426 Atlas of Nuclear CardiologyPathologic Substrates for Imaging Vulnerable PlaquesPlaque rupture is responsible for up to 75 % of acute coronary events [3, 4]. The rupture of the ﬁbrous cap exposesa thrombogenic core to the luminal blood and leads to acute thrombosis. Disrupted plaques have distinct patho-logic characteristics; they are generally large both cross-sectionally and longitudinally. These voluminous plaquesmay not necessarily impose signiﬁcant luminal obstruction because the arterial wall at the lesion site is outwardly(positive or expansively) remodeled. These plaques contain large necrotic cores. The disrupted ﬁbrous caps arethin and inﬁltrated by macrophages.a bFIGURE 12-1. Pathologic characteristics of a stable and a rup-tured plaque. The stable plaque is rich in collagen and smoothmuscle with minimal lipid accumulation (a). On the other hand,ruptured plaque is formed predominantly by a large necroticcore (asterisk) and covered by a thin ﬁbrous cap (b). The site ofplaque rupture (arrow) exposes the necrotic core to luminalblood and allows thrombotic occlusion of the vessel. Thepathologic examination of culprit plaques from the victims ofACS reveals that these plaques are usually signiﬁcantly volumi-nous. Up to 95 % of the disrupted plaques demonstrate greaterthan 50 % cross-sectional vascular area involvement, andabout 50 % of the ruptured plaques occupy more than 75 % ofthe cross-sectional area of the vessel (Adapted from Shapiroet al. ).baFIGURE 12-2. (a) Disrupted plaques usually demonstrate largenecrotic cores (NC). In the culprit plaques, the NC usuallyoccupy greater than 25 % of the plaque area and show morethan 120° circumferential involvement of the vessel in at least75 % of instances. The NC extend 2–22 mm in longitudinaldimension (median, 9 mm). The larger the plaque area andthe larger the NC size, the higher the likelihood of plaque insta-bility [3, 4]. (b) It is reasonable to presume that before theacute event, plaques vulnerable to rupture harbor the samehistopathologic signatures, except that the thin ﬁbrous cap isstill intact. Up to 40 % of the vulnerable plaques occupy morethan 75 % of the cross-sectional vascular area and an addi-tional 50 % encroach on 50–75 % of the vascular area. In thelatter instances, the large plaque volume is accommodatedby positive remodeling of the vessel (Adapted from Shapiroet al. ).
Molecular Imaging of Atherosclerosis 427a bcd eFIGURE 12-3. (a–e) Evolution of necrotic core (NC) in the plaque.The ongoing death of lipid-laden macrophages contributes tothe formation of the NC in atherosclerotic plaques. Worseninghypoxia in the enlarging plaque perpetuates macrophagedeath, enlarges the NC, and promotes neovascularization (b). These nascent vessels are inherently leaky and allowextravasation of red blood cells (RBC) into the plaque (c). It iswell appreciated that the cholesterol content of erythrocytemembranes exceeds that of most other cells in the body andlikely contributes to the cholesterol pool of the growing NC.Intraplaque hemorrhage (c) due to the rupture of these imma-ture vessels further leads to the accumulation of a large num-ber of RBC and, hence, cholesterol. The plaque hemorrhagesare common in the coronary arteries in patients dying fromplaque rupture. The extent of iron deposits (e) in the plaque (Fe)and that of glycophorin A (d) (GpA, a protein exclusively asso-ciated with RBC membrane) staining is directly proportional tothe size of the NC [7, 8]. Plaque neovascularization is accompa-nied by proliferation of vasa vasorum (a) [8, 9]. Disruptedplaques have a fourfold higher vasa vasorum density com-pared with stable plaques with severe luminal narrowing.Microvessels that perforate from the adventitial layer to themedial layer are well formed with the smooth muscle cell (SMC)envelope, unlike those that extend to the neointima, whichappear immature and leaky. Abundant T-helper cells found atthe medial wall perforation site likely inhibit SMC proliferationthrough interferon. The density of vasa vasorum, measured bymicro-CT, increases markedly during hypercholesterolemia andresolves with statin treatment. The increase in vasa vasorum isassociated with vascular endothelial growth factor expressionin the neointima and neoangiogenesis. Interestingly, erythro-cyte membrane-derived cholesterol is elevated in patients pre-senting with ACS and is sensitive to statin therapy (a – Adaptedfrom Kwon et al. ; b – Adapted from Kolodgie et al. ).
