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T H E Y E A R I N I M A G I N G

The Year in Molecular Imaging

Eric A. Osborn, MD, PHD,*† Farouc A. Jaffer, MD, PHD†‡

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Molecular imaging is devoted to the discoveryand application of specific biological imagingapproaches that complement traditional anatom-ical imaging. This field continues to witnessimpressive growth, particularly in the study ofoncology, neurology, and cardiovascular disease(CVD). Interest in molecular imaging technolo-gies stems from its great potential, not only toheighten our understanding and diagnostic capa-bility of common CVD scenarios, but also to offerthe prospect of personalized treatment and earlymonitoring of therapeutic response. Targetedimaging reporters are now spawning the devel-opment of combined diagnostic and therapeuticagents that can deliver therapy to individual cellsin affected tissues. Recently, diagnostic imagingprobes for myocardial infarction (MI), stem celltracking, and atherosclerotic vascular disease havedemonstrated significant advances in preclinicalresearch and development (also see the OnlineAppendix). Clinical molecular imaging studieshave further expanded into the areas of aorticdissection and aneurysm disease, and have pro-vided new insights into aspects of heart failureand transplant medicine. In this review, we high-light outstanding CVD molecular imaging stud-ies published over the past year. A summary of

From the *Cardiology Division, Beth Israel Deaconess Medical Cen†Cardiovascular Research Center, Cardiology Division, MassachBoston, Massachusetts; and the ‡Center for Molecular ImagingMassachusetts General Hospital, Harvard Medical School, BostonInstitutes of Health grant R01 HL108229, American Heart Assoca Howard Hughes Medical Institute Career Development Award. DCorporation, GE Medical Systems, and Merck & Co. Dr. Osbornthe contents of this paper to disclose. Review period: January 1-D

Manuscript received October 18, 2011; revised manuscript received De

important clinical and preclinical imaging agentsand applications is provided in Table 1.

Clinical Investigations

A major goal of molecular imaging is to fostertranslation of innovative technology into theclinical arena. Clinical molecular imaging stud-ies of human atherosclerosis remain prominent.In addition, new strategies have been devel-oped for imaging myocardial disease, as wellother areas of vascular disease.

Atherosclerosis

The overarching goal of atherosclerosis molecularimaging is to identify features associated withat-risk (vulnerable) plaques that are prone torupture. Such plaques may harbor inflammation,hemorrhage, thrombus, neovascularization, orapoptotic cells, aspects suitable for molecularimaging. Studies investigating atherosclerosisbased on 18-fluorodeoxyglucose (18F-FDG) pos-tron emission tomography (PET) imaging oflaque metabolism/inflammation, and possiblyypoxia, lead the efforts in clinical CVD molec-lar imaging.

Harvard Medical School, Boston, Massachusetts;ts General Hospital, Harvard Medical School,earch and Wellman Center for Photomedicine,assachusetts. This study was funded by Nationaln Scientist Development Grant #0830352N, andffer has received honoraria from Boston Scientificreported that he has no relationships relevant tober 31, 2010.

cember 14, 2011, accepted December 15, 2011.

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18F-FDG PET imaging of carotid plaque inflammation.18F-FDG is a radiolabeled glucose analog trans-ported into metabolically active cells, and its pres-ence is correlated with plaque macrophage content.18F-FDG PET imaging, therefore, is a surrogatereporter of this critical cell involved in atherogenesisand plaque rupture. On the basis of the commercialavailability of the 18F-FDG tracer and clinical PETcanners, 18F-FDG PET has become one of the mostidely employed clinical molecular imaging strategies

o study the presence and evolution of endovascularnflammation, particularly in the larger arterial bedsi.e., carotid, aorta).

CAROTID PLAQUE INFLAMMATION AND RISK OF

MICROEMBOLI. Microemboli emanating from carotidlaques are associated with an increased risk of stroke, asell as larger macrophage-rich areas in carotid atheroma.

gents for Molecular Imaging of Cardiovascular Disease

Modality Primary Target

PET Glucose transporter-1, hexokin

CMR Macrophages

SPECT Annexin-A5/macrophages

Spectral CT Macrophages

PET � CMR Macrophages

SPECT Folate receptor/macrophages

CMR, NIRF Macrophages

esicles CMR, NIRF Macrophages

CMR Macrophages

CMR, NIRF Macrophages

CT Macrophages

NIRF Cysteine proteases

NIRF Matrix metalloproteinases

SPECT Matrix metalloproteinases

CMR Matrix metalloproteinases

rticles CMR, NIRF �v�3 integrins

SPECT �v�3 integrins

paramagnetic CMR CD13 aminopeptidase

SPECT Matrix metalloproteinases

CMR Fibrin

Spectral CT Fibrin

CMR GP�IIb�3 receptor/platelets

PET Benzodiazepine receptor/macr

NIRF Hydroxyapatite

PET Herpes simplex virus thymidin

beled leukocytes SPECT White blood cells

CMR Myeloperoxidase activity

glucose; CLIO � crosslinked iron oxide; CMR � cardiac magnetic resonance; cNSV-tk � herpes simplex virus thymidine kinase; L-PLP � liposomal prednisolon

aphy; RIP � radiolabeled imaging peptide; SPECT � single-photon emission com

n a cross-sectional study of 16 patients with recent

nterior circulation transient ischemic attack or minortroke and 50% to 99% ipsilateral carotid stenosis, 18F-

FDG PET imaging was performed (1). Carotid micro-emboli signals (MES) were detected on transcranialDoppler ultrasound (middle cerebral artery, 1-h dura-tion, same day as PET imaging). 18F-FDG PET dis-criminated between MES� and MES� plaques (p �0.005) on the basis of their degree of local inflammation.Notably, plaque percent stenosis did not provide discrim-inatory power between MES� and MES� plaques inthe pilot study (p � 0.48). Prospective studies areindicated to determine whether 18F-FDG PET imagingf carotid plaque inflammation/metabolism will improveisk prediction of stroke beyond percent stenosis derivedrom anatomical imaging.

