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Virtual Histology Intravascular Ultrasound Analysis of Non-CulpritAttenuated Plaques Detected by Grayscale IntravascularUltrasound in Patients With Acute Coronary Syndromes†

Xiaofan Wu, MD, PhDa, Akiko Maehara, MDa,*, Gary S. Mintz, MDa, Takashi Kubo, MD, PhDa,Kai Xu, MDa, So-Yeon Choi, MD, PhDa, Yong He, MDa, Ning Guo, MDa, Jeffrey W. Moses, MDa,

Martin B. Leon, MDa, Bernard De Bruyne, MD, PhDb, Patrick W. Serruys, MDc, andGregg W. Stone, MDa

Noncalcific attenuated plaques identified by grayscale intravascular ultrasound (IVUS) areoften seen in patients with acute coronary syndromes and have been associated with noreflow and creatine kinase-MB elevation after percutaneous coronary intervention. Histo-pathology has shown cholesterol clefts, microcalcification, or organized thrombus. Onehundred twenty-four vessels in 64 patients with acute coronary syndromes from thePROSPECT trial were identified for inclusion in the present analysis. After excluding 4vessels with severe calcification, 9 vessels with <40% plaque burden, and 3 vessels with toofew (<3) virtual histology (VH)–IVUS frames for analysis, complete grayscale IVUS andVH-IVUS was available for 108 vessels in 64 patients that contained 39 VH-IVUS thin-capped fibroatheromas (VH-TCFA), 40 thick-capped fibroatheromas (VH-ThFA), and 33pathologic intimal thickening but no fibrotic or fibrocalcific plaques. Overall, there were 47grayscale IVUS attenuated plaques in 43 vessels. Compared to the minimum luminal sitesof the remaining 65 vessels (controls), attenuated plaques contained larger necrotic coreareas (1.5 � 0.9 vs 0.9 � 0.8 mm2 in controls, p � 0.001). Fibroatheromas (VH-TCFA orVH-ThFA) were more common at the sites of attenuated plaques than at control sites(VH-TCFA 42.5% vs 29.2%, VH-ThFA 53.2% vs 23.1%, pathologic intimal thickening 4.3%vs 47.7%, p <0.0001). In conclusion, grayscale IVUS attenuated plaques are associatedwith a large amount of VH-IVUS necrotic core and are markers of the presence offibroatheromas (VH-TCFA or VH-ThFA). This may explain the biologic instability of these

lesions. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:48–53)

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Noncalcific attenuated plaques seen during grayscale in-ravascular ultrasound (IVUS) imaging are defined as hy-oechoic or mixed atheromas with ultrasound attenuationespite little evidence of calcium. Histopathologic analysisf a small number of attenuated plaques has shown micro-alcification, thrombus, or cholesterol crystals.1,2 Attenu-ted plaques are more often seen in patients with acuteoronary syndromes than in those with stable angina and areharacterized by positive remodeling and nearby calcifica-ion.3 Recent data have indicated that attenuated plaques aressociated with no reflow and creatine kinase-MB elevation

aColumbia University Medical Center and Cardiovascular Researchoundation, New York, New York; bCardiovascular Center, OLV Hospi-

al, Aalst, Belgium; and cThoraxcenter, Erasmus Medical Center, Rotter-am, The Netherlands. Manuscript received August 3, 2009; revised manu-cript received and accepted August 11, 2009.

*Corresponding author: Tel: 212-851-9234; fax: 212-851-9230.E-mail address: amaehara@crf.org (A. Maehara).

† Conflicts of interest: Dr. Mintz is a member of the speakers bureau of,erves as a consultant for, and has received research and grant support fromolcano Corporation, Rancho Cordova, California. Dr. Stone serves as a

onsultant for Volcano Corporation. Dr. Leon serves as a consultant forolcano Corporation. Dr. Kubo has received research and grant support

erom Volcano Corporation.

