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In Vivo Comparison of Optical Coherence Tomography and Angioscopy for the Evaluation of Coronary Plaque Characteristics
In Vivo Comparison of Optical Coherence Tomography and Angioscopy for the Evaluation of Coronary Plaque Characteristics Masamichi Takano, MD, PhDa,*, Ik-Kyung Jang, MD, PhDb, Shigenobu Inami, MD, PhDa, Masanori Yamamoto, MDa, Daisuke Murakami, MDa, Kentaro Okamatsu, MD, PhDa, Koji Seimiya, MD, PhDa, Takayoshi Ohba, MDa, and Kyoichi Mizuno, MD, PhDc Atherosclerotic yellow plaques identified by coronary angioscopy are considered as vulnerable plaques. However, characteristics of yellow plaques are not well understood. Optical coherence tomography (OCT) provides accurate tissue characterization in vivo and has the capability to measure fibrous cap thickness covering a lipid plaque. Characteristics of yellow plaques identified by angioscopy were evaluated by OCT. We examined 205 plaques of 41 coronary arteries in 26 patients. In OCT analysis, plaques were classified as fibrous or lipid. Minimal lumen area of the plaque, arch of the lipid, and fibrous cap thickness on the lipid plaque were measured. Yellow grade of the plaque was defined as 0 (white), 1 (light yellow), 2 (medium yellow), or 3 (dark yellow) based on the angioscopy. A total of 149 plaques were diagnosed as lipid plaques. Neither the minimal lumen area nor the arch of the lipid was related to the yellow grade. There was an inverse relationship between color grade and the fibrous cap thickness (grade 0 [n ⴝ 45] 218 ⴞ 89 m, grade 1 [n ⴝ 40] 101 ⴞ 8 m, grade 2 [n ⴝ 46] 72 ⴞ 10 m, and grade 3 [n ⴝ 18] 40 ⴞ 14 m; p <0.05). Sensitivity and specificity of the angioscopy-identified yellow plaque for having a thin fibrous cap (thickness <110 m) were 98% and 96%, respectively. In conclusion, angioscopy-identified yellow plaques frequently were lipid tissue with an overlying thin fibrous cap. Fibrous caps of the intense yellow plaques were very thin, and these plaques might be structurally vulnerable. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:471– 476)
Previous angioscopic examinations in living patients revealed that ruptured yellow plaques and intracoronary thrombi were common in the culprit lesions of acute coronary syndrome (ACS).1–5 Therefore, yellow plaques detected by angioscopy have been considered vulnerable. However, there are no available data on the histopathological characteristics of yellow plaques in vivo. Optical coherence tomography (OCT) provides high-resolution (⬇ 10 m) cross-sectional coronary imaging. Therefore, OCT is useful for the detection of fine intracoronary structures, such as neointimal hyperplasia after implantation of a sirolimuseluting stent6 and thin-cap atheroma.7,8 OCT is capable of making an accurate measurement of the thickness of thin fibrous caps covered with lipid.8 Furthermore, the OCT characteristics of various components of atheromatous plaques have been validated in a histology-controlled study.9,10 In this study, the characteristics of yellow plaques were investigated in comparison with the OCT findings.
a Department of Internal Medicine, Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan; bCardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; cDivision of Cardiology, Nippon Medical School, Tokyo, Japan. Manuscript received July 14, 2007; revised manuscript received and accepted September 21, 2007. *Corresponding author: Tel.: 81-476-99-1111; fax: 81-476-99-1908. E-mail address: [email protected] (M. Takano).
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.09.106
Methods Patient population and clinical demographics: Between August 2006 and January 2007, 26 consecutive patients who consented to undergo catheter procedures using OCT and angioscopy were enrolled in the study. The exclusion criteria included unprotected left main disease (n ⫽ 4), renal insufficiency with baseline serum creatinine ⱖ2.0 mg/dl (n ⫽ 6), congestive heart failure (n ⫽ 4), low ejection fraction (⬍40%; n ⫽ 5), or conditions that required emergency coronary intervention (n ⫽ 22). Patients with extremely tortuous vessels (n ⫽ 9), angiographic small vessels (ⱕ2 mm; n ⫽ 10), vessels with ostial stenosis (n ⫽ 8), or with heavy calcified vessels (n ⫽ 9) were excluded due to the expected difficulty in advancing the imaging catheter. Finally, the arterial segments that had previously undergone percutaneous coronary intervention and had diffuse lesions (lesion length ⬎15 mm) and plaques located in bifurcation of major side branches were excluded from the image analysis. Written informed consent approved by review boards in Chiba-Hokusoh Hospital was obtained from all patients before the catheterization. Acute myocardial infarction was defined as an elevation of serum troponin-T level and documented ST elevation or depression on an electrocardiogram. Unstable angina was classified as a new-onset, accelerated, or angina at rest without elevation of troponin-T. Stable angina pectoris (SAP) was defined as a positive stress test and no change in the frequency, duration, or intensity of symptoms within 4 weeks. A culprit plaque was identified by the combination www.AJConline.org
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Figure 1. Corresponding OCT and angioscopic images. The upper panels show OCT and the lower panels show angioscopic images. (A) A white plaque (yellow grade 0) on angioscopy is diagnosed as a complete fibrous plaque (*) by OCT. (B) Angioscopic white plaque (yellow grade 0) contains lipid tissue (*) under a fibrous cap. The fibrous plaque thickness at the thinnest part (white arrow) is 130 m. (C) Dark yellow plaque (grade 3) is presented as a lipid plaque (*) with very thin fibrous cap (white arrow). Minimal thickness of the fibrous cap is 20 m. Arch of lipid was measured as an angle between the two straight lines that joined the center of lumen to both ends of lipid area. (D) A red thrombus on a yellow plaque is observed by angioscopy. Protruding thrombus (white arrow) overlying thin cap lipid plaque (*) is recognized by OCT. GW ⫽ guide wire.