PLAQUE INFLAMMATION AND CARDIOVASCULAR

RISK FACTORS. Extending the application of 18F-

Application Clinical

Atherosclerosis, aneurysm (metabolism) Yes

Atherosclerosis (inflammation) Yes

Atherosclerosis, myocardial infarction(apoptosis)

Yes

Atherosclerosis (inflammation) No





Atherosclerosis (inflammation) [Theranostic] No

Atherosclerosis (inflammation) [Theranostic] No





Atherosclerosis, aneurysm (inflammation) No

Atherosclerosis (neovascularization) No

Myocardial infarction (fibrosis) Yes

Myocardial infarction (neovascularization) No

Aneurysm, myocardial infarction, vascularinjury (inflammation)

No

Thrombosis (coagulation) Yes

Thrombosis (coagulation) No

Thrombosis (platelet activity) No

ages Vasculitis (inflammation) Yes

Valvular disease (calcification) No

ase Stem cell therapy (cell tracking) No

Heart failure/transplant (inflammation) Yes

Heart failure/transplant (oxidative stress) No

cyclic Asn-Gly-Arg; CT � computed tomography; Gd � gadolinium; HDL �osphate; MPO � myeloperoxidase; NIRF � near-infrared fluorescence; PET �d tomography; USPIO � ultrasmall superparamagnetic iron oxide.

Table 1. Promising A

Agent

18F-FDG ase

USPIO99mTc-annexin A5

Au-HDL

CLIO-64Cu99mTc-EC20

Apoferritin cages

Synthetic Gd anionic v

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CLIO-THPC-AF750

N1177

ProSense

MMPsense99mTc-RP805

P947

�v�3-targeted nanopa99mTc-RIP

cNGR peptide–labeledquantum dot

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[11C]-PK11195 oph

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18F-FDG � 18-fluorodeoxy GR �high-density lipoprotein; H e ph

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litus, Kim et al. (2) studied 90 age- and sex-matched subjects without known cardiovasculardisease, who were divided evenly between normal,impaired glucose tolerance, and type 2 diabetes.Images revealed that carotid artery 18F-FDG up-ake increased incrementally with the degree oflucose intolerance, and the mean and maximumlaque target-to-background ratios (TBRs) corre-

ated with several cardiovascular risk factors andetabolic biomarkers. The same subjects stratified

y Framingham Risk Scores of �10%, 10% to 20%,nd �20% also showed increasing maximum TBRsf 1.2, 2.0, and 2.3, respectively, (p � 0.001).nterestingly, however, concomitantly obtained ca-otid intima-media thicknesses were similar amongll 3 groups, providing further evidence that inflam-ation cannot be routinely evaluated using structural-

ased imaging approaches.

RELATIONSHIP BETWEEN CAROTID PLAQUE IN-

FLAMMATION AND PLAQUE ECHOGENICITY. Thessociation between carotid plaque ultrasoundchogenicity and 18F-FDG PET inflammation was

evaluated prospectively in 33 patients with symp-tomatic carotid arterial disease (3). Although echo-genic lesions demonstrated minimal 18F-FDG up-take, echolucent atheroma, a putative ultrasoundmarker of vulnerable carotid plaques, exhibited awide range of 18F-FDG–assessed inflammation.Plaque inflammation in vivo correlated positivelywith CD68� macrophages on endarterectomy his-topathology specimens (r � 0.501). Therefore,within a range of suspected high-risk plaquesbased on echolucency, 18F-FDG PET may fur-her stratify at-risk lesions by their degree of localnflammation. Stated another way, this studyhows that all echolucent plaques are not in-amed. In addition, similar to other studies,tenosis was not significantly associated with theegree of plaque inflammation, or with plaquechogenicity.

PLAQUE INFLAMMATION AND NEW BIOMARKERS.

In a validation study, Yoo et al. (4) positivelycorrelated elevated circulating blood adipocyte fattyacid binding protein with carotid 18F-FDG PETuptake in a cross-sectional study of 87 men withoutpreviously diagnosed CVD or diabetes. Multipleregression analysis accounting for other CVD riskfactors further identified adipocyte fatty acid bind-ing protein as an independent predictor of 18F-FDG–etermined vascular inflammation. This study dem-nstrates the ability of molecular imaging strategies to

alidate potential biomarkers in human subjects. c

NATURAL HISTORY OF 18F-FDG PET INFLAMMATION

SIGNALS. A prospective study has demonstratedhe stability of 18F-FDG plaque signal over a-week period; however, longer-term data are lim-ted. In a retrospective study, Menezes et al. (5)xamined the records of 50 patients that had at least

PET/computed tomography (CT) scans per-ormed over a mean follow-up period of 27 months.he authors measured aortic and carotid 18F-FDGET uptake, as well as CT-determined Hounsfieldnit tissue density (i.e., calcification). Notably, nonitial 18F-FDG–positive site remained positive onubsequent PET studies, suggesting that inflamma-ion in a particular plaque may not persist for years.rospective studies are needed to better understand

he natural history of plaque inflammation, andhese data may arise from ongoing serial imagingrials assessing the inflammatory-modulating effectsf new pharmacotherapeutics.

18F-FDG PET imaging of coronary plaque inflammation.A noninvasive method to detect coronary arterialinflammation could be highly useful. Major chal-lenges for 18F-FDG PET imaging include relativelyow spatial resolution and high background signalrom metabolically active myocardium underlyinghe coronary bed. Encouragingly, there has beenecent progress in this area, aided by dietary ma-ipulations that can suppress background myocar-ial 18F-FDG signal.

