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Clinical Classification and Plaque Morphology Determined by Optical Coherence Tomography in Unstable Angina Pectoris
Clinical Classification and Plaque Morphology Determined by Optical Coherence Tomography in Unstable Angina Pectoris Masato Mizukoshi, MD, Toshio Imanishi, MD, Atsushi Tanaka, MD, Takashi Kubo, MD, Yong Liu, MD, Shigeho Takarada, MD, Hironori Kitabata, MD, Takashi Tanimoto, MD, Kenichi Komukai, MD, Kohei Ishibashi, MD, and Takashi Akasaka, MD* Unstable angina pectoris (UAP) is categorized with the Braunwald classification. However, the association of clinical presentation and plaque structure/function has not yet been elucidated in relation to cause. We used optical coherence tomography to investigate this relation. One hundred fifteen patients with primary UAP were categorized according to the Braunwald classification. Patients with class I UAP had the highest frequency of ulcers without fibrous cap disruption (p ⴝ 0.003) and the smallest minimum lumen area (class I, median 0.70 mm2, quartiles 1 to 3 0.42 to 1.00; class II, 1.80 mm2, 1.50 to 2.50; class III, 2.31 mm2, 1.21 to 3.00; p <0.001). Patients with class II UAP had the highest frequency of coronary spasm (p <0.001) and the lowest frequency of thrombi (p <0.001). Patients with class III UAP had the highest frequency of plaque ruptures (p <0.001), the thinnest fibrous cap (class I, median 140 m, quartile 1 to 3 90 to 160; class II, 150 m, 120 to 160; class III, 60 m, 40 to 105; p <0.001), and the highest frequency of thin cap fibroatheromas (p <0.001) and spotty calcifications (p <0.001). In conclusion, the structures/functions of culprit lesions on optical coherence tomograms differ in the Braunwald classes of UAP. Plaque vulnerability, progressive stenosis, and vasoconstriction may be related to the cause of the distinct presentations. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:323–328) Intravascular optical coherence tomography (OCT) has been used as a high-resolution imaging technique for plaque characterization.1– 4 OCT is an optical analog of intravascular ultrasound, with a resolution of approximately 10 to 20 m. Histologic studies have shown that OCT has the capability to reveal the various microstructures of an atherosclerotic plaque, including thin cap fibroatheroma, lipid core, and thrombus.5–7 In acute myocardial infarction, OCT has revealed the structure/function of the culprit lesion in detail.8 The aims of this study were to analyze plaque characteristics for each clinical classification of unstable angina pectoris (UAP) using OCT and to clarify the relation between clinical presentation and plaque structure/function in various types of UAP.9,10 Methods From January 2008 to June 2009, 118 consecutive patients with primary UAP who underwent coronary angiography were enrolled in this study. Patients were categorized into 3 groups according to the Braunwald clinical classification: class I (new onset of severe angina or accelerated angina, no pain at rest, n ⫽ 49), class II Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. Manuscript received December 28, 2009; revised manuscript received and accepted March 4, 2010. Dr. Akasaka was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Tokyo, Japan. *Corresponding author: Tel: 81-73-447-2300; fax: 81-73-446-0631. E-mail address: [email protected] (T. Akasaka). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.03.027
(angina at rest within previous month but not within preceding 48 hours, n ⫽ 30), and class III (angina at rest within 48 hours, n ⫽ 40). Patients with secondary UAP and postinfarction angina were not included. Exclusion criteria from optical coherence tomographic examination were presence of congestive heart failure, history of myocardial infarction, and cardiogenic shock. Demographic and clinical data were collected prospectively. The study protocol was approved by the ethics committee of Wakayama Medical University, and all patients provided informed consent before participation. The study was conducted in compliance with the Declaration of Helsinki. Oral aspirin (162 mg) and intravenous heparin (100 U/kg) were administered before coronary catheterization. Patients did not receive any thrombolytic therapy before angioplasty. Coronary catheterization was performed by the conventional femoral approach using 6-F sheaths and catheters. The culprit lesion was identified by the findings of coronary angiogram and those of electrocardiogram and transthoracic echocardiogram. If coronary angiogram showed no significant organic stenosis, a provocation test using acetylcholine was conducted. Acetylcholine was injected in incremental doses into the coronary artery (20, 50, and 100 g in the left coronary artery, 20 and 50 g in the right coronary artery). Thereafter, coronary angiography was repeated and an intracoronary injection of nitroglycerin was performed. Coronary spasm was defined as a transient total or subtotal obstruction with electrocardiographic changes and/or chest pain. After completion of diagnostic coronary angiography, optical coherence tomographic evaluation was performed in the culprit coronary artery before percutaneous coronary www.ajconline.org
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Table 1 Patient characteristics Variable Age (years) Men Systemic hypertension Diabetes mellitus Dyslipidemia* Smoking Obesity† Culprit coronary artery Left anterior descending Left circumflex Right
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Vaue
62 (56–71) 37 (79%) 32 (68%) 19 (40%) 26 (55%) 10 (21%) 25 (53%)
63 (58–72) 20 (67%) 21 (70%) 11 (37%) 20 (66%) 9 (30%) 16 (53%)
66 (58–73) 27 (71%) 26 (68%) 21 (55%) 24 (63%) 14 (37%) 19 (50%)
0.71 0.48 0.98 0.24 0.57 0.28 0.95 0.53
19 (40%) 10 (23%) 18 (38%)
18 (60%) 5 (17%) 7 (23%)
20 (53%) 7 (18%) 11 (30%)
Values are medians (quartiles 1 to 3) or numbers (percentages). * Total cholesterol level ⬎220 mg/dl, low-density lipoprotein level ⬎140 mg/dl, or triglycerides ⬎150 mg/dl. † Body mass index ⬎25 kg/m2.
