J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 1 1 , N O . 6 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

Uncovered Culprit Plaque Ruptures inPatients With ST-Segment ElevationMyocardial Infarction Assessed byOptical Coherence Tomography andIntravascular Ultrasound With iMap

Mikkel Hougaard, MD, PHD, Henrik Steen Hansen, MD, DMSCI, Per Thayssen, MD, DMSCI, Lisbeth Antonsen, MD, PHD,Lisette Okkels Jensen, MD, PHD, DMSCI

ABSTRACT

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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 symp-

toms. 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 ¼ 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 ¼ 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. (J Am Coll Cardiol Img 2018;11:859–67) © 2018 by the American College of Cardiology Foundation.

C oronary plaque ruptures are regarded as thepreceding cause of myocardial infarctionsand are in many cases located in lesions

with a high plaque burden together with a necroticcore covered by a thin fibrous cap (1–3). These

N 1936-878X/$36.00

m the Department of Cardiology, Odense University Hospital, Odense, Den

titution from Terumo, Biotronik, St. Jude Medical, and Biosensors; and ho

dical, and Biotronik. All other authors have reported that they have no re

close.

nuscript received January 9, 2017; revised manuscript received February

features make up what is known as thin-cap fibroa-theromas (TCFA). In the setting of ST-segment eleva-tion myocardial infarction (STEMI), an occlusion ofthe vessel occurs due to thrombus formation, plaquehemorrhage, and vessel spasm (4). The angiographic

http://dx.doi.org/10.1016/j.jcmg.2017.03.019

mark. Dr. Jensen has received research grants to her

noraria from Abbott Vascular, AstraZeneca, St. Jude

lationships relevant to the contents of this paper to

15, 2017, accepted March 9, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

CT = calcific tissue

characterized by iMap

EEM = external elastic

membrane

FT = fibrotic tissue

characterized by iMap

IVUS = intravascular

ultrasound

LT = lipid tissue characterized

by iMap

NC = necrotic tissue

characterized by iMap

OCT = optical coherence

tomography

TCFA = thin cap fibroatheroma

(thickness: <65-mm separation

of lipid plaque from the vessel

lumen)

VH = virtual histology

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presentation is a disruption of the luminalcontinuity that has been caused by either anocclusion or a severe stenosis of the coronaryvessel. The site with the angiographic culpritlesion is the target for percutaneous coronaryintervention (PCI), but the true culprit lesionmay not be lumen compromising and may belocated proximal or distal to the target ofintervention (5). For this reason, there willbe a risk of incomplete stent coverage whenintervention is guided by angiography alone.

Intravascular imaging with optical coher-ence tomography (OCT) or intravascularultrasound (IVUS) can assist in the identifi-cation of the site of the true culprit and maylead to better stent coverage of these lesions.Due to the high resolution of OCT, a directassessment of the TCFA is possible (6,7), andwith IVUS, a further remodeling assessmentand characterization of the plaque composi-

tion can be achieved by spectral analysis of theultrasound scatter, known as iMap (Boston Scientific,Marlborough, Massachusetts), which enables differ-entiation of plaque composition into necrotic core(NC), fibrotic tissue (FT), calcific tissue (CT), and lipidtissue (LT) (8).

SEE PAGE 868

In the present study, blinded OCT and IVUS withiMap was performed in a first-time STEMI populationwithin 48 h after their primary PCI procedure and wasrepeated after 12 months. We identified the uncov-ered plaque ruptures by OCT and subcategorizedthose showing signs of culprit features. The associ-ated plaque volume and composition was assessed inthe proximal and distal stent edge segments by usingIVUS with iMap.

METHODS

SETTING AND DESIGN. The present study was a sub-study of the OCTIVUS (Plaque Composition in Patientswith acute ST Segment Elevation Myocardial Infarc-tion assessed by Optical Coherence Tomographyand IntraVascular UltraSound with iMap) trial (9)(NCT01385631), which was a single-center double-blinded randomized trial that enrolled statin-naïvepatients with first-time STEMI.