CORONARY PLAQUE INFLAMMATION IN PATIENTS

WITH ACUTE CORONARY SYNDROMES AND STABLE

ANGINA. Rogers et al. (6) examined ascending aortand left main coronary artery 18F-FDG PET uptaken 25 patients 1 to 2 weeks after presenting with acuteoronary syndrome (ACS) or stable angina. In the leftain coronary artery, greater 18F-FDG–based in-ammatory activity was present in subjects withCS compared with stable angina (Fig. 1) (plaqueBR: 2.48 vs. 2.00, p � 0.03). In stented epicardial

oronary artery segments, similar findings werebserved, with plaque TBRs in ACS patientsigher than those with stable angina (TBR: 2.61 vs..74, p � 0.02). Impressively, 96% of coronaryET segments were analyzable after dietary-baseduppression of background myocardial signal, in-luding 89% of stented culprit lesions. The resultsemonstrate that hybrid molecular PET/CT mayave utility for noninvasive evaluation of left mainoronary arterial inflammation, as the left main isarger, more remote from myocardium, and less

obile, leading to improved image quality and

o-registration with coronary CT angiography.

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LEFT ANTERIOR DESCENDING ARTERIAL INFLAMMA-

TION. In an attempt to extend 18F-FDG to theroximal coronary arteries, Saam et al. (7) examined

18F-FDG uptake in the proximal left anteriordescending coronary artery (LAD) in a consecutiveseries of oncology patients. The authors found amodest, but significant, correlation with variouscardiac risk factors (R � 0.2), and further notedhat patients with a TBR in the upper tertile had aarger calcified plaque burden and higher pericardialat volume than patients in the lower tertile. How-ver, LAD data from 45% of the patients were notsable due to background myocardial 18F-FDGptake, limiting image analysis. Further advances,ossibly such as electrocardiogram-based triggeringf CT acquisitions, are needed to extend 18F-FDG

reliably into the non–left main coronary tree.Statin pharmacotherapy and 18F-FDG PET plaquectivity. The effect of increasing statin dose on

18F-FDG PET atheroma uptake was prospectivelyevaluated in 30 coronary artery disease patients

Figure 1. Co-Registered 18F-FDG PET/CT Imaging of Inflammatio

(A) In a patient with an acute coronary syndrome (ACS), the left maindeoxyglucose (18F-FDG) uptake. (B) A patient with stable angina and r18F-FDG signal. Note also the focal 18F-FDG signal in the mixed compopatient with stable angina shows comparatively modest 18F-FDG activwith acute coronary syndrome. In panels A to D, the dashed arrow idthe stented region. CT � computed tomography; PET � positron emissio

randomized to atorvastatin 5 mg versus 20 mg daily i

(8). All patients were scheduled for percutaneouscoronary intervention to treat stable angina symp-toms, and none of them had received lipid-loweringmedications for at least the previous 12 months.The day after percutaneous coronary intervention,baseline 18F-FDG PET/CT imaging was per-formed, and the 18F-FDG activity in the aorta andemoral artery quantified. The patients were thenandomized to high- or low-dose statin therapy,ith a follow-up 18F-FDG PET imaging study

performed 6 months later. The arterial 18F-FDGBR was significantly reduced in the high-dose

tatin arm (aorta baseline TBR: 1.15 vs. 1.05, p �.007; femoral baseline TBR: 1.12 vs. 1.02, p �.012). Although there were similar significanteductions in low-density lipoprotein and high-ensitivity C-reactive protein levels in both theigh-dose and the low-dose statin groups, the

ow-dose group did not show significant changes inrterial 18F-FDG uptake. This suggests that highertatin doses may be required to reduce plaque

Human Coronary Arteries

) coronary artery and culprit stented lesion show enhanced 18-fluoro-t percutaneous coronary intervention reveals less stented segmentn LM coronary artery plaque. (C) A lesion stented months earlier in aD) 18F-FDG uptake at the LM coronary artery trifurcation in a patientes the LM coronary artery and, when present, the solid arrow points tomography. Reproduced, with permission, from Rogers et al. (6).

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Near-infrared fluorescence imaging of carotid plaqueprotease activity. Augmented inflammatory pro-tease activity is a marker of vulnerable plaques.Using near-infrared fluorescence (NIRF) imagingsystems in concert with protease-activatable NIRFimaging agents, Kim et al. (9) investigated ex vivomatrix metalloproteinase and cysteine protease ac-tivity in samples obtained from 56 subjects under-going either carotid endarterectomy or carotidstenting with filter devices. On macroscopic NIRFimaging, enhanced cathepsin B and MMP 2/9protease activity were identified both in retrievedemboli and in bifurcations of carotid endarterec-tomy specimens (Fig. 2). Plaques demonstratedunstable histopathological features (rupture withthrombus, hemorrhage, and thin, inflamed cap).Symptomatic patients (ipsilateral stroke within 1month) harbored plaques with greater proteaseactivity compared with asymptomatic patients. In-triguingly, cathepsin B protease activity was dimin-ished in patients taking statins, consistent with theanti-inflammatory properties associated with thismedication class. Protease signal correlated mod-estly with anatomic stenosis or ultrasound echolu-cency, a suggested marker of plaque instability,indicating that protease-identified inflammationlikely provides independent, complementary dataon plaque stability. Although NIRF molecular im-aging agents are not yet approved for clinical study,the current data, along with a recent report of aclinical targeted fluorescence imaging trial (10),provide momentum for future clinical testing ofNIRF protease sensors in human subjects.

