IPIoADKTB

Cgatcibflvps

McMIg

a

Journal of the American College of Cardiology Vol. 48, No. 9, 2006© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00P

Cardiac Imaging

n Vivo 18F-Fluorodeoxyglucoseositron Emission Tomography

maging Provides a Noninvasive Measuref Carotid Plaque Inflammation in Patientshmed Tawakol, MD,* Raymond Q. Migrino, MD,† Gregory G. Bashian, MD,* Shahinaz Bedri, MBBS,‡avid Vermylen, BA,* Ricardo C. Cury, MD,† Denise Yates, PHD,† Glenn M. LaMuraglia, MD,�aren Furie, MD,§ Stuart Houser, MD,‡ Henry Gewirtz, MD,* James E. Muller, MD,*homas J. Brady, MD,† and Alan J. Fischman, MD, PHD†oston, Massachusetts

OBJECTIVES Given the importance of inflammation in atherosclerosis, we sought to determine ifatherosclerotic plaque inflammation could be measured noninvasively in humans usingpositron emission tomography (PET).

BACKGROUND Earlier PET studies using fluorodeoxyglucose (FDG) demonstrated increased FDG uptake inatherosclerotic plaques. Here we tested the ability of FDG-PET to measure carotid plaqueinflammation in patients who subsequently underwent carotid endarterectomy (CEA).

METHODS Seventeen patients with severe carotid stenoses underwent FDG-PET imaging 3 h afterFDG administration (13 to 25 mCi), after which carotid plaque FDG uptake was determinedas the ratio of plaque to blood activity (target to background ratio, TBR). Less than 1 monthafter imaging, subjects underwent CEA, after which carotid specimens were processed toidentify macrophages (staining with anti-CD68 antibodies).

RESULTS There was a significant correlation between the PET signal from the carotid plaques and themacrophage staining from the corresponding histologic sections (r � 0.70; p � 0.0001).When mean FDG uptake (mean TBR) was compared with mean inflammation (meanpercentage CD68 staining) for each of the 17 patients, the correlation was even stronger (r �0.85; p � 0.0001). Fluorodeoxyglucose uptake did not correlate with plaque area, plaquethickness, or area of smooth muscle cell staining.

CONCLUSIONS We established that FDG-PET imaging can be used to assess the severity of inflammationin carotid plaques in patients. If subsequent natural history studies link increased FDG-PETactivity in carotid arteries with clinical events, this noninvasive measure could be used toidentify a subset of patients with carotid atherosclerosis in need of intensified medical therapyor carotid artery intervention to prevent stroke. (J Am Coll Cardiol 2006;48:1818–24)

ublished by Elsevier Inc. doi:10.1016/j.jacc.2006.05.076

© 2006 by the American College of Cardiology Foundation

as

dwfladteme(Facti

urrent management of carotid atherosclerotic disease isuided primarily by determination of degree of carotidrtery stenosis and does not take advantage of imagingechniques that could provide information about plaqueomposition and biological activity. Among the targets formaging, detection of inflammation is likely to be of valueecause of the well-documented association between in-ammatory processes and plaque rupture (1–6). A nonin-asive method to characterize inflammation in carotidlaques may be of value for determination of prognosis,election of appropriate medical or surgical therapy, and

From the *Departments of Medicine (Cardiac Unit), †Radiology and Nuclearedicine, ‡Pathology, and §Neurology, and the �Division of Vascular and Endovas-

ular Surgery, Massachusetts General Hospital and Harvard Medical School, Boston,assachusetts. Supported in part by grants from NIH (RR16046) and the Center for

ntegration of Medicine and Innovative Technologies and by unrestricted researchrants from Pfizer and GlaxoSmithKline.

iManuscript received July 27, 2005; revised manuscript received April 27, 2006,

ccepted May 2, 2006.

ssessment of novel therapies designed to stabilize athero-clerotic plaques.

