Limitation of Angiography to Identify the Culprit Plaque in Acute Myocardial Infarction With Coronary Total Occlusion

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1 Journal of the American College of Cardiology Vol. 50, No. 23, by the American College of Cardiology Foundation ISSN /07/$32.00 Published by Elsevier Inc. doi: /j.jacc CLINICAL RESEARCH Acute Myocardial Infarction Limitation of Angiography to Identify the Culprit Plaque in Acute Myocardial Infarction With Coronary Total Occlusion Utility of Coronary Plaque Temperature Measurement to Identify the Culprit Plaque Takuro Takumi, MD,* Souki Lee, MD,* Shuichi Hamasaki, MD, Kouichi Toyonaga, MD,* Daisuke Kanda, MD,* Keisuke Kusumoto, MD,* Hitoshi Toda, MD,* Toshihiro Takenaka, MD, Masaaki Miyata, MD, Ryuichiro Anan, MD, Yutaka Otsuji, MD, Chuwa Tei, MD Kagoshima, Japan Objectives Background Methods Results Conclusions The purpose of this study was to test the hypothesis that the maximal temperature (Tmax) site, as measured by thermal wire, coincides with the culprit plaque by intravascular ultrasound (IVUS) in patients with acute myocardial infarction (AMI). Subsequent thrombosis developing to the proximal region from the site of plaque rupture or erosion can potentially complicate the ability of coronary angiography to identify the accurate culprit plaque in patients with coronary total occlusion. In 45 consecutive patients with a first anterior AMI, the Tmax site by thermal wire and the culprit plaque by IVUS were evaluated in the left anterior descending coronary artery (LAD). Twenty-five patients had LAD total occlusion, and the remaining 20 had LAD reperfusion. In both groups of patients, the Tmax site was significantly more distal to the angiographically most stenotic site or occlusive site (reperfusion: mean distance [MD] 1.1 mm distal, 95% confidence interval [CI] 0.3 to 1.9 mm, p 0.01; total occlusion: MD 8.8 mm distal, 95% CI 8.0 to 9.6 mm, p ). The culprit plaques by IVUS approximately coincided with those by angiography or thermal wire in patients with reperfusion. However, the angiographic occlusive site was significantly more proximal to the culprit plaque by IVUS (MD 9.2 mm, 95% CI 7.9 to 10.6 mm, p ), but the Tmax site coincided with the culprit plaque by IVUS (MD 0.3 mm distal, 95% CI 0.3 mm proximal to 1.0 mm distal, p 0.293) in patients with total occlusion. Temperature measurement of coronary plaque enables accurate localization of the culprit plaque in AMI with coronary total occlusion. (J Am Coll Cardiol 2007;50: ) 2007 by the American College of Cardiology Foundation Plaque rupture or erosion with superimposed thrombosis is the main cause of acute myocardial infarction (AMI) (1 4) and leads to the formation of a stagnated thrombosis propagating upstream and/or downstream from the culprit plaque (5,6). Therefore, it can potentially be difficult to identify the culprit plaque by coronary angiography in patients with coronary total occlusion, owing to the subsequent thrombosis developing to the proximal region. From the *Department of Cardiology, Kagoshima City Hospital, Kagoshima, Japan; and the Department of Cardiovascular, Respiratory, and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan. A portion of this study was presented at the 55th Annual Scientific Session of the American College of Cardiology, Atlanta, GA, March 11 14, Manuscript received February 9, 2007; revised manuscript received July 5, 2007, accepted July 30, The accumulation of inflammatory cells was observed in the culprit plaque (2,3), and inflammation plays an important role in the destabilization of coronary atherosclerotic plaque (1 3,7,8). A previous study has shown that heat is released by the activated inflammatory cells in atherosclerotic plaque of the human carotid artery (9). Recent ad- See page 2204 vances have enabled the direct measurement of atherosclerotic plaque temperature, and several studies have demonstrated that the temperature elevation of coronary atherosclerotic plaque is present in the culprit lesion of patients with AMI (10 13). Therefore, the temperature measurement of coronary atherosclerotic plaque can potentially enable the identification of the culprit plaque in AMI even

