This Article Free upon publication Abstract Full Text (PDF) All Versions of this Article: 108/20/2473    most recent 01.CIR.0000097121.95451.39v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujii, K. Articles by Moses, J. W. Search for Related Content PubMed PubMed Citation Articles by Fujii, K. Articles by Moses, J. W. Related Collections Acute coronary syndromes

(Circulation. 2003;108:2473.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

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

Kenichi Fujii, MD; Yoshio Kobayashi, MD; Gary S. Mintz, MD; Hideo Takebayashi, MD; George Dangas, MD, PhD; Issam Moussa, MD; Roxana Mehran, MD; Alexandra J. Lansky, MD; Edward Kreps, MD; Michael Collins, MD; Antonio Colombo, MD; Gregg W. Stone, MD; Martin B. Leon, MD; Jeffrey W. Moses, MD

From the Cardiovascular Research Foundation, Lenox Hill Heart and Vascular Institute, New York, NY.

Correspondence to Jeffrey W. Moses, MD, Lenox Hill Heart and Vascular Institute, 130 East 77th St, 9th Floor, New York, NY 10021. E-mail jmoses{at}lenoxhill.net

Received May 6, 2003; de novo received July 14, 2003; revision received August 20, 2003; accepted August 20, 2003.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— It is not clear why some plaque ruptures lead to acute coronary syndromes (ACS) but others do not.

Methods and Results— We analyzed 80 plaque ruptures in 74 patients and compared culprit lesions of ACS patients with nonculprit lesions of ACS patients and lesions of non-ACS patients; both culprit and nonculprit plaque ruptures were studied in 6 of 54 ACS patients. Intravascular ultrasound findings suggesting thrombus were observed more frequently in culprit lesions of ACS patients (n=35) compared with nonculprit lesions of ACS patients (n=19) and lesions of non-ACS patients (n=26): 60% versus 32% versus 8% (P<0.001). At the minimal lumen site, smaller lumen areas (3.3±1.5 versus 5.4±2.6 versus 6.1±2.0 mm², P<0.001) and greater area stenosis (61±15% versus 50±14% versus 46±18%, P=0.002) and plaque burden (80±8% versus 71±8% versus 69±10%, P<0.001) were observed in culprit lesions of ACS patients compared with nonculprit lesions of ACS patients and lesions of non-ACS patients. Lesions were longer (18.7±6.4 versus 154.9±6.1 versus 12.0±4.9 mm, P<0.001) and rupture site remodeling indices were greater (1.26±0.21 versus 1.24±0.21 versus 1.09±0.05, P=0.002). Independent predictors of culprit plaque ruptures in ACS patients were smaller minimum lumen areas (P=0.02) and presence of thrombus (P=0.01).

Conclusions— Ruptured plaques in culprit lesions of ACS patients have smaller lumens; greater plaque burdens, area stenosis, and remodeling indices; and more thrombus. Plaque rupture itself does not lead to symptoms. The association of plaque rupture with a smaller lumen area and/or thrombus formation causes lumen compromise and leads to symptoms.

Key Words: ultrasonics • atherosclerosis • coronary disease

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Plaque rupture or endothelial erosion with subsequent thrombus formation are the most frequent cause of acute coronary syndromes (ACS).^1–3 One intravascular ultrasound (IVUS) study reported a high incidence of multiple plaque ruptures in ACS patients.⁴ Another IVUS study showed that plaque ruptures occur not only in ACS patients but also in patients with stable angina or asymptomatic ischemia.⁵ Furthermore, pathological studies reported plaque ruptures in coronary arteries of patients with noncardiac death.^6,7 Thus, it is not clear why some plaque ruptures lead to clinical manifestations, whereas others remain asymptomatic and heal, perhaps leading to disease progression. Therefore, we undertook the present study to compare ruptured plaques in culprit lesions of ACS patients with ruptured plaques in nonculprit lesions of ACS patients and ruptured plaques in lesions of non-ACS patients. We used IVUS to identify anatomic features that lead to the development of culprit lesions causing ACS after plaque rupture.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient and Lesion Population
Between December 1999 and December 2002, 983 patients (1325 lesions) underwent preintervention IVUS. One investigator reviewed all IVUS studies to identify high-quality images showing ulcerated plaque ruptures in de novo native coronary lesions. Clinical demographics were obtained by hospital chart review. Unstable angina was new-onset severe angina, accelerated angina, or rest angina. Recent myocardial infarction (MI) occurred within 4 weeks. Stable angina was no change in frequency, duration, or intensity of symptoms within 4 weeks. Asymptomatic patients were typically studied because of positive stress tests. Patients with unstable angina or recent MI were categorized as ACS, whereas non-ACS patients had stable angina or asymptomatic ischemia.

