Author + information
- Received January 9, 2017
- Revision received February 15, 2017
- Accepted March 9, 2017
- Published online July 19, 2017.
- Mikkel Hougaard, MD, PhD∗ (, )
- Henrik Steen Hansen, MD, DMSci,
- Per Thayssen, MD, DMSci,
- Lisbeth Antonsen, MD, PhD and
- Lisette Okkels Jensen, MD, PhD, DMSci
- ↵∗Address for correspondence:
Dr. Mikkel Hougaard, Department of Cardiology, Odense University Hospital, 5000 Odense C, Denmark.
Objectives This study assessed the incidence and course of healing of uncovered plaque ruptures (PR) following primary percutaneous coronary intervention.
Background The infarct-related occlusion is frequently located at the lesion site with maximum thrombus burden, whereas the culprit PR may be situated more proximally or distally.
Methods Uncovered PR in segments adjacent to the stent were identified by optical coherence tomography and intravascular ultrasound using iMap (Boston Scientific, Marlborough, Massachusetts) within 48 h and after 12 months. The percentages of necrotic core, fibrotic tissue, lipid tissue, and calcific tissue were determined.
Results Eleven uncovered PR were found in 10 of 77 patients (13.0%). Eight of these ruptures (10.4%) were identified as culprit and were located proximal to the stent. Two patients were treated before follow-up due to recurrent symptoms. After 12 months, 3 PR had healed incompletely without causing symptoms. The lumen area at the PR site was reduced (7.5 mm2 [interquartile range (IQR): 4.8 to 9.3 mm2] to 3.6 mm2 [IQR: 2.8 to 8.0 mm2]; p = 0.012). Proximal segments with uncovered PR had greater plaque volumes (62.1 mm3 [IQR: 50.2 to 83.6 mm3] vs. 38.7 mm3 [IQR: 29.6 to 47.6 mm3], respectively; p < 0.001), vessel volumes (110.7 mm3 [IQR: 92.3 to 128.1 mm3] vs. 76.0 mm3 [IQR: 63.8 to 100.3 mm3], respectively; p < 0.001), and greater percentages of necrotic core (34.0% [IQR: 29.0% to 44.5%] vs. 20.5% (IQR: 10.0% to 29.0%]; p < 0.001). Conversely, percentages of fibrotic tissue were lower (44.0% [IQR: 32.0% to 47.0%] vs. 56.0% [IQR: 46.0% to 66.0%]; p = 0.001), whereas no differences were found for lipid tissue and calcific tissue.
Conclusions Uncovered culprit ruptures detected by optical coherence tomography were common following primary percutaneous coronary intervention and were found to be associated with significant lumen reduction during the healing process.
Coronary plaque ruptures are regarded as the preceding cause of myocardial infarctions and are in many cases located in lesions with a high plaque burden together with a necrotic core covered by a thin fibrous cap (1–3). These features make up what is known as thin-cap fibroatheromas (TCFA). In the setting of ST-segment elevation myocardial infarction (STEMI), an occlusion of the vessel occurs due to thrombus formation, plaque hemorrhage, and vessel spasm (4). The angiographic presentation is a disruption of the luminal continuity that has been caused by either an occlusion or a severe stenosis of the coronary vessel. The site with the angiographic culprit lesion is the target for percutaneous coronary intervention (PCI), but the true culprit lesion may not be lumen compromising and may be located proximal or distal to the target of intervention (5). For this reason, there will be a risk of incomplete stent coverage when intervention is guided by angiography alone.
Intravascular imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) can assist in the identification of the site of the true culprit and may lead to better stent coverage of these lesions. Due to the high resolution of OCT, a direct assessment of the TCFA is possible (6,7), and with IVUS, a further remodeling assessment and characterization of the plaque composition can be achieved by spectral analysis of the ultrasound scatter, known as iMap (Boston Scientific, Marlborough, Massachusetts), which enables differentiation of plaque composition into necrotic core (NC), fibrotic tissue (FT), calcific tissue (CT), and lipid tissue (LT) (8).