Preliminary data from our group and others haveemonstrated that positron emission tomography (PET)ith 18F-fluorodeoxyglucose (FDG) can identify in-amed atherosclerotic plaques in an animal model oftherosclerosis (7–9). Furthermore, Rudd et al. (10,11)emonstrated increased carotid uptake of FDG in pa-ients with evidence of a recent ischemic cerebrovascularvent. The same group demonstrated in ex vivo experi-ents that FDG co-localizes with macrophages within

xcised carotid specimens that are incubated with FDG10). However, that ex vivo experiment used quantities ofDG that cannot be used in vivo in patients. Moreover,lthough it is evident that symptomatic vascular lesionsan be detected using FDG-PET, it remains unknown ifhe imaging technique can be used to noninvasively character-ze the severity of vascular inflammation in patients. Accord-

ngly, in this study, we tested the hypothesis that inflammation

iv

M

Pscccng1tsPiiHvimwPfiAHaAmpaiipt

(mMPbec

wa

eekebfucdfTFwpwpmoualatpvAdb

bttsopwsHC1s3iswsasa

iCoeD

1819JACC Vol. 48, No. 9, 2006 Tawakol et al.November 7, 2006:1818–24 FDG-PET Measures Vascular Inflammation in Humans

n human carotid arteries could be measured noninvasively, inivo, using 18FDG-PET.

ETHODS

atients. Seventeen adult patients (11 men, 6 women) withevere carotid artery stenosis already scheduled to undergoarotid endarterectomy (CEA) were recruited. Eligibilityriteria included a 70% to 99% stenosis of the internalarotid artery detected by carotid Doppler ultrasound, mag-etic resonance angiography, or computed tomography an-iography. All patients were expected to undergo CEA withinmonth of enrollment. The study protocol was approved by

he local Human Research Committee, and informed con-ent was obtained from each subject.ET imaging. FDG was administered (13 to 25 mCi)

ntravenously after an overnight fast. Three hours later,maging was performed using a Siemens ECAT Exact

R� system (Siemans, Knoxville, Tennessee), which pro-ides 63 planes, a 15.5-cm field of view, and 4.2-mmntrinsic resolution. Data were acquired in 3-dimensional

ode. The choice of time interval was based on our previousork in animals and on the work of Rudd et al. (10).atients were imaged in the supine position using a headxation device. Images were obtained over 20 min.ttenuation-corrected images were reconstructed using aanning filter with a conventional, filtered back-projection

lgorithm, yielding an effective resolution of 5 mm.natomic imaging, image co-registration, and measure-ent of FDG uptake. Metabolic imaging with PET

rovides limited structural data. Accordingly, anatomic im-ging with either multidetector computed tomographicmaging (MDCT) (n � 11 patients) or magnetic resonancemaging (MRI) (n � 6 patients) was performed usingreviously reported methods (12,13) for structural delinea-ion of the carotid arteries and their atherosclerotic plaques.

The PET images were co-registered with the structuralMDCT or MRI) images using a workstation that enablesultimodal standard (rigid) image fusion (REVEAL-VS; Mirada Solutions, Oxford, United Kingdom). The

ET and CT (or MR) images were manually co-registeredy an investigator blinded to the histologic analysis usingxtravascular anatomic landmarks (such as brain, spinalord, spine, and jaw) that were apparent on both images.

After co-registration of the images, carotid FDG uptakeas measured along the length of the carotid vessel, starting

Abbreviations and AcronymsCEA � carotid endarterectomyFDG � 18F-fluorodeoxyglucosehsCRP � high-sensitivity C-reactive proteinPET � positron emission tomographySUV � standardized uptake valueTBR � target-to-background ratio

t the bifurcation and extending inferiorly and superiorly o

very 4 mm. Because the length of carotid plaque that wouldventually be removed during endarterectomy was notnown at the time of image analysis, the measurements werextended, at 4-mm intervals, to points 4 cm above and 2 cmelow the carotid bifurcation. However, only those sectionsor which carotid histology was eventually obtained weresed for analysis. At each axial plane along the length of thearotid, regions of interest (ROIs) (approximately 8 mm iniameter) were placed within the wall of the carotid vesselor determination of the standardized uptake value (SUV).he SUV is the decay-corrected tissue concentration ofDG (in kBq/ml) divided by the injected dose per bodyeight (kBq/g). The CT and MRI data were used to guidelacement of the ROI within the plaque (area of greatestall thickening) at each axial plane. In cases where thelaque occupied more than 180° of the vessel wall the SUVeasurement was taken at the most metabolically active half