The coronary artery and lesion underlying the atherosclerotic event (ie, culprit) were identified by the association of precrisis and intercrisis ECGs, left ventricle wall motion abnormalities, and angiographic lesion appearance. Two experienced cardiologists (K.F. and Y.K.) independently reviewed all clinical and angiographic data to decide angina status and culprit lesions. There was no disagreement on angina status or culprit lesion assignment.

Ulcerated ruptured plaques and thrombus required the agreement of 2 independent experienced observers (K.F. and H.T.). The rate of agreement for ulcerated ruptured plaques was 0.98 (80/82). Disagreements were reviewed by the third observer (Y.K.). The rate of agreement for thrombus was 0.94 (30/32). The 2 cases of thrombus disagreement were excluded. Finally, 80 ulcerated ruptured plaques in 74 patients (54 with ACS) were included. In ACS patients, IVUS was performed in only culprit lesions in 32 patients, only nonculprit lesions in 12, and both in 6 patients (ulcerated ruptured plaques were observed in 3 culprit and 7 nonculprit lesions). Multiple ruptures were observed in 3 of 6 ACS patients (2 in both culprit and nonculprit lesions and 1 in 2 nonculprit lesions). There were no non-ACS patients with multiple ruptures. Ulcerated ruptured plaques were divided into 3 groups: culprit lesions of ACS patients (n=35), nonculprit lesions of ACS patients (n=19), and non-ACS patients (n=26).

Angiographic Analysis
Cineangiograms were analyzed with a computer-assisted, automated edge detection algorithm (CMS, MEDIS) by a core laboratory using standard qualitative and quantitative definitions and measurements. The outer diameter of the contrast-filled catheter was used for calibration, and the minimal lumen diameter was obtained from the single "worst" view.

IVUS Imaging Protocol
Before all procedures, written informed consent was obtained. All IVUS studies were performed before any intervention (after intracoronary administration of 100 to 200 µg nitroglycerin) with a commercially available system (Boston Scientific). The 30- or 40-MHz IVUS catheter was advanced >10 mm beyond the lesion, and an imaging run (using automated transducer pullback at 0.5 mm/s) was performed to a point >10 mm proximal to the lesion. IVUS imaging was recorded only during transducer pullback onto 1/2-inch high-resolution s-VHS videotape for offline analysis.

IVUS Analysis
Qualitative and quantitative IVUS measurements were performed using published definitions, especially for ruptured plaque.^4,5,8 Two observers (K.F. and H.T.) blinded to clinical and angiographic information (including ACS versus non-ACS) performed all IVUS analysis. An ulcerated ruptured plaque contained a cavity that communicated with the lumen with an overlying residual fibrous cap fragment (Figure 1).⁸ A fissure without a cavity communicating with the true lumen was not included.^5,8 Rupture sites separated by a length of artery containing 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.^9,10 Plaque composition was assessed visually. Plaque morphology was classified as soft when >75% was less bright than the adventitia; otherwise, plaque composition was classified as hard. Calcium was brighter than the adventitia with acoustic shadowing; the arc of calcium was measured with a protractor centered on the lumen.

View larger version (217K): [in this window] [in a new window]   Figure 1. An ulcerated ruptured plaque contains a cavity that communicated with lumen with an overlying residual fibrous cap fragment (A). Schema shows measurements of EEM CSA, lumen CSA, and ruptured plaque cavity area (CA) (B). IVUS image at minimal lumen site (C). Note thrombus (arrowheads). Lumen was compromised by thrombus (arrow) at minimum lumen site (C). Schema demonstrates EEM CSA, lumen CSA, and thrombus (arrow) (D).