From June 2011 to June 2013, a total of 1,062 patientswith STEMI were admitted, and of these, 87 patientswere included. The main inclusion criteria were: first-time STEMI, no prior treatment with statins or otherlipid-lowering drugs, and a nonsignificant lesion inone of the 2 nonculprit coronary arteries (angiographic

diameter stenosis >20% and <50%). The main exclu-sion criteria were: 1) age <18 years or >81 years;2) impaired kidney function; 3) women with child-bearing potential who were not using chemical ormechanical contraception; 4) history of malignancy,unless a disease-free period of more than 5 years waspresent; 5) participation in another randomized trial;and 6) treatment with cyclosporine or fibrates.

Patients were examined using OCT and IVUS withiMap within 48 h after undergoing their primary PCI.IVUS acquisition with tissue characterization and OCTof the implanted stent in the infarcted artery wereperformed together with a plaque study in a non-culprit artery. After 12 months, the IVUS with tissuecharacterization and OCT were repeated.

INTRACORONARY IMAGING ACQUISITION. Prior tothe procedure, unfractionated heparin (5,000 IU) wasadministered. Nitroglycerin, 200 mg, was adminis-tered by intracoronary route prior to the pullback.

OCT was performed using the Lightlab model Cx7(St. Jude Medical, Little Canada, Minnesota) and laterthe Ilumien System, both using a Dragonfly OCTcatheter (St. Jude Medical). The catheters wereinitially flushed with contrast (Visipaque, GE Health-care, Chicago, Illinois) and wiped with heparinizedsaline water, activating the hydrophilic coating.Catheter placement was guided angiographically byvisualization of the placed coronary stent, and thecatheter was placed at least 5 mm distal to the distalstent edge. Pullback was initiated automatically bymanually flushing the vessel with 20 ml of contrast(Visipaque). Pullback speedwas 20mm/s, and the totalpullback distance of the system was 55 mm. Repeatedpullback was performed in case of insufficient imagequality or incomplete acquisition of the segment ofinterest.

The IVUS pullback was performed using the iLabsystemwith a mechanical 40 MHz Atlantis SR Pro IVUScatheter (both, Boston Scientific). An automatic pull-back was performed with a standard pullback speed of0.5 mm/s. The IVUS catheter was advanced $5 mmdistal to the stented segment, and imaging wasperformed throughout the stent to $5 mm of theproximal reference segment site. iMap data wereobtained at every 30th frame (0.5 mm).

All intravascular image acquisition was documen-tary and not shared with the operator and did notinfluence the clinical decision making. During off-linereview, the examiner was blinded to the patient data.

OFF-LINE ANALYSIS. OCT pullbacks were analyzedusing proprietary software (St. Jude Medical). Thestent and its adjacent 5-mm distal and proximalreference segments were marked and processed with

FIGURE 1 Intracavity Neoendothelialization

Freshrupture

Olderrupture

Neoendothealization

(Left) A recent plaque rupture cavity with diffusely defined borders. (Right) Same plaque rupture site 1 year later, at which time

neoendothelialization can be seen.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 6 , 2 0 1 8 Hougaard et al.J U N E 2 0 1 8 : 8 5 9 – 6 7 Uncovered Plaque Ruptures in STEMI Patients

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the automatic lumen contour with supplementarymanual correction when needed. In the referencesegments, all frames were inspected for signs of pla-que ruptures.

Plaque ruptures were identified and defined asblunt intimal disruptions exposing an underlyingfibroatheroma. Ruptures were considered culprits incases with large and empty plaque cavities, togetherwith signs of thrombotic material or lack of signs ofneoendothelialization in accordance with availableresearch (10) (Figure 1).

Using OCT, we assessed the baseline presentationand healing course of uncovered plaque ruptures at12-month follow-up with respect to proximal or distallocalization, maximum traced cavity area, rupturelength, and distance to stent edge.

