Author + information
- Received August 19, 2013
- Revision received October 9, 2013
- Accepted October 10, 2013
- Published online April 1, 2014.
- Yong Xie, MD∗,†,‡,
- Gary S. Mintz, MD†,
- Junqing Yang, MD∗,†,
- Hiroshi Doi, MD, PhD∗,†,
- Andrés Iñiguez, MD§,
- George D. Dangas, MD, PhD†,‖,
- Patrick W. Serruys, MD, PhD¶,
- John A. McPherson, MD#,
- Bertil Wennerblom, MD∗∗,
- Ke Xu, PhD†,
- Giora Weisz, MD∗,†,
- Gregg W. Stone, MD∗,† and
- Akiko Maehara, MD∗,†∗ ()
- ∗Division of Cardiology, Columbia University Medical Center, New York, New York
- †Clinical Trials Center, Cardiovascular Research Foundation, New York, New York
- ‡Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, China
- §Interventional Cardiology Unit, Hospital Meixoeiro, Vigo, Spain
- ‖Division of Cardiology, Icahn School of Medicine at Mount Sinai, New York, New York
- ¶Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands
- #Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- ∗∗Cardiology Department, Sahlgrenska University Hospital, Göteborg, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Akiko Maehara, Cardiovascular Research Foundation/Columbia University Medical Center, 111 East 59th Street, 12th Floor, New York, New York 10022.
Objectives The aim of this study was to report the frequency, patient and lesion-related characteristics, and outcomes of subclinical, nonculprit plaque ruptures in the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study.
Background Plaque rupture and subsequent thrombosis is the most common cause of acute coronary syndrome (ACS). Secondary, subclinical, nonculprit plaque ruptures have been seen in both stable patients and patients with ACS; however, reports of the natural history of these secondary plaque ruptures are limited.
Methods After successful stenting in 697 patients with ACS, 3-vessel grayscale and intravascular ultrasound virtual histology (IVUS-VH) was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective multicenter study.
Results Among 660 patients with complete IVUS data, 128 plaque ruptures were identified in 105 nonculprit lesions in 100 arteries from 93 patients (14.1%). Although the minimum lumen area (MLA) was similar, the plaque burden was significantly greater in nonculprit lesions with a plaque rupture compared with nonculprit lesions without a plaque rupture (66.0% [95% confidence interval: 64.5% to 67.4%] vs. 56.0% [95% confidence interval: 55.6% to 56.4%]; p < 0.0001). IVUS-VH analysis revealed that a nonculprit lesion with a plaque rupture was more often classified as a fibroatheroma than a nonculprit lesion without a plaque rupture (77.1% vs. 51.4%; p < 0.0001). Independent predictors of a plaque rupture were lesion length (per 10 mm; odds ratio: 1.30; p < 0.0001), plaque burden at the MLA site (per 10%; odds ratio: 2.56; p < 0.0001), vessel area at the MLA site (per 1 mm2; odds ratio: 1.13; p < 0.0001), and VH–thin-cap fibroatheroma (odds ratio: 1.80; p = 0.016). During 3 years of follow-up, the incidence of overall major adverse cardiac events did not differ significantly between the patients with and patients without subclinical, nonculprit plaque ruptures.
Conclusions Secondary, nonculprit plaque ruptures were seen in 14% of patients with ACS and were associated with a fibroatheroma phenotype with a residual necrotic core but not with adverse outcomes if patients were treated with optimal medical therapy as part of a multicenter study. (Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT]; NCT00180466)
The most common cause of an acute coronary syndrome (ACS) is rupture of an atherosclerotic lesion followed by acute luminal thrombosis (1,2). Pathological studies have suggested that the precursor of a ruptured plaque is a thin-cap fibroatheroma (TCFA). Although in vivo studies of TCFAs and their evolution into a ruptured plaque are rare, intravascular ultrasound (IVUS) studies (3,4) have reported that a plaque rupture occurs not only in culprit lesions but also in nonculprit or secondary atherosclerotic plaques in patients with ACS. Reports of the natural history of these secondary plaque ruptures are limited and include only small numbers of patients (5–7). The present study uses the 3-vessel IVUS data from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study to assess the prevalence, clinical features, angiographic appearance, IVUS–virtual histology (VH) morphology, and clinical outcomes of nonculprit plaque ruptures in patients with ACS.