Image slices with the largest intraplaque cavity, image slices with the minimum lumen cross-sectional area (CSA), and the proximal and distal references were identified and measured.⁵ Reference sites were the sections with the largest lumen and the least plaque <5 mm proximal and distal to the lesion but before any side branch.⁵ With planimetry software (TapeMeasure, INDEC Systems), external elastic membrane (EEM) CSA, lumen CSA with and without thrombus, and minimal and maximal plaque+media thickness were measured (Figure 2). The largest intraplaque cavity was measured and extrapolated to the ruptured capsule area; when there was thrombus in the cavity, the area occupied by thrombus was included in the cavity area measurement. The interobserver correlation coefficient for cavity area was 0.97. Lengths (in millimeters) were calculated from the pullback speed of the transducer. Lesion length was the distance between the proximal and distal references. Cavity length was the distance between the proximal and distal edges of the cavity. Plaque+media CSA, including cavity area (EEM minus lumen CSA), plaque burden (plaque+media divided by EEM CSA), area stenosis [(mean reference lumen minus lesion lumen CSA) divided by mean reference lumen CSA], plaque+media eccentricity [(maximum minus minimum plaque+media thickness) divided by maximum plaque+media thickness], remodeling index (lesion EEM divided by mean reference EEM CSA), and cavity area/plaque ratio (cavity divided by plaque+media CSA) were calculated (Figure 2).

View larger version (31K): [in this window] [in a new window]   Figure 2. Scheme of IVUS measurements. a indicates maximal plaque diameter; b, minimal plaque diameter; and ref., reference. Plaque+media area includes plaque cavity to create an estimate of plaque area before rupture.

Statistical Analysis
Statistical analysis was performed with StatView 5.0 software (SAS Institute). Continuous variables were reported as mean±SD and (except the arc of calcium) compared by factorial ANOVA; the Bonferroni correction was used for post hoc analysis, in which a value of P<0.0167 (0.05 divided by 3) was the threshold for significance. Arc of calcium was analyzed by Kruskal-Wallis test. Categorical variables were reported as frequencies and compared by ² statistics. A value of P<0.05 was considered significant. Stepwise logistic regression with entry and stay criteria of 0.10 was used to find independent predictors of culprit ulcerated ruptured plaques in ACS patients.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline patient characteristics and angiographic findings are presented in Tables 1 and 2. Five non-ACS patients had a previous MI; 2 underwent culprit-lesion percutaneous coronary intervention during the MI. In 2 of the other 3 patients, the culprit lesion was in another vessel; in the third patient, the culprit lesion was in the same vessel. No patient received thrombolytic therapy. Before IVUS, glycoprotein IIb/IIIa inhibitors were given to 6 patients in the culprit-lesion ACS group, 1 patient in the nonculprit-lesion ACS group, and no non-ACS patient (P=NS).

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Angiographic Analysis

Qualitative IVUS Findings
Table 3 shows qualitative lesion site findings. IVUS findings suggesting thrombus were observed more frequently in culprit lesions of ACS patients compared with nonculprit lesions of ACS patients (P=0.04) and lesions of non-ACS patients (P<0.001) as well as in nonculprit lesions of ACS patients compared with lesions of non-ACS patients (P=0.03). Five of 7 patients who received glycoprotein IIb/IIIa inhibitors had IVUS findings suggesting thrombi. Most of the ulcerated ruptured plaques in culprit lesions of ACS patients were proximal to the minimal lumen site, compared with half of the ulcerated ruptured plaques in lesions of non-ACS patients (P=0.02).

View this table: [in this window] [in a new window]   TABLE 3. Qualitative IVUS Analysis

Quantitative IVUS Findings
Quantitative analyses are presented in Table 4. Proximal reference measurements were similar in the 3 groups. The distal reference lumen CSA was smaller in culprit lesions of ACS patients than nonculprit lesions of ACS patients and lesions of non-ACS patients (P=0.03 and P=0.004, respectively).