f the vessel wall. To obtain a background value for FDGptake, SUV was measured in a venous structure. Toccomplish this, an ROI was placed within the center of aarge vein (such as the subclavian or internal jugular vein) inn area devoid of significant spill-over activity. Afterward, aarget-to-background ratio (TBR) was calculated as carotidlaque SUV divided by venous blood SUV, and an averagedalue of TBR was calculated for each patient (mean TBR).dditionally, we calculated the plaque-to-blood SUV gra-ient as the difference between the carotid plaque SUVs andlood background SUV (�SUV).Blinding was maintained between investigators responsi-

le for the registration of PET and structural images, andhe determination of PET uptake, on the one hand, andhose responsible for the histologic analyses of the CEApecimens, on the other hand. To determine the variabilityf the measurement (mean plaque TBR), images from 10atients were twice co-registered and analyzed, severaleeks apart in a blinded manner. The mean (� SD) intraob-

erver difference was 8.9 � 9.0%.istology and immunohistochemistry. At the time ofEA, the atherosclerotic plaques were immediately fixed in0% buffered formalin and subsequently decalcified in thetandard fashion. Specimens were transversely sectioned at-mm intervals. Each interval section was embedded face upn paraffin and cut at 5-�m thickness to yield 4 slices forubsequent staining. For immunohistochemistry, sectionsere mounted on gelatin-coated slides and subsequently

tained with a macrophage-specific, anti-CD68 monoclonalntibody (mAb KP-1; Dako, Glostrup, Denmark) and amooth muscle cell-specific antibody (anti-smooth muscle celllpha-actin antibody; Dako).

Assessment of macrophage and smooth muscle cell stain-ng was performed using the methods of Jander et al. (14).omputer-assisted planimetry was used to quantitate areasf staining. The sections were computerized as color-ncoded digitized images (Sony CCD camera, HamamatsuVS video image processing unit, and National Institutes

f Health image analyzing software on an Apple Macintosh

prtamsAptpwitcPtatCdsctai(dsocieHsa0SWCSbtiuomr

R

PpIosT

(Tposba%s

F(faCsgmacu00(e(hcdp

D

Ticc1

hui

T

AGSDSSASDLC

Cl

1820 Tawakol et al. JACC Vol. 48, No. 9, 2006FDG-PET Measures Vascular Inflammation in Humans November 7, 2006:1818–24

ersonal computer). Total section areas and areas of mac-ophage infiltration were outlined manually by comparinghe computerized image with the microscopic image at 4�nd 20� magnification. Macrophage staining was deter-ined at each carotid slice and reported as the absolute area

taining for macrophages (mm2) at each carotid level.dditionally, inflammation was recorded as percentage oflaque staining. In cases where the plaque occupied morehan 180° of the vessel wall, the value for percentagelaque staining in the most inflamed half of the vesselall (% CD68 staining) was reported. This was done for

mproved registration with the imaging findings, becausehe imaging values were derived from the most metaboli-ally active half of the vessel wall at each axial section of theET images. Smooth muscle cell staining was defined as

he percentage of plaque staining for antismooth muscle cellntibody. Morphometric measurement of lipid area, caphickness, and collagen content were performed.

o-registration and comparison of histologic and PETata. The axial PET images were registered to histologyections on the basis of the distance from the commonarotid bifurcation. The carotid bifurcation was defined ashe apex of the luminal flow divider (which divides internalnd external carotid artery) as identified on the CT (or MR)mages as well as the pathologic specimens. Contractiondue to axial elastic recoil) of the endarterectomy specimenuring histologic processing (between its relatively stretchedtate in vivo to a more contracted state ex vivo) wasbserved. To account for this change in tissue length, 25%ontraction in the length of the specimens along thenferior-superior dimension was assumed, based on earlierxperience of the lab.

igh-sensitivity C-reactive protein. Serum high-ensitivity C-reactive protein (hsCRP) was measured usingn automatic immunonephelometer with a sensitivity of.02 mg/dl (Behring, Deerfield, Illinois).tatistical methods. Data were analyzed using SPSS forindows version 13.0 (SPSS, Inc, Chicago, Illinois).

ontinuous parameters are reported as mean values �D. Spearman method was used to assess the correlationetween the 18FDG uptake (FDG TBR) and the his-opathologic assessment of inflammation (% CD68 stain-ng), as well as the correlation between mean FDGptake (mean TBR) and the serum hsCRP level. A valuef p � 0.05 was considered significant. To correct forultiple tests, the alpha was adjusted using the Bonfer-

oni method.