Myocardial Infarction

Following irreversible myocardial damage, necroticmuscle is replaced by collagen-dense scar that maypromote maladaptive tissue remodeling, myocardialdysfunction, and clinical heart failure and malig-nant arrhythmias. Typically, the true degree ofdysfunction and scar burden are not fully realizeduntil months after the index event, at a time whenthere may be little reversibility. Therefore, earlydetection of these changes may allow subsequentintervention to prevent adverse outcomes.Single-photon emission computed tomography im-aging of fibrogenesis post-MI, and its relationship tofinal infarct size at 1 year. In 10 patients presenting

ith MI, Verjans et al. (11) serially evaluatedhanges in interstitial extracellular matrix via anntravenous injection of an integrin receptor–

argeted arginine-glycine-aspartic acid–radiolabeled

maging peptide (RIP). RIP has been shown pre-iously to target up-regulated integrin expressione.g., �v�3) found on myofibroblasts that manufac-

ture collagen. At 3 and 8 weeks post-MI, 99mTc-IP–enhanced single-photon emission computed

omography (SPECT) imaging revealed uptake in0% of patients involving the infarct zone identifiedn myocardial perfusion imaging. Importantly,IP-based SPECT signal typically extended be-

Figure 2. NIRF Imaging of MMP and Cysteine Protease ActivityResected Human Carotid Plaques

(A) Matrix metalloproteinase (MMP) near-infrared fluorescence (NIRFcolocalizes with hemorrhagic, ulcerated carotid plaque regions (linebut is only weakly present in uncomplicated segments without the(line 4). Of note, similar MMP activity is present in echolucent (lineand echogenic locations (line 3) identified by duplex ultrasonograp(Duplex U.S.). (B) Tissue immunohistochemistry (IHC) at representatregions corresponding with lines 1 to 4 in A reveal enhanced CD68macrophage content that colocalizes with MMP-9 immunoreactivityroscopic MMP activity on NIRF imaging. (Inset) MMP-9 staining at tlabeled by a hash mark not apparent in the low power view is evidhigher magnification. (C) MMP-2 immunoreactive regions overlap wMMP-9 (compare the regions labeled with an asterisk and a hash mand C). (D and E) MMP-9 colocalizes with MMP activity on NIRF micThe arrowhead in B identifies the location of the magnified regionE. White scale bars � 5 mm; black scale bars � 2 mm; blue scale200 �m. Cy5.5 F-micro� cyanine 5.5 fluorescence microscopy; Intra

in

) signals 1 to 3),se featuress 1 and 2)hyive� (CD-68)and mac-he regionent atith that ofark in Broscopy.in D andbars �-OP �

intraoperative. Reproduced, with permission, from Kim et al. (9).

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yond the fixed perfusion defect. At 1-year follow-up, the pattern of early myocardial RIP uptake wasobserved to be similar to the final infarct size asmeasured by cardiac magnetic resonance (CMR)late gadolinium enhancement (Fig. 3). RIP im-aging early after infarction may therefore predictthe final extent of post-MI myocardial scarring,and offer opportunities for earlier intervention.

Heart Failure and Transplant MedicineSarcoid cardiomyopathy and inflammation imagingby 18F-FDG PET. Congestive heart failure is a wide-reaching condition and a leading cause of hospital-ization and death. Sarcoid cardiomyopathy is arelatively uncommon, but important, cause of heartfailure that may be successfully treated if detectedearly. Tahara et al. (12) studied cardiac inflamma-tion in 24 patients with systemic sarcoid disease, ofwhich half had recognized cardiac involvement byendomyocardial biopsy or clinical criteria. Com-pared with healthy normal subjects or age-matchedcontrols with dilated cardiomyopathy, fasting 18F-FDG uptake in cardiac sarcoidosis patients showedsignificantly more heterogeneous myocardial signal.Heterogeneity was quantified by the coefficient ofvariation, defined as the 18F-FDG standard devia-

Figure 3. Clinical SPECT 99mTc-RIP Imaging of Myofibroblast AcMyocardial Fibrosis at 1 Year

(Top) In 2 different patients, scar in the left anterior descending colinium-enhanced cardiac magnetic resonance (CMR) at 1 year. (Midsimilar views for the same patients months earlier, with yellow arroemission computed tomography (SPECT)/CMR fusion images are sh

VLA � vertical long axis. Reproduced, with permission, from Verjans et

ion divided by the mean uptake in a 17-segmentardiac model. At a cutoff coefficient of variationalue of 0.18, this metric demonstrated excellentperating characteristics, with 100% sensitivity and7% specificity. Following corticosteroid therapy,erial repeat 18F-FDG PET assessment over 12onths follow-up confirmed that the 18F-FDG

ptake variation returned to that of control subjectsFig. 4). Thus, 18F-FDG PET imaging mightrovide useful diagnostic and treatment responsive-ess in patients with sarcoid cardiomyopathy.

Detecting infected left ventricular assist devices us-ing integrated SPECT/CT of leukocyte foci. The

oninvasive diagnosis of left ventricular assist deviceLVAD) infection, a potentially life-threateningondition, remains challenging. Imaging modalitiesuch as CT or magnetic resonance imaging (MRI)re limited due to metallic artifacts and contraindi-ations. A noninvasive imaging approach may avoiddditional testing and treatment that in certainases may be costly and unnecessary. Furthermore,uch an imaging approach could help assess theesponse to antibiotic therapy in the LVAD itself.

ithin this context, Litzler et al. (13) performed alinical cellular imaging study in 8 consecutiveatients with suspected LVAD infection, using

y 3 Weeks Post-MI, With Follow-Up CMR-Measured

ry artery distribution (yellow arrows) is identified with late gado-99mTc-radiolabeled imaging peptide (RIP) uptake (blue arrows) inplaced for comparison to the CMR-identified scar. Single-photonin the bottom row. MI � myocardial infarction; SA � short axis;

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99mTc-exametazime–labeled radioactive leukocytes(�99% viability with 90% labeling efficacy) andhybrid SPECT/CT imaging. At 4 and 24 h afterinjection of the radiolabeled autologous leukocytes,pockets of infection were identified in all patients.Images discriminated superficial from deep infec-tion, and depicted the extent of LVAD involvementand any remote involved sites. On the basis of thelocation and severity of the 99mTc-labeled leukocyteuptake, the duration of antibiotic therapy could beeffectively tailored, with follow-up scans in 5 sub-jects demonstrating infection resolution in theLVAD or in a non–LVAD-related source.

