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Distribution and Frequency of Thin-Capped Fibroatheromas andRuptured Plaques in the Entire Culprit Coronary Artery in

Patients With Acute Coronary Syndrome as Determined by OpticalCoherence Tomography

Atsushi Tanaka, MD*, Toshio Imanishi, MD, Hironori Kitabata, MD, Takashi Kubo, MD,Shigeho Takarada, MD, Hideaki Kataiwa, MD, Akio Kuroi, MD, Hiroto Tsujioka, MD,

Takashi Tanimoto, MD, Nobuo Nakamura, MD, Masato Mizukoshi, MD, Kumiko Hirata, MD,and Takashi Akasaka, MD

The aim of this study was to investigate the distribution and frequency of thin-cappedfibroatheromas (TCFAs) within the entire length of culprit coronary arteries in patientswith acute coronary syndrome. Our population was drawn from 43 consecutive patientswith acute coronary syndrome (with or without ST-segment elevation) who underwentoptical coherence tomography to visualize the entire culprit coronary artery using anonocclusive optical coherence tomographic technique. Patients were categorized dividedinto a TCFA group or a no-TCFA group on the basis of the optical coherence tomographicfindings. There were no differences in baseline characteristics or angiographic findingsbetween the 2 groups. High-sensitive C-reactive protein in the TCFA group was signifi-cantly higher than in the no-TCFA group (median 3.3 mg/L, interquartile 3.1, vs 1.7 mg/L,interquartile 2.2, p � 0.03). Plaque rupture was found in 28 patients (65%) and multipleplaque ruptures in 5 patients (12%). Optical coherence tomogram revealed 21 TCFAs in 18patients (42%). Multiple TCFAs were found in the same vessel in 3 patients (7%). Thedistribution of TCFAs in the right coronary arteries of our subject population was relativelyeven (proximal 2 [12%], mid 5 [29%], distal 3 [18%], p � 0.42), whereas TCFAs in the leftanterior descending artery were common in proximal sites (proximal 6 [27%], mid 2 [9%],distal 0, p � 0.018). In conclusion, the use of optical coherence tomography to look forTCFAs and identify their distribution when combined with C-reactive protein may con-tribute to forming a strategy for preventing impending coronary events. © 2008 Elsevier

Inc. All rights reserved. (Am J Cardiol 2008;102:975–979)

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he recent development of intravascular optical coherenceomography has provided a high-resolution imaging methodor plaque characterization.1–5 Optical coherence tomogra-hy is an optical analog of intravascular ultrasound with aesolution of approximately 10 to 20 �m. Histologic studiesave shown that optical coherence tomography can identifyicrostructures in atherosclerotic plaques, including thin-

apped fibroatheromas (TCFAs) and lipid core.6,7 However,ptical coherence tomography cannot be used to visualizeery proximal coronary lesions because proximal ballooncclusion is required to obstruct blood flow while the lumens flushed with Ringer lactate to clear the lumen of bloodnd allow imaging in the conventional optical coherenceomographic (OCT) technique. To overcome this, we haveecently developed a continuous-flushing technique thatoes not require balloon occlusion during OCT image ac-uisition, and this technique is employed in this study. The

Department of Cardiovascular Medicine, Wakayama Medical Univer-ity, Wakayama, Japan. Manuscript received February 24, 2008; revisedanuscript received and accepted May 27, 2008.

*Corresponding author: Tel: 81-73-447-2300; fax: �81-73-446-0631.

bE-mail address: a-tanaka@wakayama-med.ac.jp (A. Tanaka).

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.05.062

ims of this study were to investigate the distribution ofCFAs and ruptured plaques in “culprit” coronary arteriesnd clarify the relation between high-sensitive C-reactiverotein (CRP) and the presence of TCFAs in patients withcute coronary syndrome (ACS) using optical coherenceomography with the continuous-flushing technique.

ethods

ur population was drawn from 43 consecutive patientsith ACS (with or without ST-segment elevation) who were

dmitted to Wakayama Medical University Hospital andho underwent optical coherence tomography using theush-only technique. Our exclusion criteria were congestiveeart failure, previous myocardial infarction, cardiogenichock, and failure to attain Thrombolysis In Myocardialnfarction (TIMI) grade 3 flow from initial aspiration throm-ectomy before OCT imaging.