ESULTS

atient characteristics. Patient characteristics are dis-layed in Table 1.maging and histology. The 17 carotid plaque specimensbtained during the course of the study yielded 107 plaqueections (7 � 4 plaque sections/patient) after sectioning.

here was a significant correlation between the PET signal a

judged as the ratio of target to background PET emissions,BR) and macrophage staining, for both the absolute macro-hage area (r � 0.68; p � 0.0001) and the % CD68 stainingf the plaque sections (r � 0.70; p � 0.0001) (Figs. 1 to 3). Aignificant but somewhat weaker correlation was observedetween absolute FDG uptake (absolute SUV) and bothbsolute macrophage area (r � 0.49; p � 0.0001), and the

CD68 staining (r � 0.58; p � 0.0001) of the plaqueections.

A stronger relationship was noted when mean values forDG uptake (mean TBR) and histologic inflammation

CD68 staining) were generated for each of the 17 patients,or % CD68 staining, (r � 0.85; p � 0.0001; Fig. 4) as wells absolute macrophage area (r � 0.76; p � 0.0001).oncordant with those observations, there was a highly

ignificant correlation between the plaque-to-blood SUVradient (�SUV) and plaque inflammation, measured asean % CD68 staining (r � 0.88; p � 0.001) as well as

bsolute macrophage area (r � 0.80; p � 0.001). Inontrast, there was no significant correlation between FDGptake (mean TBR) and smooth muscle cell staining (r �.15; p � 0.40) (Fig. 5), collagen staining (r � �0.48; p �.11), plaque thickness (r � 0.15; p � 0.49), or plaque arear � 0.00; p � 0.99). There was no correlation betweenither FDG uptake (mean TBR) or plaque inflammationmean % CD68 staining) and the following variables:sCRP, age, gender, blood pressure, serum lipids (totalholesterol, low-density lipoprotein cholesterol, high-ensity lipoprotein cholesterol, or triglycerides), statin use,resence of diabetes, body mass index, or smoking.

ISCUSSION

he primary finding of this study is that noninvasive PETmaging can be used to assess the degree of inflammation inarotid atherosclerotic plaques in vivo as documented byorrelations in patients undergoing CEA.8FDG uptake in vascular inflammation. Several groupsave established that inflamed blood vessels have increasedptake of 18FDG. This 18FDG enhancement by vascularnflammation has been demonstrated in animal models of

able 1. Subject Characteristics

Characteristic Mean (� SEM)

ge (yrs) 62 � 6ender (M/F) 11/6

ymptoms (%) 24iabetes (%) 24

moking (%) 29tatin Rx (%) 65spirin Rx (%) 100BP (mm Hg) 137 � 4BP (mm Hg) 68 � 3DL cholesterol (mg/dl) 96 � 9RP (mg/l) 3.6 � 1.5

RP � C-reactive protein; DBP � diastolic blood pressure; LDL � low-densityipoprotein; Rx � therapy; SBP � systolic blood pressure.

therosclerosis (15) and verified in human studies of patients

wr1

opse

ustuo

wtcrscsw

ifetlspstp[tpotastasC

Fmc(tch andh ch is

1821JACC Vol. 48, No. 9, 2006 Tawakol et al.November 7, 2006:1818–24 FDG-PET Measures Vascular Inflammation in Humans

ith Takayasu’s arteritis, giant cell arteritis, polymyalgiaheumatica, and nonspecific aortitis (16–19). More recently,8FDG uptake was shown to be greater in carotid plaquesbtained from patients with clinical evidence of carotidlaque instability (10). However, in that study, the relation-hip between inflammation and imaging findings was notstablished.

The present study for the first time demonstrates that FDGptake, determined noninvasively with PET, correlatestrongly with the degree of plaque inflammation. Accordingly,his study provides histologic validation in humans that carotidptake of 18FDG may be useful for noninvasive measurementf atherosclerotic plaque inflammation.