2 2198 JACC Vol. 50, No. 23, 2007 Abbreviations and Acronyms AMI acute myocardial infarction CI confidence interval CSA cross-sectional area EEM external elastic membrane IVUS intravascular ultrasound LAD left anterior descending coronary artery MD mean distance P/T pressure/ temperature PCI percutaneous coronary intervention TIMI Thrombolysis In Myocardial Infarction Tmax maximal temperature T temperature difference with coronary total occlusion. We hypothesized: 1) that the site of coronary total occlusion by angiography is often more proximal to the culprit plaque by intravascular ultrasound (IVUS); and 2) that the maximal temperature (Tmax) site of coronary atherosclerotic plaque coincides not with the site of angiographic total occlusion but with the culprit plaque by IVUS. The purpose of this study was to test these hypotheses by comparing the angiographic findings, the atherosclerotic plaque temperature of infarct-related artery, and the IVUS findings in patients with an anterior AMI. Methods Study population. The subjects consisted of 49 consecutive patients with anterior AMI and without a prior history of myocardial infarction. Inclusion criteria were as follows: 1) typical chest pain lasting 30 min and 12 h from symptom onset; 2) STsegment elevation 0.2 mv in pericardial leads; and 3) subsequent increase of 2-fold the upper limit of normal in serum creatine kinase. Four patients were excluded from this study, either because of the presence of cardiogenic shock (n 2) with expected extremely reduced coronary flow affecting plaque temperature or because patients had received corticosteroids or nonsteroidal antiinflammatory drugs except for aspirin (n 2). Finally, the number of patients recruited in this study was 45. The institutional committee of Kagoshima City Hospital approved this study protocol. All patients provided written informed consent before emergent coronary angiography. In addition, the IVUS study was performed only in patients who provided informed consent. Emergent coronary angiography. Emergent coronary angiography was performed in all patients by the femoral approach with a 6-F standard catheter and INNOVA 2000 (GE Medical Systems, Waukesha, Wisconsin). All patients received oral aspirin (162 mg), intravenous heparin (5,000 U) and intracoronary isosorbide dinitrate (2 mg). Several views of the left anterior descending coronary artery (LAD) were digitally acquired, and the minimum lumen diameter, the proximal reference diameter, and the percent diameter stenosis were quantified with a computer-assisted, automated edge detection algorithm (Cardiac QCA, GE Medical Systems) with a 6-F catheter as the reference. The angiographic Thrombolysis In Myocardial Infarction (TIMI) flow grade was evaluated according to a previous study (14), and TIMI flow grade 1 to 3 was defined as LAD reperfusion. Temperature measurement of coronary plaque. Immediately after coronary angiography, temperature measurement of coronary plaque was performed with a commercially available inch pressure/temperature (P/T) guidewire (Pressure wire RADI 5, Radi Medical Systems, Uppsala, Sweden), which can be used instead of a standard guidewire during percutaneous coronary intervention (PCI). The wire has a microsensor located 3 cm from the wire tip, which enables simultaneous recordings of coronary pressure and temperature measurement. The accuracy of pressure and temperature was 1 mm Hg and 0.02 C, respectively (15,16). Continuous signals of pressure and temperature were displayed and recorded on a suitable interface (Radi-Analyzer, Radi Medical Systems). Five minutes after the last injection of contrast medium, the P/T guidewire was advanced into the distal LAD through a 6-F guide catheter with a standard PCI system. The sensor was calibrated, and the wire was manually pulled back in a distal-to-proximal manner to yield continuous recordings of coronary pressure and temperature. Temperature difference ( T) between the Tmax and the temperature of the proximal healthy vessel wall was calculated, and the average of 2 measurements was used for the data analysis. Reproducibility of T by the P/T guidewire. To assess the reproducibility of T, the first measurement of T by the P/T guidewire was compared with the second measurement in patients with LAD total occlusion. Measurement of the distance between the Tmax site and angiographic occlusive or most stenotic site. The Tmax site was determined