long-term follow up. 13 It has also been demonstrated that elevation of troponin T is relatively common among patients with stable CAD undergoing PCI and is an independent prognostic indicator of ischemic complications. 4,5 Prasad et al found that an isolated minor elevation in troponin T after PCI without a rise in CK-MB following PCI provided long-term prognostic information regarding mortality and MI. 6 Several reports have shown that an increase in cardiac troponin T can be found in a proportion of patients after PCI ranging from less than 10% to almost 50%. 2,3 The proportion of elevation of troponin T after PCI in our study was 33.5% (70/209). This supports that cardiac troponin T elevation was quite common after PCI in patients with stable CAD. The mechanisms responsible for cardiac enzyme release after PCI were related to myocardial ischemic injury or necrosis, caused by occlusion due to embolization, 14,15 side branch occlusion due to plaque shifting, 16,17 coronary dissection, 18 coronary spasm, 16 hypotension requiring administration of vasopressors, 19 and prolonged ischemia due to balloon inflations. 20 There were few studies comprehensively elaborating the risk factors of troponin T elevation after PCI in patients with stable CAD. Prasad et al 6 found that patients with elevated postprocedural troponin T underwent more multivessel coronary intervention and had more complicated procedural outcomes, such as coronary artery dissection and branch vessel occlusion. Furthermore, patients with a rise in troponin T were older, more likely to have moderate to severe angina, a history of congestive heart failure, an ejection fraction <40%, and peripheral vascular disease In our study, we analyzed the risk factors of postprocedural troponin T elevation from 3 aspects, including clinical factors (age, gender, history of hypertension, diabetes, and smoking), laboratorytest factors (serum cholesterol, triglyceride, uric acid, and fibrinogen), and angiographic factors (angiographic characteristics, Gensini score, number of stenosed vessels, 771

5 (A) (B) (C) (D) Figure3. The difference of the prevalence of (A) diffuse lesions, (B) bifurcation lesions, (C) calcified lesions, and (D) thrombus present between patients with or without postprocedural troponin T elevation after PCI. Abbreviation: PCI, percutaneous coronary intervention. Table 2. Multivariate Logistic Regression Analysis for Troponin T Elevation in Patients With Stable CAD After Elective PCI r 95% Confidence Intervals Age Hypertension Total cholesterol LDL-C Gensini score Number of stenosed vessels Number of stents implantation Abbreviations: CAD, coronary artery disease; LDL-C, low density lipoprotein-cholesterol; PCI, percutaneous coronary intervention. Bold indicates P is less than and number of implanted stents). According to the univariate and multivariate analysis, we found that age, serum total cholesterol, number of stenosed vessels, and number of stents implanted were independent risk factors of troponin T elevation after elective DES implantation. The relationship between postprocedural cardiac marker elevation and adverse long-term outcome was very intriguing. One possible explanation was that regional myocardial damages occurred or local scar formed in patients with elevated troponin T. 21 Myocardial injury could impair left ventricular function and predispose to arrhythmic events, P which influenced the survival and clinical outcomes. Alternatively, postprocedural troponin T elevation per se could be a biomarker of severe coronary artery disease, vulnerable coronary plaques, 22 or complicated coronary procedure. Our study supported the latter opinion. Older age, higher cholesterol, and higher Gensini score in patients with elevated troponin T implied more severe CAD. The atherosclerotic plaque burden in these patients might be greater than that of younger patients and patients with lower cholesterol levels. Therefore, the incidence of troponin T elevation could be higher after coronary angioplasty and stent implantation. Of course, multivessel stenosed and multistent implantation could also result in more atherosclerotic debris dropping, which impaired or occluded coronary microcirculation. Interestingly, Gensini score was not an independent predictive factor for postprocedural elevated troponin T (OR = 1.014; P = 0.268) after multivariate analysis, although we found a significant difference in Gensini score between 2 groups of patients after univariate analysis. After further analysis, we found that if the factor number of stenosed vessels was excluded from the independent variables, the OR of the Gensini score will reach statistical difference (OR = 1.032; 95% CI, ; P = 0.003). We speculate that there might be an overlapping or similar effect between Gensini score and number of stenosed vessels on troponin T, which influenced the statistical result of the Gensini score. In addition, the small sample size of this study might be another reason. This study had several limitations: (1) small number of patients included; (2) lack of postprocedural echocardiography data for each patient; (3) classical biomarkers 772

6 of inflammation, such as C-reactive protein (CRP), were not routinely detected; and (4) angiographic characteristics were not further measured by intracoronary ultrasound. These limitations will be taken into account in our further clinical research and prospective studies. Conclusion Cardiac troponin T elevation in patients with stable CAD after elective PCI was associated with age, hypertension, cholesterol, Gensini score, diffuse lesion, bifurcation lesion, number of stenosed vessels, and number of implanted stents. This implies that troponin T elevation was linked to the severity of CAD. Age, serum total cholesterol, number of stenosed vessels, and number of implanted stents could be independent risk factors of troponin T elevation in patients with stable CAD after elective DES implantation. References 1. Alpert JS, Thygesen K, Antman E, et al. 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