002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2009.08.649

fter percutaneous coronary intervention because of distalmbolization.4,5 Virtual histology (VH)–IVUS has 94% to7% ex vivo accuracy when used to identify different ath-rosclerotic plaque elements.6 Available data have shownarger VH-IVUS necrotic cores (NCs) in lesions responsibleor acute coronary syndromes compared to stable angina,nd the presence and sizes of VH-IVUS NCs are related tohe liberation of small embolic particles during coronarytenting, especially in patients with acute coronary syn-romes.7,8 We hypothesized that attenuated plaques containarge amounts of NC that would also explain the unstableature of such lesions.

ethods

The multicenter, prospective, international Providing Re-ional Observations to Study Predictors of Events in theoronary Tree (PROSPECT) trial (ClinicalTrials.gov iden-

ifier NCT00180466) was designed to identify imaging anderologic predictors of vulnerable plaque events in patientsho underwent percutaneous coronary intervention for

cute coronary syndromes. After their culprit lesions werereated, patients underwent 3-vessel grayscale IVUS andH-IVUS imaging of culprit and nonculprit arteries. The

nclusion criteria were (1) acute cardiac pain, or angina

quivalent, consistent with unstable angina or myocardial

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49Coronary Artery Disease/VH Analysis of Attenuated Plaques

nfarction, lasting �10 minutes within the past 72 hours,nd (2) the presence of any of the following: elevatednzymes (creatine kinase-MB isoenzyme or troponin I or T)reater than the upper limits of normal; ST depression �1m in �2 contiguous leads or transient ST elevation �1m in �2 contiguous leads lasting �30 minutes; ST ele-

ation myocardial infarction with onset �24 hours previ-usly, diagnosed with the typical triad of nitrate-unrespon-ive chest pain lasting �30 minutes, ST elevation �1 mmn �2 contiguous leads, or new left bundle branch block;nd increase and decrease of creatine kinase isoenzyme.isk factors included hypertension (medication dependentr documented history), diabetes (diet controlled, oral agentreated, or insulin treated), or hypercholesterolemia (medi-ation treated or a measurement �200 mg/dl), and cigarettemoking. This study was approved by the institutional re-iew boards of the centers at which the procedures wereerformed, and written informed consent was obtained fromll patients before cardiac catheterization. From this IVUSmaging registry of 697 patients, we randomly selected 124essels in 64 patients for inclusion in the present analysis.

A phased-array, 20 MHz, 3.2Fr IVUS catheter (Eagleye; Volcano Corporation, Rancho Cordova, California)as placed at the distal coronary artery and pulled back to

he aorto-ostial junction using motorized catheter pullbackt 0.5 mm/s. During pullback, grayscale IVUS was re-orded, raw radiofrequency data were captured at the top ofhe R wave, and reconstruction of the color-coded map by aH-IVUS data recorder was performed (In-Vision Gold;olcano Corporation). The grayscale and radiofrequencyata were written onto CD-ROMs or DVDs for off-linenalysis. Offline grayscale IVUS and VH-IVUS analysisere performed using (1) QCU-CMS (Medis Medical Im-

ging Systems, Inc., Leiden, The Netherlands) for contour-

igure 1. Attenuated plaque versus nonattenuated plaque in grayscaleVUS and VH-IVUS. An attenuated plaque studied using grayscale IVUSA) and VH-IVUS (B) and a nonattenuated plaque studied using grayscaleVUS (C) and VH-IVUS (D).

ng, (2) pcVH 2.1 (Volcano Corporation) for contouring and c

H data output, and (3) qVH (developed at the Cardiovas-ular Research Foundation, New York, New York) for seg-ental qualitative assessment and data output.We identified nonculprit, untreated lesions having plaque

urdens �40% of �1.5 mm in length (approximately 3onsecutive VH-IVUS frames) and compared coronary ar-eries with �1 untreated attenuated plaque by grayscaleVUS (attenuated plaque group) to coronary arteries withoutny attenuated plaques (nonattenuated plaque group). Theaximum arc of attenuation was measured with an elec-

ronic protractor centered on the lumen. The lesion site washe slice with the maximum attenuation arc in the attenuatedlaque group, while the lesion site was the slice with theinimal luminal area and �40% plaque burden in the

onattenuated plaque group (Figure 1). Attenuated plaquesere considered independent if there was a gap �5 mmetween them. External elastic membrane (EEM) and lumi-al borders were contoured for all recorded frames (approx-mately every 0.5 mm in length depending on the RR in-erval). Quantitative IVUS measurements included EEM,umen, and plaque and media cross-sectional area andlaque burden (defined as plaque and media divided byEM).9 The proximal and distal reference segments were