Patient selection and protocol
The enrollment criteria and methodology of the PROSPECT study have been described in detail (8). Briefly, 697 patients with ACS (ST-segment elevation myocardial infarction >24 h, non–ST-segment elevation myocardial infarction, or unstable angina with electrocardiographic changes) underwent coronary angiography and multimodality intracoronary imaging of the proximal 6 to 8 cm of all 3 coronary arteries after treatment of the culprit lesion and any other planned interventions. Patients were then followed up for a median of 3.4 years to relate subsequent events to the morphologies of the lesions detected at baseline. Medications, including dual antiplatelet therapy and statin therapy, were recorded at discharge and during follow-up. The study was approved by the institutional review board or medical ethics committee at each participating center, and all patients signed written informed consent. Of 697 patients enrolled in the PROSPECT study, 660 patients with complete grayscale and IVUS-VH data comprised the current study population.
Quantitative coronary angiography and IVUS
Intracoronary imaging, both grayscale and IVUS-VH, was performed with the use of a synthetic aperture array, 20-MHz, 3.2-F catheter (Eagle Eye, In-Vision Gold, Volcano Corp., Rancho Cordova, California) with motorized catheter pullback (0.5 mm/s). Baseline angiographic as well as grayscale and IVUS-VH images were analyzed at the Cardiovascular Research Foundation (New York, New York) in a core laboratory that was blinded to the clinical outcomes. Off-line grayscale and IVUS-VH analyses of all imaged segments were performed prospectively at an independent IVUS core laboratory at the Cardiovascular Research Foundation by investigators who were blinded to the angiographic analysis and to the clinical events. Detailed angiographic and grayscale and IVUS-VH methodology has been described previously (9).
An IVUS nonculprit lesion was defined as a plaque burden of ≥40% in at least 3 consecutive frames. Lesions were considered separate if there was a ≥5-mm-long segment with <40% plaque burden between them. A plaque rupture was defined as a cavity that communicated with the lumen with an overlying residual fibrous cap fragment (Fig. 1). One lesion could have multiple plaque ruptures. Rupture sites separated by ≥3 consecutive frames (approximately 1.5 mm) of artery containing smooth lumen contours and no cavity were considered to represent discrete and separate plaque ruptures.
On the basis of IVUS-VH, plaque components were categorized as dense calcium, fibrous tissue, fibrofatty plaque, or necrotic core and reported as percentages of total plaque areas and volumes. Lesions were then classified by IVUS-VH as 1 of the following: VH-TCFA, thick-cap fibroatheroma (ThCFA), pathological intimal thickening, fibrotic plaque, or fibrocalcific plaque, as previously reported. Fibroatheromas were subclassified as having single or multiple confluent necrotic cores. The total length of each VH-TCFA was analyzed and summed per lesion.
Clinical endpoints and definitions
The primary endpoint was the incidence of major adverse cardiovascular events (MACE) (the composite of death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina according to the Braunwald classification of unstable angina and the Canadian Cardiovascular Society classification of angina). The primary endpoint was adjudicated by an independent clinical events committee. On the basis of follow-up angiography, MACE were attributed to a nonculprit lesion site if the site associated with an event was previously untreated. If follow-up angiography was not performed, the lesion site was classified as indeterminate and was excluded from this analysis.
All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). Categorical variables were summarized using percentages and counts and were compared using chi-square statistics or Fisher exact test where appropriate. Continuous variables were compared using analysis of variance and unpaired t tests. For fibroatheroma and lesion-level data, a model with a generalized estimating equation approach was used to compensate for potential cluster effects of multiple lesions in the same patient and presented as least squares means with 95% confidence intervals (CIs). Multivariate logistic regression analysis was used to determine independent predictors of a plaque rupture. Kappa statistics were used to assess the interobserver and intraobserver variability for qualitative analyses. A p value of <0.05 was considered statistically significant.