Demographic and clinical data were collected prospec-ively. This study complied with the Declaration of Hel-inki, and the protocol for the study was approved by thethics committee of Wakayama Medical University. Welso obtained written informed consent from all participants

efore initial coronary angiography.

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In all patients, coronary angiography was performed us-ng a 6Fr Judkins-type catheter through the femoral ap-roach. All patients received an intravenous bolus injectionf heparin 2,000 IU and intracoronary isosorbide dinitrate (2g) before angiography. The culprit lesion was identified

n the basis of findings on coronary angiogram, electrocar-iogram, and transthoracic echocardiogram.

Coronary angiograms were reviewed separately by 2ndependent observers (H.K. and T.T.) unaware of the OCTndings.

Oral aspirin (162 mg) and additional intravenous heparin8,000 U) were administered before coronary intervention.o patients received any thrombolytic therapy before an-ioplasty. After completion of diagnostic coronary angiog-aphy, aspiration thrombectomy was performed using anspiration catheter (Export, Medtronic Japan, Tokyo, Japan)efore OCT imaging if coronary flow did not show TIMIrade 3 flow. After thrombectomy, optical coherence to-ography was used to observe the culprit coronary artery. A

.016-inch OCT catheter (Imagewire, LightLab Imaging,nc., Westford, Massachusetts) was advanced to as distal aosition in the culprit coronary artery as possible. If the

igure 1. OCT images of the entire culprit coronary artery in a patient witntire culprit coronary artery from a distal bifurcation to the ostium. Angioderate stenosis in the distal vessel. (A) An additional TCFA in a proxim

B) A proximal TCFA; the center of the fibrous cap is the cap’s thinnest soint is the shoulder of the cap (50 �m) (white arrows). (D) A culprit plaquulprit thrombus; optical coherence tomogram clearly shows a mass protruhe 3 layers of the arterial wall and a branch. (G) Distal lesion; a thick fi

esion presented with severe tortuosity, severe stenosis, or a p

eavy calcium burden, we first advanced a conventionalercutaneous coronary intervention guidewire (0.014 inch)cross the lesion before exchanging it for the OCT Im-gewire using a microcatheter (Renegade, Boston Scientific,atick, Massachusetts). OCT imaging in the right coronary

rtery was performed from the crux to the ostium.We used the continuous-flushing (nonocclusive) technique

or OCT image acquisition, which is a newly developed alter-ative to the balloon occlusion technique. To flush the vessel,e infused commercially available dextran-40 and lactatedinger solution (Low Molecular Dextran L Injection, Otsukaharmaceutical Factory, Tokushima, Japan) directly from theuiding catheter at a rate from 2.5 to 4.5 ml/second using annjector pump (Mark V, MEDRAD, Inc., Warrendale, Penn-ylvania). The entire length of the culprit coronary artery wasmaged in this way with an automatic pullback device movingt 1 mm/second. The OCT images were digitalized and ana-yzed by the M2CV OCT console.

All OCT images were analyzed by 2 independent investi-ators (A.T. and M.M.) who were blinded to the clinicalresentations. When there was discordance between observers,consensus reading was obtained. The presence of TCFA,

Optical coherence tomography using the flush-only technique imaged thehows a severe lesion in the midportion of the right coronary artery and athe shoulder of the fibrous cap is its thinnest part (40 �m) (white arrows).60 �m) (white arrows). (C) Proximal end of a culprit TCFA; the thinnestre; the cavity formation is clearly visible (white arrow). (E) Representativeo the vessel lumen from the surface of the vessel wall (white arrows). (F)ap can be observed at 4 o’clock (240 �m) (white arrows).

h ACS.ogram sal site;ection (e ruptuding int

laque rupture, or intracoronary thrombus was noted.

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977Coronary Artery Disease/TCFA in ACS

Lipid was semiquantified according to the number ofnvolved quadrants on the cross-sectional OCT image.

hen lipid was present in �2 quadrants in any of themages within a plaque, it was classed as a lipid-rich plaque.or each patient, the cross-sectional image with the largestumber of lipid quadrants was used for analysis. A TCFAas defined as a plaque with lipid contents in �2 quadrants

nd with the thinnest part of its fibrous cap measuring �70m (Figure 1).