Figure 2. Discrepancy of diagnosis between OCT and angioscopy. The upper panels show OCT and the lower panels show angioscopic images. (A) A yellow plaque (grade 1) is observed by angioscopy. However, the diagnosis by OCT is not as lipid plaque but a superficial calcified plaque (*). (B) A lipid plaque (*) visualized by OCT. The fibrous cap thickness measures 80 m. Plaque disruption (white arrow) is clearly found. The angioscopic diagnosis is a light yellow plaque (grade 1) without disruption. Plaque disruption is only identified by OCT. (C) In the OCT analysis, the area of rapid signal attenuation (*) is recognized to be lipid. However, angioscopy reveals the existence of a red thrombus on a light yellow plaque. GW ⫽ guide wire.
of the electrocardiographic findings, nuclear imaging tests, left ventricle wall motion abnormalities on echocardiography, and angiographic lesion morphology. OCT image acquisition: All patients were given intravenous 100 IU/kg heparin prior to the catheter procedures. A 7 Fr guiding catheter was engaged into the coronary artery via the transfemoral approach, and nitroglycerin (200 g) was administered through the guiding catheter. The OCT procedure has been previously reported.6 In brief, an image wire (ImageWire, LightLab Imaging, Inc., Westford, Massachusetts) was pulled from distal to proximal with a motorized pullback system at 1.0 mm/s, and continuous digital images were stored for subsequent analysis. The
exact position of the OCT catheter was recorded by fluoroscopy to ensure a reliable comparison. Definition of the OCT image: Characterization of the plaque components, such as lipid, fibrous, or calcified tissue, was validated based on the established criteria (Figures 1 and 2).9 When lipid tissue was present in any of the images within the plaque, it was defined as a lipid plaque. A plaque with no lipid component was defined as a fibrous plaque. For all images with an OCT-determined lipid plaque, the fibrous cap thickness was measured at its thinnest part, and the minimal lumen area was measured by a manual trace. In addition, the arch of the lipid in the same cross-sectional image was measured. The arch of lipid was defined as an angle between
Coronary Artery Disease/Coronary Plaque Characteristics With OCT and Angioscopy
the two straight lines that joined the center of coronary lumen to both ends of lipid area (Figure 1). Plaque disruption was defined as an intimal interruption and thrombus as an irregular high- or low-backscattering mass protruding into the lumen (Figures 1 and 2).11 Angioscopic image acquisition: An angioscopic catheter (Vecmova Neo, FiberTech Co., Chiba, Japan) was used as previously reported.5 Prior to observation, the white balance was adjusted for color correction. Light power was adjusted to avoid reflection and to obtain images with adequate brightness for determination of plaque color. During angioscopic observation, an exclusive assistant adjusted the light power to keep a regular degree of brightness on the target plaque. Angioscopic images and fluoroscopy during the angioscopic observations were recorded simultaneously on digital videotape for later analysis. The exact position of the angioscopic catheter at the site of the target plaque was recorded by an angiogram. Moreover, branch vessels and luminal shapes were utilized as landmarks in order to ensure the same location corresponding with OCT images. Definition of the angioscopic image: The yellow grade of the plaque was classified semiquantitatively based on the surface color as 0: white; 1: light yellow; 2: medium yellow; or 3: dark yellow (Figure 1) as described in a previous report.12 A ruptured plaque was defined as a complex plaque and included a tear, flap, or ulceration. A thrombus was defined as a coalescent white or red superficial or protruding mass adhering to the vessel surface but clearly a separate structure that remained after flushing with Ringer’s lactate. Analysis of the OCT and angioscopic images: Two independent investigators who were blinded to the clinical presentation and the results of the other imaging modality analyzed 2 kinds of images. Angioscopic images were analyzed in the same condition (on the same monitor and under the same room light). When there was discordance between the observers, a consensus reading was obtained. Inter- and intraobserver variability was assessed by an evaluation of all images by 2 independent readers and by the same reader at 2 separate time points, respectively. Clinical follow-up: Regular clinical visits occurred every month or every other month after catheter procedure. Major adverse cardiac events were defined as an ACS, sudden cardiac death, and repeat target lesion revascularization. Statistical analysis: The statistical analysis was performed using Statistical Analysis Software version 8 (SAS Institute, Cary, North Carolina). Continuous quantitative data are presented as the mean ⫾ SD. Continuous data (thickness of the fibrous cap, angle of the lipid distribution, and lumen area) were tested by 1-way analysis of variance test between the different categories (yellow grade) and post hoc Fisher’s protected least significant difference test was performed in case of a significant difference. A cut-off value of the fibrous cap thickness for identification of angioscopic yellow plaques was determined by the receiver-operator characteristic curve. Inter- and intraobserver variability was measured by the test of concordance. A value of p ⬍0.05 was considered to be statistically significant.
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Table 1 Baseline characteristics of the patients Patients Age (yrs) Men Diabetes mellitus Hypertension Hyperlipidemia Smoker Obesity Family history of coronary disease Reason for catheterization ACS ST-elevation myocardial infarction Non–ST-elevation myocardial infarction Unstable angina pectoris SAP Stent follow-up Distribution of observed coronary arteries Right Left anterior descending Left circumflex
n ⫽ 26 64 ⫾ 13 19 (73%) 6 (23%) 17 (65%) 18 (69%) 8 (31%) 5 (19%) 4 (15%) 7 (28%) 2 (8%) 2 (8%) 3 (12%) 9 (35%) 10 (37%) 13 (50%) 19 (73%) 9 (35%)
Table 2 Plaque characteristics by optical coherence tomography (OCT) and angioscopy Analyzed plaques Distribution of the plaque Right coronary artery Left anterior descending artery Left circumflex artery OCT findings Fibrous plaque Lipid plaque Calcified plaque Plaque disruption Thrombus Angioscopic findings White plaque (grade 0) Yellow plaque Light yellow plaque (grade 1) Medium yellow plaque (grade 2) Dark yellow plaque (grade 3) Plaque disruption Thrombus
n ⫽ 205 74 (36%) 79 (39%) 52 (25%) 56 (27%) 149 (73%) 38 (19%) 15 (7%) 16 (8%) 97 (47%) 108 (53%) 44 (21%) 46 (22%) 18 (9%) 12 (6%) 18 (9%)
Results Baseline characteristics: The clinical characteristics of 26 patients are listed in Table 1. Ten patients underwent catheterization as follow-up studies after stent implantation. There were no procedure-related complications except for transient myocardial ischemia during angioscopic and OCT observations. Plaque characteristics: A total of 205 plaques were recognized, and 16 plaques were culprit plaques (7 in ACS and 9 in SAP). The plaque characteristics are listed in Table 2. Based on OCT findings, 56 plaques were diagnosed as fibrous plaques and 149 as lipid plaques. In the OCT analysis, plaque disruption was found in 15 plaques (5 culprit plaques [71%] in ACS, 2 culprit plaques [22%] in SAP, and 8 nonculprit plaques [4%]). Thrombus was observed on 16
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Figure 3. Relationship between the angioscopic yellow grade and lumen area as measured by OCT. The minimal lumen area showed similar findings between the different groups of yellow grades.