Aortic DiseaseAbdominal aortic aneurysm. Inflammation andweakening of the vessel wall may lead to frankrupture, especially in aneurysms that rapidly expandor reach a critical size. New molecular imagingmethods are being directed to evaluate aneurysmmarkers of instability such as inflammation, hem-orrhage, and neovascularization.

CMR OF MACROPHAGES IN AORTIC ANEURYSM.

Fourteen patients with infrarenal abdominal aorticaneurysm (4.0- to 5.5-cm diameter) underwent

Figure 4. Serial Cardiac 18F-FDG PET Imaging in Cardiac Sarcoid

(A) Compared with the strong baseline signal heterogeneity (high Ction of heterogeneous myocardial 18F-FDG activity (low COV). (B) Aheterogeneous 18F-FDG uptake. COV � coefficient of variation; Rx �mission, from Tahara et al. (12).

CMR of aneurysm inflammation following intrave-

nous injection of Sinerem (ferumoxtran, Guerbet,Villepinte, France) 2.6 mg Fe/kg, an ultrasmallsuperparamagnetic iron oxide (USPIO) nanoparticleagent phagocytosed by resident macrophages (14).Compared with pre-USPIO injection, post-injectionCMR aneurysm signals were significantly lowerin macrophage-rich atherosclerotic areas. If vali-dated prospectively, USPIO-enhanced CMRcould identify high-risk subjects with aneurysminflammation more likely to expand or rupture,motivating increased surveillance and/or earliertreatment.

A similarly sized study by Nchimi et al. (15)detected biologically active macrophages within in-traluminal thrombi of abdominal aortic aneurysmsvia the superparamagnetic iron oxide (SPIO) agentEndorem (ferumoxide, Guerbet, Villepinte, France).Compared with USPIO, SPIO have relativelylarger size and shorter circulation half-life due torapid hepatic clearance, restricting distribution toluminal surface targets and other well-perfusedtissues. Exploiting these properties, SPIO local-ized in leukocyte-dense intraluminal thrombi 1 hafter injection, much earlier than the 24 to 36 hnecessitated by longer-circulating USPIOs. Ex

Patients

), a patient treated with corticosteroids reveals complete resolu-treated patient at a similar follow-up time point exhibits moreeatment; other abbreviations as in Figure 1. Reproduced, with per-

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specimens obtained within 2 weeks of in vivoimaging confirmed thrombus inflammatory cellinfiltration with iron particle retention, as well aselevated matrix metalloproteinase 9 (MMP-9)enzymatic activity.Aortic dissection. Disruption of the aortic wall is alife-threatening event that often requires immediatesurgical intervention. However, autopsy series indi-cate that incidental aortic dissection is present in upto 1% to 2% of subjects, suggesting that manychronic aortic dissections can be managed conser-vatively. Because anatomic imaging modalities donot reliably distinguish acute from chronic dissec-tions, new imaging strategies are needed.18F-FDG PET IMAGING OF INFLAMMATION IN

ACUTE VERSUS CHRONIC AORTIC DISSECTION.

Reeps et al. (16) evaluated 18F-FDG PET imagingto discriminate acute from chronic type B aorticdissection in 18 patients. 18F-FDG enhancement

as observed at the injured aortic wall in all acuteissection patients 3 to 13 days after presentationFig. 5). Quantitative analysis revealed that thetandardized uptake value (SUV) ratio, or TBR,erformed significantly better in discriminatingcute from chronic stable dissection (SUV ratio:.20 vs. 1.24, respectively, p � 0.001) than simplyeasuring maximum SUV at the site of injury,hich suffered from false-negative and false-ositive outliers. This preliminary study suggestshat 18F-FDG PET may help distinguish acute

from chronic aortic dissection on the basis of thedegree of vessel wall inflammation.18F-FDG AND AORTIC DISSECTION PROGNOSIS.

The prognostic value of 18F-FDG uptake in med-ically managed acute aortic dissection was addressed

Figure 5. 18F-FDG PET Imaging of Arterial Wall Inflammation in

(A) Sagittal and (C) coronal hybrid PET/CT fusion images with corre

tions as in Figure 1. Reproduced, with permission, from Reeps et al. (16

in 28 patients. PET scans were obtained approxi-mately 2 weeks after CT diagnosis (17). All patientshad type B dissections except for 2 poor surgicalcandidates with type A. Over 6 months, there were8 unfavorable outcomes (death, surgical repair, ordissection progression), predicted by the initialinflammatory 18F-FDG uptake at the dissectionite with an odds ratio of 7.72 for adverse events onultivariate analysis. 18F-FDG provided a sensitiv-

ity and specificity of 75% and 70%, respectively, formean SUV � 3.029. Furthermore, in patients withfavorable outcomes, a lower 18F-FDG uptake corre-sponded to a greater likelihood of dissection healing orregression. These results provide intriguing prelimi-nary evidence that 18F-FDG PET imaging mayrisk-stratify aortic dissection populations that benefitfrom aggressive earlier surgical intervention.Vasculitis. Giant cell arteritis and Takayasu ar-teritis are large-vessel inflammatory diseases thatcan result in arterial occlusion, thrombosis, an-eurysm, and accelerated atherosclerosis. New ap-proaches are needed to understand the pathogen-esis of these diseases in vivo.