View this table: [in this window] [in a new window]   TABLE 4. Quantitative IVUS Analysis

Rupture site EEM CSA was greater than at the minimum lumen site in culprit lesions of ACS patients (P=0.01) but not in nonculprit lesions of ACS patients or non-ACS patients. Rupture site lumen CSA was greater than at the minimum lumen site in all groups (P<0.001, P=0.02, and P=0.02, respectively). Rupture site remodeling index was greater than the minimal lumen site in all groups (P=0.008, P<0.001, and P<0.001, respectively). There was no significant difference in plaque+media CSA, plaque burden, plaque+media eccentricity, and arc of calcium comparing the rupture site versus the minimal lumen site in each group.

At the minimal lumen site, a smaller lumen CSA and greater plaque burden and area stenosis were observed in culprit lesions of ACS patients compared with nonculprit lesions of ACS patients (P=0.003, P=0.006, and P=0.03, respectively) and lesions of non-ACS patients (P<0.001 for all). Remodeling index was greater in culprit lesions of ACS patients than in lesions of non-ACS patients (P=0.02). Lesions were longer in (1) culprit lesions of ACS patients than nonculprit lesions of ACS patients (P=0.02) and lesions of non-ACS patients (P<0.001) and (2) in nonculprit lesions of ACS patients than lesions of non-ACS patients (P=0.04). Similar quantitative IVUS findings were observed at the rupture site. Cavity area and cavity length were similar among the groups.

Multivariate logistic regression analysis was used to compare culprit ulcerated plaque ruptures in ACS patients with nonculprit ulcerated plaque ruptures in ACS patients and ulcerated plaque ruptures in non-ACS patients. The following variables were identified as independent predictors of culprit ulcerated plaque ruptures in ACS patients: smaller minimum lumen CSA (P=0.02) and presence of thrombus (P=0.01).

When patients who received glycoprotein IIb/IIIa inhibitors were excluded from analysis (n=7), the results of qualitative and quantitative IVUS shown in Tables 3 and 4 were virtually identical. Multivariate logistic regression analysis showed that independent predictors of culprit ulcerated plaque ruptures in ACS patients were the minimum lumen CSA (P=0.02) and thrombus (P=0.07); 5 of 6 with culprit ulcerated plaque ruptures in ACS patients who received glycoprotein IIb/IIIa inhibitors had IVUS evidence of thrombus.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates that ulcerated ruptured plaques leading to ACS have smaller lumen CSA, greater plaque burden and remodeling index, and more frequent IVUS evidence of thrombus formation. Independent predictors of ACS in association with ulcerated plaque rupture were (1) smaller lumen CSA and (2) IVUS evidence of thrombus.

Plaque Rupture
Pathological studies have demonstrated that plaque rupture with subsequent thrombus formation is the initiating event of most ACS.^1–3 Plaque rupture is a mechanical event that depends on an imbalance between stress imposed on the plaque cap and innate strength (resistance to fracture) of the cap.^11,12 The mechanical strength of the cap depends on the amount and organization of the collagen produced by smooth muscle cells.^13,14 The cap is increasingly recognized as a dynamic structure in which collagen synthesis is modulated by positive and negative growth factors produced by inflammatory cells and in which collagen is degraded by metalloproteinases derived from activated macrophages.^15–17 Loss of smooth muscle cells because of apoptosis may be an important element in weakening of cap tissue.¹⁸ Intrinsic plaque instability may develop owing to the expansion of intraplaque contents (eg, lipid-pool swelling).^1–3,19 Thus, plaques vulnerable to rupture are described as those with a large lipid pool under a thin fibrous cap.

When plaque rupture occurs, it exposes tissue factor and collagen, promoting thrombosis.²⁰ Plaque composition determines its thrombogenic potential. Tissue factor and plasminogen activator inhibitor-1 contents of vulnerable plaques are twice that of stable plaque and parallel the macrophage area.²¹ Increased activity of platelet and clotting factors in ACS patients intensifies the thrombogenic potential of ruptured plaques.²²