In the present study, blinded OCT and IVUS with iMap was performed in a first-time STEMI population within 48 h after their primary PCI procedure and was repeated after 12 months. We identified the uncovered plaque ruptures by OCT and subcategorized those showing signs of culprit features. The associated plaque volume and composition was assessed in the proximal and distal stent edge segments by using IVUS with iMap.
Setting and design
The present study was a substudy of the OCTIVUS (Plaque Composition in Patients with acute ST Segment Elevation Myocardial Infarction assessed by Optical Coherence Tomography and IntraVascular UltraSound with iMap) trial (9) (U.S. Clinical Trials identifier: NCT01385631), which was a single-center double-blinded randomized trial that enrolled statin-naïve patients with first-time STEMI.
From June 2011 to June 2013, a total of 1,062 patients with STEMI were admitted, and of these, 87 patients were included. The main inclusion criteria were: first-time STEMI, no prior treatment with statins or other lipid-lowering drugs, and a nonsignificant lesion in one of the 2 nonculprit coronary arteries (angiographic diameter stenosis >20% and <50%). The main exclusion criteria were: 1) age <18 years or >81 years; 2) impaired kidney function; 3) women with child-bearing potential who were not using chemical or mechanical contraception; 4) history of malignancy, unless a disease-free period of more than 5 years was present; 5) participation in another randomized trial; and 6) treatment with cyclosporine or fibrates.
Patients were examined using OCT and IVUS with iMap within 48 h after undergoing their primary PCI. IVUS acquisition with tissue characterization and OCT of the implanted stent in the infarcted artery were performed together with a plaque study in a nonculprit artery. After 12 months, the IVUS with tissue characterization and OCT were repeated.
Intracoronary imaging acquisition
Prior to the procedure, unfractionated heparin (5,000 IU) was administered. Nitroglycerin, 200 μg, was administered by intracoronary route prior to the pullback.
OCT was performed using the Lightlab model Cx7 (St. Jude Medical, Little Canada, Minnesota) and later the Ilumien System, both using a Dragonfly OCT catheter (St. Jude). The catheters were initially flushed with contrast (Visipaque, GE Healthcare, Chicago, Illinois) and wiped with heparinized saline water, activating the hydrophilic coating. Catheter placement was guided angiographically by visualization of the placed coronary stent, and the catheter was placed at least 5 mm distal to the distal stent edge. Pullback was initiated automatically by manually flushing the vessel with 20 ml of contrast (Visipaque). Pullback speed was 20 mm/s, and the total pullback distance of the system was 55 mm. Repeated pullback was performed in case of insufficient image quality or incomplete acquisition of the segment of interest.
The IVUS pullback was performed using the iLab system with a mechanical 40 MHz Atlantis SR Pro IVUS catheter (both, Boston Scientific). An automatic pullback was performed with a standard pullback speed of 0.5 mm/s. The IVUS catheter was advanced ≥5 mm distal to the stented segment, and imaging was performed throughout the stent to ≥5 mm of the proximal reference segment site. iMap data were obtained at every 30th frame (0.5 mm).
All intravascular image acquisition was documentary and not shared with the operator and did not influence the clinical decision making. During off-line review, the examiner was blinded to the patient data.
OCT pullbacks were analyzed using proprietary software (St. Jude Medical). The stent and its adjacent 5-mm distal and proximal reference segments were marked and processed with the automatic lumen contour with supplementary manual correction when needed. In the reference segments, all frames were inspected for signs of plaque ruptures.
Plaque ruptures were identified and defined as blunt intimal disruptions exposing an underlying fibroatheroma. Ruptures were considered culprits in cases with large and empty plaque cavities, together with signs of thrombotic material or lack of signs of neoendothelialization in accordance with available research (10) (Figure 1).
