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CLINICAL STUDY: ULTRASOUND CORONARY IMAGING

Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound

Akiko Maehara, MD^*, Gary S. Mintz, MD, FACC, Anh B. Bui, MD^*, Olga R. Walter, RN^*, Marco T. Castagna, MD^*, Daniel Canos, MPH^*, August D. Pichard, MD, FACC^*, Lowell F. Satler, MD, FACC^*, Ron Waksman, MD, FACC^*, William O. Suddath, MD, FACC^*, John R. Laird, Jr, MD, FACC^*, Kenneth M. Kent, MD, PhD, FACC^* and Neil J. Weissman, MD, FACC^*,*

^* Cardiovascular Research Institute, Washington Hospital Center, Washington, DC, USA
Cardiovascular Research Foundation, New York, New York, USA

Manuscript received December 19, 2001; revised manuscript received May 2, 2002, accepted May 24, 2002.

^* Reprint requests and correspondence: Dr. Neil J. Weissman, Cardiovascular Research Institute, 110 Irving St, NW Suite 4B-1, Washington, DC 20010, USA
Neil.J.Weissman{at}medstar.net

	Abstract

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OBJECTIVES: This study was designed to report the clinical and angiographic correlates of plaque rupture detected by intravascular ultrasound (IVUS).

BACKGROUND: Acute coronary syndromes result from spontaneous plaque rupture and thrombosis.

METHODS: We report 300 plaque ruptures in 257 arteries in 254 patients. Plaque ruptures were detected during pre-intervention IVUS. Standard clinical, angiographic, and IVUS parameters were collected and/or measured. One lesion per patient was analyzed.

RESULTS: Multiple ruptures were observed in 39 of 254 patients (15%), 36 in the same artery. Plaque rupture occurred not only in patients with unstable angina (46%) or myocardial infarction (MI, 33%), but also stable angina (11%) or no symptoms (11%). The tear in the fibrous cap could be identified in 157 of 254 patients; 63% occurred at the shoulder of the plaque and 37% in the center of the plaque. Thrombi were more common in patients with unstable angina or MI (p = 0.02) and in multiple ruptures (p = 0.04). The plaque rupture site contained the minimum lumen area (MLA) site in only 28% of patients; rupture sites had larger arterial and lumen areas and more positive remodeling than MLA sites. Intravascular ultrasound plaque rupture strongly correlated with complex angiographic lesion morphology: ulceration in 81%, intimal flap in 40%, thrombus in 7%, and aneurysm in 7%.

CONCLUSIONS: Plaque ruptures occur with varying clinical presentations, strongly correlate with angiographic complex lesion morphology, may be multiple, and usually do not cause lumen compromise.

Abbreviations and Acronyms   CABG   coronary artery bypass grafting   CSA   cross-sectional area   EEM   external elastic membrane   IVUS   intravascular ultrasound   MI   myocardial infarction   MLA   minimum lumen area   PCI   percutaneous coronary intervention

	Methods

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Patient population.   We identified 300 plaque ruptures in 257 de novo native artery lesions in 254 patients. The clinical, angiographic, and IVUS features of these 254 patients are the basis of this report.

Clinical demographics
Patient demographics were confirmed by hospital chart review. Risk factors included diabetes mellitus (diet-controlled and oral agent or insulin-treated), hypertension (medication-treated), hypercholesterolemia (treated or >240 mg/dl), and current smoking. Stable angina was no change in frequency, duration, or intensity of symptoms within six weeks. Unstable angina was new-onset severe angina, accelerated angina, or rest angina. Recent myocardial infarction (MI) occurred within six weeks. Asymptomatic patients were typically studied because of positive stress tests in the absence of symptoms. Previous myocardial infarction (>6 weeks before IVUS imaging), coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) in other lesions, and left ventricular function were tabulated.