Ruptured Plaque With ACS
Pathological studies have reported that plaque disruption can occur without symptoms and is found in 5% to 10% of noncardiac deaths.^6,7 Recently, IVUS studies have demonstrated that ruptured plaques do not always cause ACS.^4,5 One IVUS study showed a high incidence of ruptured plaques (79%) in coronary segments remote from the culprit lesion of ACS patients.⁴ Maehara et al⁵ reported that plaque ruptures occurred not only in patients with unstable angina (46%) or MI (33%) but also in stable angina (11%) or asymptomatic ischemia (11%). Plaque rupture may be a frequent event that only occasionally leads to an ACS. The present study found 2 risk factors linking ulcerated ruptured plaques to ACS: smaller lumens and evidence of thrombus. Angiographic studies have shown that MIs often occur at sites that were previously only a mild-to-moderate stenosis.^23,24 Conversely, postmortem examinations demonstrated that ruptured plaques leading to ACS were often within the segment of significant stenosis.^19,25,26 When patients have increased thrombogenic potential, ruptured plaques in lesions with mild-to-moderate stenosis may lead to ACS. Conversely, because atherosclerosis is a progressive disease, angiography may not show the degree of stenosis immediately before plaque rupture.

In the present analysis, the size of the residual cavity was, if anything, smaller in culprit plaque ruptures. This suggests that it is not the size of the underlying lipid pool or necrotic core that leads to post-plaque rupture thrombus formation and ACS but rather the thrombogenicity of the resulting cavity. In addition, it is conceivable that a smaller "prerupture" lumen requires less thrombus to precipitate an acute event.

Ruptured Plaque Without ACS
Previous studies showed a high incidence of recurrent events in ACS patients.^27,28 Because ACS correlates with systemic markers of inflammation, high recurrent events may be related to additional vulnerable lesions distant from the culprit lesion. These observations support the concept that plaque instability is not merely a local vascular accident but rather probably reflects more generalized pathophysiological processes with the potential to destabilize atherosclerotic plaques throughout the coronary tree. This may also explain the high incidence of multiple plaque ruptures in ACS patients reported by one IVUS study.⁴ Thus, it may be reasonable to prescribe platelet-receptor inhibitors to prevent thrombus formation and anti-inflammatory drugs and lipid-lowering medications to stabilize plaques in ACS patients.^29,30

Pathological studies have reported that healed ruptured plaque is associated with lesion progression.^31,32 Subclinical episodes of plaque disruption, local thrombin activation, and subsequent healing with incorporation of thrombus into the vessel wall may represent one pathway for episodic progression superimposed on the slower systemic process. This concept is supported by previous angiographic studies showing rapid progression of stenosis with complex angiographic features.^33–35

Study Limitations
This was a retrospective study. IVUS was not performed in all segments of all coronary arteries in all patients. Some selection bias is inevitable, beginning with selection of patients to undergo cardiac catheterization and IVUS and which arteries are imaged before intervention. Thus, the frequency of plaque ruptures remains unknown. Some ruptured plaques with small cavities might be missed, especially when the cavity was filled by thrombus. The diagnosis of thrombus by IVUS is typically considered to be presumptive. Two different IVUS catheters were used during the study; thrombus detection may be dependent on transducer frequency. Finally, the lag between symptom onset and IVUS was not known and may have influenced both IVUS and angiographic findings. The distinction between culprit and nonculprit lesions in ACS patients is sometimes difficult.

Conclusions
Ulcerated ruptured plaques in culprit lesions of ACS patients have smaller lumens; greater plaque burdens, area stenosis, and remodeling indices; and more thrombus formation. Plaque rupture itself does not lead to symptoms. Instead, it is the association of plaque rupture with a smaller lumen area and/or thrombus formation causing lumen compromise that leads to symptoms.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Davies M, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984; 310: 1137–1140.[Abstract]

2. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992; 326: 242–250, 310–318.[Medline] [Order article via Infotrieve]

3. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657–671.[Free Full Text]

4. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.[Abstract/Free Full Text]

5. Maehara A, Mintz GS, Bui AB, et al. Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound. J Am Coll Cardiol. 2002; 40: 904–910.[Abstract/Free Full Text]

6. Thomas AC, Knapman PA, Krikler DM, et al. Community study of the causes of "natural" sudden death. BMJ. 1988; 297: 1453–1456.[Abstract/Free Full Text]