Using OCT, we assessed the baseline presentation and healing course of uncovered plaque ruptures at 12-month follow-up with respect to proximal or distal localization, maximum traced cavity area, rupture length, and distance to stent edge.
IVUS pullbacks were analyzed using Echoplaque version 4.0 software (Indec Medical Systems, Santa Clara, California). The 5-mm proximal and distal reference segments were marked and cross-sectional areas (CSA) for lumen and external elastic membrane (EEM) were traced manually in every iMap-containing frame (i.e., every 30th frame). The guidewire artefact was omitted from the iMap analysis by applying special masks within the software. Vessel and lumen volumes were calculated within the software as ∑EEMCSA and ∑LUMENCSA, respectively, where EEMCSA = external elastic membrane cross-sectional area, and LUMENCSA = luminal cross-sectional area. Plaque volume was defined as vessel volume minus lumen volume. Plaque burden was defined as [(plaque volume/vessel volume) × 100%]. We used iMap to assess the relative distributions of NC, FT, CT, and LT for the distal and proximal reference segment sites.
All statistical analysis was performed using commercially available software (SPSS version 21.0, IBM Corp., Armonk, New York). Categorical data are presented as frequencies and percentages and were compared using the chi-square test. Normally distributed continuous data are presented as mean ± SD and were compared using Student t test or presented as median (interquartile range [IQR]) and compared using Mann-Whitney U test when normality testing failed. A paired samples t test or a Wilcoxon matched-pair signed-rank test was used to compare changes from baseline to follow-up. A 2-sided p value <0.05 was considered statistically significant.
A total of 87 patients were enrolled in the study. Baseline OCT examinations failed or were of insufficient quality in 10 patients, leaving 77 patients for baseline assessment. During follow-up, 3 patients were lost to invasive follow-up (1 patient died, 1 patient declined the follow-up due to concurrent cancer, and 1 patient withdrew consent for personal reasons). Thus, 74 patients were included in complete OCT baseline and follow-up data. IVUS pullbacks were available in 80 patients at baseline and in 77 patients at 12-month follow-up. For technical reasons, iMap data were only available in 71 patients for the distal segments and in 69 patients for the proximal segments. Overall, complete iMap data were available in 63 patients. Among the patients identified with plaque rupture, baseline IVUS was not available in 2 patients, iMap was unavailable at follow-up in 1 patient, and entire follow-up examinations were missing in 2 patients due to target lesion revascularization prior to follow-up.
Baseline and procedure characteristics are listed for the patients with and without uncovered plaque ruptures in Table 1. Male sex was predominant, most patients were active smokers, and patients with uncovered plaque rupture tended to have shorter angiographically assessed primary lesions than patients with uncovered plaque ruptures (12.0 mm [IQR: 10.0 to 15.0 mm] vs. 15.0 mm [IQR: 12.0 to 20.0 mm], respectively; p = 0.06).
OCT findings post-PCI and after 12 months are presented in Table 2, an illustration of a typical culprit plaque rupture is provided in Figure 2, and all identified plaque ruptures are presented in Online Figure 1, showing pre- and post-angiographic appearance, OCT, IVUS, and iMap presentation at baseline and after 1 year.
At baseline, a total of 11 uncovered plaque ruptures were identified (13.0%). Eight of these ruptures were identified as culprit ruptures in 8 patients (10.4%), and all ruptures were located in the proximal reference segments (0.15 mm [IQR: 0.0 to 3.1 mm] from the stent edge). Three of the culprit ruptures (38%) were partially covered by the stent. The remaining 3 plaque ruptures were located >5 mm from the stent’s edge and were showing signs of neoendothelialization, and they were therefore considered nonculprit lesions.
The morphology of these ruptures differed. Two of the ruptures (Online Figure 1, ruptures 9 and 10) were found in the same patient, located proximally to and remote from the stent’s edge. One of these (Online Figure 1, rupture 10) had a large cavity without thrombus at baseline, the other (Online Figure 1, rupture 9) was small and had a more classic appearance but with significant neoendothelialization of the cavity. The last nonculprit rupture (Online Figure 1, rupture 11) was covered by dense fibrosis at baseline and was considered an old lesion.