Angiographic analysis
Angiograms were available for comparison with 265 IVUS plaque ruptures in 225 arteries in 223 patients (88%). All angiograms were analyzed by an independent angiographic core laboratory (A.B.B.) using standard methodology and blind to the clinical and IVUS findings (6). Briefly, ulceration was defined as a small crater consisting of a discrete luminal widening with luminal irregularity. Intimal flap was defined as a radiolucent extension of the vessel wall into the arterial lumen. Thrombus was defined as a discrete intraluminal filling defect. Lumen irregularity was defined as an irregular lumen border that was not classified as ulceration. Aneurysm was defined conservatively as a lumen dilation >25% larger than the normal segment, with a smooth lumen border, which would mean the aneurysm diameter is approximately 50% to 100% larger than the reference diameter. Lesions were considered as complex if they had one or more of the following specific morphologies: ulceration, intimal flap, lumen irregularity, thrombus, and aneurysm (7,8). Otherwise, they were considered as simple.

IVUS imaging and analysis
All IVUS studies were performed before any intervention and after intracoronary administration of 200 µg nitroglycerin using a commercially available system (Boston Scientific Corporation/SCIMED, Minneapolis, Minnesota). The IVUS catheter was advanced distal to the lesion and imaging performed retrograde back to the aorto-ostial junction (motorized pullback speed = 0.5 mm/s).

Qualitative and quantitative analysis were performed according to criteria of the ACC Clinical Expert Consensus document on IVUS (9).

Qualitative analysis
A ruptured plaque contained a cavity that communicated with the lumen with an overlying residual fibrous cap fragment (Figs. 1 and 2) (3–5). A fissure without a cavity communicating with the true lumen was not included in the analysis. Rupture sites separated by a length of artery containing a smooth lumen contours and no cavity were considered to represent different plaque ruptures. Thrombus was an intraluminal mass having a layered or lobulated appearance, evidence of blood flow (microchannels) within the mass, and speckling or scintillation (10–12).

View larger version (103K): [in this window] [in a new window]   Figure 1 Angiography shows a right coronary artery with three complex lesions containing ulcerations (A, B, and C); each has a corresponding intravascular ultrasound (IVUS) imaging run. In this figure and in Figure 2, each IVUS imaging run contains multiple image slices that are equidistantly spaced and that were selected to illustrate both the cross-sectional and longitudinal anatomy. The following consistent labeling will be used: double-headed white arrows outline the lipid core/crater with or without hemorrhage, arrow #1 indicates thrombus, arrow #2 indicates the actual rupture site, arrow #3 indicates the residual fibrous cap, and arrow #4 indicates calcium. In lesion A the slices are 0.5 mm apart, in lesion B the slices are 1.5 mm apart, and in lesion C the slices are 1.0 mm apart. Lesion A shows plaque disruption, probable thrombus, and a lipid core/crater; the actual site of rupture and the residual fibrous cap are not clearly evident. Lesion B shows all of the elements: lipid core/crater (double-headed arrow), site of rupture with residual fibrous cap (arrow #2), and thrombus (arrow #1). The rupture appeared to have occurred in the center of the fibrous cap. Lesion C shows a lipid core/crater (double-headed arrow), site of rupture, and residual fibrous cap (arrow #2), but no thrombus. The rupture appeared to have occurred at the shoulder of the fibrous cap.

View larger version (67K): [in this window] [in a new window]   Figure 2 Angiography shows a right coronary artery with an aneurysm. Intravascular ultrasound revealed a plaque rupture with a lipid core/crater(double-headed arrow), site of rupture (arrow #2), and thrombus (arrow #1), but no residual fibrous cap. Image slices are 1.5 mm apart.