7. Davies MJ, Bland JM, Hangartner JR, et al. Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischaemic death. Eur Heart J. 1989; 10: 203–208.[Abstract/Free Full Text]

8. von Birgelen C, Klinkhart W, Mintz GS, et al. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol. 2001; 37: 1864–1870.[Abstract/Free Full Text]

9. Chemarin-Alibelli MJ, Pieraggi MT, Elbaz M, et al. Identification of coronary thrombus after myocardial infarction by intracoronary ultrasound compared with histology of tissues sampled by atherectomy. Am J Cardiol. 1996; 77: 344–349.[CrossRef][Medline] [Order article via Infotrieve]

10. Kearney P, Erbel R, Rupprecht HJ, et al. Differences in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty: an in vivo study with intravascular ultrasound. Eur Heart J. 1996; 17: 721–730.[Abstract/Free Full Text]

11. MacIsaac AI, Thomas JD, Topol EJ. Toward the quiescent coronary plaque. J Am Coll Cardiol. 1993; 22: 1228–1241.[Abstract]

12. Lee RT, Kamm RD. Vascular mechanics for the cardiologist. J Am Coll Cardiol. 1994; 23: 1289–1295.[Abstract]

13. Davies MJ, Richardson PD, Woolf N, et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993; 69: 377–381.[Abstract/Free Full Text]

14. Burleigh MC, Briggs AD, Lendon CL, et al. Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations. Atherosclerosis. 1992; 96: 71–81.[CrossRef][Medline] [Order article via Infotrieve]

15. Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995; 92: 1565–1569.[Medline] [Order article via Infotrieve]

16. Galis ZS, Sukhova GK, Lark MW, et al. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994; 94: 2493–2503.[Medline] [Order article via Infotrieve]

17. Sukhova GK, Schonbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999; 99: 2503–2509.[Abstract/Free Full Text]

18. Kockx MM, Herman AG. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res. 2000; 45: 736–746.[Abstract/Free Full Text]

19. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J. 1983; 50: 127–134.[Abstract/Free Full Text]

20. Barstad RM, Hamers MJ, Kierulf P, et al. Procoagulant human monocytes mediate tissue factor/factor VIIa-dependent platelet-thrombus formation when exposed to flowing nonanticoagulated human blood. Arterioscler Thromb Vasc Biol. 1995; 15: 11–16.[Abstract/Free Full Text]

21. Shindo J, Ishibashi T, Kijima M, et al. Increased plasminogen activator inhibitor-1 and apolipoprotein (a) in coronary atherectomy specimens in acute coronary syndromes. Coron Artery Dis. 2001; 12: 573–579.[CrossRef][Medline] [Order article via Infotrieve]

22. Thompson SG, Kienast J, Pyke SD, et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995; 332: 635–641.[Abstract/Free Full Text]

23. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988; 78: 1157–1166.[Abstract/Free Full Text]

24. Fishbein MC, Siegel RJ. How big are coronary atherosclerotic plaques that rupture? Circulation. 1996; 94: 2662–2666.[Free Full Text]

25. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989; 2: 941–944.[CrossRef][Medline] [Order article via Infotrieve]

26. Qiao JH, Fishbein MC. The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis. J Am Coll Cardiol. 1991; 17: 1138–1142.[Abstract]

27. Theroux P. Angiographic and clinical progression in unstable angina: from clinical observations to clinical trials. Circulation. 1995; 91: 2295–2298.[Free Full Text]

28. Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000; 343: 915–922.[Abstract/Free Full Text]

29. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.[Abstract/Free Full Text]

30. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.[Abstract/Free Full Text]

31. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001; 103: 934–940.[Abstract/Free Full Text]

32. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999; 82: 265–268.[Abstract/Free Full Text]

33. Kaski JC, Chester MR, Chen L, et al. Rapid angiographic progression of coronary artery disease in patients with angina pectoris: the role of complex stenosis morphology. Circulation. 1995; 92: 2058–2065.[Abstract/Free Full Text]

34. Yokoya K, Takatsu H, Suzuki T, et al. Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis. Circulation. 1999; 100: 903–909.[Abstract/Free Full Text]