Patients and baseline characteristics
Among 660 patients with complete IVUS data, 128 nonculprit plaque ruptures were identified in 105 nonculprit lesions in 100 arteries from 93 patients (14.1%). Among the 105 nonculprit lesions with a plaque rupture, 40 (38%) were located in the culprit vessel and 65 (62%) in the nonculprit vessel. There was no difference of lesion morphology between them (data not shown). Overall, 49% of ruptured plaques were located in the right coronary artery (n = 63), 35% in the left anterior descending artery (n = 45), and 16% in the left circumflex artery (n = 20). Intraobserver and interobserver concordance for the detection of plaque ruptures was good (kappa: 0.90 [0.59 to 1.0] and 0.85 [0.54 to 1.0]). Table 1 shows the baseline characteristics of the 93 patients with at least 1 nonculprit plaque rupture compared with the 567 patients without a detectable nonculprit plaque rupture. Patients with a plaque rupture were more likely to be male, have had a prior cardiac intervention, and have a higher body mass index. Although the prevalence of hypercholesterolemia requiring medication was similar between the 2 groups, the lipid profile tended to be worse in patients with a plaque rupture (total cholesterol: 184.0 mg/dl [155.0 to 205.0 mg/dl] vs. 169.0 mg/dl [147.0 to 197.0 mg/dl], p = 0.02; triglycerides: 145.0 mg/dl [100.5 to 196.0 mg/dl] vs. 122.0 mg/dl [88.6 to 177.1 mg/dl], p = 0.02). Other risk factors, such as diabetes, hypertension, and smoking, were similar between the 2 groups. The clinical presentation did not differ between the 2 groups.
Patient-level angiographic and IVUS analysis
Angiographically, patients with a plaque rupture showed a trend toward more and longer nonculprit lesions (Table 2). There was no difference in the angiographic qualitative parameters between the 2 groups except that there was a trend for patients with plaque ruptures to have more aneurysmal lesions (p = 0.09). By IVUS, the percent total plaque volume (total plaque volume divided by external elastic membrane volume over the combined lengths of the lesions identified in each patient) was significantly greater in patients with at least 1 nonculprit plaque rupture than in patients without a plaque rupture (51.1% [48.5% to 53.2%] vs. 48.9% [46.5% to 51.7%]; p < 0.0001). Patients with at least 1 secondary plaque rupture were more likely to have at least 1 nonculprit lesion with a plaque burden ≥70% (50.5% vs. 30.5%; p = 0.0001). IVUS-VH analysis showed that there were more VH-TCFAs in patients with at least 1 nonculprit plaque rupture than in patients without a plaque rupture (p = 0.01).
Lesion-level grayscale IVUS analysis
Overall, there were 3,229 nonculprit lesions with a plaque burden ≥40% identified by IVUS; among these lesions, 128 plaque ruptures were identified in 105 lesions (4%). IVUS analysis showed that a nonculprit lesion with a plaque rupture was twice as long as a lesion without a plaque rupture (29.7 mm [95% CI: 26.7 to 32.8 mm] vs. 15.4 mm [95% CI: 14.9 to 16.0 mm]; p < 0.0001). Lesions with a plaque rupture had a greater percent plaque volume than did lesions without a plaque rupture (53.4% [95% CI: 52.5% to 54.3%] vs. 48.3% [95% CI: 48.0% to 48.5%]; p < 0.0001). Although the minimum lumen area (MLA) was similar in both groups (secondary lesions with vs. without a plaque rupture), the plaque burden at the MLA site and area stenosis (along with a larger external elastic membrane area) were significantly greater in the plaque rupture group (66.0% [95% CI: 64.5% to 67.4%] vs. 56.0% [95% CI: 55.6% to 56.4%]; p < 0.0001) compared with the nonplaque rupture group (40.5% [95% CI: 37.9% to 43.2%] vs. 26.5% [95% CI: 25.9% to 27.2%]; p < 0.0001) (Table 3).
