Non ST-elevation acute coronary syndromes (NSTE-

Elevated Troponin T Levels and Lesion Characteristics in Non ST-Elevation Acute Coronary Syndromes Kentaro Okamatsu, MD; Masamichi Takano, MD; Shunta Sakai, MD; Fumiyuki Ishibashi, MD; Ryota Uemura, MD; Teruo Takano, MD; Kyoichi Mizuno, MD Background Elevated troponin T levels in non ST-elevation acute coronary syndromes (NSTE-ACS) have been shown to predict an adverse outcome. Furthermore, it has been reported that troponin T could help improve the effectiveness of such new antithrombotic drugs as platelet GPIIb/IIIa antagonists and low-molecular-weight heparins. We hypothesized that such elevated troponin T levels in NSTE-ACS indicate the presence of thrombus at culprit lesions, and this hypothesis was verified through the use of coronary angioscopy. Methods and Results We studied 57 consecutive patients with NSTE-ACS who underwent preinterventional angioscopy. Before catheterization, we obtained blood samples to determine troponin positivity, and the patients were then classified as either troponin-positive or troponin-negative groups (diagnostic threshold, 0.1 ng/ml). Using angioscopy at the culprit lesions, we examined the presence of coronary thrombus, yellow plaque, and complex plaque. Moreover, we compared the preinterventional angiographic parameters (thrombus and complexity of the culprit lesion, and TIMI flow) between the two groups. Twenty-two patients were troponin-positive and 35 patients were troponin-negative. Univariate analyses indicated that the TIMI flow and the incidence of coronary thrombus detected with angioscopy correlate with the elevated troponin T levels. A multivariate logistic regression analysis showed the presence of coronary thrombus detected with angioscopy to be the only independent factor associated with elevated troponin T levels in patients with NSTE-ACS (odds ratio, 22.1; 95% CI, 2.59 to 188.42; P 0.0046). Conclusions Using angioscopy, the elevated troponin T levels in NSTE-ACS were confirmed to be strongly associated with the presence of coronary thrombus. (Circulation. 2004;109:465-470.) Key Words: coronary diseases thrombus plaque Non ST-elevation acute coronary syndromes (NSTE- ACS) are heterogeneous disorders in which patients demonstrate a wide range of prognoses. Elevated troponin T levels in NSTE-ACS have been shown to independently predict an adverse outcome in particular, a subsequent major myocardial infarction or sudden death. 1,2 Furthermore, patients with an elevated troponin T level and NSTE-ACS have been reported to particularly benefit from such new antithrombotic drugs as platelet GPIIb/IIIa antagonists and low-molecular-weight heparins (LWMH). 3 6 From these studies, it is reasonable to hypothesize that the elevated troponin T levels in patients with NSTE-ACS indicate the presence of a thrombus at culprit lesions, and such an elevation may thus be a marker for consequent thromboembolization at distal vascular beds. 7,8 However, this hypothesis has not yet been directly verified. Coronary angioscopy can provide direct images of the endoluminal surface of culprit lesions. Therefore, coronary angioscopy is a more sensitive and specific method for detecting coronary thrombi than other methods, and it can also differentiate the composition of the thrombi. 9,10 The purposes of this study were to verify the hypothesis that elevated troponin T levels in patients with NSTE-ACS may indicate thrombus formation at culprit lesions and to investigate the relation between the angioscopic lesion characteristics and troponin T release in patients with NSTE-ACS. Methods Patient Population This study population comprised 57 consecutive patients with NSTE-ACS undergoing preinterventional angioscopy. NSTE-ACS was defined as newly developed or increased severe angina pectoris, angina at rest during the previous 48 hours, or ongoing chest pain suggestive of myocardial infarction. These symptoms must have been accompanied by ECG evidence believed to indicate ischemia (transient or persistent pathological ST-segment depression 0.1 mv or T-wave inversion in at least two adjacent leads without pathological Q waves) for this study. The exclusion criteria included new Q waves, a pacemaker, cardiomyopathy, uncontrolled hypotension, CABG, or PTCA performed within the last 6 months, renal failure, and serious intercurrent disease. Received March 4, 2003; de novo received June 4, 2003; revision received October 24, 2003; accepted October 28, 2003. From the Department of Internal Medicine, Nippon Medical School, Chiba Hokusoh Hospital, Chiba, Japan (K.O., M.T., S.S., F.I., R.U., K.M.); and the First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan (T.T.). Correspondence to Kyoichi Mizuno, MD, Department of Internal Medicine, Nippon Medical School, Chiba Hokusoh Hospital, 1715 Kamakari, Inba, Inba, Chiba, Japan 270-1694. E-mail Mizunok@nms.ac.jp 2004 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000109696.92474.92 465