Table 2 Clinical classification and plaque disruption in culprit lesion Variable Plaque rupture Ulcer Neither
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Value
20 (43%)* 15 (32%)*† 12 (25%)
4 (13%) 2 (7%) 24 (80%)*‡
27 (71%)‡ 3 (8%) 8 (21%)
⬍0.001 0.003 ⬍0.001
* p ⬍0.01, class I versus class II. p ⬍0.01, class I versus class III. ‡ p ⬍0.01, class II versus class III. †
intervention. A 0.016-inch optical coherence tomographic imaging catheter (ImageWire, LightLab Imaging, Westford, Massachusetts) was advanced to the distal end of the culprit lesion through a 3-F occlusion balloon catheter (Helios, LightLab Imaging).11 To remove blood cells from the field of view during pullback image acquisition, the occlusion balloon was inflated to 0.5 atm proximal to the culprit lesion, and lactated Ringer solution was infused into the coronary artery from the distal tip of the occlusion balloon catheter at a rate of 0.5 ml/s, as described previously.8,12 For proximal lesions, a continuous-flushing (nonocclusive) technique was performed instead of the balloon-occlusion technique, as previously reported.12 In this continuousflushing technique, a mixture of commercially available dextran 40 and lactated Ringer solution (low-molecularweight Dextran L Injection, Otsuka Pharmaceutical Factory, Tokushima, Japan) was infused from the guiding catheter at 2.5 to 4.5 ml/s with an injector pump (Mark V, Medrad, Inc., Warrendale, Pennsylvania) to remove the blood during image acquisition. The entire length of the culprit coronary artery was imaged with an automatic pullback device moving at 1 mm/s. All optical coherence tomograms were recorded digitally and analyzed by 2 independent investigators (MM and TA) who were blinded to clinical presentations. When there was discordance between observers, a consensus reading was obtained. Presence of a plaque rupture, an ulcer in a fibrous cap, intracoronary thrombus, or thin cap fibroatheroma was recorded and the minimum lumen area at the culprit site was
measured. A plaque rupture was identified by the presence of fibrous cap discontinuity and cavity formation in the plaque.8 An ulcer in a fibrous cap was defined by loss of luminal integrity without fibrous cap disruption. An intracoronary thrombus was defined by the presence of an intraluminal mass protruding from the surface of the vessel wall.7,8 Optical coherence tomograms were analyzed with previously validated criteria for plaque characterization, and fibrous cap thickness was determined as described previously.5– 8 Lipid plaque was semiquantified according to the number of involved quadrants on the cross-sectional image. When lipid was present in ⱖ2 quadrants in any of the images within a plaque, the plaque was considered lipid rich. A thin cap fibroatheroma was defined as a plaque with lipid content in ⱖ2 quadrants and the thinnest part of the fibrous cap measuring ⬍70 m.8,12 Spotty calcification was identified as a calcified plaque within an arc of ⬍90° in ⬎1 cross-sectional image of the culprit lesion.13–15 The 30mm–long culprit lesion segment (15 mm proximal and 15 mm distal to the culprit lesion site) was used for assessment of frequency of thin cap fibroatheroma and spotty calcification. In patients with coronary spasm, optical coherence tomograms were analyzed during and after relief of the spasm. PASW Statistics 17.0 (SPSS, Inc., Chicago, Illinois) software was used for statistical analysis. Continuous variables are expressed as median (quartiles 1 to 3) and were compared using Kruskal-Wallis test. If significant, pairwise comparisons using Bonferroni test were performed for mul-
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A
C
E
B
D
F
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Figure 1. Representative cases in each class of the Braunwald classification. (Left) Typical optical coherence tomograms in class I. (A) Severe arterial stenosis surrounded by fibrous plaque. (B) Ulcer without fibrous cap disruption. (Middle) Typical optical coherence tomograms during coronary spasm in class II. (C) Spasm caused severe luminal narrowing and folding of the intima (arrows). (D) Intracoronary administration of nitroglycerin relieved coronary spasm. No significant stenosis was observed and the folding of the intima disappeared. (Right) Typical optical coherence tomograms in class III. (E) Plaque rupture. The fibrous cap was broken and its thin fibrous cap could be observed (arrows). Cavity formation could also be observed (arrowheads). (F) Plaque rupture in culprit lesion with large lumen. Tiny thrombus was observed near the site of plaque rupture (arrows).