IVUS pullbacks were analyzed using Echoplaqueversion 4.0 software (Indec Medical Systems, SantaClara, California). The 5-mm proximal and distalreference segments were marked and cross-sectionalareas (CSA) for lumen and external elasticmembrane (EEM) were traced manually in everyiMap-containing frame (i.e., every 30th frame). Theguidewire artefact was omitted from the iMapanalysis by applying special masks within the soft-ware. Vessel and lumen volumes were calculatedwithin the software as

PEEMCSA and

PLUMENCSA,

respectively, where EEMCSA ¼ external elastic mem-brane cross-sectional area, and LUMENCSA ¼ luminalcross-sectional area. Plaque volume was defined as

vessel volume minus lumen volume. Plaque burdenwas defined as [(plaque volume/vessel volume) �100%]. We used iMap to assess the relative distribu-tions of NC, FT, CT, and LT for the distal and proximalreference segment sites.

STATISTICAL ANALYSIS. All statistical analysis wasperformed using commercially available software(SPSS version 21.0, IBM Corp., Armonk, New York).Categorical data are presented as frequencies andpercentages and were compared using the chi-squaretest. Normally distributed continuous data arepresented as mean � SD and were compared usingStudent’s t-test or presented as median (interquartilerange [IQR]) and compared using Mann-WhitneyU test when normality testing failed. A paired sam-ples t test or a Wilcoxon matched-pair signed-ranktest was used to compare changes from baseline tofollow-up. A 2-sided p value <0.05 was consideredstatistically significant.

RESULTS

PATIENT POPULATION. A total of 87 patients wereenrolled in the study. Baseline OCT examinationsfailed or were of insufficient quality in 10 patients,leaving 77 patients for baseline assessment. Duringfollow-up, 3 patients were lost to invasive follow-up(1 patient died, 1 patient declined the follow-updue to concurrent cancer, and 1 patient withdrewconsent for personal reasons). Thus, 74 patients were

TABLE 1 Baseline and Procedure Characteristics

UncoveredPlaque Rupture

(n ¼ 11)