After 12 months, 3 culprit plaque ruptures (Online Figure 1, ruptures 2, 3, and 8) showed signs of insufficient healing. One nonculprit rupture (Online Figure 1, rupture 11) could be identified at follow-up. The healing of the other 2 nonculprit ruptures (Online Figure 1, ruptures 9 and 10) was accompanied by stenosis. For all plaque ruptures, the luminal area at the rupture site was reduced from 7.5 mm2 (IQR: 4.8 to 9.3 mm2) to 3.6 mm2 (IQR: 2.8 to 8.0 mm2; p = 0.012).
IVUS with iMap findings
Results are presented in Table 3. The patients with culprit plaque ruptures were more homogeneous than the 2 patients with nonculprit ruptures. The groups differed with respect to rupture site localization (1 distal and 2 very proximal) and because the proximal ruptures resided outside the proximal reference segment, a direct comparison between the 2 groups was not meaningful and data are therefore presented for the patients with culprit rupture only. The EEM and plaque volumes in patients with uncovered culprit plaque ruptures were higher in the proximal reference segment (110.7 mm3 [IQR: 92.3 to 128.1 mm3] vs. 76.0 mm3 [IQR: 63.8 to 100.3 mm3], respectively; p = 0.005; and 62.1 mm3 [IQR: 50.2 to 83.6 mm3] vs. 38.7 mm3 [IQR: 29.6 to 47.6 mm3], respectively; p < 0.001). No differences between groups were found in the peri-stent or distal reference segment sites. iMap analysis showed that the relative amount of NC in the proximal reference segment was higher in patients with uncovered culprit plaque ruptures (34.0% [IQR: 29.0% to 44.5%] vs. 20.5% [IQR: 10.0% to 29.0%], respectively; p = 0.006), and conversely, the amount of FT was lower (44.0% [IQR: 32.0% to 47.0%] vs. 56.0% [IQR: 46.0% to 66.8%], respectively; p = 0.007). In the distal segment, the amount of CT was slightly higher in patients without culprit plaque rupture (1.0% [IQR: 0.0% to 1.0%] vs. 1.0% [IQR: 1.0% to 2.0%], respectively; p = 0.038).
A graphic presentation of culprit plaque ruptures associated with ischemic events is presented in Figure 3. One patient (Online Figure 1, rupture 3) had an uncovered culprit plaque rupture treated after 100 days due to stable angina pectoris and stenosis just proximal to the stent; and in another patient (Online Figure 1, rupture 6), an occlusion of the infarct-related artery was discovered at follow-up and treated with PCI. Both of the patients had exercise-related chest pain and a positive myocardial perfusion imaging scan.
The main finding of the present study was that uncovered plaque ruptures identified by OCT are not an uncommon finding and often appear to be located proximally to the stent. Furthermore, a lumen reduction at the previous plaque rupture site was found during the healing process. IVUS showed that EEM and plaque volumes in the proximal reference segments were significantly larger in patients with plaque rupture than in patients without. In the same segments, iMap showed a higher proportion of NC and less FT.
Plaque ruptures have been found to be the underlying mechanism in 79% of all cases of myocardial infarctions, with the highest occurrence among men and elderly patients (11). OCT studies in STEMI patients have confirmed these findings (12). TCFAs are thought to be the main precursor for plaque ruptures, and it has been shown in autopsy studies that TCFAs tend to cluster in the proximal segments of the major coronary arteries in the same areas as most ruptures and thrombus formations are found (13). In the clinical setting of a STEMI, the assessment of coronary disease is most often based on angiography findings that mainly focus on the area with the most lumen obstruction. Although the cross-sectional luminal narrowing is known to be higher in sites with plaque rupture (14), the site with most angiographic lumen reduction may, as mentioned earlier, reside in adjacent areas to the true culprit. A possible explanation for this phenomena could be a higher degree of vasoconstriction in the culprit area (15) together with red thrombus formation and embolization (16).