PET IMAGING OF MACROPHAGES IN VASCULITIS

USING [11C]-PK11195. Pugliese et al. (18) tested thePET imaging probe [11C]-PK11195, an establishedhuman neuroimaging agent that selectively bindsthe benzodiazepine receptor on activated macro-phages. Six patients with giant cell arteritis orTakayasu arteritis were compared with 9 asymp-tomatic controls. Symptomatic subjects exhibitedenhanced [11C]-PK11195 signal on vascular PETcans (TBR: 2.41 vs. 0.98 for asymptomatic pa-ients, p � 0.001). In 1 patient treated with 20eeks of corticosteroid therapy, a follow-up [11C]-

7-Year-Old Male With an Acute Type B Aortic Dissection

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PK11195 PET scan demonstrated markedly re-duced vascular PET signal (TBR decreased from1.63 to 0.87), associated with symptomatic im-provement and decreased inflammatory biomarkers.Compared with 18F-FDG, which reports on all

etabolically active cells, [11C]-PK11195 PETmay provide a more macrophage-specific readout,given its ligand selectivity. In addition, [11C]- or[18F]-PK11195 may also improve coronary athero-sclerosis PET imaging of inflammation, becausebackground uptake by metabolically active myocytesshould be lower than in 18F-FDG PET imaging.

Advances in Preclinical Imaging Approaches

Atherosclerosis

In the last year, new atherosclerosis-targeted imag-ing agents and devices have been developed to senseplaque inflammation, angiogenesis, and oxidativestress. In vivo studies of pharmacotherapeutic effi-cacy, as well as the area of integrated therapeuticand diagnostic targeted imaging (“theranostics”),particularly via nanotechnological approaches, arealso in a growth phase.Inflammatory macrophages. Macrophages are piv-otal cells in atherogenesis, driving plaque expansionand plaque complications. Macrophages are themost established imaging target for atherosclerosismolecular imaging studies, with clinical detection ofplaque macrophages enabled by 18F-FDG PET andUSPIO-enhanced CMR. Although these ap-proaches have proven valuable, new reporter agentsare diversifying imaging platforms and aiming toimprove sensitivity.

PET AGENTS. The positron emitter [11C]-PK11195has been studied to image activated macrophages inclinical vasculitis, as discussed in the previous text.11C-choline, a source of cell membrane lipids foundin high levels in proliferating cells, including plaquemacrophages (19), was shown to colocalize withmurine plaques by autoradiography, and was able todistinguish noninflamed and inflamed, macrophage-richplaques (20). A head-to-head comparison with18F-FDG may be informative in understanding anypotential advantages with respect to achievableTBRs.

SPECT AGENTS. Folate receptor beta is expressedn activated macrophages and thus offers anotherolecular imaging target for atherosclerosis. The

PECT tracer 99mTc-labeled folate-targeted probe(99mTc-EC20) was investigated in murine athero-

clerosis (21). In vivo SPECT imaging demon-

trated greater SPECT signal in animals on aigh-cholesterol diet compared with a regular chowiet. Uptake of 99mTc-EC20 was also reduced in

animals treated with clodronate liposomes, a mac-rophage apoptosis–inducing therapeutic agent.Whether the additional macrophage specificityconferred by a folate receptor–based SPECT ap-proach is advantageous compared with 18F-FDGemains to be tested in clinical subjects.

CMR AGENTS. Based on the natural affinity ofmacrophages for ferritin, targeted imaging agentscomprised of bioengineered polypeptide apoferritin(iron-free ferritin) cages were developed as NIRF orCMR agents by coupling apoferritin to the NIRfluorochrome cyanine 5.5 or to magnetite nanopar-ticles, respectively (22). In diabetic, high-fat diet–fed mice, the imaging agents localized to themacrophage-rich lesions of ligated carotid arteries.Loading of other imaging agents or even therapeu-tic drugs into the apoferritin protein cage architec-ture is possible, providing versatility for thismacrophage-avid agent.

Maiseyeu et al. (23) synthesized gadolinium-containing anionic vesicles comprised of phosphati-dylserine and a novel synthetic oxidized cholesterolester derivative that avidly binds low-density lipopro-tein. Reporter vesicles were internalized by macro-phages via scavenger receptors in culture, and in rabbitatheroma in vivo, as shown by 1.5-T CMR. Thisliposomal agent can also be formulated with fluores-cently labeled lipids, and has potential advantages fora good safety profile, easy manufacturing, and scalabil-ity that could facilitate clinical testing.

DUAL-MODAL PET-MRI REPORTERS. Extendingrior work with PET-MRI high-resolution/high-ensitivity macrophage reporters based on 64Cu-

labeled crosslinked iron oxide (CLIO-64Cu), Jarrettet al. (24) tested CLIO-64Cu, as well asadolinium/64Cu-labeled maleylated bovine serum

albumin for targeting of the macrophage scavengerreceptor A (SRA). Macrophages in injured carotidarteries in 3 different rodent models were visualizedwith both 64Cu-based PET reporters, as well as by7-T MR (T1-weighted for gadolinium-basedagents, T2-weighted for CLIO-based agents) forhigher-resolution imaging.