No UncoveredPlaque Rupture

(n ¼ 76) p Value

Age, yrs 57.4 � 11.0 56.1 � 10.0 0.70*

Males 10 (90.9) 65 (85.5) 0.63†

Hypertension 2 (18.2) 13 (17.1) 0.93†

Current smoking 8 (72.7) 40 (52.6) 0.44†

Family disposition 6 (54.5) 35 (46.0) 0.60†

Diabetes 0 (0.0) 2 (2.6) 0.59†

HbA1c, mmol/mol 39.0 (36.0–40.0) 37.0 (36.0–41.0) 0.80‡

LDL, mmol/l 3.86 � 0.38 3.85 � 0.87 0.99*

Total cholesterol >5 mmol/l 7 (63.6) 55 (72.4) 0.55†

Systolic blood pressure, mm Hg 125.0 (114.0–140.0) 124.5 (115.5–139.5) 0.95‡

Diastolic blood pressure, mm Hg 75.0 (61.0–90.0) 80.0 (70.0–80.0) 0.62‡

Heart rate, beats/min 66.0 (60.0–72.0) 70.0 (60.0–83.5) 0.31‡

Weight, kg 85.0 (76.0–89.0) 86.5 (78.0–95.0) 0.45‡

LVEF, % 50 (50–60) 50 (45–55) 0.15‡

BMI, kg/m2 27.9 (27.2–28.7) 27.1 (24.8–29.4) 0.60‡

Cardiovascular medications prior to admission

b-blockers 1 (9.1) 1 (1.3) 0.11†

Calcium antagonists 1 (9.1) 6 (7.9) 0.89†

ACE inhibitors 1 (9.1) 6 (7.9) 0.89†

ATII inhibitors 0 (0.0) 1 (1.3) 0.70†

Diuretics 1 (9.1) 3 (3.9) 0.45†

Stents per lesion, n 1.0 (1.0, 1.0) 1.0 (1.0, 1.0) 0.89‡

Stent length, mm 15.0 (14.0–22.0) 18.0 (15.0–22.0) 0.27‡

Lesion length, mm 12.0 (10.0–15.0) 15.0 (12.0–20.0) 0.06‡

Nominal stent diameter, mm 3.0 (2.8–3.5) 3.0 (2.8–3.5) 0.89‡

Reference luminal diameter, mm 3.1 � 0.4 3.1 � 0.5 0.96*

Balloon diameter, mm 3.3 � 0.4 3.4 � 0.5 0.63*

Maximum balloon pressure, Atm 16.0 � 2.8 14.7 � 2.9 0.16*

Diseased vessels 0.18†

1 6 (54.5) 56 (73.7)

2 5 (45.5) 16 (21.1)

3 0 (0.0) 4 (5.3)

Infarct-related artery 0.57†

RCA 5 (45.5) 26 (34.2)

LAD 4 (36.4) 38 (50.0)

LCx 2 (18.2) 12 (15.8)

Dominance 0.52†

Balanced 0 (0.0) 8 (10.5)

Right 10 (90.9) 61 (80.3)

Left 1 (9.1) 7 (9.2)

Values are mean � SD, n (%), or median (interquartile range). *Student’s t-test. †Chi-square test. ‡Mann-WhitneyU test.

ACE ¼ angiotensin-converting enzyme; ATII ¼ angiotensin II; BMI ¼ body mass index; HbA1c ¼ glycosylatedhemoglobin; LAD ¼ left anterior descending artery; LCx ¼ left circumflex artery; LDL ¼ low density lipoprotein;LVEF ¼ left ventricular ejection fraction; RCA ¼ right coronary artery.

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included in complete OCT baseline and follow-updata. IVUS pullbacks were available in 80 patients atbaseline and in 77 patients at 12-month follow-up. Fortechnical reasons, iMap data were only available in71 patients for the distal segments and in 69 patientsfor the proximal segments. Overall, complete iMapdata were available in 63 patients. Among thepatients identified with plaque rupture, baseline IVUSwas not available in 2 patients, iMap was unavailable

at follow-up in 1 patient, and entire follow-upexaminations were missing in 2 patients due totarget lesion revascularization prior to follow-up.

Baseline and procedure characteristics are listedfor the patients with and without uncovered plaqueruptures in Table 1. Male sex was predominant, mostpatients were active smokers, and patients withuncovered plaque rupture tended to have shorterangiographically assessed primary lesions thanpatients with uncovered plaque ruptures (12.0 mm[IQR: 10.0 to 15.0 mm] vs. 15.0 mm [IQR: 12.0 to20.0 mm], respectively; p ¼ 0.06).

OCT FINDINGS. OCT findings post-PCI and after12 months are presented in Table 2, an illustration of atypical culprit plaque rupture is provided in Figure 2,and all identified plaque ruptures are presented inOnline Figure 1, showing pre- and post-angiographicappearance, OCT, IVUS, and iMap presentation atbaseline and after 1 year.

At baseline, a total of 11 uncovered plaque ruptureswere identified (13.0%). Eight of these ruptures wereidentified as culprit ruptures in 8 patients (10.4%),and all ruptures were located in the proximal refer-ence segments (0.15 mm [IQR: 0.0 to 3.1 mm] from thestent edge). Three of the culprit ruptures (38%) werepartially covered by the stent. The remaining 3 plaqueruptures were located >5 mm from the stent’s edgeand were showing signs of neoendothelialization, andthey were therefore considered nonculprit lesions.