Several additional, potentially important, observationsere made. It is apparent that the imaging method enables

he characterization of inflammation within a range ofarotid inflammation that has been shown to be clinicallyelevant. The study by Jander et al. (14) previously demon-trated that carotid plaques from patients with symptomaticarotid disease are more severely inflamed (18 � 10% CD68taining) compared with plaques removed from patients

igure 1. Axial positron emission tomographic (PET) images and the co-reanifested low 18F-fluorodeoxyglucose (FDG) uptake in the region of th

arotid plaque. The region of the excised carotid plaque is noted with arropatient A). The corresponding trichrome-stained histologic specimen demhe high-powered images demonstrates limited macrophage infiltration. Thlinically stable plaque. (B) Carotid plaque specimen taken from the patiistologic specimen demonstrates a complex plaque with a necrotic core,istologic features are consistent with a metabolically unstable plaque whi

ith asymptomatic carotid stenosis (11 � 4% CD68 stain- t

ng). Crisby et al. (20) demonstrated that plaques takenrom symptomatic patients subjected to modest lipid low-ring (40 mg/day pravastatin for 3 months) are less inflamedhan plaques from patients that did not receive lipid-owering therapy (15.0 � 10.2% vs. 25.3 � 12.5% CD68taining; p � 0.05). Further, others demonstrated thatlaques taken from predominantly asymptomatic patientsubjected to aggressive lipid lowering (80 mg/day atorvasta-in for 1 month) are less inflamed than plaques fromatients that did not receive lipid-lowering therapy (2.5%0.1 to 5.2] vs. 9.7 [3.1 to 15.5] % CD68 staining) (21). Inhe present study, we analyzed the ability to characterizelaques that fall into groups that bear relevance to the levelsf inflammation shown to be important in the aforemen-ioned histologic studies (�5%, 5% to 15%, and �15%),nd found a significant difference between the 3 groups,uggesting that the imaging method may prove useful forhe identification of plaques that may become symptomatic,nd for following the response to plaque stabilizationtrategies such as lipid lowering therapy (Fig. 6).linical implications. Based on the results of large clinical

ed computed tomographic (CT) images from 2 patients, 1 (patient A) whotid plaque and 1 (patient B) with high FDG uptake in the region of the) Carotid plaque specimen taken from the patient with low FDG uptake

ates a collagen-rich plaque with low lipid content, and CD68 staining onistologic features are consistent with a metabolically stable and potentiallyith high FDG uptake (patient B). The corresponding trichrome-stainedthe CD68 staining demonstrates intense macrophage infiltration. Thesevulnerable to rupture.

gistere carows. (Aonstrese h

ent w

rials, carotid revascularization is strongly recommended for

cmbrcpalpe

ohcteawt

F gnificb to th

FoPried

Fvspsbb

1822 Tawakol et al. JACC Vol. 48, No. 9, 2006FDG-PET Measures Vascular Inflammation in Humans November 7, 2006:1818–24

ases of severe symptomatic stenoses, whereas for cases ofoderate symptomatic or severe asymptomatic stenoses, the

enefit in terms of stroke risk reduction is modest andevascularization is often limited to select cases in surgicalenters with high experience (22–24). The findings of theresent study suggest that PET studies of the carotidrteries could aid in the risk stratification of patients withess stenotic or asymptomatic lesions by identifying inflamedlaques that may be associated with a higher risk of a clinicalvent.

igure 2. Trichrome- (10� magnification) and CD68-stained (200� maoxes in the trichrome-stained images indicate the regions corresponding

igure 3. Noninvasive positron emission tomography (PET) measurementf 18F-fluorodeoxyglucose (FDG) uptake versus macrophage staining. TheET measurement of carotid plaque FDG uptake (target-to-background

atio [T/B]) in patients was compared with histologic assessment ofnflammation in the corresponding sections taken during carotid endarter-

ctomy. There was a significant correlation between T/B and macrophageensity.