Figure 5. Relationship between the angioscopic yellow grade and the fibrous cap thickness measured by OCT. The fibrous cap thickness by OCT decreased significantly as the yellow grade by angioscopy rose.
Angioscopic yellow plaques and lipid plaques by OCT: A total of 149 lipid plaques (45 plaques in the yellow grade 0, 40 in grade 1, 46 in grade 2, and 18 in grade 3) were analyzed. There were no differences in the minimal lumen area between the different yellow grades as identified by angioscopy (Figure 3). The arch of the lipid was also comparable with the different yellow grades (Figure 4). Range of the fibrous cap thickness was from 100 to 420 m in grade 0, from 80 to 110 m in grade 1, from 50 to 100 m in grade 2, and from 20 to 70 m in grade 3. There was an inverse relationship between the yellow grade and the fibrous cap thickness (Figure 5). Angioscopic yellow plaques can be identified as lipid plaques with high sensitivity and specificity based on the thickness of the fibrous cap measured at ⱕ110 m (98% and 96%, respectively). Figure 4. Relationship between the angioscopic yellow grade and the arch of lipid as measured by OCT. The arch of lipid did not differ among the grades of yellow plaque.
plaques (6 culprit plaques [86%] in ACS, 3 culprit plaques [33%] in SAP, and 7 nonculprit plaques [4%]). In the angioscopic analysis, plaque disruption was found in 12 plaques (5 culprit plaques [71%] in ACS, 2 culprit plaques [22%] in SAP, and 5 nonculprit plaques [3%]). Thrombus was observed on 18 plaques (7 culprit plaques [78%] in ACS, 3 culprit plaques [33%] in SAP, and 8 nonculprit plaques [4%]). Plaque disruption in 3 plaques was detectable only by OCT (Figure 2), and thrombus on 2 plaques was visualized only by angioscopy (Figure 2). Angiographic abnormalities such as wall irregularity, haziness, filling defect, or ulceration were recognized in 6 disrupted plaques (40%) and in 8 thrombosed plaques (44%). In the angioscopic analysis, there were 97 white plaques and 108 yellow plaques. The angioscopic yellow plaques included 44 plaques in grade 1, 46 in grade 2, and 18 in grade 3. Comparing those plaques with the OCT images validated 52 of the 97 white plaques as fibrous plaques and the other 45 plaques as lipid plaques. Four of the yellow plaques in grade 1 were not lipid plaques but superficial calcified plaques (Figure 2); 40 plaques in grade 1 and all plaques in grade 2 and grade 3 were lipid plaques.
Intraobserver and interobserver variability: Intraobserver and interobserver variability yielded acceptable concordance for angioscopic and OCT findings. The values for the intraobserver agreement of yellow grade, ruptured plaque, and thrombus on angioscopic findings were 0.90, 0.92, and 0.94, respectively; the values for the interobserver agreement were 0.88, 0.90, and 0.89, respectively. The values for the intraobserver agreement of plaque type, ruptured plaque, and thrombus on OCT findings were 0.91, 0.94, and 0.88, respectively; the values for the interobserver agreement of those values were 0.85, 0.89, and 0.86, respectively. Clinical outcome: Among studied patients, one patient died of intracranial hemorrhage; other patients were free from any adverse cardiac events during clinical follow-up (9.7 ⫾ 1.6 months). Discussion This study verified the pathohistological characterization of the angioscopic yellow plaque in coordination with OCT. The yellow plaques frequently had lipid under the thin fibrous cap. The overlying fibrous cap thickness became thinner in plaques with higher yellow grades. Although yellow plaques identified by angioscopy have been viewed as vulnerable, there has been limited histopathological investigation of these
Coronary Artery Disease/Coronary Plaque Characteristics With OCT and Angioscopy
plaques. Previous examination using specimens obtained by directional coronary atherectomy reported that yellow plaques identified by angioscopy were closely related to degenerated plaques or atheromas.13 Nevertheless, specimens acquired by atherectomy are crushed and contain only part of the plaque. OCT is applicable for the visualization and tissue characterization of a whole vessel and for the measurement of the complete dimensions of the plaque. Therefore, the plaque characterization determined by OCT set the standard for diagnosis. This study showed that 54% of white plaques (52 of 97) identified by angioscopy were fibrous plaques and 46% had lipid contents under the fibrous cap. These results indicate that angioscopy has limitations in the detection of lipid tissue because of its superficial appearance in the lumen. Two lipid plaques with a fibrous cap thickness ⱕ110 m showed as white plaques, which may be because halation by the light source of the angioscope distorts the image of light yellow plaques and they appear as white plaques. With respect to lipid detection, therefore, OCT was superior to angioscopy. Recently, it has been determined that OCT could evaluate intracoronary thrombus.11 In this study, 2 red thrombi identified by angioscopy were read as lipid plaques by OCT investigators (Figure 2). Red (erythrocyte-rich) thrombi and lipid plaques show similar OCT signal patterns, showing high-backscatter with rapid attenuation. A nonprotruding red thrombus with smooth surface may be misinterpreted as lipid plaque. Angioscopy can clearly distinguish a red thrombus from a yellow plaque based on the color and might be more sensitive method for the detection of thrombi than OCT. Two disrupted plaques were detectable only by OCT. The differences in image resolution may have contributed to these results. Postmortem histological investigation revealed that eroded plaques without rupture caused occluded intracoronary thrombus formation and sudden cardiac death.14 High-resolution OCT imaging may have an advantage in the detection of shallow plaque injury, such as plaque erosion. Lipid tissue visualized by OCT was described as a signal