35. Ojio S, Takatsu H, Tanaka T, et al. Considerable time from the onset of plaque rupture and/or thrombi until the onset of acute myocardial infarction in humans: coronary angiographic findings within 1 week before the onset of infarction. Circulation. 2000; 102: 2063–2069.[Abstract/Free Full Text]

This article has been cited by other articles:

				S Lavi, J-H Bae, C S Rihal, A Prasad, G W Barsness, R J Lennon, D R Holmes Jr, and A Lerman Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques Heart, September 15, 2009; 95(18): 1525 - 1530. [Abstract] [Full Text] [PDF]

				T. T. de Weert, S. Cretier, H. C. Groen, P. Homburg, H. Cakir, J. J. Wentzel, D. W.J. Dippel, and A. van der Lugt Atherosclerotic Plaque Surface Morphology in the Carotid Bifurcation Assessed With Multidetector Computed Tomography Angiography Stroke, April 1, 2009; 40(4): 1334 - 1340. [Abstract] [Full Text] [PDF]

				Y. J. Hong, M. H. Jeong, Y. H. Choi, J. S. Ko, M. G. Lee, W. Y. Kang, S. E. Lee, S. H. Kim, K. H. Park, D. S. Sim, et al. Plaque characteristics in culprit lesions and inflammatory status in diabetic acute coronary syndrome patients. J. Am. Coll. Cardiol. Img., March 1, 2009; 2(3): 339 - 349. [Abstract] [Full Text] [PDF]

				J. A. Goldstein Coronary plaque characterization by computed tomographic angiography: present promise and future hope. J. Am. Coll. Cardiol. Img., February 1, 2009; 2(2): 161 - 163. [Full Text] [PDF]

				J H Bae, T-G Kwon, D-W Hyun, C S Rihal, and A Lerman Predictors of slow flow during primary percutaneous coronary intervention: an intravascular ultrasound-virtual histology study Heart, December 1, 2008; 94(12): 1559 - 1564. [Abstract] [Full Text] [PDF]

				F. J. H. Gijsen, J. J. Wentzel, A. Thury, F. Mastik, J. A. Schaar, J. C. H. Schuurbiers, C. J. Slager, W. J. van der Giessen, P. J. de Feyter, A. F. W. van der Steen, et al. Strain distribution over plaques in human coronary arteries relates to shear stress Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1608 - H1614. [Abstract] [Full Text] [PDF]

				J. Ohayon, G. Finet, A. M. Gharib, D. A. Herzka, P. Tracqui, J. Heroux, G. Rioufol, M. S. Kotys, A. Elagha, and R. I. Pettigrew Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H717 - H727. [Abstract] [Full Text] [PDF]

				Y. J. Hong, M. H. Jeong, Y. Ahn, D. S. Sim, J. W. Chung, J. S. Cho, N. S. Yoon, H. J. Yoon, J. Y. Moon, K. H. Kim, et al. Plaque prolapse after stent implantation in patients with acute myocardial infarction an intravascular ultrasound analysis. J. Am. Coll. Cardiol. Img., July 1, 2008; 1(4): 489 - 497. [Abstract] [Full Text] [PDF]

				F. Bamberg, N. Dannemann, M. D. Shapiro, S. K. Seneviratne, M. Ferencik, J. Butler, W. Koenig, K. Nasir, R. C. Cury, A. Tawakol, et al. Association Between Cardiovascular Risk Profiles and the Presence and Extent of Different Types of Coronary Atherosclerotic Plaque as Detected by Multidetector Computed Tomography Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 568 - 574. [Abstract] [Full Text] [PDF]

				S. Waxman, F. Ishibashi, and J. E. Muller Detection and Treatment of Vulnerable Plaques and Vulnerable Patients: Novel Approaches to Prevention of Coronary Events Circulation, November 28, 2006; 114(22): 2390 - 2411. [Full Text] [PDF]

				A. A. Elesber, C. A. Conover, A. E. Denktas, R. J. Lennon, D. R. Holmes Jr, M. T. Overgaard, M. Christiansen, C. Oxvig, L. O. Lerman, and A. Lerman Prognostic value of circulating pregnancy-associated plasma protein levels in patients with chronic stable angina Eur. Heart J., July 2, 2006; 27(14): 1678 - 1684. [Abstract] [Full Text] [PDF]