tiple analyses. Categorical data are summarized as frequencies and percentages. Categorical variables were compared using Fisher’s exact test. A p value ⬍0.05 was considered statistically significant. Results Of the enrolled 118 patients with primary UAP, 2 with congestive heart failure and 1 with cardiogenic shock were excluded from optical coherence tomographic examination. Thus, 115 patients with primary UAP constituted the final study population (Braunwald clinical classification: class I, n ⫽ 47; class II, n ⫽ 30; and class III, n ⫽ 38). Clinical characteristics of all 115 patients are presented in Table 1. Patients in different groups showed no significant differences in age, gender, classic coronary risk factors, or culprit vessels. Culprit arteries were successfully observed in all patients using OCT without any serious procedural complications. Optical coherence tomographic findings for plaque disruption are presented in Table 2. Representative cases in each class of the Braunwald classification are shown in Figure 1. Incidence of plaque rupture was significantly different in culprit lesions of patients with Braunwald class I, II, and III UAP (p ⬍0.001). Incidence of plaque rupture in class III was the highest in the 3 classes. In addition, plaque rupture was significantly more common in class I than in class II (p ⫽ 0.007). A significant difference in the incidence of ulcers without fibrous cap disruption was found among the 3
Figure 2. Frequencies of lipid-rich plaque, thrombus, plaque rupture, ulcer without disruption, and coronary spasm in patients with each Braunwald class.
classes of Braunwald classification (p ⫽ 0.003), and those were detected most frequently in class I. Incidence of a culprit lesion without any disruptions including plaque rupture and ulceration was significantly higher in class II than in class I or III (p ⬍0.001). Plaque characteristics are presented in Figure 2 and Table 3. Number of quadrants involved by lipid did not significantly differ among the 3 classes (p ⫽ 0.187). Lipid-rich plaques were frequently detected in culprit lesions in all 3 classes, and their incidences did not differ significantly among classes (p ⫽
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Table 3 Clinical classification and plaque characteristics in culprit lesion Variable Lipid plaque in quadrants 1/2/3/4 Lipid-rich plaque (ⱖ2 quadrants) Fibrous cap thickness, m Thin cap fibroatheroma Spotty calcification Minimum lumen area (mm2) Coronary spasm Thrombus
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Value
7/10/25/5 40 (85%) 140 (90–160) 1 (0–1) 1 (0–2)* 0.70 (0.42–1.0)*† 0 34 (72%)
6/8/7/9 24 (80%) 150 (120–160) 0 (0–1) 0 (0–0) 1.80 (1.50–2.50) 10 (33%)* 9 (30%)*‡
5/10/17/6 33 (87%) 60 (40–105)†‡ 1.5 (1–2)†‡ 1 (1–2)‡ 2.31 (1.21–3.00) 5 (13%) 28 (73%)
0.187 0.730 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Values are numbers (percentages) or medians (quartiles 1 to 3). * p ⬍0.01, class I versus class II. † p ⬍0.01, class I versus class III. ‡ p ⬍0.01, class II versus class III.
Figure 3. Fibrous cap thickness in each Braunwald class (box-and-whisker plot), medians (lines within boxes), 25th and 75th percentiles (top and bottom borders of boxes, respectively), and 10th and 90th percentiles (whiskers above and below boxes, respectively) are depicted.
Figure 4. Minimum lumen area in each Braunwald class (box-and-whisker plot), medians (lines within boxes), 25th and 75th percentiles (top and bottom borders of boxes, respectively), and 10th and 90th percentiles (whiskers above and below boxes, respectively).
0.730). Fibrous cap thickness in class III was the thinnest among the 3 classes (p ⬍0.001; Figure 3). Frequency of thin cap fibroatheromas in the culprit artery was further evaluated. Thin cap fibroatheromas were observed most frequently in class III (p ⬍0.001). Incidence of thin cap fibroatheroma in class I tended to be higher than in class II, although not significantly. Incidence of spotty calcification was significantly different
among the 3 classes (p ⬍0.001), and it was observed more frequently in classes I and III. Spontaneous coronary spasm was detected in 3 patients and the acetylcholine test provoked coronary spasm in 12 patients without significant coronary artery stenosis. Coronary spasm was most often observed in patients with class II; its incidence in class III was more frequent than that in class I. Minimum lumen area measured using OCT in class I was
Coronary Artery Disease/Plaque Morphology in Unstable Angina Pectoris
the smallest among the 3 classes (p ⬍0.001; Figure 4). Thrombus was frequently detected in classes I and III (p ⬍0.001). In contrast, in class II, incidence of thrombus was the lowest among the 3 classes. Discussion The Braunwald classification has been widely used because of its effectiveness in evaluating severity and prognosis of UAP. Severity and clinical setting of UAP have been related to lesion complexity.16 –18 Moreover, Braunwald19 proposed different causal processes: (1) a nonocclusive thrombus on preexisting plaque, (2) dynamic obstruction (coronary spasm), (3) progressive mechanical obstruction, and (4) inflammation and/or infection. In the present study, OCT allowed us to analyze the complexity of the culprit lesions for each Braunwald class. This analysis revealed the characteristics of plaque structure/function in relation to the causal factors described by Braunwald. Lipid-rich plaques were observed predominantly in each Braunwald class. Lipid-rich plaques are thought to be the basis of UAP.18 Several morphologic and structural markers such as fissured plaque, thin cap fibroatheroma, and superficial calcified nodules have been proposed for defining a vulnerable plaque.20 Patients with class I had not only occasional plaque ruptures but also more ulcers without fibrous cap disruption. Minimum lumen area was the smallest in class I. Based on theories on the natural history of coronary atherosclerosis, excessive remodeling is thought to be associated with acute coronary syndrome, and constrictive remodeling may lead to erosions.21–23 Stenotic plaque may undergo local erosion, which leads to focal thrombus formation.24 Plaques in class I were characterized by severe luminal narrowing and ulcers. These features are thought to represent progressive mechanical obstruction. Fibrous cap thickness in class I was not always thin, but plaque rupture was observed in many patients with class I (43%). Our previous study demonstrated that plaque rupture could occur in even thick fibrous caps, depending on exertion levels.12 