with the P/T guidewire, and a view of the LAD was digitally acquired after the microsensor site of the P/T guidewire was located at the Tmax site. From this view, the angiographic distance between the Tmax site and the angiographic occlusive or most stenotic site was measured with a 6-F guide catheter as the reference (Cardiac QCA system) (Fig. 1). Protocol of IVUS images. Immediately after temperature measurement of the LAD by the P/T guidewire and before coronary intervention, an IVUS study was performed with a commercially available system equipped with a 40-MHz imaging catheter (Atlantis SR Pro2, Boston Scientific, Natick, Massachusetts). The IVUS catheter was carefully advanced into the distal LAD beyond the Tmax site and angiographic occlusive or most stenotic site, and IVUS imaging was performed while retracting the probe proximally at a rate of 0.5 mm/s. The IVUS imaging was recorded on super-vhs videotape for offline analysis. After IVUS imaging, PCI was performed immediately. Analysis of IVUS images. Qualitative and quantitative IVUS analyses were performed according to the criteria of the American College of Cardiology clinical expert consensus document on IVUS (17). A ruptured plaque was defined as a cavity that communicated with the lumen with an

3 JACC Vol. 50, No. 23, Figure 1 Methods to Measure the Distance Between the Tmax Site and the Occlusive or Most Stenotic Site Methods to measure the distance between the maximal temperature (Tmax) site by the pressure/temperature (P/T) guidewire and the occlusive site by angiography in patients with left anterior descending coronary artery (LAD) total occlusion (top panel) and that between the Tmax site and the most stenotic site in patients with LAD reperfusion (bottom panel). overlying residual fibrous cap fragment (18). A lipid core image was defined as a pooling of low-echoic material or echolucent material covered with a high-echoic layer (19). A ruptured plaque and a large lipid core were defined as the culprit plaque. Furthermore, the echoes at the surface of the lumen that were brighter than the adventitia with acoustic shadowing and an arc of 90 were defined as superficial calcified nodules (20). Quantitative IVUS measurement was performed with computer planimetry software (ClearView Ultra, Boston Scientific). The proximal reference segment was the most normal-looking cross-section within 5 mm proximal to the lesion or angiographic occlusive site but before major side branches. Cross-sectional images were quantified at the Tmax site and angiographic occlusive or most stenotic site as follows: external elastic membrane (EEM) cross-sectional area (CSA) (mm 2 ), lumen CSA (mm 2 ), and plaque and media (P&M) CSA (P&M EEM lumen, mm 2 ). Plaque burden (%) was defined as (P&M CSA)/EEM CSA 100 and calculated at each site. Furthermore, a remodeling index was calculated as the lesion EEM/the proximal reference EEM. These diagnoses required independent review and agreement by 2 experienced observers. The distance between the culprit plaque by IVUS and angiographic occlusive site was also measured as previously described. Statistical analysis. One-sample t test was used to evaluate the results of the distance, which are given as a mean value with the 95% confidence interval (CI). Other results are expressed as a mean SD. The chi-square test was used to compare the incidence of categorical variables, and continuous variables were compared between 2 groups by the Mann- Whitney U test. The Spearman rank correlation coefficient was used to assess the reproducibility of T. The McNemar and the Wilcoxon signed-rank tests were applied to evaluate the IVUS findings. Statistical analysis was performed with Stat View software (Abacus Concepts Inc., Piscataway, New Jersey). A value of p 0.05 was considered significant. Results Patient characteristics and clinical results. Patient profiles are summarized in Table 1. Twenty-five patients had LAD total occlusion, and the remaining 20 had LAD reperfusion as assessed by emergent coronary angiography. The time from symptom onset to angiography was h. Compared with patients with reperfusion, patients with total occlusion had a significantly greater peak creatine kinase and a lower left ventricular ejection fraction. There was no patient with a residual stenosis 50% after PCI. Temperature measurement of coronary plaque. Temperature difference ( T) was significantly higher in patients with LAD total occlusion than in patients with LAD reperfusion ( C vs C, p ) (Table 1). There was no significant difference in T between patients receiving statins (n 9) and those not receiving statins (n 36) ( C vs. 0.15