466 Circulation February 3, 2004 First, we enrolled 75 consecutive patients with NSTE-ACS. They immediately received aspirin and ticlopidine after they were diagnosed to have NSTE-ACS. Catheter procedures were performed within 48 hours after the onset of acute coronary events. In patients with single-vessel disease, the culprit lesion was considered to be the most severely stenosed lesion in the affected vessel. In patients with multivessel disease, the culprit lesion was defined as a substantially stenosed lesion in the vessel that corresponded most closely to the ischemic area, as determined by ST-T segment changes during chest pain. Any patients in whom no culprit lesions were detected (n 4) were excluded. Any lesions that demonstrated severe tortuosity in a proximal segment (n 3) and ostial lesions (n 5) were also excluded because the angioscope catheter could not reach the site to perform optimal image acquisition. Any cases with inadequate angioscopic images (n 4) and cases of disagreement between the observers resulting from the discussion concerning the angioscopic findings (n 2) were also excluded. As a result, 57 patients (40 men and 17 women) were finally included in this study analysis. All patients had a single culprit lesion in the native coronary arteries. The clinical data and information about the clinical presentation were collected on the basis of the patients charts. Written informed consent approved by our institutional review board was obtained from all patients before catheterization. Blood Samples for Biochemical Markers Just before catheterization, we obtained blood samples from the patients and used these samples to determine troponin positivity by using a point-of-care system (Cardiac reader, Roche Diagnostics). The measuring range of this system is 0.1 to 2.0 ng/ml; levels between 0.05 and 0.1 ng/ml are indicated as low, and levels 0.05 ng/ml are indicated as negative. The prespecified positive threshold used in this study was a troponin T level 0.1 ng/ml, based on studies that have identified this level as optimal for clinical risk and therapeutic stratification. 3,4,6 In addition, we measured the serum creatine kinase (CK) and CK-MB levels by using standard laboratory methods based on these samples. The patients were divided into two groups, consisting of a troponin-positive group and troponin-negative group. Coronary Angioscopic Procedures After performing routine coronary angiography, an additional 100 U/kg of heparin was administered, and an 8F guiding catheter was used for engaging the coronary artery. Coronary angioscopy was performed with the use of an image catheter (Vecmova, Clinical Supply Co). Before use, the white balance was adjusted for color correction. The light power was adjusted to avoid reflections and to determine the color of the plaque and the thrombus. Angioscopic images were recorded on digital videotape for review and storage. Qualitative Angiographic and Angioscopic Analysis The angiographic and angioscopic images were reviewed separately by two experienced observers blinded to the troponin T status and the patient history. All preinterventional angiograms were assessed for the Thrombolysis In Myocardial Infarction (TIMI) flow and morphology of the culprit lesion. The angiographic lesion morphology was categorized according to the classification proposed by Ambrose et al 11 and the American Heart Association/American College of Cardiology (AHA/ACC) classification. Additional data regarding the visibility of coronary thrombus were collected. Angiographic coronary thrombus was defined as a filling defect or haziness, near the lesion, which was visible on at least 2 orthogonal views. All angioscopic assessments were made from antegrade visualization of the culprit lesion. Angioscopic definitions were based on an angioscopic classification system developed by the European Working Group on Coronary Angioscopy 12 and our reports as previously described. 13 Thrombus was defined as a coalescent red, white, or Figure 1. Angioscopic images of lesions in the setting of NSTE- ACS. A, Lesion with yellow plaque and fissure (arrow). B, Lesion with yellow plaque and white thrombi (arrow). C, Lesion with mixed (red and white) thrombi (arrow and arrowhead). D, Lesion with red thrombi (arrow). mixed (white and red) intraluminal, superficial, or protruding mass adherent to the vessel surface but clearly a separate structure that persisted despite being flushed with a saline solution. A white thrombus had to fulfill the additional criteria of having a shaggy, irregular, and cotton-wool like appearance. A plaque was defined as a nonmobile, elevated, and/or protruding structure that could be clearly demarcated from the adjacent vessel wall. The predominant