The present results are consistent with the typical presentation of patients with class I, that is, accelerated exertional pain. In class II, optical coherence tomographic findings indicated that plaque vulnerability and involvement of progressive mechanical obstruction may be less. Van Mitenburgvan Zijl et al16 reported that class II had the best prognosis. Our findings may also indicate a favorable prognosis in class II based on vulnerability and obstruction. In contrast, coronary spasm was most frequent in class II. Coronary vasoconstriction can be considered an important characteristic of the culprit site in class II. Severity of coronary spasm may affect degree of thrombus formation and clinical manifestations. These characteristics correspond to dynamic obstruction proposed by Braunwald.19 In class III, fibrous cap thickness was the thinnest of all classes and plaque rupture, thin cap fibroatheroma, and spotty calcification were detected more frequently. These findings indicate that plaques in patients with class III may have more vulnerability, which can result in more plaque ruptures and subsequent thrombus formation. A higher incidence of coronary thrombi and histopathologic instability
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in the plaque were considered correlated with clinical severity.25,26 Thus, plaque vulnerability measured by OCT may also be an indicator of poor prognosis in class III. This study had several limitations. First, it was conducted at a single center with a small sample. Larger cohort studies would be necessary to confirm our findings. Second, the borders of the endothelium are difficult to distinguish on optical coherence tomograms of the intima. Therefore, we cannot detect precise erosion. However, small ulcers without discontinuity of the fibrous cap were observed. Third, thrombus may affect analysis of the plaque behind. Fourth, we included coronary spasm without significant organic coronary stenosis in each Braunwald class. Therefore, our results on degree of coronary artery stenosis differed from those of other reports.27 Coronary spasm was recently shown to be important in acute coronary syndrome.28,29 An acetylcholine provocation test was performed only in cases without significant stenosis, and vasomotor condition of the remaining cases could not be evaluated. It may be necessary to assess involvement of coronary spasm in UAP in greater detail. Fifth, it must be noted that plaque structure/function is not uniform in any of the clinical classes, although certain optical coherence tomographic findings predominate in each clinical class. 1. Jang IK, Bouma BE, Kang DH, Park SJ, Park SW, Seung KB, Choi KB, Shishkov M, Schlendorf K, Pomerantsev E, Houser SL, Aretz HT, Tearney GJ. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol 2002;39:604 – 609. 2. Brezinski ME, Tearny GJ, Bouma BE, Izatt JA, Hee MR, Swanson EA, Southern JF, Fujimoto JG. Optical coherence tomography for optical biopsy: properties and demonstration of vascular pathology. Circulation 1996;93:1206 –1213. 3. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary intimamedia thickness by optical coherence tomography: comparison with intravascular ultrasound. Circ J 2005;69:903–907. 4. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary arterial plaque by optical coherence tomography. Am J Cardiol 2006;97:1172–1175. 5. Jang IK, Tearney GJ, MacNeill B, Takano M, Moselewski F, Iftima N, Shishkov M, Houser S, Aretz HT, Halpern EF, Bouma BE. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–1555. 6. Yabushita H, Bouma BE, Houser S, Aretz HT, Jang IK, Schlendorf KH, Kauffman CR, Shishkov M, Kang DH, Halpern EF, Tearney GJ. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106:1640 –1645. 7. 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. 8. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T, Matsuo Y, Masho T, Kitabata H, Tsuda K, Tomobuchi Y, Akasaka T. Assessment of culprit lesion morphology in acute myocardial infarction. J Am Coll Cardiol 2007;50:933–939. 9. Braunwald E. Unstable angina. Circulation 1989;80:410 – 414. 10. Hamm CW, Braunwald E. A classification of unstable angina revisited. Circulation 2000;102:118 –122. 11. Kubo T, Akasaka T. Recent advances in intracoronary imaging techniques: focus on optical coherence tomography. Expert Rev Med Devices 2008;5:691– 697. 12. Tanaka A, Imanishi T, Kitabata H, Kubo T, Takarada S, Tanimoto T, Kuroi A, Tsujioka H, Ikejima H, Ueno S, Kataiwa H, Okouchi K, Kashiwaghi M, Matsumoto H, Takemoto K, Nakamura N, Hirata K, Mizukoshi M, Akasaka T. Morphology of exertion-triggered plaque
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The American Journal of Cardiology (www.ajconline.org) rupture in patients with acute coronary syndrome: an optical coherence tomography study. Circulation 2008;118:2368 –2373. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary arterial plaque by optical coherence tomography. Am J Cardiol 2006;97:1172– 1175. Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D, Nakamura Y, Yamashita H, Yamagishi H, Takeuchi K, Naruko T, Haze K, Becker A, Yoshikawa J, Ueda M. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction. An intravascular ultrasound study. Circulation 2004;110:3424 –3342. Cilingiroglu M, Oh JH, Sugunan B, Kemp NJ, Kim J, Lee S, Zaatari HN, Escobedo D, Thomsen S, Milner TE, Feldman MD. Detection of vulnerable plaque in a murine model of atherosclerosis with optical coherence tomography. Catheter Cardiovasc Interv 2006;67:915–923. van Mitenburg-van Zijl AJ, Simoons ML, Veehoek RJ, Bossuyt PM. Incidence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol 1995;25:1286 –1292. Ahmed WH, Bittl JA, Braunwald E. Relation between clinical presentation and angiographic findings in unstable angina pectoris, and comparison with hat in stable angina. Am J Cardiol 1993;72:544 –550. De Servi S, Arbustini E, Marsico F, Bramucci E, Angoli L, Porcu E, Costante AM, Kubica J, Boschetti E, Valentini P, Specchia G. Correlation between clinical and morphologic findings in unstable angina. Am J Cardiol 1996;77:128 –132. Braunwald E. Unstable angina an etiologic approach to management. Circulation 1998;98:2219 –2222. Naghavi M, Libby P, Falk E, Casscells W, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick D, de Korte CL, Aikawa M, Airaksinen KEJ, Assmann G, Becke CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W, Schwartz R, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient a call for new definitions and risk assessment strategies: part I. Circulation 2003;108:1664 –1672.