Lesion-level IVUS-VH analysis
IVUS-VH analysis revealed that a nonculprit lesion with a plaque rupture was more often classified as a fibroatheroma than a nonculprit lesion without a plaque rupture (77.1% vs. 51.4%; p < 0.0001), whereas pathological intimal thickening was more common in lesions without a plaque rupture (36.8% vs. 19.0%; p = 0.0004). When subdivided into types of fibroatheromas, IVUS-VH indicated that a nonculprit lesion was more often classified as a VH-TCFA than a nonculprit lesion without a plaque rupture (38.1% vs. 21.7%; p < 0.0001). Furthermore, a lesion with a plaque rupture that was identified as a fibroatheroma more often had multiple necrotic cores whether the lesion was classified as a VH-TCFA or a ThCFA (32.4% vs. 15.3% [p < 0.0001] and 36.2% vs. 24.6% [p = 0.005], respectively) (Table 4).
In 105 lesions with at least 1 plaque rupture, 1 lesion contained 3 discrete plaque ruptures, 21 lesions had 2 discrete plaque ruptures, and 83 lesions had 1 plaque rupture. Among these 128 plaque ruptures, when the image slice with the largest plaque cavity was analyzed, there was a residual confluent necrotic core in 62.5% of plaque ruptures either at the bottom of the cavity or at the shoulder of the cavity. A VH-TCFA was located proximal to the cavity in 37.3% of the plaque ruptures, and a VH-TCFA was located distal to the cavity in 32.5% of plaque ruptures so that 46.1% of plaque ruptures had a VH-TCFA either proximal or distal to the plaque rupture segment (Fig. 1).
Predictors of plaque rupture
Including patient and lesion characteristics, we evaluated the independent predictors for existence of rupture. After univariate analysis, the following 10 variables (all of the variables with p < 0.1 in the univariate model) were included in the final multivariate model: white race, body mass index, low-density lipoprotein cholesterol level, triglyceride level, lesion length by IVUS, mean dense calcium cross-sectional area (CSA) per lesion, mean necrotic core CSA per lesion, plaque burden at the MLA site, external elastic membrane CSA at the MLA site, and VH-TCFA. Independent predictors of plaque rupture were lesion length (per 10 mm; odds ratio: 1.30 [95% CI: 1.15 to 1.46]; p < 0.0001), plaque burden at the MLA site (per 10%; odds ratio: 2.56 [95% CI: 2.04 to 3.21]; p < 0.0001), external elastic membrane CSA at the MLA site (per 1 mm2; odds ratio: 1.13 [95% CI: 1.09 to 1.17]; p < 0.0001), and VH-TCFA (odds ratio: 1.80 [95% CI: 1.11 to 2.89]; p = 0.016).
Medications and clinical outcomes
There was no difference in cardiac medications, including statin therapy and dual antiplatelet therapy, between the 2 groups (patients with vs. without a secondary plaque rupture) at discharge and during 3 years of follow-up (Table 1). Table 5 summarizes the 3-year clinical outcomes in patients with versus without a plaque rupture. During follow-up, 6 patients developed a myocardial infarction, and 68 patients were rehospitalized due to unstable or progressive angina. The incidence of overall MACE, however, did not differ significantly between the 2 patient groups. Nevertheless, there was a trend for lesions with a plaque rupture to result in more nonculprit MACE (4.0% vs. 1.8%; p = 0.09) because of a trend toward more rehospitalizations (4.0% vs. 1.7%; p = 0.07).