Quantitative analysis
The image slices with the largest intraplaque cavity, the image slices with the minimum lumen cross-sectional area (CSA), and the proximal and distal reference sites were identified and measured. Reference sites were the sections with the largest lumen and the least plaque within 5 mm proximal and distal to the lesion. Lesion length was the distance between the proximal and distal references. Using planimetry software (TapeMeasure, INDEC Systems Inc., Mountain View, California), measurements included external elastic membrane (EEM) CSA (mm²); true lumen CSA (mm²); and the area and length of the ruptured plaque cavity. Lengths (in mm) were calculated from the pullback speed of the transducer. Eccentric plaques had a maximum/minimum plaque plus media thickness >2. A remodeling index was lesion divided by mean reference EEM CSA. Positive remodeling was a lesion greater than mean reference EEM CSA.

Reproducibility of IVUS analysis
Plaque ruptures and thrombus required the agreement of two independent observers (A.M. and G.S.M.). The rate of agreement for plaque rupture was 0.99 (300/304). Four plaque ruptures with disagreement were excluded. The rate of agreement of thrombus was 0.93 (239/257 arteries). The intraclass correlation coefficient for repeated (three months apart) measurement of the rupture site EEM CSA was 0.99, lumen CSA = 0.94, plaque cavity CSA = 0.98, and rupture length = 0.92. The interclass correlation coefficient for the measurement of EEM was 0.99, lumen CSA = 0.93, plaque cavity CSA = 0.97, and rupture length = 0.92.

Statistics
Statistical analysis was performed using SAS (SAS Institute). Continuous variables were presented as mean ± 1 SD and categorical variables as frequencies. Categorical variables were compared by chi-square statistics or Fisher exact test. Continuous variables were compared using Student t test. A p value <0.05 was considered statistically significant. One lesion per patient was selected at random for analysis.

	Results

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Clinical and angiographic findings.   Multiple ruptures were observed in 39 of 254 (15%) patients; 29 patients had two IVUS ruptures in the same artery, seven patients had three ruptures in the same artery, and three patients had ruptures in two separate arteries. However, only 33 of 254 patients had multivessel IVUS imaging.

Table 1 shows the clinical demographics in these 254 patients. There were 83 patients with acute or recent MI; 52% (43/83) were treated with fibrinolytic agents. The duration between MI onset and IVUS imaging was 6.1 ± 7.5 days.

View larger version (21K): [in this window] [in a new window]   Figure 3 A flow chart of the intravascular ultrasound (IVUS) and angiographic analyses shows the relationship between multiple plaque ruptures detected by the two techniques.

Thrombi were found in 45% of patients. Thrombi were more frequent in 1) patients with MI (58%) or unstable angina (42%) versus stable angina (36%) or no symptoms (30%), (p = 0.02), and 2) in patients with multiple plaque ruptures (p = 0.04).

In 53% of patients (134/254) there was a branch near the rupture site (43 proximal and 91 distal). The distance between the rupture site and the branch measured 1.7 ± 2.2 mm.

Lesion length measured 18.2 ± 11.3 mm. The site with minimum lumen CSA (MLA) was located within the rupture site in only 72 of 254 patients (28%). The MLA site was located proximal to the rupture site in 65 patients and distal to it in 117. The distance between the rupture site and the MLA site measured 4.2 ± 5.8 mm. Rupture sites had larger EEM and lumen CSAs and more positive remodeling than MLA sites (Table 3). Plaque composition was similar. The distribution of lumen CSAs, both at the rupture site and MLA site, was shown in Figure 4.

View larger version (13K): [in this window] [in a new window]   Figure 4 This histogram shows the distribution of lumen CSA at rupture and MLA sites. The lumen CSA at rupture sites varied widely and was larger than at the MLA site. CSA = cross-sectional area; MLA = minimum lumen CSA.

	Discussion

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The main findings of the current study are 1) plaque ruptures occur not only in patients with MI or unstable angina, but are also found in patients with stable angina or no symptoms; 2) IVUS plaque ruptures strongly correlate with angiographic complex lesion morphology; 3) plaque ruptures may be multiple; and 4) ruptured plaques are eccentric, positively remodeled, may contain deep calcium, are not associated with lumen compromise, but are close to a significant stenosis and to a side branch. The in vivo IVUS findings strongly agree with reported pathologic observations.