21. Stone PH, Coskun AU, Kinlay CS, Popma JJ, Sonka M, Whale A, Yeghiazarians Y, Maynard C, Kuntz RE, Feldman CL. Regions of low endothelial shear stress are the sites where coronary plaque progresses and vascular remodeling occurs in humans: an in vivo serial study. Eur Heart J 2007;28:705–710. 22. Feldman CL, Coskun AU, Yeghiazzarians Y, Kinlay S, Wahle A, Olszewski ME, Rossen JD, Sonka M, Popma JJ, Orav J, Kuntz RE, Stone PH. Remodeling characteristics of minimally diseases coronary arteries are consistent along the length of the artery. Am J Cardiol 2006;97:13–16. 23. Sipahi I, Tuzcu EM, Schoenhagen P, Nicholls SJ, Chen MS, Crowe T, Loyd AB, Kapadia S, Nissen SE. Paradoxical increase in lumen size during progression of coronary atherosclerosis: observations from the REVERSAL trial. Atherosclerosis 2006;189:229 –235. 24. Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 2007;49:2379 –2393. 25. Owa M, Origasa H, Saito M. Predictive validity of the Braunwald classification of unstable angina for angiographic findings, short-term prognosis, and treatment selection. Angiology 1997;48:663– 670. 26. Depre C, Wijns W, Robert AM, Renkin JP, Havaux X. Pathology of unstable plaque: correlation with the clinical severity of acute coronary syndromes. J Am Coll Cardiol 1997;30:694 –702. 27. Dangas G, Mehran R, Wallenstein S, Courcoutsakis NA, Kakarala V, Hollywood J, Ambrose JA. Correlation of angiographic morphology and clinical presentation in unstable angina. J Am Coll Cardiol 1997; 29:519 –525. 28. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary artery spasm as a frequent cause of acute coronary syndrome: the CASPER (Coronary Artery Spasm in Patients with Acute Coronary Syndrome) study. J Am Coll Cardiol 2008;52:523– 527. 29. Wakabayashi K, Suzuki H, Honda Y, Wakatsuki D, Kawachi K, Ota K, Koba S, Schimizu N, Asano F, Sato T, Takeyama Y. Provoked coronary spasm predicts adverse outcome in patients with acute myocardial infarction: a novel predictor of prognosis after acute myocardial infarction. J Am Coll Cardiol 2008;52:518 –552.
(angina at rest within previous month but not within preceding 48 hours, n ⫽ 30), and class III (angina at rest within 48 hours, n ⫽ 40). Patients with secondary UAP and postinfarction angina were not included. Exclusion criteria from optical coherence tomographic examination were presence of congestive heart failure, history of myocardial infarction, and cardiogenic shock. Demographic and clinical data were collected prospectively. The study protocol was approved by the ethics committee of Wakayama Medical University, and all patients provided informed consent before participation. The study was conducted in compliance with the Declaration of Helsinki. Oral aspirin (162 mg) and intravenous heparin (100 U/kg) were administered before coronary catheterization. Patients did not receive any thrombolytic therapy before angioplasty. Coronary catheterization was performed by the conventional femoral approach using 6-F sheaths and catheters. The culprit lesion was identified by the findings of coronary angiogram and those of electrocardiogram and transthoracic echocardiogram. If coronary angiogram showed no significant organic stenosis, a provocation test using acetylcholine was conducted. Acetylcholine was injected in incremental doses into the coronary artery (20, 50, and 100 g in the left coronary artery, 20 and 50 g in the right coronary artery). Thereafter, coronary angiography was repeated and an intracoronary injection of nitroglycerin was performed. Coronary spasm was defined as a transient total or subtotal obstruction with electrocardiographic changes and/or chest pain. After completion of diagnostic coronary angiography, optical coherence tomographic evaluation was performed in the culprit coronary artery before percutaneous coronary www.ajconline.org
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Table 1 Patient characteristics Variable Age (years) Men Systemic hypertension Diabetes mellitus Dyslipidemia* Smoking Obesity† Culprit coronary artery Left anterior descending Left circumflex Right
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Vaue
62 (56–71) 37 (79%) 32 (68%) 19 (40%) 26 (55%) 10 (21%) 25 (53%)
63 (58–72) 20 (67%) 21 (70%) 11 (37%) 20 (66%) 9 (30%) 16 (53%)
66 (58–73) 27 (71%) 26 (68%) 21 (55%) 24 (63%) 14 (37%) 19 (50%)
0.71 0.48 0.98 0.24 0.57 0.28 0.95 0.53
19 (40%) 10 (23%) 18 (38%)
18 (60%) 5 (17%) 7 (23%)
20 (53%) 7 (18%) 11 (30%)
Values are medians (quartiles 1 to 3) or numbers (percentages). * Total cholesterol level ⬎220 mg/dl, low-density lipoprotein level ⬎140 mg/dl, or triglycerides ⬎150 mg/dl. † Body mass index ⬎25 kg/m2.