Using OCT, 2 distinct morphologies have previously been described: a group with plaque rupture, large thrombus burden, and TCFA at the target lesion site and another group without rupture, lesser amounts of thrombus but significant stenosis at the target lesion site (12). In the present study, a large proportion of the patients without uncovered plaque rupture probably have a thrombotic cause for their infarction, which is concealed by the stent. In a previous IVUS virtual histology (VH) study, Legutko et al. (5) examined 20 patients admitted for primary PCI with blinded IVUS-VH prior to and after PCI. It was found that the true culprit (defined as a IVUS-VH TCFA) remained uncovered following PCI in 50% of patients and that plaque rupture was present by IVUS in 12 patients (60%). Eleven of these ruptures (92%) were located proximal to the minimum luminal area site.
In the present study, OCT and IVUS analyses were performed post-PCI, and it was not possible to assess the overall prevalence of plaque rupture but only the ruptures uncovered by stent. Pre-intervention IVUS and OCT might have improved distinguishing culprit from nonculprit plaque ruptures. To our knowledge, this is the first study to report the prevalence of uncovered plaque rupture following primary PCI in STEMI patients, and our finding of uncovered proximal culprit plaque rupture in nearly 9% of the patient population stresses the importance of increased attention towards the fact that the site of plaque rupture may differ from the target site with most stenosis. In accordance with the findings by Legutko et al. (5), the current iMap analysis showed a greater proximal plaque burden and relative content of NC, which suggests that some vessel wall disease in the proximal reference segment site is geographically missed during primary PCI and left uncovered. We did not perform a TCFA evaluation based on the iMap data as this technique remains unvalidated for that purpose, and data may not be directly comparable to IVUS-VH data.
In a prospective multicenter trial on patients admitted for PCI due to stable or unstable angina pectoris (17), it was found that insufficient lesion coverage (longitudinal geographical miss) and balloon versus reference segment size mismatch (axial geographical miss) was of clinical importance. The rate of 1-year target lesion revascularization was 5.1% in the group with geographical miss compared with 2.5% in the group with no geographical miss. This assessment was based on angiography alone and may not be fully applicable to a STEMI population.
In a way, the topic of the present study represents a variant of longitudinal geographic miss, but in contrast to the common use of the term, we did not assess geographic miss as longitudinal stent alignment relative to plaque burden or lipid content in the arterial wall. Near-infrared spectroscopy with IVUS has shown that angiographic determined target lesion length is considerably shorter than the length determined by near-infrared spectroscopy with IVUS (18). This correlates well with our findings of an increased plaque burden and a high lipid content together with NC in the proximal reference segments compared to the patients without plaque rupture. The clinical implication of geographic miss has previously been reported (17), and furthermore this finding seems to have the greatest impact in patients presenting with acute coronary syndrome (19). A possible explanation for this could be a relation to an increased plaque instability in this subgroup related to more plaque burden and inflammation of the vessel wall (11).
A potential reduction in cardiovascular event rates by IVUS guided stent deployment has been investigated in randomized trials with neutral results (20–22), although a meta-analysis pooling the results with observational studies has suggested positive results (23).
In the present study, we did encounter a need for target lesion revascularization in 2 patients within the first year, and it is noteworthy that these patients were among the patients with uncovered culprit plaque ruptures and that none of the plaque ruptures here were evident on coronary angiograms. The finding of lumen reduction at the rupture site corresponds well with previously reported observations of the spontaneous healing process of plaque ruptures in autopsy studies (24). Similarly, longitudinal IVUS studies of the noninfarct-related arteries in ACS patients have shown in vivo that clinically silent ruptures are frequent and that most heal on statin treatment without plaque modifications (25). An IVUS-VH study using similar study design has shown that patients with ACS have higher frequencies of multiple VH-TCFA than patients with stable angina (26). The actual prevalence of uncovered plaque ruptures in the general STEMI population and its clinical significance remain uncertain and should be addressed in future trials.