The morphology of these ruptures differed. Two ofthe ruptures (Online Figure 1, ruptures 9 and 10) werefound in the same patient, located proximally to andremote from the stent’s edge. One of these (OnlineFigure 1, rupture 10) had a large cavity withoutthrombus at baseline, the other (Online Figure 1,rupture 9) was small and had a more classic appear-ance but with significant neoendothelialization of thecavity. The last nonculprit rupture (Online Figure 1,rupture 11) was covered by dense fibrosis at baselineand was considered an old lesion.

After 12 months, 3 culprit plaque ruptures (OnlineFigure 1, ruptures 2, 3, and 8) showed signs of insuf-ficient healing. One nonculprit rupture (OnlineFigure 1, rupture 11) could be identified at follow-up.The healing of the other 2 nonculprit ruptures (OnlineFigure 1, ruptures 9 and 10) was accompanied bystenosis. For all plaque ruptures, the luminal area atthe 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 ¼ 0.012).

IVUS WITH iMap FINDINGS. Results are presented inTable 3. The patients with culprit plaque ruptureswere more homogeneous than the 2 patients with

TABLE 2 OCT Plaque Rupture Assessment Post-PCI and After 12 Months

Post-PCI Post 12 Months p Value

Plaque ruptures 11 (12.8) 4 (4.9) <0.001*

Proximal, % of ruptures 8 (72.7) 4 (100.0) <0.001*

Culprit, % of ruptures 8 (72.7) 3 (75.0) <0.001*

Distance from stent edge,all ruptures, mm

2.0 (0.0–5.0) NA NA

Distance of culprit ruptures fromstent edge, mm

0.15 (0.0–3.1) NA NA

Cavity rupture area, mm2 1.2 (0.4–2.7) 0.0 (0.0–0.0) 0.012†

Rupture length, mm 1.9 (1.5–4.7) 0.0 (0.0–0.6) 0.012†

Luminal area of rupture site, mm2 7.5 (4.8–9.3) 3.6 (2.8–8.0) 0.012†

Values are n (%) or median (interquartile range). *Chi-square test. †Wilcoxon signed rank test.

OCT ¼ optical coherence tomography; PCI ¼ percutaneous coronary intervention.

FIGURE 2 Culprit Plaque Rupture Visualized by OCT

CavityPlaquerupture

Necroticcore

Macrophages

A large underlying lipid plaque with 2 rupture sites can be seen

together with a large empty rupture cavity. OCT ¼ optical

coherence tomography.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 6 , 2 0 1 8 Hougaard et al.J U N E 2 0 1 8 : 8 5 9 – 6 7 Uncovered Plaque Ruptures in STEMI Patients

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nonculprit ruptures. The groups differed with respectto rupture site localization (1 distal and 2 very prox-imal) and because the proximal ruptures residedoutside the proximal reference segment, a directcomparison between the 2 groups was not meaningfuland data are therefore presented for the patients withculprit rupture only. The EEM and plaque volumes inpatients with uncovered culprit plaque ruptures werehigher in the proximal reference segment (110.7 mm3

[IQR: 92.3 to 128.1 mm3] vs. 76.0 mm3 [IQR: 63.8 to100.3 mm3], respectively; p ¼ 0.005; and 62.1 mm3

[IQR: 50.2 to 83.6 mm3] vs. 38.7 mm3 [IQR: 29.6 to47.6 mm3], respectively; p < 0.001). No differencesbetween groups were found in the peri-stent or distalreference segment sites. iMap analysis showed thatthe relative amount of NC in the proximal referencesegment was higher in patients with uncoveredculprit plaque ruptures (34.0% [IQR: 29.0% to 44.5%]vs. 20.5% [IQR: 10.0% to 29.0%], respectively;p ¼ 0.006), and conversely, the amount of FT waslower (44.0% [IQR: 32.0% to 47.0%] vs. 56.0% [IQR:46.0% to 66.8%], respectively; p ¼ 0.007). In thedistal segment, the amount of CT was slightly higherin patients without culprit plaque rupture (1.0% [IQR:0.0% to 1.0%] vs. 1.0% [IQR: 1.0% to 2.0%], respec-tively; p ¼ 0.038).