In the current study, using the 3-vessel IVUS data from the PROSPECT study, we analyzed the frequency, morphology, and outcome of the largest series of patients with ACS with secondary, nonculprit plaque ruptures. The main findings of our analysis are as follows. First, the prevalence of secondary, nonculprit plaque rupture was 14.1% and was not different between patients with ST-segment elevation myocardial infarction and patients with non–ST-segment elevation myocardial infarction. Second, more than three-fourths of the plaque rupture sites were part of a lesion that had the phenotype of a fibroatheroma, suggesting that this may have been the rupture-prone morphological precursor. Third, secondary, nonculprit plaque ruptures were associated with a greater prevalence of other lesions with high-risk morphologies. Fourth, patients with a nonculprit lesion plaque rupture had a higher overall percent plaque volume with a greater plaque burden at the MLA site as well as more VH-TCFA lesions. Fifth, the incidence of overall MACE was low, with no difference between patients with versus without silent plaque ruptures.
Frequency of secondary, nonculprit plaque ruptures
In the first 3-vessel IVUS study by Rioufol et al. (4), the frequency of secondary, nonculprit plaque ruptures in patients with biomarker-positive ACS was 79%. However, this was not substantiated by a 3-vessel IVUS study from Hong et al. (3) or by 3-vessel optical coherence tomography studies from Kubo et al. (10), Fujii et al. (11), or Tanaka et al. (12), who reported rates of 12% to 31%. The current study supports the lower prevalence of nonculprit plaque ruptures in these latter studies, which is consistent with pathological findings (13). However, because IVUS of the culprit lesions was not performed before the intervention, we cannot assess the prevalence of secondary plaque ruptures according to the underlying culprit lesion morphology, that is, plaque rupture versus erosion versus calcified nodules.
Nevertheless, the current study extends the findings of other studies to indicate that patients with ACS who have secondary plaque ruptures have additional lesions with high-risk morphologies, albeit without frank plaque rupture, supporting the hypothesis that this may represent a multifocal phenomenon. Furthermore, the current study indicates that patients with ACS who have secondary plaque ruptures have a greater overall plaque burden of the identified nonculprit lesions. Combining data from 6 clinical trials that used serial IVUS, Nicholls et al. (14) reported that the overall plaque burden was a risk factor for future events (myocardial infarction, coronary revascularization, or MACE) during an average follow-up of 21 months.
The criteria for the IVUS-VH diagnosis of a TCFA have evolved from histopathological concepts. In our current study, IVUS-VH analysis revealed a residual confluent necrotic core (either at the bottom or shoulder of the cavity) in 62.5% of plaque ruptures, with 46.1% of plaque ruptures having a VH-TCFA phenotype either proximal or distal to the cavity. Although part of the necrotic core may be expelled at the time of plaque rupture, there is still a considerable amount of residual necrotic core, and the amount of necrotic core when comparing ruptures with nonruptures (including nonfibroatheroma nonruptures) was almost identical. Therefore, the pre-rupture lesion should have had a larger necrotic core than the nonruptures. This provides in vivo evidence suggesting that the pre-rupture IVUS-VH morphology may have been that of a fibroatheroma.
Outcomes of secondary, nonculprit plaque ruptures
Plaque rupture is the most common cause of ACS, but as previously reported (3,4,10–12,15) and as also seen in the current study, not all plaque ruptures cause events. Fujii et al. (16) showed that plaque ruptures cause symptoms in the setting of thrombus formation and lumen compromise; comparing culprit lesions with plaque ruptures in patients with ACS versus nonculprit plaque ruptures in patients with ACS versus plaque ruptures in patients with stable angina, the MLA measured 3.3 ± 1.5 mm2 versus 5.4 ± 2.6 mm2 versus 6.1 ± 2.0 mm2, respectively, which helps explain why the secondary plaque ruptures in the current study were “silent.” Other studies have indicated that non–symptom-producing plaque ruptures tend to heal and subsequently contributed to the development of a stenosis (17,18).