color of the culprit lesion, either yellow or white, was recorded. A complex plaque was considered to be present when the surface of the lesion had an irregular appearance with ulcerations, flaps, or fissures. Representative angioscopic images of lesions in the setting of NSTE-ACS are shown in Figure 1. The intraobserver agreement on the angioscopic images was measured by having an observer repeat the assessment of 20 images (presented in random order) after 1 week. The interobserver agreement on the angioscopic images was measured by comparing the assessment of 59 images by the two observers. The intraobserver agreements for the evaluated angioscopic items (thrombus, yellow plaque, and complex plaque) were 95%, 100%, and 95%, respectively. The interobserver agreements of those items were 95%, 98%, and 93%, respectively. The values for the intraobserver agreement of thrombus, yellow plaque, and complex plaque were 0.93, 1.00, and 0.88, respectively. The values for the interobserver agreement of those items were 0.93, 0.95, and 0.84, respectively. In case of disagreement, the observers tried to obtain consensus by discussion. If no consensus was obtained even by discussion for all the angioscopic items listed above, then the data were excluded from the study. Statistical Analysis Continuous variables are expressed as mean SD. Comparisons between the two groups were performed with the unpaired Student s t test. Comparisons of categorical variables presented as numbers (%) were performed by either the 2 test or Fisher s exact test. A multivariate logistic regression analysis was used to determine the factors associated with elevated troponin T levels in patients with NSTE-ACS. Independent variables included in the analysis were classic coronary risk factors, the timing of the catheter procedure (onset to catheterization time), the serum CK level, the angiographic findings (thrombus, TIMI flow, and the complexity of the culprit lesion), and the angioscopic findings (thrombus, yellow plaque, and complex plaque). We set the level of statistical significance at P 0.05. For coronary thrombus with different cutoff levels of troponin T, we computed the sensitivity, specificity, and accuracy,

Okamatsu et al Troponin T and Lesion Characteristics 467 TABLE 1. Clinical Baseline Characteristics TABLE 2. Angiographic Findings Troponin Positive (n 22) defined as the sum of the concordant cells divided by the sum of the all cells in the 2 2 table. Results Troponin Negative (n 35) P Age, y 59.8 9.7 64.5 11.0 0.10 Gender: male 17 (77) 23 (66) 0.39 Risk factor Hypertension 12 (54) 19 (54) 0.99 Diabetes mellitus 4 (18) 12 (34) 0.23 Hyperlipidemia 10 (45) 24 (68) 0.17 Smoking 11 (50) 18 (51) 0.99 Onset to catheterization 15.0 8.8 17.7 8.7 0.25 time, h CK, IU/L (50 230)* 140.5 108.7 95.2 61.7 0.049 CK-MB, IU/L ( 10)* 12.2 5.4 9.1 5.5 0.059 Values are mean SD or No. (%). *Normal range in our laboratory methods. Patient Population Approximately one fourth of the patients enrolled initially were excluded from our analysis for various reasons, as stated in the Methods section. No excessive tendency for the proportion of the troponin T status was seen among the excluded patients (positive versus negative, 39% versus 61%). Among the patients included in the final analysis, 22 patients (39%) were troponin-positive and 35 patients (61%) were troponin-negative. The clinical baseline characteristics of patients and the serum CK and CK-MB levels for both groups are summarized in Table 1. There were no significant differences in the frequency of risk factors for coronary artery disease and in the timing of the catheter procedure between the troponin-positive group and the troponin-negative group. The serum CK levels in the troponin-positive group were significantly higher than those in the troponin-negative group (P 0.05). However, there was no significant difference in the serum CK-MB levels between the two groups. Angiographic Findings The angiographic findings before intervention on the 57 patients are summarized in Table 2. There were no significant differences in the distribution of the culprit lesion, the frequency of angiographic thrombus, and the angiographic morphology of the culprit lesion between the two groups. There were no patients with TIMI flow grade 0 in our series. A grade 2 frequency of TIMI flow in the troponin-positive group was significantly higher than that in the troponinnegative group (32% versus 9%; P 0.05). Angioscopic Findings Preinterventional coronary angioscopy was performed in all patients without any serious procedural complications. The angioscopic findings on the 57 patients are summarized in Table 3. Troponin Positive (n 22) Troponin Negative (n 35) P Multivessel disease 10 (45) 12 (34) 0.41 Culprit lesion location RCA 10 (45) 7 (20) 0.11 LAD 9 (41) 23 (66) LCx 3 (14) 5 (14) Thrombus 4 (18) 3 (9) 0.41 Lesion morphology Ambrose s classification Simple 11 (50) 21 (60) 0.46 complex 11 (50) 14 (40) AHA/ACC classification Type A 4 (18) 8 (23) 0.96 Type B1 9 (41) 14 (40) Type B2 8 (36) 12 (34) Type C 1 (5) 1 (3) TIMI flow grade 2 7 (32) 3 (9) 0.035 Values are No. (%). RCA indicates right coronary artery; LAD, left anterior descending artery; and LCx, left circumflex artery. Coronary thrombi at culprit lesions were observed in 54% (31 of 57) of patients with NSTE-ACS. All coronary thrombi were nonocclusive. Patients in the troponin-positive group were frequently observed to have coronary thrombi (19 of 22, 86%); however, coronary thrombi were seen in only 34% (12 of 35) of patients in the troponin-negative group (P 0.0005; Figure 2). The sensitivity and specificity for coronary thrombus with troponin T were 61% and 89%, respectively, when 0.1 ng/ml was used as a cutoff level (Table 4). With regard to the type of thrombus, white thrombi, mixed (white and red) thrombi, and red thrombi were observed in 48% (15 of 31), 35% (11 of 31), and 16% (5 of 31) of the all patients with thrombi, respectively. There were no significant differences in the type of thrombus between the troponin-positive group and the troponin-negative group. There were no significant differences in the incidence of yellow plaque and the incidence of complex plaque between TABLE 3. Angioscopic Findings Troponin Positive (n 22) Troponin Negative (n 35) P Thrombus 19 (86) 12 (34) 0.0001 White 9 (41) 6 (17) 0.61 Mixed 6 (27) 5 (14) Red 4 (18) 1 (3) Yellow plaque 17 (77) 29 (83) 0.73 Complex plaque 14 (64) 24 (68) 0.77 Ulcerated 7 (32) 10 (28) 0.14 Flap 4 (18) 13 (37) Fissure 3 (14) 1 (3) Values are No. (%).

468 Circulation February 3, 2004 Figure 2. Percentage of patients with coronary thrombus detected with angioscopy as related to troponin T concentration. Shaded bars indicate positive troponin levels ( 0.1 ng/ml). the two groups (yellow plaque, 77% versus 83%; complex plaque, 64% versus 68%). A multivariate logistic regression analysis showed the presence of coronary thrombus detected with angioscopy to be the only independent factor associated with elevated troponin T levels in patients with NSTE-ACS (OR, 22.1; 95% CI, 2.59 to 188.42; P 0.0046). Discussion The present study demonstrated the frequency of coronary thrombus to be significantly higher in patients with troponinpositive NSTE-ACS than that in patients with troponinnegative NSTE-ACS, and this type of the thrombus tended to be mainly white or mixed (white and red). Pathological studies showed such a white thrombus to be a platelet-rich thrombus, 14 and such a platelet-rich thrombus was the cause of embolization in the distal vascular beds in patients with unstable angina. 15 A rupture or erosion of an atherosclerotic plaque in a coronary artery is believed to be the major pathogenetic mechanism for acute coronary syndromes (ACS). Platelet adhesion, activation, and aggregation may follow plaque disruption and thus result in platelet-rich thrombus formation. This process has been reported to be pivotal in the pathophysiology of NSTE-ACS. 16 Therefore, in addition to aspirin or ticlopidine, more aggressive antithrombotic therapy (eg, GP IIb/IIIa antagonists or LWMH) has been reported to be effective in patients with NSTE-ACS. 17 19 However, some studies of patients with NSTE-ACS have shown the treatment efficacy of GPIIb/IIIa antagonists or LWMH to be higher among those patients who were troponin-positive, whereas no benefit was observed after the administration of GPIIb/IIIa antagonists or LWMH in troponin-negative patients. 3 6 It remains unclear as to why the clinical treatment effect differs if the substrate is similar. The answer to this question remains unknown; however, the findings of the present study may partially solve this question. Most patients with troponinpositive NSTE-ACS have platelet-rich thrombi in their coronary arteries. The presence of platelet-rich thrombus at the culprit lesion has been reported to possibly be indicative of an active thrombotic process with a high local thrombotic propensity. 9 Therefore, GPIIb/IIIa antagonists, which can prevent the final pathway to platelet aggregation, or LWMH, which have a greater anti factor Xa activity that inhibits thrombin generation more effectively with less platelet activation than heparin, are thought to be efficacious in patients with troponin-positive NSTE-ACS. On the other hand, most patients with troponin-negative NSTE-ACS do not demonstrate any coronary thrombi. Previous studies with angiography have shown that patients with an elevated troponin T level and NSTE-ACS had more complex lesions 20 and more often demonstrated impaired TIMI flow 20,21 and thrombi at the site of a culprit lesion. 