ISCHEMIC EVENTS. A graphic presentation of culpritplaque ruptures associated with ischemic events ispresented in Figure 3. One patient (Online Figure 1,rupture 3) had an uncovered culprit plaque rupturetreated after 100 days due to stable angina pectorisand stenosis just proximal to the stent; and in anotherpatient (Online Figure 1, rupture 6), an occlusion ofthe infarct-related artery was discovered at follow-upand treated with PCI. Both of the patients hadexercise-related chest pain and a positive myocardialperfusion imaging scan.

DISCUSSION

The main finding of the present study was thatuncovered plaque ruptures identified by OCT are notan uncommon finding and often appear to be locatedproximally to the stent. Furthermore, a lumenreduction at the previous plaque rupture site wasfound during the healing process. IVUS showed thatEEM and plaque volumes in the proximal referencesegments were significantly larger in patients withplaque rupture than in patients without. In the samesegments, iMap showed a higher proportion of NCand less FT.

Plaque ruptures have been found to be the under-lying mechanism in 79% of all cases of myocardialinfarctions, with the highest occurrence among men

and elderly patients (11). OCT studies in STEMIpatients have confirmed these findings (12). TCFAsare thought to be the main precursor for plaqueruptures, and it has been shown in autopsy studiesthat TCFAs tend to cluster in the proximal segmentsof the major coronary arteries in the same areas asmost ruptures and thrombus formations are found(13). In the clinical setting of a STEMI, the assessmentof coronary disease is most often based on angiog-raphy findings that mainly focus on the area with themost lumen obstruction. Although the cross-sectionalluminal narrowing is known to be higher in sites withplaque rupture (14), the site with most angiographiclumen reduction may, as mentioned earlier, reside in

TABLE 3 IVUS Measurements Comparing Patients With Identified Culprit Plaque

Ruptures (n ¼ 8) With Patients Without Plaque Ruptures (n ¼ 79)

Uncovered CulpritPlaque Ruptures

No Uncovered CulpritPlaque Ruptures p Value

Gray scale IVUS

Proximal reference

EEM volume, mm3 110.7 (92.3–128.1) 76.0 (63.8–100.3) 0.005*

Lumen volume, mm3 46.4 (38.8–55.7) 40.0 (30.1–53.5) 0.40*

Plaque volume, mm3 62.1 (50.2–83.6) 38.7 (29.6–47.6) <0.001*

Plaque burden, % 58.7 � 9.0 49.2 � 9.5 0.009†

Peri-stent

EEM volume, mm3 336.3 (261.1–423.1) 307.3 (241.0–402.9) 0.81*

Lumen volume, mm3 148.2 (90.3–158.1) 137.4 (109.7–183.3) 0.48*

Plaque volume, mm3 201.3 (158.0–265.9) 171.2 (127.7–239.1) 0.43*

Distal reference

EEM volume, mm3 79.1 (53.4–107.5) 66.6 (40.2–80.5) 0.27*

Lumen volume, mm3 46.1 (23.9–58.9) 36.4 (24.6–43.8) 0.42*

Plaque volume, mm3 33.9 (28.7–39.2) 25.9 (15.1–38.5) 0.18*

Plaque burden, % 46.5 � 9.3 42.2 � 10.6 0.27†

iMap

Proximal reference

NC, % 34.0 (29.0–44.5) 20.5 (10.0–29.0) 0.006*

FT, % 44.0 (32.0–47.0) 56.0 (46.0–66.8) 0.007*

CT, % 1.0 (0.3–1.8) 1.0 (1.0–3.0) 0.53*

LT, % 9.0 (7.5–10.0) 8.5 (6.0–10.8) 0.64*

Distal reference

NC, % 13.5 (5.8–19.8) 9.0 (6.0–17.8) 0.53*

FT, % 62.5 (49.5–69.0) 68.0 (55.3–73.0) 0.38*

CT, % 1.0 (0.0–1.0) 1.0 (1.0–2.0) 0.038*

LT, % 7.0 (5.3–10.3) 5.5 (4.0–9.8) 0.33*

Values are median (interquartile range) or mean � SD. *Mann-Whitney U test. †Student’s t-test.