he most normal looking segments (largest lumen with leastlaque) �5 mm proximal and distal to the lesion, but beforemajor side branch. The remodeling index was the lesionEM divided by the mean reference EEM. Positive remod-ling was defined as a remodeling index �1.05, negativeemodeling as a remodeling index �0.95, and intermediater negative remodeling as a remodeling index of 0.95 to.05.10 Eccentricity was the ratio of maximum to minimumlaque thickness; lesions were characterized as concentricplaque with a ratio �2), eccentric (ratio �2), or eccentricith arc of normal intima (ratio �2 and minimum plaque

hickness �0.3 mm).11 Calcification was identified as veryright echoes (brighter than the adventitia) with acoustichadowing of deeper tissue zones.12

Four VH-IVUS plaque components were color-coded ashite (dense calcium), red (NC), light green (fibrofatty),

nd dark green (fibrotic tissue) and reported as cross-sec-ional area and percentages of total plaque area.13,14 Ac-ording to the relative amounts of the 4 components, lesionsere classified as (1) thin-capped fibroatheroma, (2) thick-

apped fibroatheroma, (3) pathologic intimal thickening, (4)brotic plaque, or (5) fibrocalcific plaque. Fibroatheromaad �10% confluent NC. The axial resolution of the 20-Hz transducer was approximately 200 �m. Because the

athologic definition of a thin fibrous cap was �65 �mbelow the resolution of the IVUS catheter), if �30° of theC abutted to the lumen in 3 consecutive frames, the fibro-

theroma was classified as a VH-IVUS thin-capped fibrotheroma; otherwise, it was categorized as thick-cappedbroatheroma. Fibrotic plaque was defined as mainly fi-rous plaque (�10% of confluent NC, �10% of confluentense calcium, �15% of fibrofatty plaque), and fibrocalcificlaque was defined as mainly fibrous plaque with �10% con-uent dense calcium and �10% of confluent NC. All otherlaques were categorized as pathologic intimal thickeningaving a mixture of all plaque components, but dominantlybrofatty plaque with �10% of confluent NC and �10% of

onfluent dense calcium. Qualitative and quantitative IVUS

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50 The American Journal of Cardiology (www.AJConline.org)

nalyses were performed by 2 independent, experiencedbservers (XW and AM), and the consensus interpretationas included in the subsequent analysis.Statistical analysis was performed using SPSS version

5.0 (SPSS, Inc., Chicago, Illinois). Continuous variablesexpressed as mean � SD) were compared using unpairedtudent’s t test. Categorical variables (expressed as frequen-ies) were compared using chi-square statistics or Fisher’sxact probability test. Linear regression analysis was per-ormed to evaluate the correlation between NC area andorphometric parameters. A p value �0.05 was considered

tatistically significant. Intraobserver and interobserverariability for lesion type classifications were assessed byhe � test of concordance.

esults

After excluding 4 vessels with severe calcification, 9essels with �40% plaque burden, and 3 vessels with tooew (�3) VH-IVUS frames correlated to the grayscaleVUS attenuated plaque for analysis, complete grayscaleVUS and VH-IVUS images were available for 108 vesselsf 64 patients. We analyzed all nonstented segments in these08 vessels and identified 47 attenuated plaques (in 43essels of 34 patients) and 65 nonattenuated plaques (in 65emaining vessels of 30 patients, the control group). Base-ine patient characteristics are listed in Table 1.