mass with rapid attenuation.9,10 Therefore, the depth and area of the lipid plaque were not measurable. The arch of the lipid was thus measured, and the relationship between the superficial extent of the lipid area and the yellow grade was investigated in this study. The results demonstrated that the yellow grade was related neither to the arch of the lipid nor to the luminal narrowing. The coronary lumen was maintained sufficiently in the majority of the mature atheromas, such as the intense yellow plaques. This fact may suggest that an angiogram is inadequate to predict the occurrence of ACS.15 The thickness of fibrous cap determined by OCT measurement decreased as yellow grade determined by angioscopy rose. A lipid plaque with a fibrous cap thickness ⱕ110 m can be identified as a yellow plaque with high sensitivity and specificity. Previous investigations demonstrated that computer-assisted determination of yellow plaques depends on the fibrous cap thickness of atheroma evaluated by histopathology.16,17 Although thresholds of the fibrous cap thickness in detectable yellow plaques differed from other methods (range 100 m to 300 m), these results suggest that the thickness of the fibrous cap might be a deter-
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minant factor in the plaque color. In addition, the more intense yellow plaques were lipid plaques with thinner fibrous caps. Structural characteristics of the plaques, especially the thickness of the fibrous caps that covered the lipid pools, play an important role in the plaque vulnerability.18 –20 A previous study showed that ACS occurred frequently in patients with glistening yellow plaques, which probably means intense yellow plaques.21 Furthermore, it has been documented that a plaque is prone to rupture when the fibrous cap thickness is ⬍65 m.18 That type of plaque is expected to be visualized as an intense yellow plaque by angioscopy. Prospective follow-up studies for the patients who have intense yellow plaques or thin-cap atheromas may provide the definitive definition of vulnerable plaques. There were several limitations to this study. The number of analyzed patients and plaques, especially culprit plaques, was limited. However, a total of 205 plaques were analyzed. The 2 imaging modalities were not performed in all coronary arteries in all patients. Some selection bias was therefore inevitable in the selection of patients and vessels to undergo intracoronary imaging. In the OCT analysis, lipid area was not measurable as a function of its image characteristics. Therefore, the estimation of vessel remodeling, which is an important factor in plaque vulnerability,3 was impossible. Assessment of angioscopic yellow grade was not absolute. However, interobserver variability between well-trained readers yielded acceptable concordance. Acknowledgment: We thank Kenichi Tokuyama, MD, Kenichiro Tajika, MD, Shunsuke Shimada, MSc, Toshihiro Chiba, MSc, Nobuyuki Igawa, MSc, and Masaki Suzuki, MSc, for their excellent assistance in our catheter laboratory. 1. Mizuno K, Miyamoto A, Satomura K, Kurita A, Arai T, Sakurada M, Yanagida S, Nakamura H. Angioscopic macromorphology in patients with acute coronary disorders. Lancet 1991;337:809 – 812. 2. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287–291. 3. Takano M, Mizuno K, Okamatsu K, Yokoyama S, Ohba T, Sakai S. Mechanical and structural characteristics of vulnerable plaques: analysis by coronary angioscopy and intravascular ultrasound. J Am Coll Cardiol 2001;38:99 –104. 4. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, Mizuno K. Elevated troponin T levels and lesion characteristics in non–ST-elevation acute coronary syndromes. Circulation 2004;109: 465– 470. 5. Sakai S, Mizuno K, Yokoyama S, Tanabe J, Shinada T, Seimiya K, Takano M, Ohba T, Tomimura M, Uemura R, Imaizumi T. Morphologic changes in infarct-related plaque after coronary stent placement: a serial angioscopy study. J Am Coll Cardiol 2003;42:1558 –1565. 6. Takano M, Inami S, Jang IK, Yamamot M, Murakami D, Seimiya K, Ohba T, Mizuno K. Evaluation by optical coherence tomography of neointimal coverage of sirolimus-eluting stent 3 months after implantation. Am J Cardiol 2007;99:1033–1038. 7. Jang IK, Tearney GJ, MacNeill, Takano M, Moselewski F, Iftima N, Shishkov M, Houser S, Aretz T, Halpern EF, Bouma BE. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–1555. 8. Kume T, Akasaka T, Kawamoto T, Okura H, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J 2006;152:755.e1–755.e4.
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9. Yabushita H, Bouma BE, Houser SL, Aretz HT, Jang IK, Schlendorf KH, Kauffman CR, Shishkov M, Kang DH, Halpern E, Tearney GJ. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106:1640 –1645. 10. Kawasaki M, Bouma BE, Bressner J, Houser SL, Nadkarni SK, MacNeill BD, Jang IK, Fujiwara H, Tearney GJ. Diagnostic accuracy of optical coherence tomography and integrated backscatter intravascular ultrasound images for tissue characterization of human coronary plaques. J Am Coll Cardiol 2006;48:81– 88. 11. Kume T, Akasaka T, Kawamoto T, Ogasawara Y, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary arterial thrombus by optical coherence tomography. Am J Cardiol 2006;97:1713–1717. 12. Takano M, Mizuno K, Yokoyama S, Seimiya K, Ishibashi F, Okamatsu K, Uemura R. Changes in coronary plaque color and morphology by lipid-lowering therapy with atorvastatin: serial evaluation by coronary angioscopy. J Am Coll Cardiol 2003;42:680 – 686. 13. Thieme T, Wernecke KD, Meyer R, Brandenstein E, Habedank D, Hinz A, Felix SB, Baumann G, Kleber FX. Angioscopic evaluation of atherosclerotic plaques: validation by histomorphologic analysis and association with stable and unstable coronary syndromes. J Am Coll Cardiol 1996;1:1– 6. 14. Farb A, Burke AP, Tang AL, Ling TY, Mannan P, Smialek J, Virmani R. Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354 –1363.