cw

The important role of inflammation in the pathophysi-logy of atherosclerosis has been well established (1,2). Bothistopathologic and epidemiologic data demonstrate therucial role of inflammation in plaque formation and rup-ure. Plaques that have ruptured are often found to havextensive macrophage infiltrates (25–31). The macrophagesre capable of destabilizing plaques by release of enzymeshich degrade matrix proteins and inhibit collagen forma-

ion. Therefore, the use of 18FDG-PET imaging to char-

ation) carotid specimens that correspond to the images in Figure 1. Thee high-powered CD68 stains. (A and B) As described in Figure 1.

igure 4. Mean within-patient 18F-fluorodeoxyglucose (FDG) uptakeersus inflammation in carotid endarterectomy patients. For each of the 17ubjects, all histologic sections were averaged to generate a mean per-atient value for percentage macrophage staining. Likewise, the corre-ponding imaging data were combined to generate a mean target-to-ackground ratio (T/B) for each patient. There was a significant correlationetween mean T/B and mean inflammation (r � 0.85; p � 0.001). The

orrelation remained significant (r � 0.82; p � 0.001) even after the outlierith the highest plaque inflammation was removed from the analysis.

aauehmSidsiotlissw

iptrmromabal(as

teFecs(pmPFtdmpCcvdt

crdwbtanwt

Ftamaimlb

FflPpsca

1823JACC Vol. 48, No. 9, 2006 Tawakol et al.November 7, 2006:1818–24 FDG-PET Measures Vascular Inflammation in Humans

cterize plaques according to the degree of inflammationdds functional to anatomic data and might eventually proveseful for predicting which patients are at greatest risk ofxperiencing progression of disease or a clinical event. Naturalistory studies will be needed to determine whether suchetabolic imaging will aid in risk assessment.

tudy limitations. A concern regarding this study is thatnflammation is likely to be a dynamic process which canevelop and regress with time. Therefore, the inflammatorytate observed on the day of noninvasive imaging may not bendicative of the degree of inflammation present on the dayf endarterectomy. To minimize this potential effect, theime from imaging to obtaining histologic specimens wasimited to �1 month in the present study. Changes innflammation during the interval between imaging andurgery could have decreased the statistical power of thetudy. Despite this delay, highly significant correlationsere observed.Another concern is that the method for co-registering the

maging and histologic sections is imperfect. There isotential error in the registration of the PET images withhe histology. Although plaque specimens were carefullyemoved and marked to preserve orientation, several speci-ens were macerated or fractured, and varying degrees of

ecoil of the specimens was anticipated (perhaps dependingn plaque composition). Such factors could have causedisregistration between the plaque specimens and images

nd may therefore have reduced the correlation coefficientetween the individual imaging data and histology. Innticipation of this potential registration error, we calcu-ated the average FDG uptake measured for each patientaverage TBR for each patient) and compared it with theverage inflammation seen in all of that patient’s histologic

igure 5. Positron emission tomography (PET) measurement of 18F-uorodeoxyglucose (FDG) uptake versus smooth muscle cell staining. TheET measurement of FDG uptake (target-to-background ratio [T/B]) inatients was compared with histologic assessment of smooth muscle celltaining (anti-SMA stain) in the corresponding sections taken duringarotid endarterectomy. There was no correlation between FDG uptakend smooth muscle cell staining (r � 0.15; p � 0.54).

ections (thereby removing the potential for misregistra-vb

ion). With this approach, the observed correlation wasspecially strong (r � 0.85; p � 0.001)uture research directions. In addition to the imaging ofxtracardiac vessels, 18FDG may potentially be used toharacterize coronary arterial plaques. Although small vesselize, mobility, and high myocardial uptake of 18FDG32–34) are potential obstacles to coronary imaging, severalossible solutions exist. These include techniques to reduceyocardial uptake of 18FDG and the use of combinedET-CT cameras to improve localization of tracer activity.urthermore, novel intravascular positron-sensitive cathe-

ers can detect vascular FDG out of proportion to myocar-ial FDG, and may develop into a clinically useful imagingodality. Novel radiopharmaceuticals with greater macro-

hage specificity may further enhance the method.onclusions. We demonstrated that FDG-PET imaging

an determine macrophage content of carotid plaques inivo. This observation has important implications for drugevelopment and, if supported by natural history studies, forhe clinical care of patients at risk of stroke.