Plaque rupture was identified by the presence of fi-rous cap discontinuity and a cavity formation in thelaque (Figure 1). Intracoronary thrombus was identifieds a mass protruding into the vessel lumen from theurface of the vessel wall (Figure 1). OCT images werenalyzed using previously validated criteria for plaqueharacterization and fibrous cap thickness was deter-ined as reported previously.6,7

We applied a modified Bypass Angioplasty Revascular-zation Investigation numeric codec system for TCFA loca-ion.8 Patients were then categorized into 2 groups accord-ng to whether or not optical coherence tomographydentified any TCFAs in the culprit site.

Blood was collected in the emergency room at time ofdmission. Blood samples were centrifuged, and serum was

able 1atient characteristics

ariable

ge (yrs)en

ystemic hypertensioniabetes mellitusyslipidemia (serum triglyceride �150 mg/dl and/or serum high-densitylipoprotein cholesterol �40 mg/dl)

mokerbesity (body mass index �25 kg/m2)T-segment elevation myocardial infarction

able 2ngiographic findings

ariable TCFA p Value

Yes(n � 18)

No(n � 25)

ulprit coronary arteryLeft anterior descending 7 (39%) 15 (60%) 0.39Left circumflex 2 (11%) 2 (8%)Right coronary 9 (50%) 8 (32%)IMI grade flow on initial

angiograms0 4 (22%) 7 (28) 0.331 2 (11%) 02 4 (22%) 4 (16%)3 8 (44%) 14 (56%)eference lumen diameter (mm) 3.6 � 0.7 3.3 � 0.6 0.54inimum lumen diameter (mm) 0.66 � 0.7 0.68 � 0.6 0.94iameter stenosis (%) 82.6 � 17 73.8 � 27 0.45

emoved and stored at �80°C until assay could be per- c

ormed. High-sensitive CRP was analyzed using a commer-ially available testing kit (N-Latex CRP II, Dade Behringarburg GmbH, Marburg, Germany).Statistical analysis was performed using StatView 5.0J

SAS Institute Inc., Cary, North Carolina). Results are ex-ressed as mean �SD for continuous variables. Qualitativeata are presented as number (percentage). Continuous vari-bles were compared using analysis of variance and cate-orical data with chi-square test and Fisher’s exact test.igh-sensitive CRP was compared using the Mann-Whit-ey U test. A p value �0.05 was considered statisticallyignificant.

esults

atient characteristics of the 2 groups are presented in Table 1.here were no differences in terms of age, gender, or classic

TCFA p Value

Yes(n � 18)

No(n � 25)

69.1 � 11 64.3 � 12 0.2013 (72%) 21 (84%) 0.4611 (61%) 15 (62%) 0.996 (33%) 11 (44%) 0.548 (44%) 12 (48%) 0.99

7 (39%) 18 (72%) 0.062 (11%) 4 (16%) 0.997 (39%) 10 (40%) 0.99

able 3ngiographic findings of patients with thrombectomy

ariable TCFA p Value

Yes No

hrombectomy use 10 11IMI grade flow after thrombectomy2 3 (30%) 2 (18%) 0.643 7 (70%) 9 (82%)IMI blush grade after thrombectomy0 0 0 0.371 0 1 (9%)2 1 (10%) 03 9 (90%) 10 (91%)

able 4ptical coherence tomographic findings for culprit arteries

ariable TCFA p Value

Yes(n � 18)

No(n � 25)

hrombus 17 (94%) 23 (92%) 0.99laque rupture at culprit site 13 (72%) 15 (60%) 0.52ultiple ruptures 5 (28%) 0 0.009emote-site TCFA 3 (17%) 0 0.07

oronary risk factors between the 2 groups. High-sensitive

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RP in patients with TCFAs was significantly higher thann those without (median 3.3 mg/L, interquartile 3.1, vs 1.7g/L, interquartile 2.2, p � 0.03).Angiographic findings are presented in Table 2. Throm-

ectomy was performed in 21 patients (49%). There wereo significant differences in angiographic findings betweenhe 2 groups. TIMI grade flow and TIMI blush grade afterhrombectomy are presented in Table 3.