Table 2 Clinical classification and plaque disruption in culprit lesion Variable Plaque rupture Ulcer Neither
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Value
20 (43%)* 15 (32%)*† 12 (25%)
4 (13%) 2 (7%) 24 (80%)*‡
27 (71%)‡ 3 (8%) 8 (21%)
⬍0.001 0.003 ⬍0.001
* p ⬍0.01, class I versus class II. p ⬍0.01, class I versus class III. ‡ p ⬍0.01, class II versus class III. †
intervention. A 0.016-inch optical coherence tomographic imaging catheter (ImageWire, LightLab Imaging, Westford, Massachusetts) was advanced to the distal end of the culprit lesion through a 3-F occlusion balloon catheter (Helios, LightLab Imaging).11 To remove blood cells from the field of view during pullback image acquisition, the occlusion balloon was inflated to 0.5 atm proximal to the culprit lesion, and lactated Ringer solution was infused into the coronary artery from the distal tip of the occlusion balloon catheter at a rate of 0.5 ml/s, as described previously.8,12 For proximal lesions, a continuous-flushing (nonocclusive) technique was performed instead of the balloon-occlusion technique, as previously reported.12 In this continuousflushing technique, a mixture of commercially available dextran 40 and lactated Ringer solution (low-molecularweight Dextran L Injection, Otsuka Pharmaceutical Factory, Tokushima, Japan) was infused from the guiding catheter at 2.5 to 4.5 ml/s with an injector pump (Mark V, Medrad, Inc., Warrendale, Pennsylvania) to remove the blood during image acquisition. The entire length of the culprit coronary artery was imaged with an automatic pullback device moving at 1 mm/s. All optical coherence tomograms were recorded digitally and analyzed by 2 independent investigators (MM and TA) who were blinded to clinical presentations. When there was discordance between observers, a consensus reading was obtained. Presence of a plaque rupture, an ulcer in a fibrous cap, intracoronary thrombus, or thin cap fibroatheroma was recorded and the minimum lumen area at the culprit site was
measured. A plaque rupture was identified by the presence of fibrous cap discontinuity and cavity formation in the plaque.8 An ulcer in a fibrous cap was defined by loss of luminal integrity without fibrous cap disruption. An intracoronary thrombus was defined by the presence of an intraluminal mass protruding from the surface of the vessel wall.7,8 Optical coherence tomograms were analyzed with previously validated criteria for plaque characterization, and fibrous cap thickness was determined as described previously.5– 8 Lipid plaque was semiquantified according to the number of involved quadrants on the cross-sectional image. When lipid was present in ⱖ2 quadrants in any of the images within a plaque, the plaque was considered lipid rich. A thin cap fibroatheroma was defined as a plaque with lipid content in ⱖ2 quadrants and the thinnest part of the fibrous cap measuring ⬍70 m.8,12 Spotty calcification was identified as a calcified plaque within an arc of ⬍90° in ⬎1 cross-sectional image of the culprit lesion.13–15 The 30mm–long culprit lesion segment (15 mm proximal and 15 mm distal to the culprit lesion site) was used for assessment of frequency of thin cap fibroatheroma and spotty calcification. In patients with coronary spasm, optical coherence tomograms were analyzed during and after relief of the spasm. PASW Statistics 17.0 (SPSS, Inc., Chicago, Illinois) software was used for statistical analysis. Continuous variables are expressed as median (quartiles 1 to 3) and were compared using Kruskal-Wallis test. If significant, pairwise comparisons using Bonferroni test were performed for mul-
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A
C
E
B
D
F
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Figure 1. Representative cases in each class of the Braunwald classification. (Left) Typical optical coherence tomograms in class I. (A) Severe arterial stenosis surrounded by fibrous plaque. (B) Ulcer without fibrous cap disruption. (Middle) Typical optical coherence tomograms during coronary spasm in class II. (C) Spasm caused severe luminal narrowing and folding of the intima (arrows). (D) Intracoronary administration of nitroglycerin relieved coronary spasm. No significant stenosis was observed and the folding of the intima disappeared. (Right) Typical optical coherence tomograms in class III. (E) Plaque rupture. The fibrous cap was broken and its thin fibrous cap could be observed (arrows). Cavity formation could also be observed (arrowheads). (F) Plaque rupture in culprit lesion with large lumen. Tiny thrombus was observed near the site of plaque rupture (arrows).