20 22 In our study, no significant differences were seen in the frequency of angiographic thrombus and the angiographic complexity of the culprit lesion between the troponinpositive group and the troponin-negative group. The reason for these conflicting results may be explained by the fact that the number of patients evaluated in this study was too small. We observed a significant difference in TIMI flow similar to that observed in previous studies. Moreover, we observed the frequency of angiographic thrombus to be, although not statically significant, 2-fold higher in troponin-positive pa- TABLE 4. Sensitivity and Specificity for Coronary Thrombus With Different Cutoff Levels of Troponin T: Coronary Thrombus Detected With Angioscopy Used as the Gold Standard Troponin T Cutoff Level, ng/ml Sensitivity Specificity % (95% CI) Positive Predictive Value Negative Predictive Value Accuracy 0.05 67 (52 84) 73 (56 90) 75 (59 91) 66 (49 83) 70 0.1 61 (45 78) 89 (77 99) 86 (72 99) 66 (50 81) 74 0.2 42 (25 59) 96 (89 99) 93 (81 99) 58 (44 72) 67 0.5 26 (11 41) 96 (89 99) 89 (73 99) 52 (38 66) 58

Okamatsu et al Troponin T and Lesion Characteristics 469 tients. These data are in line with previous, much larger angiographic studies. However, it is also a fact that angiograms provide insufficient information regarding true lesion complexity and coronary thrombus, whereas coronary angioscopy is a superior tool for demonstrating precise plaque complexity and coronary thrombus. 9,10,23 In the angiographic studies, low incidences of thrombus were observed, even in troponin-positive patients (at most 22%). In the present study, using coronary angioscopy, we found the presence of coronary thrombus to be the most distinguishing lesion characteristic between troponin-positive and troponin-negative patients (88% versus 37%; P 0.0005) and the incidence of complex plaque to be equally high between the two groups (64% versus 68%; P 0.77). Angiographic lesion complexity does not always identify the presence of complex plaque. It is possible that the presence of coronary thrombus has exerted a great influence on the frequency of angiographic complex lesion in the previous study. 20 Furthermore, the previous study reported that impaired TIMI flow in troponin-positive patients with NSTE-ACS was improved by the treatment with a GP IIb/IIIa antagonist without coronary intervention. 20 This suggests that the impaired TIMI flow in troponin-positive patients might, at least in part, be caused by the presence of coronary thrombus. Thus, we consider that the presence of coronary thrombus is a mainstay in the lesion characteristics in troponin-positive patients with NSTE-ACS. The fact that GPIIb/IIIa antagonists can neutralize the heightened risk of troponin-positive patients with NSTE-ACS 5 also supports our proposition that the presence of thrombus may be the only lesion characteristic that distinguishes troponin-positive patients from troponin-negative patients with NSTE-ACS. Our study using coronary angioscopy shows that the incidence of yellow plaque and the incidence of complex plaque in troponin-negative patients are as high as those in troponin-positive patients. Our findings are consistent with the theory that the pathogenetic mechanism for ACS is associated with a disruption of atherosclerotic plaque. However, the reason coronary thrombus formation after plaque disruption, which is large enough to obstruct the distal vascular beds as a result of embolization, did not occur in troponin-negative patients remains unclear. The amount of thrombus varies according to the interplay among such factors as vessel injury, coagulation, and the blood flow. 24 The differences in these factors may cause different responses to plaque disruption. Study Limitations Our study population excluded any culprit lesions that were not anatomically suitable for angioscopy. We used a pointof-care system for troponin T assay instead of a central laboratory ELISA. However, the results with the point-ofcare system have been reported to show a good agreement compared with the troponin T levels with the central laboratory ELISA. 25 In the present study, coronary angioscopy was obtained after the patients had been treated with aspirin, ticlopidine, and heparin. A previous study demonstrated the treatment efficacy of heparin regarding the resolution of thrombus formation. 20 Accordingly, treatment with aspirin, ticlopidine, and heparin in this study population most likely led to a decrease in the incidence of coronary thrombi and modified the composition of coronary thrombi before coronary angioscopy was performed. Conclusions Troponin-positive patients with NSTE-ACS have a higher incidence of platelet-rich thrombi at the culprit lesions. We found that the most important factor for distinguishing troponin-positive versus troponin-negative patients with NSTE-ACS was the presence of coronary thrombus. 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