4 2200 JACC Vol. 50, No. 23, 2007 Patient Characteristics and Clinical Results Table 1 Patient Characteristics and Clinical Results Total Occlusion (n 25) Reperfusion (n 20) p Value Age, yrs NS Male/female, n 17/8 13/7 NS BMI, kg/m NS HR, beats/min NS SBP, mm Hg NS Risk factors, n (%) Hypertension 16 (64) 10 (50) NS Hypercholesterolemia 14 (56) 14 (70) NS Diabetes mellitus 8 (32) 6 (30) NS Current smoking 14 (56) 10 (50) NS Statin use, n (%) 5 (20) 4 (20) NS Time from onset to angiography, h NS Peak creatine kinase, IU/l 5,337 2,909 2,352 1, Q-wave infarction, n (%) 22 (88) 12 (60) 0.03 Angiographic findings Segment 6/segment 7, n 12/13 8/12 NS RD, mm NS MLD, mm DS, % TIMI flow grade, n LVEF, % T, C IVUS study performed, n (%) 16 (64) 14 (70) NS Values are mean SD. BMI body mass index; T temperature difference; DS diameter stenosis; HR heart rate; IVUS intravascular ultrasound; LVEF left ventricular ejection fraction; MLD minimal lumen diameter; RD reference diameter; SBP systolic blood pressure; TIMI Thrombolysis In Myocardial Infarction C, p 0.39). Temperature measurement assessed by the P/T guidewire was obtained successfully without any complications in all patients. Reproducibility of T. There was a significant correlation between the first measurement of T and the second in 25 patients with LAD total occlusion (r 0.91, p ). The variability of T between 2 measurements was C. Distance between the Tmax site and the angiographic occlusive or most stenotic site. In both patients with reperfusion and total occlusion, the Tmax site was significantly more distal to the angiographically most stenotic site or occlusive site (reperfusion: mean distance [MD] 1.1 mm distal, 95% CI of 0.3 to 1.9 mm, p 0.01; total occlusion: MD 8.8 mm distal, 95% CI 8.0 to 9.6 mm, p ). The distance between the 2 sites was significantly longer in patients with total occlusion (p ) (Fig. 2). Relations between culprit plaque by IVUS, the Tmax site, and angiographic occlusive or most stenotic site. The IVUS study was performed in 30 of the 45 patients; 14 patients had LAD reperfusion, and 16 had LAD total occlusion (Table 1). In patients with reperfusion, Figure 2 Distance Between the Tmax Site and the Occlusive or Most Stenotic Site Distance between the maximal temperature (Tmax) site and the occlusive or most stenotic site by angiography. In both patients with reperfusion and total occlusion, the Tmax site was significantly distal to the occlusive or most stenotic site. However, the distance between these 2 sites was significantly longer in patients with total occlusion. a ruptured plaque and a large lipid core by IVUS were observed in 7 (50%) and 2 (14%) patients, respectively (Table 2). In these 9 patients, both the angiographically most stenotic site and the Tmax site coincided with the culprit plaque by IVUS (MD 0.3 mm distal, 95% CI 0.7 proximal to 1.2 mm distal, p 0.52; and MD 0.6 mm distal, 95% CI 0.2 mm proximal to 1.5 mm distal, p 0.14) (Fig. 3). There was a significant difference between the Tmax site and the most stenotic site only in terms of the lumen CSA ( mm 2 vs mm 2,p ) and plaque burden ( % vs %, p ). Remodeling index was similar when comparing the Tmax site and the most stenotic site and tended to be positive at both sites (Table 3). In patients with total occlusion, a ruptured plaque or a large lipid core by IVUS were similarly observed in 4 (25%) and 5 (31%) patients, respectively (Table 2). In these 9 patients, however, the angiographic occlusive site was significantly more proximal to culprit plaque by IVUS (MD 9.2 mm, 95% CI 7.9 to 10.6 mm proximal, p ), but the Tmax site coincided with the culprit plaque by IVUS Detection of the Culprit Plaque by IVUS Table 2 Detection of the Culprit Plaque by IVUS Total Occlusion (n 16) Reperfusion (n 14) p Value Ruptured plaque, n (%) 4 (25) 7 (50) NS Large lipid core, n (%) 5 (31) 2 (14) NS No ruptured plaque or large lipid core, n (%) 7 (44) 5 (36) NS The chi-square test was used. IVUS intravascular ultrasound.