tiple analyses. Categorical data are summarized as frequencies and percentages. Categorical variables were compared using Fisher’s exact test. A p value ⬍0.05 was considered statistically significant. Results Of the enrolled 118 patients with primary UAP, 2 with congestive heart failure and 1 with cardiogenic shock were excluded from optical coherence tomographic examination. Thus, 115 patients with primary UAP constituted the final study population (Braunwald clinical classification: class I, n ⫽ 47; class II, n ⫽ 30; and class III, n ⫽ 38). Clinical characteristics of all 115 patients are presented in Table 1. Patients in different groups showed no significant differences in age, gender, classic coronary risk factors, or culprit vessels. Culprit arteries were successfully observed in all patients using OCT without any serious procedural complications. Optical coherence tomographic findings for plaque disruption are presented in Table 2. Representative cases in each class of the Braunwald classification are shown in Figure 1. Incidence of plaque rupture was significantly different in culprit lesions of patients with Braunwald class I, II, and III UAP (p ⬍0.001). Incidence of plaque rupture in class III was the highest in the 3 classes. In addition, plaque rupture was significantly more common in class I than in class II (p ⫽ 0.007). A significant difference in the incidence of ulcers without fibrous cap disruption was found among the 3
Figure 2. Frequencies of lipid-rich plaque, thrombus, plaque rupture, ulcer without disruption, and coronary spasm in patients with each Braunwald class.
classes of Braunwald classification (p ⫽ 0.003), and those were detected most frequently in class I. Incidence of a culprit lesion without any disruptions including plaque rupture and ulceration was significantly higher in class II than in class I or III (p ⬍0.001). Plaque characteristics are presented in Figure 2 and Table 3. Number of quadrants involved by lipid did not significantly differ among the 3 classes (p ⫽ 0.187). Lipid-rich plaques were frequently detected in culprit lesions in all 3 classes, and their incidences did not differ significantly among classes (p ⫽
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Table 3 Clinical classification and plaque characteristics in culprit lesion Variable Lipid plaque in quadrants 1/2/3/4 Lipid-rich plaque (ⱖ2 quadrants) Fibrous cap thickness, m Thin cap fibroatheroma Spotty calcification Minimum lumen area (mm2) Coronary spasm Thrombus
Class I (n ⫽ 47)
Class II (n ⫽ 30)
Class III (n ⫽ 38)
p Value
7/10/25/5 40 (85%) 140 (90–160) 1 (0–1) 1 (0–2)* 0.70 (0.42–1.0)*† 0 34 (72%)
6/8/7/9 24 (80%) 150 (120–160) 0 (0–1) 0 (0–0) 1.80 (1.50–2.50) 10 (33%)* 9 (30%)*‡
5/10/17/6 33 (87%) 60 (40–105)†‡ 1.5 (1–2)†‡ 1 (1–2)‡ 2.31 (1.21–3.00) 5 (13%) 28 (73%)
0.187 0.730 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Values are numbers (percentages) or medians (quartiles 1 to 3). * p ⬍0.01, class I versus class II. † p ⬍0.01, class I versus class III. ‡ p ⬍0.01, class II versus class III.
Figure 3. Fibrous cap thickness in each Braunwald class (box-and-whisker plot), medians (lines within boxes), 25th and 75th percentiles (top and bottom borders of boxes, respectively), and 10th and 90th percentiles (whiskers above and below boxes, respectively) are depicted.
Figure 4. Minimum lumen area in each Braunwald class (box-and-whisker plot), medians (lines within boxes), 25th and 75th percentiles (top and bottom borders of boxes, respectively), and 10th and 90th percentiles (whiskers above and below boxes, respectively).
0.730). Fibrous cap thickness in class III was the thinnest among the 3 classes (p ⬍0.001; Figure 3). Frequency of thin cap fibroatheromas in the culprit artery was further evaluated. Thin cap fibroatheromas were observed most frequently in class III (p ⬍0.001). Incidence of thin cap fibroatheroma in class I tended to be higher than in class II, although not significantly. Incidence of spotty calcification was significantly different
among the 3 classes (p ⬍0.001), and it was observed more frequently in classes I and III. Spontaneous coronary spasm was detected in 3 patients and the acetylcholine test provoked coronary spasm in 12 patients without significant coronary artery stenosis. Coronary spasm was most often observed in patients with class II; its incidence in class III was more frequent than that in class I. Minimum lumen area measured using OCT in class I was
Coronary Artery Disease/Plaque Morphology in Unstable Angina Pectoris
the smallest among the 3 classes (p ⬍0.001; Figure 4). Thrombus was frequently detected in classes I and III (p ⬍0.001). In contrast, in class II, incidence of thrombus was the lowest among the 3 classes. Discussion The Braunwald classification has been widely used because of its effectiveness in evaluating severity and prognosis of UAP. Severity and clinical setting of UAP have been related to lesion complexity.16 –18 Moreover, Braunwald19 proposed different causal processes: (1) a nonocclusive thrombus on preexisting plaque, (2) dynamic obstruction (coronary spasm), (3) progressive mechanical obstruction, and (4) inflammation and/or infection. In the present study, OCT allowed us to analyze the complexity of the culprit lesions for each Braunwald class. This analysis revealed the characteristics of plaque structure/function in relation to the causal factors described by Braunwald. Lipid-rich plaques were observed predominantly in each Braunwald class. Lipid-rich plaques are thought to be the basis of UAP.18 Several morphologic and structural markers such as fissured plaque, thin cap fibroatheroma, and