The current study was a small observational study that selected patients with first-time STEMI. The results from the present study may not be generalized, as we studied <10% of the entire STEMI population.
The distinction between “acute” culprit and pre-existing ruptures is, in our study, based on the assessment of neoendothelialization of the plaque rupture cavity. The existing knowledge about the pathogenesis behind coronary infarction is based mainly on autopsy studies showing a prevalence for multiple ruptures in patients who died from ACS, not all necessarily culprits. Because no pre-intervention OCT or IVUS was performed, we do not know exactly the extension and/or morphology of the culprit lesions, particularly for the patients without detected uncovered plaque ruptures. Some patients might have had more than 1 culprit lesion covered by the stent.
Finally, the IVUS assessment was limited to the stented segment and the adjacent 5-mm reference segments, and areas with significant plaque contents might have escaped analysis due to a more distal or proximal localization. The study was nonrandomized and not powered to assess the clinical significance of uncovered culprit lesions and further studies are required to determine whether seeking out and treating uncovered plaque ruptures in acute coronary syndromes is warranted.
OCT-detected uncovered culprit plaque rupture was not an uncommon finding in patients treated with primary PCI, and they were primarily located proximal to the implanted stent. Uncovered plaque ruptures were associated with significant lumen reduction during the 12-month spontaneous healing process.
COMPETENCY IN MEDICAL KNOWLEDGE: Uncovered OCT-detected culprit plaque ruptures in STEMI patients are not uncommon and may result in restenosis during the healing process.
TRANSLATIONAL OUTLOOK: Further studies in a broader population of STEMI patients are needed to clarify the clinical significance of this finding.
For a supplemental figure, please see the online version of this article.
Dr. Jensen has received research grants to her institution from Terumo, Biotronik, St. Jude Medical, and Biosensors; and honoraria from Abbott Vascular, AstraZeneca, St. Jude Medical, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- calcific tissue characterized by iMap
- external elastic membrane
- fibrotic tissue characterized by iMap
- intravascular ultrasound
- lipid tissue characterized by iMap
- necrotic tissue characterized by iMap
- optical coherence tomography
- thin cap fibroatheroma (thickness: <65-μm separation of lipid plaque from the vessel lumen)
- virtual histology
- Received January 9, 2017.
- Revision received February 15, 2017.
- Accepted March 9, 2017.
- 2017 American College of Cardiology Foundation
- Schaar J.A.,
- Muller J.E.,
- Falk E.,
- et al.
- Legutko J.,
- Jakala J.,
- Mintz G.S.,
- et al.
- Choi S.-Y.,
- Maehara A.,
- Cristea E.,
- et al.
- Hougaard M.,
- Hansen H.S.,
- Thayssen P.,
- et al.
- Falk E.,
- Nakano M.,
- Bentzon J.F.,
- Finn A.V.,
- Virmani R.
- Wang L.,
- Parodi G.,
- Maehara A.,
- et al.
- Bentzon J.F.,
- Otsuka F.,
- Virmani R.,
- Falk E.
- Bogaty P.,
- Hackett D.,
- Davies G.,
- Maseri A.
- Falk E.
- Hanson I.D.,
- Goldstein J.A.,
- Dixon S.R.,
- Stone G.W.
- Calvert P.A.,
- Brown A.J.,
- Hoole S.P.,
- Obaid D.R.,
- West N.E.J.,
- Bennett M.R.
- Kim J.-S.,
- Kang T.-S.,
- Mintz G.S.,
- et al.
- Jang J.-S.,
- Song Y.-J.,
- Kang W.,
- et al.
- Burke A.P.,
- Kolodgie F.D.,
- Farb A.,
- et al.
- Rioufol G.,
- Gilard M.,
- Finet G.,
- Ginon I.,
- Boschat J.,
- André-Fouët X.