5 JACC Vol. 50, No. 23, IVUS Analysis in Patients With LAD Reperfusion Table 3 IVUS Analysis in Patients With LAD Reperfusion (MD 0.3 mm distal, 95% CI 0.3 mm proximal to 1.0 mm distal, p 0.293) (Fig. 3). Superficial calcified nodules were more frequently observed at the Tmax site than at the angiographic occlusive site (38% vs. 6%, p ). Moreover, the Tmax site had a significantly larger P&M CSA ( mm 2 vs mm 2,p ), a significantly greater plaque burden ( % vs %, p ), and larger remodeling index ( vs , p ) when compared with the angiographic occlusive site (Table 4). Figure 4 show representative patients with LAD reperfusion and total occlusion, respectively. Discussion Maximal Temperature Site Most Stenotic Site p Value EEM CSA, mm NS Lumen CSA, mm Plaque and media CSA, mm NS Plaque burden, % Remodeling index NS Superficial calcified nodule, n (%) 3 (21) 3 (21) NS n 14. Values are mean SD; McNemar test and the Wilcoxon signed-rank test were used. CSA cross-sectional area; EEM external elastic membrane; IVUS intravascular ultrasound; LAD left anterior descending coronary artery. This study demonstrated that angiographic evaluation of the culprit plaque is of limited utility, whereas temperature measurement of coronary atherosclerotic plaque enables accurate identification of the culprit plaque in patients with AMI and coronary total occlusion. The temperature measurement throughout infarct-related artery revealed that the Tmax site was located at a significantly distal site beyond the angiographic occlusive site. A ruptured plaque and a large IVUS Analysis in Patients With LAD Total Occlusion Table 4 IVUS Analysis in Patients With LAD Total Occlusion Maximal Temperature Site Angiographic Occlusive Site p Value EEM CSA, mm Lumen CSA, mm Plaque and media CSA, mm Plaque burden, % Remodeling index Superficial calcified nodule, n (%) 6 (38) 1 (6) n 16. Values are mean SD; McNemar test and the Wilcoxon signed-rank test were used. Abbreviations as in Table 3. lipid core were observed by IVUS at the Tmax site as opposed to the angiographic occlusive site. Therefore, the culprit plaque is not the angiographic occlusive site but the Tmax site. These results suggest the utility of temperature measurements of coronary plaque to identify the culprit plaque in patients with AMI and coronary total occlusion. Atherosclerosis is an inflammatory disease (21); inflammatory cells play an important role in the destabilization of atherosclerotic plaque (1 3,7,8). Furthermore, ex vivo experiments demonstrated that a thick plaque with high macrophage content was observed at the highest temperature region and there was a positive correlation between local temperature and local plaque thickness as well as macrophage content (22). Therefore, it seems reasonable that the Tmax site coincided with the culprit plaque by IVUS. Although the main cause of AMI is plaque rupture or erosion, the identification rate of ruptured plaque by IVUS is approximately 30% to 40% (23 25), and the identification of plaque erosion by IVUS is difficult. In this study, a ruptured plaque was observed in 37% of patients undergoing IVUS study, which is compatible with that found in previous studies. In all patients with total occlusion, a ruptured plaque was distal to the angiographic occlusive site Figure 3 Distance Between the Tmax Site and the Culprit Plaque Site The culprit plaque site by intravascular ultrasound (IVUS) coincided with both the angiographically most stenotic site and the maximal temperature (Tmax) site in patients with reperfusion (left). The culprit plaque site by IVUS was significantly more distal to the angiographic occlusive site but coincided with the Tmax site in patients with total occlusion (right). One-sample t test was used to compare differences in distance. P/T pressure/temperature.