superficial calcified nodules have been proposed for defining a vulnerable plaque.20 Patients with class I had not only occasional plaque ruptures but also more ulcers without fibrous cap disruption. Minimum lumen area was the smallest in class I. Based on theories on the natural history of coronary atherosclerosis, excessive remodeling is thought to be associated with acute coronary syndrome, and constrictive remodeling may lead to erosions.21–23 Stenotic plaque may undergo local erosion, which leads to focal thrombus formation.24 Plaques in class I were characterized by severe luminal narrowing and ulcers. These features are thought to represent progressive mechanical obstruction. Fibrous cap thickness in class I was not always thin, but plaque rupture was observed in many patients with class I (43%). Our previous study demonstrated that plaque rupture could occur in even thick fibrous caps, depending on exertion levels.12 The present results are consistent with the typical presentation of patients with class I, that is, accelerated exertional pain. In class II, optical coherence tomographic findings indicated that plaque vulnerability and involvement of progressive mechanical obstruction may be less. Van Mitenburgvan Zijl et al16 reported that class II had the best prognosis. Our findings may also indicate a favorable prognosis in class II based on vulnerability and obstruction. In contrast, coronary spasm was most frequent in class II. Coronary vasoconstriction can be considered an important characteristic of the culprit site in class II. Severity of coronary spasm may affect degree of thrombus formation and clinical manifestations. These characteristics correspond to dynamic obstruction proposed by Braunwald.19 In class III, fibrous cap thickness was the thinnest of all classes and plaque rupture, thin cap fibroatheroma, and spotty calcification were detected more frequently. These findings indicate that plaques in patients with class III may have more vulnerability, which can result in more plaque ruptures and subsequent thrombus formation. A higher incidence of coronary thrombi and histopathologic instability
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in the plaque were considered correlated with clinical severity.25,26 Thus, plaque vulnerability measured by OCT may also be an indicator of poor prognosis in class III. This study had several limitations. First, it was conducted at a single center with a small sample. Larger cohort studies would be necessary to confirm our findings. Second, the borders of the endothelium are difficult to distinguish on optical coherence tomograms of the intima. Therefore, we cannot detect precise erosion. However, small ulcers without discontinuity of the fibrous cap were observed. Third, thrombus may affect analysis of the plaque behind. Fourth, we included coronary spasm without significant organic coronary stenosis in each Braunwald class. Therefore, our results on degree of coronary artery stenosis differed from those of other reports.27 Coronary spasm was recently shown to be important in acute coronary syndrome.28,29 An acetylcholine provocation test was performed only in cases without significant stenosis, and vasomotor condition of the remaining cases could not be evaluated. It may be necessary to assess involvement of coronary spasm in UAP in greater detail. Fifth, it must be noted that plaque structure/function is not uniform in any of the clinical classes, although certain optical coherence tomographic findings predominate in each clinical class. 1. Jang IK, Bouma BE, Kang DH, Park SJ, Park SW, Seung KB, Choi KB, Shishkov M, Schlendorf K, Pomerantsev E, Houser SL, Aretz HT, Tearney GJ. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol 2002;39:604 – 609. 2. Brezinski ME, Tearny GJ, Bouma BE, Izatt JA, Hee MR, Swanson EA, Southern JF, Fujimoto JG. Optical coherence tomography for optical biopsy: properties and demonstration of vascular pathology. Circulation 1996;93:1206 –1213. 3. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary intimamedia thickness by optical coherence tomography: comparison with intravascular ultrasound. Circ J 2005;69:903–907. 4. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Sukmawan R, Sadahira Y, Yoshida K. Assessment of coronary arterial plaque by optical coherence tomography. Am J Cardiol 2006;97:1172–1175. 5. Jang IK, Tearney GJ, MacNeill B, Takano M, Moselewski F, Iftima N, Shishkov M, Houser S, Aretz HT, Halpern EF, Bouma BE. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–1555. 6. Yabushita H, Bouma BE, Houser S, Aretz HT, Jang IK, Schlendorf KH, Kauffman CR, Shishkov M, Kang DH, Halpern EF, Tearney GJ. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106:1640 –1645. 7. 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. 8. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T, Matsuo Y, Masho T, Kitabata H, Tsuda K, Tomobuchi Y, Akasaka T. Assessment of culprit lesion morphology in acute myocardial infarction. J Am Coll Cardiol 2007;50:933–939. 9. Braunwald E. Unstable angina. Circulation 1989;80:410 – 414. 10. Hamm CW, Braunwald E. A classification of unstable angina revisited. Circulation 2000;102:118 –122. 11. Kubo T, Akasaka T. Recent advances in intracoronary imaging techniques: focus on optical coherence tomography. Expert Rev Med Devices 2008;5:691– 697. 12. Tanaka A, Imanishi T, Kitabata H, Kubo T, Takarada S, Tanimoto T, Kuroi A, Tsujioka H, Ikejima H, Ueno S, Kataiwa H, Okouchi K, Kashiwaghi M, Matsumoto H, Takemoto K, Nakamura N, Hirata K, Mizukoshi M, Akasaka T. Morphology of exertion-triggered plaque
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