Attenuated plaque was present in 47 lesions (42.0%) in3 vessels (39.8%) of 34 patients (53.1%): 7 of 16 patients43.8%) with ST elevation myocardial infarctions and 27 of8 patients (56.3%) with non–ST elevation myocardial in-arctions. Overall, 22 patients had 1 attenuated plaque, 11atients had 2 attenuated plaques, and 1 patient had 3ttenuated plaques. The average number of attenuatedlaques was 0.4 � 0.5 per vessel; 39 vessels had 1 and 4essels had 2 attenuated plaques. Vessels studied were 4238.9%) left anterior descending, 36 (33.3%) left circum-ex, and 30 (27.8%) right coronary arteries; there were 43ulprit vessels and 65 nonculprit vessels. There was noifference in the incidence of attenuated plaques comparingulprit lesion–containing versus nonculprit vessels (34.0%s 47.7%, p � 0.15) and among the left anterior descending,

able 1aseline patient characteristics (n � 64)

ariable Value

en 52 (81%)ge (years) 59 � 12nstable angina pectoris 1 (1.6%)on–ST elevation myocardial infarction 47 (73%)T elevation myocardial infarction (�24 h) 16 (25%)ypertension* 42 (66%)ypercholesterolemia† 43 (67%)revious myocardial infarction 3 (5%)iabetes mellitus 11 (17%)urrent smoker 29 (45%)

Data are expressed as number (percentage) or as mean � SD.* Systolic blood pressure �140 mm Hg, diastolic blood pressure �90m Hg, or use of an antihypertensive drug.† Total cholesterol �200 mg/dl or medication treated.

eft circumflex, and right coronary arteries (46.5% vs 35.1% w

s 43.8%, p � 0.6). Attenuated plaques were predominatelyocated in proximal portions of coronary arteries within 40m of the ostium in 83% (39 of 47; Figure 2). Among

ulprit vessels, 13 attenuated plaques (81.3%) were proxi-al to the acutely implanted stent (an average of 20.5 �

6.6 mm proximal to the stent edge). Among nonculpritessels, only 9 attenuated plaques (29%) were located at theinimum luminal site.Grayscale IVUS findings are listed in Table 2. There

ere no differences in lesion site lumen, EEM, and plaquend media cross-sectional area and plaque burden betweenttenuated and nonattenuated plaques. Positive remodeling

igure 2. Location of attenuated plaque. Axial distribution of attenuatedlaques is shown for coronary arteries; 17 (85%), 12 (92%), and 10 (71%)ere located within 40 mm of the ostium of the left anterior descending,

eft circumflex, and right coronary arteries, respectively. The mean lengthsf imaged coronary arteries were 74.0 � 19.2 mm (left anterior descend-ng) 58.9 � 15.4 mm (left circumflex), and 81.1 � 31.8 mm (right coronaryrtery).

able 2rayscale intravascular ultrasound imaging characteristics

ariable AttenuatedPlaque

(n � 47)

NonattenuatedPlaque

(n � 65)

pValue

esionEEM CSA (mm2) 17 � 5.7 15 � 4.6 0.12Luminal CSA (mm2) 7.0 � 3.9 5.6 � 1.8 0.08P&M CSA (mm2) 9.5 � 3.1 9.0 � 3.5 0.53Plaque burden (%) 59 � 11 61 � 8.1 0.41Eccentricity index 9.0 � 8.7 5.9 � 3.4 0.02Positive remodeling (%) 50% 17% �0.005roximal reference segmentEEM CSA (mm2) 17 � 5.8 15 � 5.1 0.33Luminal CSA (mm2) 8.8 � 4.8 8.1 � 2.4 0.46P&M CSA (mm2) 7.7 � 2.9 7.1 � 3.7 0.50Plaque burden (%) 48 � 14 45 � 12 0.39istal reference segmentEEM CSA (mm2) 16 � 5.7 14 � 4.5 0.12Luminal CSA (mm2) 8.1 � 3.7 7.5 � 2.1 0.39P&M CSA (mm2) 8.2 � 2.7 6.9 � 3.6 0.13Plaque burden (%) 50 � 12 46 � 13 0.21

Data are expressed as mean � SD.CSA � cross-sectional area; P&M � plaque and media.

as more frequent in attenuated versus nonattenuated plaques

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51Coronary Artery Disease/VH Analysis of Attenuated Plaques

50% vs 17.1%, p � 0.003). All attenuated plaques wereccentric, and eccentric plaques with an arc of normal in-ima were more common in the attenuated versus the non-ttenuated plaque group (72.3% vs 44.6%, p � 0.012).

As listed in Table 3, attenuated plaques were associatedith (1) a larger NC area and a higher percentage of NC, (2)larger dense calcium area, and (3) a smaller fibrous plaquerea and a lower percentage of fibrous plaque compared toonattenuated plaques. There were no other differencesetween attenuated and nonattenuated plaques.