15. Little WC, Applegate RJ. The shadows level a doubt-the angiographic recognition of vulnerable coronary artery plaques. J Am Coll Cardiol 1999;33:1362–1364. 16. Miyamoto A, Priet AR, Friedl SE, Lin FC, Muller JE, Nesto RW, Abela GS. Atheromatous plaque cap thickness can be determined by quantitative color analysis during angioscopy: implications for identifying vulnerable plaque. Clin Cardiol 2004;27:9 –15. 17. Ishibashi F, Yokoyama S, Miyahara K, Dabreo A, Weiss ER, Iafrati M, Takano M, Okamatsu K, Mizuno K, Waxman S. Quantitative colorimetry of atherosclerotic plaque using the L*a*b color space during angioscopy for the detection of lipid cores underneath thin fibrous cap. Int J Cardiovasc Imaging 2007;6:679 – 691. 18. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275. 19. Davies MJ, Thomas AC. Plaque fissuring-the course of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373. 20. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–505. 21. Uchida Y, Nakamura F, Tomaru T, Morita T, Oshima T, Sasaki T, Morizuki S, Hirose J. Prediction of acute coronary syndromes by percutaneous coronary angioscopy in patients with stable angina. Am Heart J 1995;130:195–203.
Previous angioscopic examinations in living patients revealed that ruptured yellow plaques and intracoronary thrombi were common in the culprit lesions of acute coronary syndrome (ACS).1–5 Therefore, yellow plaques detected by angioscopy have been considered vulnerable. However, there are no available data on the histopathological characteristics of yellow plaques in vivo. Optical coherence tomography (OCT) provides high-resolution (⬇ 10 m) cross-sectional coronary imaging. Therefore, OCT is useful for the detection of fine intracoronary structures, such as neointimal hyperplasia after implantation of a sirolimuseluting stent6 and thin-cap atheroma.7,8 OCT is capable of making an accurate measurement of the thickness of thin fibrous caps covered with lipid.8 Furthermore, the OCT characteristics of various components of atheromatous plaques have been validated in a histology-controlled study.9,10 In this study, the characteristics of yellow plaques were investigated in comparison with the OCT findings.
a Department of Internal Medicine, Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan; bCardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; cDivision of Cardiology, Nippon Medical School, Tokyo, Japan. Manuscript received July 14, 2007; revised manuscript received and accepted September 21, 2007. *Corresponding author: Tel.: 81-476-99-1111; fax: 81-476-99-1908. E-mail address: [email protected] (M. Takano).
0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.09.106
Methods Patient population and clinical demographics: Between August 2006 and January 2007, 26 consecutive patients who consented to undergo catheter procedures using OCT and angioscopy were enrolled in the study. The exclusion criteria included unprotected left main disease (n ⫽ 4), renal insufficiency with baseline serum creatinine ⱖ2.0 mg/dl (n ⫽ 6), congestive heart failure (n ⫽ 4), low ejection fraction (⬍40%; n ⫽ 5), or conditions that required emergency coronary intervention (n ⫽ 22). Patients with extremely tortuous vessels (n ⫽ 9), angiographic small vessels (ⱕ2 mm; n ⫽ 10), vessels with ostial stenosis (n ⫽ 8), or with heavy calcified vessels (n ⫽ 9) were excluded due to the expected difficulty in advancing the imaging catheter. Finally, the arterial segments that had previously undergone percutaneous coronary intervention and had diffuse lesions (lesion length ⬎15 mm) and plaques located in bifurcation of major side branches were excluded from the image analysis. Written informed consent approved by review boards in Chiba-Hokusoh Hospital was obtained from all patients before the catheterization. Acute myocardial infarction was defined as an elevation of serum troponin-T level and documented ST elevation or depression on an electrocardiogram. Unstable angina was classified as a new-onset, accelerated, or angina at rest without elevation of troponin-T. Stable angina pectoris (SAP) was defined as a positive stress test and no change in the frequency, duration, or intensity of symptoms within 4 weeks. A culprit plaque was identified by the combination www.AJConline.org
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Figure 1. Corresponding OCT and angioscopic images. The upper panels show OCT and the lower panels show angioscopic images. (A) A white plaque (yellow grade 0) on angioscopy is diagnosed as a complete fibrous plaque (*) by OCT. (B) Angioscopic white plaque (yellow grade 0) contains lipid tissue (*) under a fibrous cap. The fibrous plaque thickness at the thinnest part (white arrow) is 130 m. (C) Dark yellow plaque (grade 3) is presented as a lipid plaque (*) with very thin fibrous cap (white arrow). Minimal thickness of the fibrous cap is 20 m. Arch of lipid was measured as an angle between the two straight lines that joined the center of lumen to both ends of lipid area. (D) A red thrombus on a yellow plaque is observed by angioscopy. Protruding thrombus (white arrow) overlying thin cap lipid plaque (*) is recognized by OCT. GW ⫽ guide wire.