For drug development, this capability can assist in thelinical assessment of pharmaceutical agents designed toeduce macrophage activity in atherosclerotic plaques. It cano so by identifying patients with macrophage-rich plaquesho could be randomly assigned to the agent of interest andy providing a surrogate end point for assessment ofherapeutic efficacy. The direct impact of FDG-PET im-ging on clinical care would require successful outcome of aatural history study demonstrating that a positive imageas associated with an increased risk of neurologic symp-

oms. Such a study may demonstrate that nonstenotic but

igure 6. Distribution of 18F-fluorodeoxyglucose (FDG) uptake in pa-ients grouped by average plaque inflammation. Patients were groupedccording to the average amount of inflammation in their carotid speci-ens and the average FDG uptake determined for each group. The ranges

ssigned to these groups reflect the levels of inflammation shown to bemportant in previous histologic studies (14,20,21). The box plot shows

ean values (thick lines) and 25th and 75 percentile values (upper andower box boundaries). The length of the whiskers from the boxoundaries represents standard error of the mean. The mean FDG uptake

alue for each group was significantly different. T/B � target-to-ackground ratio.

ivlabtm

RdM

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

1824 Tawakol et al. JACC Vol. 48, No. 9, 2006FDG-PET Measures Vascular Inflammation in Humans November 7, 2006:1818–24

nflamed plaques, which would not be identified for inter-ention by the current stenosis-based screening method, areikely to cause events. If a link between FDG-PET imagingnd events was established, this noninvasive measure coulde used to identify patients in need of intensified medicalherapy, carotid stenting, or CEA so that initial strokesight be prevented.

eprint requests and correspondence: Dr. Ahmed Tawakol, Car-iac Unit/YAW 5904, Massachusetts General Hospital, Boston,assachusetts 02114. E-mail: atawakol@partners.org.

EFERENCES

1. Libby P. Coronary artery injury and the biology of atherosclerosis:inflammation, thrombosis, and stabilization. Am J Cardiol 2000;86:3–8J.

2. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med1999;340:115–26.

3. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison ofC-reactive protein and low-density lipoprotein cholesterol levels in theprediction of first cardiovascular events. N Engl J Med 2002;347:1557–65.

4. Brennan M-L, Penn MS, Van Lente F, et al. Prognostic value ofmyeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595–1604.

5. Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serumlevels predict risk in patients with acute coronary syndromes. Circu-lation 2003;108:1440–5.

6. Alvarez Garcia B, Ruiz C, Chacon P, Sabin JA, Matas M. High-sensitivity C-reactive protein in high-grade carotid stenosis: riskmarker for unstable carotid plaque. J Vasc Surg 2003;38:1018–24.

7. Lederman RJ, Raylman RR, Fisher SJ, et al. Detection of atheroscle-rosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose(FDG). Nucl Med Commun 2001;22:747–53.

8. Machac J, Zhang Z, Almeida O, Chen W, Krynyckyi B, Kim CK.The relation of F-18 FDG uptake in human thoracic aortas in vivo andrisk factors for CAD. Circulation 2001;104:693.

9. Tawakol A, Migrino RQ, Hoffmann U, et al. Noninvasive in vivomeasurement of vascular inflammation with F-18 fluorodeoxyglucosepositron emission tomography. J Nucl Cardiol 2005;12:294–301.

0. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atheroscleroticplaque inflammation with [18F]-fluorodeoxyglucose positron emissiontomography. Circulation 2002;105:2708–11.

1. Davies JR, Rudd JHF, Fryer TD, et al. Identification of culprit lesionsafter transient ischemic attack by combined 18F fluorodeoxyglucosepositron-emission tomography and high-resolution magnetic reso-nance imaging. Stroke 2005;36:2642–7.

2. Corti R, Ferrari C, Roberti M, Alerci M, Pedrazzi PL, Gallino A.Spiral computed tomography: a novel diagnostic approach for inves-tigation of the extracranial cerebral arteries and its complementary rolein duplex ultrasonography. Circulation 1998;98:984–9.

3. Yuan C, Mitsumori LM, Ferguson MS, et al. In vivo accuracy ofmultispectral magnetic resonance imaging for identifying lipid-richnecrotic cores and intraplaque hemorrhage in advanced human carotidplaques. Circulation 2001;104:2051–6.