All 112 lesions (47 attenuated plaques and 65 nonattenu-ted plaques) were divided into 4 NC area quartiles (�0.45,.45 to 0.95, 0.95 to 1.5, and �1.5 mm2). Compared toonattenuated plaques, there were fewer attenuated plaquesn the lowest NC area quartile (6.4% vs 38.5%) and morettenuated plaques in the largest NC area quartile (34% vs6.9%) (Figure 3). Overall, 29 of 47 attenuated plaques61.7%) and 23 of 65 nonattenuated plaques (35.4%) had �1m2 NC area (p � 0.006).Overall, the VH-IVUS lesion phenotype included 39

able 3irtual histology intravascular ultrasound imaging characteristics

ariable AttenuatedPlaque

(n � 47)

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(n � 65)

pValue

ibrous (mm2) 3.2 � 1.6 4.0 � 2.4 0.04ibrous (%) 52 � 9.6 62 � 12 �0.001ibrofatty (mm2) 1.1 � 1.1 1.1 � 1.1 0.85ibrofatty (%) 15 � 10 17 � 13 0.50C (mm2) 1.5 � 0.9 0.9 � 0.8 0.001C (%) 25 � 9.8 15 � 11.8 �0.001ense calcium (mm2) 0.5 � 0.4 0.3 � 0.3 �0.005ense calcium (%) 8.0 � 6.1 5.4 � 7.7 0.07H-IVUS lesion phenotype �0.001Pathologic intimal thickening 2 (4%) 31 (48%)Thick-capped fibroatheroma 25 (53%) 15 (23%)Thin-capped fibroatheroma 20 (43%) 19 (29%)

Data are expressed as mean � SD or as number (percentage).

igure 3. Frequency of attenuated and nonattenuated plaques for eachuartile of NC area. Attenuated plaques were more frequent with increas-ng NC area; 34% of attenuated plaques were observed in the largest NCrea quartile.

H-IVUS thin-capped fibroatheromas, 40 thick-capped fi- V

roatheromas, and 33 lesions with pathologic intimal thick-ning, but no fibrotic or fibrocalcific plaques. Compared toonattenuated plaques, attenuated plaques were more oftenH-IVUS thin- and thick-capped fibroatheromas and lessften pathologic intimal thickening (VH-IVUS thin-cappedbroatheroma 42.5% vs 29.2%, VH-IVUS thick-capped fi-roatheroma 53.2% vs 23.1%, and pathologic intimal thick-ning 4.3% vs 47.7%, p �0.0001). Comparing fibroathero-as with attenuation to fibroatheromas without attenuation,

here were no differences in grayscale IVUS or VH-IVUSeasurements.Intraobserver variability yielded good concordance for

ttenuated plaque and VH-IVUS phenotype: � � 0.92 forttenuated plaque, � � 0.92 for pathologic intimal thicken-ng, � � 0.88 for VH-IVUS thin-capped fibroatheroma, � �.84 for VH-IVUS thick-capped fibroatheroma, � � 0.86or fibrous plaque, and � � 0.83 for fibrocalcific plaque.nterobserver variability was also acceptable: � � 0.90 forttenuated plaque, � � 0.90 for pathologic intimal thicken-ng, � � 0.86 for VH-IVUS thin-capped fibroatheroma, � �.80 for VH-IVUS thick-capped fibroatheroma, � � 0.85or fibrous plaque, and � � 0.81 for fibrocalcific plaque.

iscussion

The major novel findings in the present study were thatrayscale IVUS attenuated plaques contained a large amountf NC and were often indicative of fibroatheromas (VH-VUS thin-capped or thick-capped fibroatheromas).

Grayscale IVUS attenuated plaques are related to tran-ient deterioration in coronary flow and/or no reflow duringercutaneous coronary intervention because small embolicarticles are liberated from such plaques to induce myocar-ial damage.2,4,5,15–18 In VH-IVUS studies, NC size is alsoredictive of poststent distal embolization.7,8 The presenttudy suggests that the link among these various studiesppears to be the size of the NC detectable by VH-IVUS.