Figure 2. Discrepancy of diagnosis between OCT and angioscopy. The upper panels show OCT and the lower panels show angioscopic images. (A) A yellow plaque (grade 1) is observed by angioscopy. However, the diagnosis by OCT is not as lipid plaque but a superficial calcified plaque (*). (B) A lipid plaque (*) visualized by OCT. The fibrous cap thickness measures 80 m. Plaque disruption (white arrow) is clearly found. The angioscopic diagnosis is a light yellow plaque (grade 1) without disruption. Plaque disruption is only identified by OCT. (C) In the OCT analysis, the area of rapid signal attenuation (*) is recognized to be lipid. However, angioscopy reveals the existence of a red thrombus on a light yellow plaque. GW ⫽ guide wire.
of the electrocardiographic findings, nuclear imaging tests, left ventricle wall motion abnormalities on echocardiography, and angiographic lesion morphology. OCT image acquisition: All patients were given intravenous 100 IU/kg heparin prior to the catheter procedures. A 7 Fr guiding catheter was engaged into the coronary artery via the transfemoral approach, and nitroglycerin (200 g) was administered through the guiding catheter. The OCT procedure has been previously reported.6 In brief, an image wire (ImageWire, LightLab Imaging, Inc., Westford, Massachusetts) was pulled from distal to proximal with a motorized pullback system at 1.0 mm/s, and continuous digital images were stored for subsequent analysis. The
exact position of the OCT catheter was recorded by fluoroscopy to ensure a reliable comparison. Definition of the OCT image: Characterization of the plaque components, such as lipid, fibrous, or calcified tissue, was validated based on the established criteria (Figures 1 and 2).9 When lipid tissue was present in any of the images within the plaque, it was defined as a lipid plaque. A plaque with no lipid component was defined as a fibrous plaque. For all images with an OCT-determined lipid plaque, the fibrous cap thickness was measured at its thinnest part, and the minimal lumen area was measured by a manual trace. In addition, the arch of the lipid in the same cross-sectional image was measured. The arch of lipid was defined as an angle between
Coronary Artery Disease/Coronary Plaque Characteristics With OCT and Angioscopy
the two straight lines that joined the center of coronary lumen to both ends of lipid area (Figure 1). Plaque disruption was defined as an intimal interruption and thrombus as an irregular high- or low-backscattering mass protruding into the lumen (Figures 1 and 2).11 Angioscopic image acquisition: An angioscopic catheter (Vecmova Neo, FiberTech Co., Chiba, Japan) was used as previously reported.5 Prior to observation, the white balance was adjusted for color correction. Light power was adjusted to avoid reflection and to obtain images with adequate brightness for determination of plaque color. During angioscopic observation, an exclusive assistant adjusted the light power to keep a regular degree of brightness on the target plaque. Angioscopic images and fluoroscopy during the angioscopic observations were recorded simultaneously on digital videotape for later analysis. The exact position of the angioscopic catheter at the site of the target plaque was recorded by an angiogram. Moreover, branch vessels and luminal shapes were utilized as landmarks in order to ensure the same location corresponding with OCT images. Definition of the angioscopic image: The yellow grade of the plaque was classified semiquantitatively based on the surface color as 0: white; 1: light yellow; 2: medium yellow; or 3: dark yellow (Figure 1) as described in a previous report.12 A ruptured plaque was defined as a complex plaque and included a tear, flap, or ulceration. A thrombus was defined as a coalescent white or red superficial or protruding mass adhering to the vessel surface but clearly a separate structure that remained after flushing with Ringer’s lactate. Analysis of the OCT and angioscopic images: Two independent investigators who were blinded to the clinical presentation and the results of the other imaging modality analyzed 2 kinds of images. Angioscopic images were analyzed in the same condition (on the same monitor and under the same room light). When there was discordance between the observers, a consensus reading was obtained. Inter- and intraobserver variability was assessed by an evaluation of all images by 2 independent readers and by the same reader at 2 separate time points, respectively. Clinical follow-up: Regular clinical visits occurred every month or every other month after catheter procedure. Major adverse cardiac events were defined as an ACS, sudden cardiac death, and repeat target lesion revascularization. Statistical analysis: The statistical analysis was performed using Statistical Analysis Software version 8 (SAS Institute, Cary, North Carolina). Continuous quantitative data are presented as the mean ⫾ SD. Continuous data (thickness of the fibrous cap, angle of the lipid distribution, and lumen area) were tested by 1-way analysis of variance test between the different categories (yellow grade) and post hoc Fisher’s protected least significant difference test was performed in case of a significant difference. A cut-off value of the fibrous cap thickness for identification of angioscopic yellow plaques was determined by the receiver-operator characteristic curve. Inter- and intraobserver variability was measured by the test of concordance. A value of p ⬍0.05 was considered to be statistically significant.
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Table 1 Baseline characteristics of the patients Patients Age (yrs) Men Diabetes mellitus Hypertension Hyperlipidemia Smoker Obesity Family history of coronary disease Reason for catheterization ACS ST-elevation myocardial infarction Non–ST-elevation myocardial infarction Unstable angina pectoris SAP Stent follow-up Distribution of observed coronary arteries Right Left anterior descending Left circumflex
n ⫽ 26 64 ⫾ 13 19 (73%) 6 (23%) 17 (65%) 18 (69%) 8 (31%) 5 (19%) 4 (15%) 7 (28%) 2 (8%) 2 (8%) 3 (12%) 9 (35%) 10 (37%) 13 (50%) 19 (73%) 9 (35%)
Table 2 Plaque characteristics by optical coherence tomography (OCT) and angioscopy Analyzed plaques Distribution of the plaque Right coronary artery Left anterior descending artery Left circumflex artery OCT findings Fibrous plaque Lipid plaque Calcified plaque Plaque disruption Thrombus Angioscopic findings White plaque (grade 0) Yellow plaque Light yellow plaque (grade 1) Medium yellow plaque (grade 2) Dark yellow plaque (grade 3) Plaque disruption Thrombus
n ⫽ 205 74 (36%) 79 (39%) 52 (25%) 56 (27%) 149 (73%) 38 (19%) 15 (7%) 16 (8%) 97 (47%) 108 (53%) 44 (21%) 46 (22%) 18 (9%) 12 (6%) 18 (9%)
Results Baseline characteristics: The clinical characteristics of 26 patients are listed in Table 1. Ten patients underwent catheterization as follow-up studies after stent implantation. There were no procedure-related complications except for transient myocardial ischemia during angioscopic and OCT observations. Plaque characteristics: A total of 205 plaques were recognized, and 16 plaques were culprit plaques (7 in ACS and 9 in SAP). The plaque characteristics are listed in Table 2. Based on OCT findings, 56 plaques were diagnosed as fibrous plaques and 149 as lipid plaques. In the OCT analysis, plaque disruption was found in 15 plaques (5 culprit plaques [71%] in ACS, 2 culprit plaques [22%] in SAP, and 8 nonculprit plaques [4%]). Thrombus was observed on 16
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Figure 3. Relationship between the angioscopic yellow grade and lumen area as measured by OCT. The minimal lumen area showed similar findings between the different groups of yellow grades.