CT ¼ calcific tissue; EEM ¼ external elastic membrane; FT ¼ fibrotic tissue; IVUS ¼ intravascular ultrasound;LT ¼ lipid tissue; NC ¼ necrotic core.

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adjacent areas to the true culprit. A possible expla-nation for this phenomena could be a higher degree ofvasoconstriction in the culprit area (15) together withred thrombus formation and embolization (16).

Using OCT, 2 distinct morphologies have previ-ously been described: a group with plaque rupture,large thrombus burden, and TCFA at the target lesionsite and another group without rupture, lesseramounts of thrombus but significant stenosis at thetarget lesion site (12). In the present study, a largeproportion of the patients without uncovered plaquerupture probably have a thrombotic cause for theirinfarction, which is concealed by the stent. In aprevious IVUS virtual histology (VH) study, Legutkoet al. (5) examined 20 patients admitted for primaryPCI with blinded IVUS-VH prior to and after PCI. Itwas found that the true culprit (defined as a IVUS-VHTCFA) remained uncovered following PCI in 50% ofpatients and that plaque rupture was present by IVUSin 12 patients (60%). Eleven of these ruptures (92%)

were located proximal to the minimum luminalarea site.

In the present study, OCT and IVUS analyses wereperformed post-PCI, and it was not possible to assessthe overall prevalence of plaque rupture but only theruptures uncovered by stent. Pre-intervention IVUSand OCT might have improved distinguishing culpritfrom nonculprit plaque ruptures. To our knowledge,this is the first study to report the prevalence ofuncovered plaque rupture following primary PCI inSTEMI patients, and our finding of uncovered prox-imal culprit plaque rupture in nearly 9% of the patientpopulation stresses the importance of increasedattention towards the fact that the site of plaquerupture may differ from the target site with moststenosis. In accordance with the findings by Legutkoet al. (5), the current iMap analysis showed a greaterproximal plaque burden and relative content of NC,which suggests that some vessel wall disease in theproximal reference segment site is geographicallymissed during primary PCI and left uncovered. Wedid not perform a TCFA evaluation based on the iMapdata as this technique remains unvalidated for thatpurpose, and data may not be directly comparable toIVUS-VH data.

In a prospective multicenter trial on patientsadmitted for PCI due to stable or unstable anginapectoris (17), it was found that insufficient lesioncoverage (longitudinal geographical miss) andballoon versus reference segment size mismatch(axial geographical miss) was of clinical importance.The rate of 1-year target lesion revascularization was5.1% in the group with geographical miss comparedwith 2.5% in the group with no geographical miss.This assessment was based on angiography alone andmay not be fully applicable to a STEMI population.

In a way, the topic of the present study representsa variant of longitudinal geographic miss, but incontrast to the common use of the term, we did notassess geographic miss as longitudinal stent align-ment relative to plaque burden or lipid content in thearterial wall. Near-infrared spectroscopy with IVUShas shown that angiographic determined target lesionlength is considerably shorter than the length deter-mined by near-infrared spectroscopy with IVUS (18).This correlates well with our findings of an increasedplaque burden and a high lipid content together withNC in the proximal reference segments compared tothe patients without plaque rupture. The clinicalimplication of geographic miss has previously beenreported (17), and furthermore this finding seems tohave the greatest impact in patients presenting withacute coronary syndrome (19). A possible explanation

FIGURE 3 Baseline and Follow-Up Presentation of Uncovered Culprit Plaque Ruptures Associated With Later Ischemic Events