Microcalcification and cholesterol crystals are responsi-le for ultrasonic wave reflection and dispersion and, as aesult, attenuation within the grayscale IVUS image.1 Di-ectly coronary atherectomy specimens from attenuatedlaques have shown advanced atherosclerosis consistingredominantly of hyalinization, scattered, small areas ofalcification, and cholesterol clefts, but no lipid or foamyacrophages.2 Calcification and cholesterol clefts play a

ritical role in the pathogenesis of atheroma by enlargementf the NC. In line with a previous histologic study19 theresent in vivo VH-IVUS study confirms that attenuatedlaques are associated with a large amount of NC. However,he mechanism by which a large NC causes attenuation isot clear. The intensity of the backscattered signal dependsn a number of factors, such as the reflectivity of the tissue.he extremely irregular arrangement of microcalcificationreates multiple reflective surfaces within the NC andauses ultrasonic dispersion, resulting in less ultrasoundignal penetrating the NC, leading to backward attenuationehind the NC. Similarly, random distribution of cholesterolrystals in the NC might also cause backward attenuationue to ultrasound dispersion. Microcalcifications and cho-esterol clefts may thus be the critical mechanisms by which

H-IVUS NC causes attenuation on grayscale IVUS.

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52 The American Journal of Cardiology (www.AJConline.org)

The present study also shows that grayscale IVUS atten-ated plaques indicate fibroatheromas (VH-IVUS thin-apped or thick-capped fibroatheromas). Fibroatheromasre characterized by macrophage infiltration and apoptosis.acrophage death contributes to NC formation.20 Moreacrophage infiltration and excess apoptosis promote the

evelopment of a fibroatheroma with a thick fibrous capverlying a comparatively large NC. As plaques enlargeurther and are subject to intraplaque hemorrhage, there isvolution to a thin fibrous cap (�65 �m) infiltrated byacrophages and lymphocytes.21–23 Plaques with hemor-

hage and inflammation, large lipid cores, macrophage in-ltrates, and calcific deposits are associated with positiveemodeling.24 Thin-capped fibroatheromas are postulatedrecursors of plaque rupture. The NC area is larger and theercentage of NC greater in ruptured plaques versus thin-apped fibroatheromas versus thick-capped fibroathero-as.25 In the present data, NC size within the attenuated

laques (mean 1.5 mm2) and NC percentage (mean 24.5%)re similar to those in studies by Virmani et al,26 Kolodgiet al,27 and Cheruvu et al.25 These findings may help explainhy attenuated plaques indicate fibroatheromas, the linkeing an NC containing a comparatively large amount oficrocalcification and cholesterol crystals. Microcalcifica-

ions within the NC are associated with plaque instabilitynd rupture due to stress-induced debonding.28 The mainources of cholesterol clefts are apoptotic macrophages andrythrocyte membranes, indicating macrophage infiltrationnd intraplaque hemorrhage to result in NC expansion andlaque destabilization.22,23

In the present study, the average number of attenuatedlaques was 0.4 � 0.5 per vessel. This is similar to theongitudinal histopathologic study of vulnerable plaques byheruvu et al.25 In addition, most attenuated plaques were

ocated in the proximal segments of the major epicardialrteries, a distribution similar to thin-capped fibroatheromas,uptured plaques, and occlusive luminal thrombi.27,29,30

There were several limitations. This was a retrospectivenalysis. However, data were collected prospectively byndependent monitors at each site. We analyzed only aandom subset of the PROSPECT trial patients. Most pa-ients had 2 rather than 3 vessels studied. Therefore, thexact frequency of single and multiple attenuated plaqueser patient cannot be determined. PROSPECT used 20-Hz transducers, whereas most previous studies of attenu-

ted plaques used 40-MHz transducers; 20-MHz transduc-rs have greater penetration than 40-MHz transducers.

cknowledgment: We thank Kenichi Tsujita, MD, PhD,iroshi Doi, MD, PhD, Celia Castellanos, MD, Junqingang, MD, Carlos Oviedo, MD, Harpreet Bharaj, BS,asha Aaskar, BE, Lokesh Dani, BA, and Sinan Biro, BS,

or assistance with VH-IVUS image analysis.

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