Figure 5. Relationship between the angioscopic yellow grade and the fibrous cap thickness measured by OCT. The fibrous cap thickness by OCT decreased significantly as the yellow grade by angioscopy rose.
Angioscopic yellow plaques and lipid plaques by OCT: A total of 149 lipid plaques (45 plaques in the yellow grade 0, 40 in grade 1, 46 in grade 2, and 18 in grade 3) were analyzed. There were no differences in the minimal lumen area between the different yellow grades as identified by angioscopy (Figure 3). The arch of the lipid was also comparable with the different yellow grades (Figure 4). Range of the fibrous cap thickness was from 100 to 420 m in grade 0, from 80 to 110 m in grade 1, from 50 to 100 m in grade 2, and from 20 to 70 m in grade 3. There was an inverse relationship between the yellow grade and the fibrous cap thickness (Figure 5). Angioscopic yellow plaques can be identified as lipid plaques with high sensitivity and specificity based on the thickness of the fibrous cap measured at ⱕ110 m (98% and 96%, respectively). Figure 4. Relationship between the angioscopic yellow grade and the arch of lipid as measured by OCT. The arch of lipid did not differ among the grades of yellow plaque.
plaques (6 culprit plaques [86%] in ACS, 3 culprit plaques [33%] in SAP, and 7 nonculprit plaques [4%]). In the angioscopic analysis, plaque disruption was found in 12 plaques (5 culprit plaques [71%] in ACS, 2 culprit plaques [22%] in SAP, and 5 nonculprit plaques [3%]). Thrombus was observed on 18 plaques (7 culprit plaques [78%] in ACS, 3 culprit plaques [33%] in SAP, and 8 nonculprit plaques [4%]). Plaque disruption in 3 plaques was detectable only by OCT (Figure 2), and thrombus on 2 plaques was visualized only by angioscopy (Figure 2). Angiographic abnormalities such as wall irregularity, haziness, filling defect, or ulceration were recognized in 6 disrupted plaques (40%) and in 8 thrombosed plaques (44%). In the angioscopic analysis, there were 97 white plaques and 108 yellow plaques. The angioscopic yellow plaques included 44 plaques in grade 1, 46 in grade 2, and 18 in grade 3. Comparing those plaques with the OCT images validated 52 of the 97 white plaques as fibrous plaques and the other 45 plaques as lipid plaques. Four of the yellow plaques in grade 1 were not lipid plaques but superficial calcified plaques (Figure 2); 40 plaques in grade 1 and all plaques in grade 2 and grade 3 were lipid plaques.
Intraobserver and interobserver variability: Intraobserver and interobserver variability yielded acceptable concordance for angioscopic and OCT findings. The values for the intraobserver agreement of yellow grade, ruptured plaque, and thrombus on angioscopic findings were 0.90, 0.92, and 0.94, respectively; the values for the interobserver agreement were 0.88, 0.90, and 0.89, respectively. The values for the intraobserver agreement of plaque type, ruptured plaque, and thrombus on OCT findings were 0.91, 0.94, and 0.88, respectively; the values for the interobserver agreement of those values were 0.85, 0.89, and 0.86, respectively. Clinical outcome: Among studied patients, one patient died of intracranial hemorrhage; other patients were free from any adverse cardiac events during clinical follow-up (9.7 ⫾ 1.6 months). Discussion This study verified the pathohistological characterization of the angioscopic yellow plaque in coordination with OCT. The yellow plaques frequently had lipid under the thin fibrous cap. The overlying fibrous cap thickness became thinner in plaques with higher yellow grades. Although yellow plaques identified by angioscopy have been viewed as vulnerable, there has been limited histopathological investigation of these
Coronary Artery Disease/Coronary Plaque Characteristics With OCT and Angioscopy
plaques. Previous examination using specimens obtained by directional coronary atherectomy reported that yellow plaques identified by angioscopy were closely related to degenerated plaques or atheromas.13 Nevertheless, specimens acquired by atherectomy are crushed and contain only part of the plaque. OCT is applicable for the visualization and tissue characterization of a whole vessel and for the measurement of the complete dimensions of the plaque. Therefore, the plaque characterization determined by OCT set the standard for diagnosis. This study showed that 54% of white plaques (52 of 97) identified by angioscopy were fibrous plaques and 46% had lipid contents under the fibrous cap. These results indicate that angioscopy has limitations in the detection of lipid tissue because of its superficial appearance in the lumen. Two lipid plaques with a fibrous cap thickness ⱕ110 m showed as white plaques, which may be because halation by the light source of the angioscope distorts the image of light yellow plaques and they appear as white plaques. With respect to lipid detection, therefore, OCT was superior to angioscopy. Recently, it has been determined that OCT could evaluate intracoronary thrombus.11 In this study, 2 red thrombi identified by angioscopy were read as lipid plaques by OCT investigators (Figure 2). Red (erythrocyte-rich) thrombi and lipid plaques show similar OCT signal patterns, showing high-backscatter with rapid attenuation. A nonprotruding red thrombus with smooth surface may be misinterpreted as lipid plaque. Angioscopy can clearly distinguish a red thrombus from a yellow plaque based on the color and might be more sensitive method for the detection of thrombi than OCT. Two disrupted plaques were detectable only by OCT. The differences in image resolution may have contributed to these results. Postmortem histological investigation revealed that eroded plaques without rupture caused occluded intracoronary thrombus formation and sudden cardiac death.14 High-resolution OCT imaging may have an advantage in the detection of shallow plaque