Rioufol et al. (5) reported follow-up data in 14 patients with 28 secondary plaque ruptures without significant associated stenosis. All patients were treated with statins and dual antiplatelet agents, and there were no clinical events related to the nonculprit rupture lesions. Hong et al. (6) also reported 12-month follow-up data in 28 patients with nonstenotic ruptured plaques, one-half of which were treated with statins. Complete healing of a ruptured plaque was observed in 4 statin-treated patients (29%) and in no non–statin-treated patients, and target lesion revascularization was performed in 3 non–statin-treated patients (21%) but in no statin-treated patients. A report by Ohlmann et al. (7) also showed a low 5-year MACE rate relating to secondary plaque rupture without luminal compromise; in 17 patients, there was 1 death (6%) and 2 revascularizations (12%).
The current report is the largest series of patients with secondary, nonculprit plaque ruptures. As in previous studies, these lesions appear to be benign as long as patients receive optimal medical therapy; in the current study, 89.7% of patients were taking aspirin and 83.3% of patients were taking statins at 3 years. Furthermore, there was no difference in outcomes between patients with versus without secondary plaque ruptures.
First, in the current study, it is likely that not all plaque ruptures were detected by IVUS because the thickness of the thin fibrous cap is below the resolution of grayscale IVUS, so the thrombus may obscure the ruptures. Second, this study was a cross-sectional analysis of plaques at different stages of development and evolution; serial IVUS imaging was not performed as would be necessary to prove the cause-and-effect relationship between a TCFA and plaque rupture. Third, because IVUS imaging was performed after successful and uncomplicated percutaneous coronary intervention of all lesions responsible for the index event, the possibility cannot be excluded that contrast injection, guidewire manipulation, or the IVUS catheter itself might have created a fissure in the thin fibrous cap to create the appearance of a plaque rupture. Fourth, the culprit lesions were not included in the current analysis because culprit lesions were stented before IVUS imaging. Fifth, the current study used a 20-MHz IVUS probe with a resolution of approximately 200 μm and might have missed small plaque ruptures compared with a 40-MHz IVUS probe (especially during saline flush) and even more so compared with optical coherence tomography. Sixth, the diagnosis of thrombus by IVUS is presumptive, especially when using a 20-MHz solid-state device, and was not reported in the PROSPECT study. Finally, event rates were low in both groups and were too low to detect a difference in mortality/morbidity.
The current 3-vessel IVUS analysis of 660 patients in the PROSPECT study showed that the prevalence of secondary, nonculprit plaque ruptures in patients with ACS was 14.1%, that it was associated with a VH fibroatheroma phenotype with a residual necrotic core in three-fourths of patients and a VH-TCFA phenotype with a residual necrotic core in approximately one-half of patients, and that it was not associated with subsequent MACE in patients treated with proper medical therapy.
This study was funded by Abbott Vascular and Volcano Corp. Dr. Xie has received grants from the Jiangsu Health International Exchange Program and Jiangsu Government Scholarship for Overseas Studies. Dr. Mintz has received research support from Volcano Corp.; and has served as a consultant for Volcano Corp., Boston Scientific Corp., and Infraredx, Inc. Dr. Dangas has served as a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, Janssen Pharmaceuticals, Regado Biosciences, Maya Medical, Merck & Co., and The Medicines Company; and has received research support from The Medicines Company, Bristol-Myers Squibb/Sanofi, and Eli Lilly and Company/Daiichi-Sankyo. Dr. McPherson has served as a consultant for CardioDx, Inc. Dr. Weisz has served as a consultant for Infraredx, Inc. Dr. Stone has served as a consultant for Volcano Corp. and Infraredx, Inc. Dr. Maehara has received research support from and served as a consultant for Boston Scientific Corp.; and has received speaker fees from St. Jude Medical and Volcano Corp. All other authors have reported that they have no relationships relevant to the content of this paper to disclose. Neal S. Kleiman, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- acute coronary syndrome
- confidence interval
- cross-sectional area
- intravascular ultrasound
- major adverse cardiac event(s)
- minimum lumen area
- thin-cap fibroatheroma
- thick-cap fibroatheroma
- virtual histology
- Received August 19, 2013.
- Revision received October 9, 2013.
- Accepted October 10, 2013.
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