Plaque rupture.   Pathologically, Burke et al. showed that healed ruptures were frequent and could cause stenosis progression (13). Serial angiographic studies have shown both sudden and slow stenosis progression; however, patients with sudden progression had more complex lesions or thrombus indicating plaque rupture or erosion (14,15). Ojio et al. (16) reported that some patients undergoing angiography less than one week before an acute MI already had complex lesion morphologies with high grade stenoses. Thus, there may be a significant delay between the pathologic event (plaque rupture with or without thrombus formation) and the clinical presentation. In the current study 22% of ruptured plaques occurred in stable angina or asymptomatic patients, ruptured plaques were associated with variable lumen dimensions, and thrombi were present in only half of the lesions. These findings support the hypothesis that plaque rupture may be one of the mechanisms of stenosis progression in some patients. Clinical symptoms may depend on the severity of the original or coexisting stenosis or on thrombus formation, not just on plaque rupture.

The current study confirms previous IVUS reports showing that plaques in acute coronary syndromes are hypoechoic, eccentric, contain little calcium, and are positively remodeled (5,17–19). Furthermore, in the current study only 28% of ruptures included the MLA sites, and rupture sites had more positive remodeling than MLA sites. Matrix metalloproteinases secreted by macrophages or smooth muscle cells may digest collagen, causing not only plaque vulnerability, but also positive remodeling. Activated metalloproteinases are more common in unstable plaques, especially at the shoulder of the plaque (20–22). In the current study 63% of rupture tears were at the shoulder of the plaque, similar to pathologic findings (23).

In the finite element model, circumferential tensile stress in ruptured plaque was greater than stable plaque (23–25). Three ruptured plaque characteristics in the current study may be important. First, plaque ruptures were distinct from MLA sites in 72%; and the distance between the two measured 4.2 ± 5.8 mm. Severe stenoses produce flow turbulence that may increase stress on the nearby segment (26,27). Second, 53% of rupture sites were near branches (distance 1.7 ± 2.2 mm) that may cause flow instability. In addition, Akong et al. (28) showed that endothelial cells near branches have a reduced ability to repair wounds compared with cells from nonbranch regions. Third, calcium was infrequent; however, when present, calcium was mostly located at the bottom or adjacent to the rupture. Calcium deposits under lipid cores may adversely affect stress distribution (29).

Thrombi were found in only half of the lesions. There are three possible explanations. First, the sensitivity of IVUS in diagnosing thrombus was reported to be 57% owing to false-negative interpretation of mural thrombus indistinguishable from soft plaque (12). We included only patients in whom the evidence of thrombus formation was high. Second, 17% of all patients were treated with fibrinolytic agents and 24% were treated with glycoprotein IIb/IIIa inhibitors. This may have affected these findings. Third, pathologic studies in patients dying with acute ischemic disease have shown that not all plaque ruptures lead to thrombus formation (1,30–32). The explanations were that some plaque ruptures were old and thrombi have already been resolved, or there might be other pathophysiologic events (such as spasm) that cause flow obstruction before thrombus formation.

Multiple lesions
In the current study 91% of the angiograms had complex lesions, consistent with previous studies (7,33). Levin et al. showed that 80% of angiographic complex lesions had pathologic evidence of plaque rupture, plaque hemorrhage, or thrombus. Asakura et al. (34) used angioscopy to show that yellow plaque, indicating potentially vulnerable plaque, was observed with equal frequency in infarct-related and non-infarct-related arteries. Goldstein et al. (35) reported that 40% of patients with acute MI had multiple complex lesions and worse outcomes than did acute MI patients having a single complex lesion. In the current population multiple ruptures were observed in 15% of patients; but only 33 of 254 patients had multivessel imaging, and most multiple ruptures were in the same artery and appeared to be a single angiographic lesion.