injury, such as plaque erosion. Lipid tissue visualized by OCT was described as a signal mass with rapid attenuation.9,10 Therefore, the depth and area of the lipid plaque were not measurable. The arch of the lipid was thus measured, and the relationship between the superficial extent of the lipid area and the yellow grade was investigated in this study. The results demonstrated that the yellow grade was related neither to the arch of the lipid nor to the luminal narrowing. The coronary lumen was maintained sufficiently in the majority of the mature atheromas, such as the intense yellow plaques. This fact may suggest that an angiogram is inadequate to predict the occurrence of ACS.15 The thickness of fibrous cap determined by OCT measurement decreased as yellow grade determined by angioscopy rose. A lipid plaque with a fibrous cap thickness ⱕ110 m can be identified as a yellow plaque with high sensitivity and specificity. Previous investigations demonstrated that computer-assisted determination of yellow plaques depends on the fibrous cap thickness of atheroma evaluated by histopathology.16,17 Although thresholds of the fibrous cap thickness in detectable yellow plaques differed from other methods (range 100 m to 300 m), these results suggest that the thickness of the fibrous cap might be a deter-
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minant factor in the plaque color. In addition, the more intense yellow plaques were lipid plaques with thinner fibrous caps. Structural characteristics of the plaques, especially the thickness of the fibrous caps that covered the lipid pools, play an important role in the plaque vulnerability.18 –20 A previous study showed that ACS occurred frequently in patients with glistening yellow plaques, which probably means intense yellow plaques.21 Furthermore, it has been documented that a plaque is prone to rupture when the fibrous cap thickness is ⬍65 m.18 That type of plaque is expected to be visualized as an intense yellow plaque by angioscopy. Prospective follow-up studies for the patients who have intense yellow plaques or thin-cap atheromas may provide the definitive definition of vulnerable plaques. There were several limitations to this study. The number of analyzed patients and plaques, especially culprit plaques, was limited. However, a total of 205 plaques were analyzed. The 2 imaging modalities were not performed in all coronary arteries in all patients. Some selection bias was therefore inevitable in the selection of patients and vessels to undergo intracoronary imaging. In the OCT analysis, lipid area was not measurable as a function of its image characteristics. Therefore, the estimation of vessel remodeling, which is an important factor in plaque vulnerability,3 was impossible. Assessment of angioscopic yellow grade was not absolute. However, interobserver variability between well-trained readers yielded acceptable concordance. Acknowledgment: We thank Kenichi Tokuyama, MD, Kenichiro Tajika, MD, Shunsuke Shimada, MSc, Toshihiro Chiba, MSc, Nobuyuki Igawa, MSc, and Masaki Suzuki, MSc, for their excellent assistance in our catheter laboratory. 1. Mizuno K, Miyamoto A, Satomura K, Kurita A, Arai T, Sakurada M, Yanagida S, Nakamura H. Angioscopic macromorphology in patients with acute coronary disorders. Lancet 1991;337:809 – 812. 2. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287–291. 3. Takano M, Mizuno K, Okamatsu K, Yokoyama S, Ohba T, Sakai S. Mechanical and structural characteristics of vulnerable plaques: analysis by coronary angioscopy and intravascular ultrasound. J Am Coll Cardiol 2001;38:99 –104. 4. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, Mizuno K. Elevated troponin T levels and lesion characteristics in non–ST-elevation acute coronary syndromes. Circulation 2004;109: 465– 470. 5. Sakai S, Mizuno K, Yokoyama S, Tanabe J, Shinada T, Seimiya K, Takano M, Ohba T, Tomimura M, Uemura R, Imaizumi T. Morphologic changes in infarct-related plaque after coronary stent placement: a serial angioscopy study. J Am Coll Cardiol 2003;42:1558 –1565. 6. Takano M, Inami S, Jang IK, Yamamot M, Murakami D, Seimiya K, Ohba T, Mizuno K. Evaluation by optical coherence tomography of neointimal coverage of sirolimus-eluting stent 3 months after implantation. Am J Cardiol 2007;99:1033–1038. 7. Jang IK, Tearney GJ, MacNeill, Takano M, Moselewski F, Iftima N, Shishkov M, Houser S, Aretz T, Halpern EF, Bouma BE. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–1555. 8. Kume T, Akasaka T, Kawamoto T, Okura H, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J 2006;152:755.e1–755.e4.
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15. Little WC, Applegate RJ. The shadows level a doubt-the angiographic recognition of vulnerable coronary artery plaques. J Am Coll Cardiol 1999;33:1362–1364. 16. Miyamoto A, Priet AR, Friedl SE, Lin FC, Muller JE, Nesto RW, Abela GS. Atheromatous plaque cap thickness can be determined by quantitative color analysis during angioscopy: implications for identifying vulnerable plaque. Clin Cardiol 2004;27:9 –15. 17. Ishibashi F, Yokoyama S, Miyahara K, Dabreo A, Weiss ER, Iafrati M, Takano M, Okamatsu K, Mizuno K, Waxman S. Quantitative colorimetry of atherosclerotic plaque using the L*a*b color space during angioscopy for the detection of lipid cores underneath thin fibrous cap. Int J Cardiovasc Imaging 2007;6:679 – 691. 18. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275. 19. Davies MJ, Thomas AC. Plaque fissuring-the course of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373. 20. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–505. 21. Uchida Y, Nakamura F, Tomaru T, Morita T, Oshima T, Sasaki T, Morizuki S, Hirose J. Prediction of acute coronary syndromes by percutaneous coronary angioscopy in patients with stable angina. Am Heart J 1995;130:195–203.