6 2202 Figure 4 JACC Vol. 50, No. 23, 2007 Representatives of Coronary Pressure and Temperature With IVUS Images Coronary plaque temperature and coronary pressure by the pressure/temperature guidewire and intravascular ultrasound (IVUS) images in patients with left anterior descending coronary artery (LAD) reperfusion (top panel) and total occlusion (bottom panel). Angiographically most stenotic site (A), the maximal temperature (Tmax) site (B), and the site of culprit plaque by IVUS (C) were closely located to each other (top panel). The angiographic occlusive site (D) was considerably more proximal by 9 mm, compared with both the Tmax site (E) and the site of culprit plaque by IVUS (F), and the Tmax site and the site of culprit plaque by IVUS were located close to each other (bottom panel). but coincided with the Tmax site; thus, the Tmax site was regarded as the culprit plaque site. A previous study reported that vulnerable plaques are characterized by large lipid cores, larger plaque burden, superficial calcified nodules, and a larger remodeling index (26). In the present study, findings that reflect vulnerable plaque were clearly observed at the Tmax site but not at the angiographic occlusive site, which suggests that the Tmax site was the culprit plaque site in patients without distinct ruptured plaque demonstrated by IVUS. Previous pathological studies have reported that coronary arterial thrombi responsible for ST-segment elevated myocardial infarction are approximately 10 mm (27), and Brousius et al. (5) have reported that the length of occlusive thrombi in the LAD, left circumflex, and right coronary artery was 14, 11, and 24 mm, respectively. In this study, the proximal development of the arterial thrombosis was approximately 9 mm, which was comparable to these studies. In patients with reperfused AMI, the culprit plaque by IVUS was observed close to the angiographically most stenotic site, and the Tmax site coincided with the culprit plaque in this study. Similarly, Maehara et al. (25) have reported that a ruptured plaque is present close to the site of minimum lumen area in IVUS study. These findings indicated that the site nearest to the most stenotic site is the culprit plaque in patients with reperfused AMI. Temperature elevations in coronary plaques were also observed in patients with reperfusion, although the magnitude of the temperature elevation was less than that seen in patients with AMI and total occlusion. This likely results from the heat-lowering convection effect of residual coronary blood flow (28,29). Recently, IVUS has been widely used for detection of the culprit plaque, but there are some cases where it does not apply, owing to coronary tortuosity and calcification. Temperature measurement of coronary plaque by the P/T guidewire is able to be used even in these cases, and it is considered to be an effective option to identify the culprit plaque in patients with AMI and total occlusion. When performing PCI, use of the P/T guidewire might help determine the optimal site for interventional treatment. Study limitations. Several limitations of this study must be considered. First, the use of a thermography catheter to measure temperature of coronary plaques has previously been described (10 13,28,29). However, the present study used a P/T guidewire, which is a device designed to measure blood temperature rather than plaque surface temperature. Although we clearly showed the reproducibility of the temperature measurements with this P/T guidewire, internal validity does not guarantee external validity. This study contained a relatively small number of patients. Future investigations using the present methodology would benefit from inclusion of a larger patient population. In addition, the guidewire was not always in close contact to the coronary artery wall, and the degree of coronary stenosis and tortuosity might have affected temperature measurement.

7 JACC Vol. 50, No. 23, Furthermore, the presence of thrombus, itself, might have affected temperature measurements. Indeed, the degree of T in this study was smaller than that in previous studies by thermography catheter (10 13), which might be attributed to the use of the P/T guidewire. However, attenuated T is not expected to influence determination of the site of Tmax. This study was limited to patients with an anterior AMI of 12 h from onset who potentially required emergent PCI (30). Thus, it is not clear whether these results can be generalized to those who present with AMI of 12 h from symptom onset. Conclusions The identification of the culprit plaque by coronary angiography is of limited utility, owing to the thrombosis with development to the proximal region, whereas temperature measurement of coronary atherosclerotic plaque enables accurate localization of the culprit plaque in the acute phase in AMI with coronary total occlusion. 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