Study limitations
This was a retrospective study. There are no ex vivo comparisons between the IVUS and the histopathologic findings of plaque ruptures. We cannot exclude the possibility that contrast injection, guidewire manipulation, or the IVUS catheter itself might have created a small fissure in the thin fibrous cap. However, in the current analysis, we excluded ambiguous plaque ruptures, i.e., ones with only small fissures in size and length. Not all arteries in all patients were imaged using IVUS; therefore, the true frequency of multiple plaque ruptures and their impact on patient outcomes remains unknown. Because these cases were collected over many years during the technical evolution of IVUS imaging, the exact frequency of plaque ruptures cannot be inferred. Similarly, although approximately 20% of patients with plaque ruptures in the current cohort were asymptomatic with positive stress tests or had chronic stable angina, we cannot determine the frequency of plaque rupture in an overall cohort of asymptomatic patients or patients with chronic stable angina. The diagnosis of thrombus by IVUS is typically considered to be presumptive; however, we included only patients/lesions that contained all of the typical features. Finally, the lag between symptom onset and IVUS imaging may have influenced both the IVUS and angiographic findings.

Conclusions
Plaque ruptures occur with varying clinical presentations, strongly correlate with angiographic complex lesion morphology, may be multiple, and usually do not cause lumen compromise.

	References

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				A. N. DeMaria, J. Narula, E. Mahmud, and S. Tsimikas Imaging vulnerable plaque by ultrasound. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C32 - C39. [Abstract] [Full Text] [PDF]

				K. Sano, M. Kawasaki, Y. Ishihara, M. Okubo, K. Tsuchiya, K. Nishigaki, X. Zhou, S. Minatoguchi, H. Fujita, and H. Fujiwara Assessment of Vulnerable Plaques Causing Acute Coronary Syndrome Using Integrated Backscatter Intravascular Ultrasound J. Am. Coll. Cardiol., February 21, 2006; 47(4): 734 - 741. [Abstract] [Full Text] [PDF]

				A. W. Leber, A. Becker, A. Knez, F. von Ziegler, M. Sirol, K. Nikolaou, B. Ohnesorge, Z. A. Fayad, C. R. Becker, M. Reiser, et al. Accuracy of 64-Slice Computed Tomography to Classify and Quantify Plaque Volumes in the Proximal Coronary System: A Comparative Study Using Intravascular Ultrasound J. Am. Coll. Cardiol., February 7, 2006; 47(3): 672 - 677. [Abstract] [Full Text] [PDF]

				K. Toutouzas, M. Drakopoulou, J. Mitropoulos, E. Tsiamis, S. Vaina, M. Vavuranakis, V. Markou, E. Bosinakou, and C. Stefanadis Elevated Plaque Temperature in Non-Culprit De Novo Atheromatous Lesions of Patients With Acute Coronary Syndromes J. Am. Coll. Cardiol., January 17, 2006; 47(2): 301 - 306. [Abstract] [Full Text] [PDF]

				J. Narula, A. V. Finn, and A. N. DeMaria Picking Plaques That Pop ... J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1970 - 1973. [Full Text] [PDF]

				J. Pregowski, P. Tyczynski, G. S. Mintz, S.-W. Kim, A. Witkowski, R. Waksman, A. Pichard, L. Satler, K. Kent, M. Kruk, et al. Incidence and Clinical Correlates of Ruptured Plaques in Saphenous Vein Grafts: An Intravascular Ultrasound Study J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1974 - 1979. [Abstract] [Full Text] [PDF]

				A. Tanaka, K. Shimada, T. Sano, M. Namba, T. Sakamoto, Y. Nishida, T. Kawarabayashi, D. Fukuda, and J. Yoshikawa Multiple Plaque Rupture and C-Reactive Protein in Acute Myocardial Infarction J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1594 - 1599. [Abstract] [Full Text] [PDF]