CT AGENTS. Although coronary CT imaging hasdemonstrated substantial clinical utility, few molec-ular imaging agents are available for CT platforms.Using a high-density lipoprotein (HDL)-basedmacrophage-targeted gold nanoparticle coupled

with spectral (“multicolor”) CT, a multienergy im-

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aging approach based on the discrimination of x-rayenergy attenuation differentials, Cormode et al. (25)imaged plaque macrophages in apoE�/� mice. Cap-talizing on the multispectral capabilities, in additiono macrophage detection, simultaneous co-registeredmages of calcification (bones) and iodinated contrastangiography) were obtained in the same mice (Fig. 6).hese results expand the selection of current nanoparticleT agents for macrophages (e.g., N1177), and may

ccelerate the use of CT as a molecular and anatomicalmaging approach for coronary atherosclerosis.

Myocardial Infarction

Post-MI healing involves an orchestrated immuneresponse. Hypo- or hyperimmune cell infiltrationfollowing MI can impair myocardial healing, andmay promote mechanical complications (rupture) oradverse left ventricular (LV) remodeling (progres-sive dilation). Methods to study key effector cellsand molecules in post-MI healing may shed impor-tant insight into this process in vivo, and potentiallyoffer new therapeutic strategies.Inflammation and myocardial healing. THE EFFECTSOF HYPERLIPIDEMIA ON POST-MI INFLAMMATION

AND HEALING. In wild-type and apolipoproteinE–negative (apoE�/�) hyperlipidemic mice, Panizzi

Figure 6. Thoracoabdominal Spectral CT Imaging of Murine Ath

(A–C) Spectral computed tomography (CT) images in an apolipopro(D and E) Spectral CT images in the aortic bifurcation after co-injec

tein. Reproduced, with permission, from Cormode et al. (25).

t al. (26) first quantified monocyte recruitmentost-MI by mapping the pro- and anti-inflammatoryubtypes Ly-6Chi and Ly-6Clo via flow cytometry.

ApoE�/� mice showed significantly increased levelsof inflammatory Ly-6Chi monocytes, cells thatsecrete degradative enzymes. Using noninvasive,dual-channel fluorescence molecular tomogra-phy–CT molecular imaging of post-MI mice (Fig. 7),the authors found that in vivo inflammatory cathepsinenzymatic activity (activatable agent ProSense680,PerkinElmer, Waltham, Massachusetts) and mac-rophage activity (reporter agent CLIO-750) wasalso greater in apoE�/� mice (26). Atheroscleroticmice had 10-fold greater Ly-6Chi monocyte infil-tration in the infarct zone 5 days post-MI thanwild-type controls, as assessed by histopathology,and was associated with increased inflammatorymarkers, proteolysis, and phagocytosis. In addition,serial CMR showed that apoE�/� mice with MI

eveloped greater ventricular dilation comparedith wild-type mice, despite having similar infarct

izes initially. Furthermore, induction of Ly-6Chi

monocytosis alone by intraperitoneal lipopolysaccha-ride injection in wild-type mice without hyperlipid-emia or atherosclerosis recapitulated a similar post-MIinflammatory state. This work concludes that the

sclerosis via the Gold-Based Nanoparticle Au-HDL

-negative (apoE�/�) mouse after Au-HDL injection 24 h earlier.of Au-HDL and iodinated contrast. HDL � high-density lipopro-

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Ly-6Chi monocyte may be a therapeutic cellular targetn the post-MI setting.

Please see the Online Appendix for additionaligh-impact preclinical imaging studies.

Outlook

Molecular imaging studies are shedding importantlight on the cellular and molecular biology underlyingimportant cardiovascular diseases. Excitingly, this lastyear witnessed a growth in clinical molecular investi-gations, particularly in the areas of atherosclerosis,aneurysm disease, and MI. In the short term, weanticipate continued expansion of 18F-FDG PET–ased molecular imaging applications of vascular dis-ase. Insights from 18F-FDG PET should proveseful in predicting which atherosclerosis therapeuticsill likely be efficacious and safe. Across many areas ofVD, molecular imaging data studies will continue to

lucidate the in vivo pathogenesis of disease, and will

Figure 7. Noninvasive FMT/CT Dual-Target Molecular Imaging oControl Mice

(A) Five days post MI, CT images reveal apical infarct (arrows). Corrcence molecular tomography (FMT)/CT images of inflammatory actiinfarct macrophages) in control C57Bl/6 mice (top) and apoE�/� mrates the in vivo FMT/CT imaging results. *p � 0.05. TBR � target-tReproduced, with permission, from Panizzi et al. (26).

f key CVD events, such as acute plaque rupture anddverse LV remodeling.

Due to lower imaging agent dose requirements,ew strategies for PET and SPECT may be clini-ally available in the next 2 years. In addition, selectuorescence agents may enter the clinical arenaithin the next 1 to 3 years. These trends will

nable new clinical molecular imaging studies ofVD, and will be spurred further by advances in

linical imaging systems, especially in the emerg-ng areas of fluorescence imaging and multispec-ral CT imaging. As more agents transition fromhe bench to the patient bedside, molecular imagingtudies should prove helpful in the clinical manage-ent of CVD.

Reprint requests and correspondence: Dr. Farouc A. Jaffer,assachusetts General Hospital Cardiovascular Researchenter, Simches Research Building 3206, 185 Cam-ridge Street, Boston, Massachusetts 02114. E-mail:

flammation During Infarct Healing in Atherosclerotic and

nding fusion 2-dimensional and 3-dimensional in vivo fluores-(ProSense680 for cysteine protease activity, and CLIO-750 forbottom). (B) Ex vivo fluorescence reflectance imaging corrobo-ckground ratio; other abbreviations as in Figures 1, 3, and 6.

rovide the foundation for improved risk assessment [email protected].

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R E F E R E N C E S

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open-label, 6-month study in Japanese

1

adults scheduled for percutaneous coro-nary intervention. Clin Ther 2010;32:2337–47.