The full length of the culprit coronary arteries was suc-essfully observed in all patients by optical coherence to-ography without any serious procedural complications.nly 3 patients (7%) complained of chest pain during theCT procedure. Prolonged QT interval (corrected QT in-

erval �450 ms) was observed in 95% of patients duringushing but no critical arrhythmia occurred. OCT findingsre presented in Table 4. Plaque rupture was observed in 28atients (65%). Multiple plaque ruptures were found in 5atients (12%). All patients with multiple plaque rupturesere in the TCFA group (p � 0.009).We found a total of 21 TCFAs in 43 patients. Additional

CFAs were observed in 3 patients (7%). The distribution ofCFAs in the right coronary arteries of our subject populationas relatively even (proximal 2 [12%], mid 5 [29%], distal 3

18%], p � 0.42), whereas TCFAs in the left anterior descend-ng artery were common in proximal sites (proximal 6 [27%],

igure 2. TCFAs tend to be evenly distributed in the in the right coronaryoronary artery (LAD). LCx � left circumflex coronary artery.

id 2 [9%], distal 0, p � 0.018; Figure 2). In total, 10 (23%) i

ulprit coronary arteries contained no ruptured plaque orCFA.

iscussion

n this study we observed TCFAs in the proximal leftoronary artery more frequently than in other sites. Wang etl9 reported that culprit lesion sites on angiograms arerequently located in the proximal left coronary artery. Aecent longitudinal pathologic study also reported that 50%f all TCFAs and ruptured plaques were to be found in theroximal 22 mm of the left coronary artery and 90% withinhe proximal 33 mm.10 This localization of TCFAs was notepeated in the right coronary artery in our population; thisifference in TCFA localization may help us to resolve theechanism of developing TCFAs. We wish to emphasize

hat optical coherence tomography performed using the con-entional balloon occlusion technique is unable to visualizeCFAs in these very proximal sites.

In this study, optical coherence tomography identifiedulprit artery plaque rupture in 65% of our patients withCS. This detection rate for plaque rupture is very similar

o others from pathologic studies.11,12 Our own recent stud-es have suggested that optical coherence tomography isuperior to any other in vivo imaging modality such as

(RCA) but localized to the proximal vessel in the left anterior descending

artery

ntravascular ultrasound and angioscopy for detecting rup-

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979Coronary Artery Disease/TCFA in ACS

ured plaque.13 We believe that optical coherence tomogra-hy may even be as effective at identifying ruptured plaquesn vivo as pathologic approaches. We found nonculpritlaque rupture in distal sites in 12% of our patients withCS. The frequency for multiple plaque ruptures we ob-

erved is very similar to those reported in previous intra-ascular ultrasound studies that investigated additionallaque ruptures in culprit coronary arteries.14–16 In contrast,nly 7% of patients demonstrated multiple TCFAs in thistudy. Multiple TCFAs were also associated with multiplelaque ruptures. These findings suggest that multifocal in-tability in the coronary artery occurs in selected patients. Ife allow ourselves to think of TCFA as a plaque ruptureaiting to happen, multiple plaque ruptures may occur 1

fter another, not at the same time. This time lag may allows to intervene systemically to bolster the stability of cor-nary plaques. Indeed, early initiation of statin treatment inatients with acute myocardial infarction is associated withlower 1-year mortality.17

For cardiologists, the detection of vulnerable plaques is aey goal for predicting and preventing the course of ACS. Inhis study, we have shown that optical coherence tomogra-hy can reveal additional (multiple) TCFAs in culprit cor-nary arteries, but in only 7% of patients according to ourata. We consider that this lower rate of additional TCFAsay support the feasibility and desirability of efforts to

earch invasively for TCFAs in entire coronary arteriessing optical coherence tomography. The localization ofCFA and/or high high-sensitive CRP seen in this studyay justify the use of optical coherence tomography to

earch for TCFAs or ruptured plaques.One angiographic study has shown that proximal culprit

esion location is a strong independent predictor of poorern-hospital outcomes in patients with ST-segment elevationyocardial infarction undergoing primary percutaneous

oronary intervention.18 We previously reported that lipidool-like images, with presentations very similar to necroticores and identified by intravascular ultrasound, are associ-ted with the no-reflow phenomenon after percutaneousoronary intervention in patients with acute myocardial in-arction.19 Our findings suggest that poor outcomes in pa-ients with proximal lesions may depend not only on geo-raphic features but also on the characteristics of culpritlaques.

A number of limitations can be said to be associatedith the present study. We could not explore the entire

oronary tree in this study because our flushing techniqueor optical coherence tomography would have requiredoo large an amount of low-molecular dextran to benfused. Thrombectomy was performed for reperfusionefore optical coherence tomography in some patientsnly. The thrombectomy catheter may possibly haveaused some modification of lesion presentation. In thistudy �90% of patients presented thrombus even afterhrombectomy. This intracoronary thrombus may alsoave affected analysis of the images.

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