4. Jander S, Sitzer M, Schumann R, et al. Inflammation in high-gradecarotid stenosis: a possible role for macrophages and T cells in plaquedestabilization. Stroke 1998;29:1625–30.

5. Lederman RJ, Raylman RR, Fisher SJ, et al. Detection of atheroscle-rosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose

(FDG). Nucl Med Commun 2001;22:747–53.

6. Hara M, Goodman PC, Leder RA. FDG-PET finding in early-phaseTakayasu arteritis. J Comput Assist Tomogr 1999;23:16–8.

7. Meller J, Altenvoerde G, Munzel U, et al. Fever of unknown origin:prospective comparison of [18F]FDG imaging with a double-headcoincidence camera and gallium-67 citrate SPET. Eur J Nucl Med2000;27:1617–25.

8. Blockmans D, Maes A, Stroobants S, et al. New arguments for avasculitic nature of polymyalgia rheumatica using positron emissiontomography. Rheumatology (Oxford) 1999;38:444–7.

9. Derdelinckx I, Maes A, Bogaert J, Mortelmans L, Blockmans D.Positron emission tomography scan in the diagnosis and follow-up ofaortitis of the thoracic aorta. Acta Cardiol 2000;55:193–5.

0. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J.Pravastatin treatment increases collagen content and decreases lipidcontent, inflammation, metalloproteinases, and cell death in humancarotid plaques: implications for plaque stabilization. Circulation2001;103:926–33.

1. Martin-Ventura JL, Blanco-Colio LM, Gomez-Hernandez A, et al.Intensive treatment with atorvastatin reduces inflammation in mono-nuclear cells and human atherosclerotic lesions in one month. Stroke2005;36:1796–800.

2. Executive Committee for the Asymptomatic Carotid AtherosclerosisStudy. Endarterectomy for asymptomatic carotid artery stenosis.JAMA 1995;273:1421–8.

3. European Carotid Surgery Trialists’ Collaborative Group. Random-ised trial of endarterectomy for recently symptomatic carotid stenosis:final results of the MRC European Carotid Surgery Trial (ECST).Lancet 1998;351:1379–87.

4. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotidendarterectomy in patients with symptomatic moderate or severestenosis. N Engl J Med 1998;339:1415–25.

5. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesionsin sudden cardiac ischemic death. N Engl J Med 1984;310:1137–40.

6. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion withoutrupture into a lipid core. A frequent cause of coronary thrombosis insudden coronary death. Circulation 1996;93:1354–63.

7. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site ofintimal rupture or erosion of thrombosed coronary atheroscleroticplaques is characterized by an inflammatory process irrespective of thedominant plaque morphology. Circulation 1994;89:36–44.

8. Carr S, Farb A, Pearce W, Virmani R, Yao J. Atherosclerotic plaquerupture in symptomatic carotid artery stenosis. J Vasc Surg 1996;23:755–66.

9. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R.Coronary risk factors and plaque morphology in men with coronarydisease who died suddenly. N Engl J Med 1997;336:1276–82.

0. Carr S, Farb A, Pearce W, Virmani R, Yao J. Activated inflammatorycells are associated with plaque rupture in carotid artery stenosis.Surgery 1997;122:757–63.

1. Golledge J, Cuming R, Ellis M, Davies AH, Greenhalgh RM. Carotidplaque characteristics and presenting symptom. Br J Surg 1997;84:1697–701.

2. Tawakol A, Skopicki HA, Abraham SA, et al. Evidence of reducedresting blood flow in viable myocardial regions with chronic asynergy.J Am Coll Cardiol 2000;36:2146–53.

3. Melon PG, de Landsheere CM, Degueldre C, Peters JL, KulbertusHE, Pierard LA. Relation between contractile reserve and positronemission tomographic patterns of perfusion and glucose utilization inchronic ischemic left ventricular dysfunction: implications for identi-fication of myocardial viability. J Am Coll Cardiol 1997;30:1651–9.

4. Gerber BL, Vanoverschelde JL, Bol A, et al. Myocardial blood flow,glucose uptake, and recruitment of inotropic reserve in chronic leftventricular ischemic dysfunction. Implications for the pathophysiology

of chronic myocardial hibernation. Circulation 1996;94:651–9.