9. Kim D-E, Kim J-Y, SchellingerhoutD, et al. Protease imaging of humanatheromata captures molecular in-formation of atherosclerosis, com-plementing anatomic imaging. Arte-rioscler Thromb Vasc Biol 2010;30:449 –56.

0. van Dam GM, Themelis G, CraneLM, et al. Intraoperative tumor-specific fluorescence imaging in ovar-ian cancer by folate receptor-alphatargeting: first in-human results. NatMed 2011;17:1315–9.

1. Verjans J, Wolters S, Laufer W, et al.Early molecular imaging of interstitialchanges in patients after myocardialinfarction: comparison with delayedcontrast-enhanced magnetic reso-nance imaging. J Nucl Cardiol 2010;17:1065–72.

2. Tahara N, Tahara A, Nitta Y, et al.Heterogeneous myocardial FDG up-take and the disease activity in cardiacsarcoidosis. J Am Coll Cardiol Img2010;3:1219–28.

3. Litzler P-Y, Manrique A, Etienne M,et al. Leukocyte SPECT/CT for de-tecting infection of left-ventricular-assist devices: preliminary results.J Nucl Med 2010;51:1044–8.

4. Sadat U, Taviani V, Patterson AJ, etal. Ultrasmall superparamagnetic ironoxide-enhanced magnetic resonanceimaging of abdominal aortic aneu-rysms—a feasibility study. Eur J VascEndovasc Surg 2011;41:167–74.

5. Nchimi A, Defawe O, Brisbois D, etal. MR imaging of iron phagocytosisin intraluminal thrombi of abdominalaortic aneurysms in humans. Radiol-ogy 2010;254:973–81.

6. Reeps C, Pelisek J, Bundschuh RA, etal. Imaging of acute and chronic aorticdissection by 18F-FDG PET/CT.J Nucl Med 2010;51:686–91.

7. Kato K, Nishio A, Kato N, Usami H,Fujimaki T, Murohara T. Uptake of18F-FDG in acute aortic dissection: adeterminant of unfavorable outcome.J Nucl Med 2010;51:674–81.

8. Pugliese F, Gaemperli O, Kinderl-erer AR, et al. Imaging of vascular

inflammation with [11C]-PK11195and positron emission tomography/computed tomography angiography.J Am Coll Cardiol 2010;56:653– 61.

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0. Laitinen IEK, Luoto P, Någren K, etal. Uptake of 11C-choline in mouseatherosclerotic plaques. J Nucl Med2010;51:798–802.

1. Ayala-López W, Xia W, Varghese B,Low PS. Imaging of atherosclerosis inapoliprotein e knockout mice: targetingof a folate-conjugated radiopharmaceu-tical to activated macrophages. J NuclMed 2010;51:768–74.

2. Terashima M, Uchida M, Kosuge H,et al. Human ferritin cages for imag-ing vascular macrophages. Biomateri-als 2011;32:1430–7.

3. Maiseyeu A, Mihai G, Roy S, et al.Detection of macrophages via para-magnetic vesicles incorporating oxi-datively tailored cholesterol ester: anapproach for atherosclerosis imag-ing. Nanomedicine 2010;5:1341–56.

4. Jarrett BR, Correa C, Ma KL, LouieAY. In vivo mapping of vascular in-flammation using multimodal imag-ing. PLoS One 2010;5:e13254.

5. Cormode DP, Roessl E, Thran A, etal. Atherosclerotic plaque composi-tion: analysis with multicolor CT andtargeted gold nanoparticles. Radiology2010;256:774–82.

6. Panizzi P, Swirski FK, FigueiredoJ-L, et al. Impaired infarct healing inatherosclerotic mice with Ly-6C(hi)monocytosis. J Am Coll Cardiol2010;55:1629–38.

Key Words: atherosclerosis yeart failure y molecular

maging y myocardial infarctionthrombosis.

‹ A P P E N D I X

For supplementary information on advances inpreclinical imaging approaches, please see the

online version of this paper.

The Year in Molecular ImagingClinical InvestigationsAtherosclerosis18F-FDG PET imaging of carotid plaque inflammationCarotid plaque inflammation and risk of microemboliPlaque inflammation and cardiovascular risk factorsRelationship between carotid plaque inflammation and plaque echogenicityPlaque inflammation and new biomarkersNatural history of 18F-FDG PET inflammation signals

18F-FDG PET imaging of coronary plaque inflammationCoronary plaque inflammation in patients with acute coronary syndromes and stable anginaLeft anterior descending arterial inflammation

Statin pharmacotherapy and 18F-FDG PET plaque activityNear-infrared fluorescence imaging of carotid plaque protease activity

Myocardial InfarctionSingle-photon emission computed tomography imaging of fibrogenesis post-MI, and its relationship ...

Heart Failure and Transplant MedicineSarcoid cardiomyopathy and inflammation imaging by 18F-FDG PETDetecting infected left ventricular assist devices using integrated SPECT/CT of leukocyte foci

Aortic DiseaseAbdominal aortic aneurysmCMR of macrophages in aortic aneurysm

Aortic dissection18F-FDG PET imaging of inflammation in acute versus chronic aortic dissection18F-FDG and aortic dissection prognosis

VasculitisPET Imaging of macrophages in vasculitis using [11C]-PK11195

Advances in Preclinical Imaging ApproachesAtherosclerosisInflammatory macrophagesPET agentsSPECT agentsCMR agentsDual-modal PET-MRI reportersCT agents

Myocardial InfarctionInflammation and myocardial healingThe effects of hyperlipidemia on post-MI inflammation and healing

OutlookReferencesAppendix

the year in molecular imaging - connecting repositories · 2017. 1. 27. · the year in imaging...

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