Baseline

3

6

3

6

Follow-Up

Presentationafter 100 days

Area 2.97 mm2

Area 9.26 mm2

Area 5.08 mm2

Uncovered culprit plaque ruptures detected by OCT. (Top) Angiographic presentations before primary PCI are compared with post-PCI results. Baseline OCT, GS-IVUS,

and iMap presentations are presented. (Bottom) Angiograms, OCT, GS-IVUS, and iMap after 1-year are presented. GS-IVUS ¼ gray scale intravascular ultrasound;

PCI ¼ percutaneous coronary intervention; other abbreviations as in Figures 1 and 2.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 6 , 2 0 1 8 Hougaard et al.J U N E 2 0 1 8 : 8 5 9 – 6 7 Uncovered Plaque Ruptures in STEMI Patients

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for this could be a relation to an increased plaqueinstability in this subgroup related to more plaqueburden and inflammation of the vessel wall (11).

A potential reduction in cardiovascular event ratesby IVUS guided stent deployment has been investi-gated in randomized trials with neutral results(20–22), although a meta-analysis pooling the resultswith observational studies has suggested positiveresults (23).

In the present study, we did encounter a need fortarget lesion revascularization in 2 patients within thefirst year, and it is noteworthy that these patientswere among the patients with uncovered culprit pla-que ruptures and that none of the plaque ruptureshere were evident on coronary angiograms. The

finding of lumen reduction at the rupture site corre-sponds well with previously reported observations ofthe spontaneous healing process of plaque rupturesin autopsy studies (24). Similarly, longitudinal IVUSstudies of the noninfarct-related arteries in ACSpatients have shown in vivo that clinically silentruptures are frequent and that most heal on statintreatment without plaque modifications (25). AnIVUS-VH study using similar study design has shownthat patients with ACS have higher frequencies ofmultiple VH-TCFA than patients with stableangina (26). The actual prevalence of uncoveredplaque ruptures in the general STEMI population andits clinical significance remain uncertain and shouldbe addressed in future trials.

PERSPECTIVES

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.

Hougaard et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 1 , N O . 6 , 2 0 1 8

Uncovered Plaque Ruptures in STEMI Patients J U N E 2 0 1 8 : 8 5 9 – 6 7

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STUDY LIMITATIONS. The current study was a smallobservational study that selected patients with first-time STEMI. The results from the present study maynot be generalized, as we studied <10% of the entireSTEMI population.

The distinction between “acute” culprit and pre-existing ruptures is, in our study, based on theassessment of neoendothelialization of the plaquerupture cavity. The existing knowledge about thepathogenesis behind coronary infarction is basedmainly on autopsy studies showing a prevalence formultiple ruptures in patients who died from ACS, notall necessarily culprits. Because no pre-interventionOCT or IVUS was performed, we do not know exactlythe extension and/or morphology of the culprit le-sions, particularly for the patients without detecteduncovered plaque ruptures. Some patients might havehad more than 1 culprit lesion covered by the stent.

Finally, the IVUS assessment was limited to thestented segment and the adjacent 5-mm referencesegments, and areas with significant plaque contentsmight have escaped analysis due to a more distal orproximal localization. The study was nonrandomizedand not powered to assess the clinical significance ofuncovered culprit lesions and further studies arerequired to determine whether seeking out andtreating uncovered plaque ruptures in acute coronarysyndromes is warranted.

CONCLUSIONS

OCT-detected uncovered culprit plaque rupture wasnot an uncommon finding in patients treated withprimary PCI, and they were primarily located prox-imal to the implanted stent. Uncovered plaque rup-tures were associated with significant lumenreduction during the 12-month spontaneous healingprocess.

ADDRESS FOR CORRESPONDENCE: Dr. MikkelHougaard, Department of Cardiology, OdenseUniversity Hospital, 5000 Odense C, Denmark.E-mail: Mikkel.Hougaard@outlook.com.

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KEY WORDS OCT, plaque rupture, STEMI

APPENDIX For a supplemental figure,please see the online version of this paper.