				J.-i. Kotani, G. S. Mintz, P. B. Rai, C. K. Pappas, N. Gevorkian, A. B. Bui, A. D. Pichard, L. F. Satler, W. O. Suddath, R. Waksman, et al. Intravascular ultrasound assessment of angiographic filling defects in native coronary arteries: Do they always contain thrombi? J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2087 - 2089. [Full Text] [PDF]

				G. Rioufol, M. Gilard, G. Finet, I. Ginon, J. Boschat, and X. Andre-Fouet Evolution of Spontaneous Atherosclerotic Plaque Rupture With Medical Therapy: Long-Term Follow-Up With Intravascular Ultrasound Circulation, November 2, 2004; 110(18): 2875 - 2880. [Abstract] [Full Text] [PDF]

				J.K. Lovett, P.J. Gallagher, L.J. Hands, J. Walton, and P.M. Rothwell Histological Correlates of Carotid Plaque Surface Morphology on Lumen Contrast Imaging Circulation, October 12, 2004; 110(15): 2190 - 2197. [Abstract] [Full Text] [PDF]

				B. D. MacNeill, I.-K. Jang, B. E. Bouma, N. Iftimia, M. Takano, H. Yabushita, M. Shishkov, C. R. Kauffman, S. L. Houser, H.T. Aretz, et al. Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease J. Am. Coll. Cardiol., September 1, 2004; 44(5): 972 - 979. [Abstract] [Full Text] [PDF]

				M.-K. Hong, G. S. Mintz, C. W. Lee, Y.-H. Kim, S.-W. Lee, J.-M. Song, K.-H. Han, D.-H. Kang, J.-K. Song, J.-J. Kim, et al. Comparison of Coronary Plaque Rupture Between Stable Angina and Acute Myocardial Infarction: A Three-Vessel Intravascular Ultrasound Study in 235 Patients Circulation, August 24, 2004; 110(8): 928 - 933. [Abstract] [Full Text] [PDF]

				P Avanzas, R Arroyo-Espliguero, J Cosin-Sales, G Aldama, C Pizzi, J Quiles, and J C Kaski Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes Heart, August 1, 2004; 90(8): 847 - 852. [Abstract] [Full Text] [PDF]

				J. Cosin-Sales, M. Christiansen, P. Kaminski, C. Oxvig, M. T. Overgaard, D. Cole, D. W. Holt, and J. C. Kaski Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris Circulation, April 13, 2004; 109(14): 1724 - 1728. [Abstract] [Full Text] [PDF]

				K. Fujii, Y. Kobayashi, G. S. Mintz, H. Takebayashi, G. Dangas, I. Moussa, R. Mehran, A. J. Lansky, E. Kreps, M. Collins, et al. Intravascular Ultrasound Assessment of Ulcerated Ruptured Plaques: A Comparison of Culprit and Nonculprit Lesions of Patients With Acute Coronary Syndromes and Lesions in Patients Without Acute Coronary Syndromes Circulation, November 18, 2003; 108(20): 2473 - 2478. [Abstract] [Full Text] [PDF]

				P. Schoenhagen, G. W. Stone, S. E. Nissen, C. L. Grines, J. Griffin, B. S. Clemson, D. G. Vince, K. Ziada, T. Crowe, C. Apperson-Hanson, et al. Coronary Plaque Morphology and Frequency of Ulceration Distant From Culprit Lesions in Patients With Unstable and Stable Presentation Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1895 - 1900. [Abstract] [Full Text] [PDF]

				J.-i. Kotani, G. S. Mintz, M. T. Castagna, E. Pinnow, C. O. Berzingi, A. B. Bui, A. D. Pichard, L. F. Satler, W. O. Suddath, R. Waksman, et al. Intravascular Ultrasound Analysis of Infarct-Related and Non-Infarct-Related Arteries in Patients Who Presented With an Acute Myocardial Infarction Circulation, June 17, 2003; 107(23): 2889 - 2893. [Abstract] [Full Text] [PDF]