				S.-E. Hassani, G. S. Mintz, H. S. Fong, S.-W. Kim, Z. Xue, A. D. Pichard, L. F. Satler, K. M. Kent, W. O. Suddath, R. Waksman, et al. Negative Remodeling and Calcified Plaque in Octogenarians With Acute Myocardial Infarction: An Intravascular Ultrasound Analysis J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2413 - 2419. [Abstract] [Full Text] [PDF]

				U. Hoffmann, F. Moselewski, K. Nieman, I.-K. Jang, M. Ferencik, A. M. Rahman, R. C. Cury, S. Abbara, H. Joneidi-Jafari, S. Achenbach, et al. Noninvasive Assessment of Plaque Morphology and Composition in Culprit and Stable Lesions in Acute Coronary Syndrome and Stable Lesions in Stable Angina by Multidetector Computed Tomography J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1655 - 1662. [Abstract] [Full Text] [PDF]

				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]

				C. von Birgelen, M. Hartmann, G. S. Mintz, D. Bose, H. Eggebrecht, T. Neumann, M. Gossl, H. Wieneke, A. Schmermund, M. G. Stoel, et al. Remodeling Index Compared to Actual Vascular Remodeling in Atherosclerotic Left Main Coronary Arteries as Assessed With Long-Term (>=12 Months) Serial Intravascular Ultrasound J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1363 - 1368. [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]

				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]

				C. Brasselet, E. Durand, F. Addad, A. A. H. Zen, M. B. Smeets, D. Laurent-Maquin, S. Bouthors, G. Bellon, D. de Kleijn, G. Godeau, et al. Collagen and elastin cross-linking: a mechanism of constrictive remodeling after arterial injury Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2228 - H2233. [Abstract] [Full Text] [PDF]

				A. Mauriello, G. Sangiorgi, S. Fratoni, G. Palmieri, E. Bonanno, L. Anemona, R. S. Schwartz, and L. G. Spagnoli Diffuse and Active Inflammation Occurs in Both Vulnerable and Stable Plaques of the Entire Coronary Tree: A Histopathologic Study of Patients Dying of Acute Myocardial Infarction J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1585 - 1593. [Abstract] [Full Text] [PDF]

				M. Takano, S. Inami, F. Ishibashi, K. Okamatsu, K. Seimiya, T. Ohba, S. Sakai, and K. Mizuno Angioscopic follow-up study of coronary ruptured plaques in nonculprit lesions J. Am. Coll. Cardiol., March 1, 2005; 45(5): 652 - 658. [Abstract] [Full Text] [PDF]

				R. Glaser, F. Selzer, D. P. Faxon, W. K. Laskey, H. A. Cohen, J. Slater, K. M. Detre, and R. L. Wilensky Clinical Progression of Incidental, Asymptomatic Lesions Discovered During Culprit Vessel Coronary Intervention Circulation, January 18, 2005; 111(2): 143 - 149. [Abstract] [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]

				L. G. Spagnoli, A. Mauriello, G. Sangiorgi, S. Fratoni, E. Bonanno, R. S. Schwartz, D. G. Piepgras, R. Pistolese, A. Ippoliti, and D. R. Holmes Jr Extracranial Thrombotically Active Carotid Plaque as a Risk Factor for Ischemic Stroke JAMA, October 20, 2004; 292(15): 1845 - 1852. [Abstract] [Full Text] [PDF]

				J. C. Wang, S.-L. T. Normand, L. Mauri, and R. E. Kuntz Coronary Artery Spatial Distribution of Acute Myocardial Infarction Occlusions Circulation, July 20, 2004; 110(3): 278 - 284. [Abstract] [Full Text] [PDF]

This Article Free upon publication Abstract Full Text (PDF) All Versions of this Article: 108/20/2473    most recent 01.CIR.0000097121.95451.39v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujii, K. Articles by Moses, J. W. Search for Related Content PubMed PubMed Citation Articles by Fujii, K. Articles by Moses, J. W. Related Collections Acute coronary syndromes