428 Atlas of Nuclear Cardiology25a b2015105AllCL-relatedNCL-relatedIndeterminate0 1 2 3Time, years0MACE,%188.8.131.52.9184.108.40.206.920.412.911.62.7c50151020Median3.4-yearsMACErateperlesion,%PresentAbsentTCFA TCFA + MLA≤4.0 mm2TCFA + PB≥70 %TCFA + PB≥70 % +MLA ≤ 4 mm220.127.116.11.515.317.21.5 1.850151020PresentAbsentPIT PIT + MLA≤4.0 mm2PIT + PB≥70 %PIT + PB≥70 % +MLA ≤ 4 mm20.62.7 2.31.9 18.104.22.168 1.9FIGURE 12-4. Intravascular ultrasound (IVUS) offers accurate mea-surements of the minimal lumen area (MLA), plaque burden(PB), and type of remodeling, and radiofrequency IVUS evenallows reasonable determination of ﬁbrous (green) and necroticcore-rich (red) composition of the plaque. (a) Demonstratespredominantly ﬁbrous pathologic intimal thickening (PIT, right)and predominantly lipid-rich (left) plaques. It has been pro-posed that a shallow necrotic core abutting the lumen mayrepresent a thin cap ﬁbroatheroma (TCFA). (b) In a landmarkprospective study, almost 700 patients with ACS underwentthree-vessel coronary angiography and IVUS imaging after per-cutaneous coronary intervention. Subsequent major adversecardiovascular events (MACE; death from cardiac causes, car-diac arrest, myocardial infarction, or rehospitalization due tounstable or progressive angina) were adjudicated to be relatedto either originally treated (culprit) lesions or untreated(nonculprit) lesions, over a median follow-up period of morethan 3 years. The cumulative rate of major adverse cardiovas-cular events was 20 %: 13 % related to culprit lesions (CLs) and12 % to nonculprit lesions (NCLs). Although most NCLs responsi-ble for follow-up events were angiographically mild at baseline(luminal diameter stenosis, 32±21 %), they progressed to 65±16 %diameter stenosis at the time of the follow-up event (P<0.001).(c) Event rates associated with almost 600 NCLs characterizedas TCFA and 2,000 PIT are shown according to MLA and PB, asdetected on gray-scale and radiofrequency IVUS. (Prevalencedata are for one or more such lesions per patient; lesions inpatients with indeterminate events are excluded.) The recurrentevents were associated with a PB greater than 70 % (hazardratio [HR]=5; 95 % CI, 2.5–10; P<0.001), MLA less than 4.0 mm2(HR=3; 95 % CI, 2–6; P=0.001), or TCFA (HR=3; 95 % CI, 2–6;P<0.001)  (Courtesy of Gregg Stone, MD, New York).Imaging of Morphologic CharacteristicsImaging of morphologic characteristics of atherosclerotic plaques. Intravascular ultrasound and CT angiographyoffer an excellent assessment of the magnitude of the plaque, the necrotic core size, and the extent of positiveremodeling; thin ﬁbrous caps can be quantitatively characterized by intravascular high-resolution OCT.
Molecular Imaging of Atherosclerosis 429Stable Culprita bFIGURE 12-5. Multislice CTA of stable (a) and culprit (b) coronarylesions with invasive coronary angiogram. The culprit lesion isoutwardly remodeled (yellow arrows in inset) compared withthe proximal normal vessel and contains low-attenuation (likelysoft) plaque (red arrows) . The stable lesion is not remod-eled and shows intermediate attenuation (likely ﬁbrous) plaque(green arrow). The culprit lesions have also been demonstratedto be more frequently associated with spotty calciﬁc depositsbut not large calciﬁc plates. If plaques with similar CTA charac-teristics are identiﬁed incidentally, up to one fourth of themmay develop ACS during a 2-year follow-up period .Plaques with stable characteristics are associated with a lessthan 0.5 % likelihood of an acute cardiac event. The ﬁbrouscaps are signiﬁcantly attenuated in the vulnerable plaquesand are disrupted at the weakest site in an acute coronaryevent. Based on a large set of disrupted plaques postmortem,it was proposed that ﬁbrous cap thickness of less than 65 mmpredicts vulnerability to plaque rupture. The ﬁbrous cap thick-ness can be accurately measured by OCT  (Adapted fromMotoyama et al. ).
430 Atlas of Nuclear CardiologyFIGURE 12-7. Ultrasound microbubble studies have identiﬁedincreased vasa vasorum and plaque vascularity in patientswith carotid atherosclerosis . A longitudinal image of acarotid artery has become well visualized after contrast admin-istration and distinguishes the intimal-medial thickness of theanterior and posterior walls. Note the striking pattern of vasavasorum neovascularization leading to the core of theatherosclerotic plaque (arrow). This patient had diabetes andwas not receiving statin therapy. Subsequent to the recordingof these images, the patient underwent a carotid endarterec-tomy for symptomatic cerebral vascular disease; the endart-erectomy specimen revealed a plethora of microvasculaturewithin the matrix of the plaque and residual deposits of hemo-siderin resulting from prior hemorrhage (inset).Hemorrhagewith cholesterolcrystalsRecenthemorrhageTOF T1WPDW T2WFIGURE 12-6. Noninvasive imaging of intraplaque hemorrhage.Magnetic resonance T1-weighted imaging of carotid arterieshas demonstrated high diagnostic accuracy for histologicallyveriﬁed plaque hemorrhage in resected carotid endarterec-tomy specimens . It has been demonstrated that theplaques with intraplaque hemorrhage almost invariablydemonstrate an increase in plaque volume on follow-up, evenif treated with high doses of statins. In addition, patients with noplaque hemorrhage frequently decrease their plaque volumeafter statin treatment. On the other hand, the T2* values arelower in carotid lesions with intraplaque hemorrhage .
Molecular Imaging of Atherosclerosis 431baFIGURE 12-8. Optical coherence tomography for the measure-ment of ﬁbrous cap thickness. OCT has a high resolution and isthe only current modality that allows assessment of ﬁbrous capthickness. The widely accepted threshold of less than 65 mm forthin cap ﬁbroatheroma was derived from postmortem studiesof ruptured plaques. In an OCT study of more than 100 patientswith ACS and more than 150 patients with stable anginabefore percutaneous coronary intervention, ruptured (a) andnonruptured (b) lipid-rich plaques were identiﬁed and the thin-nest and most representative ﬁbrous cap thickness was deter-mined. From the ruptured plaques, the median thinnest capthickness was 54 mm (50–60 mm). For nonruptured plaques, themedian thinnest cap thickness was 80 mm (67–104 mm). Thebest cutoffs for predicting rupture were less than 67 mm (oddsratio, 16; CI, 8–34; P<0.001) for the thinnest cap thickness(Adapted from Yonetsu et al. ).
432 Atlas of Nuclear CardiologyInﬂammation, Plaque Vulnerability, and Molecular ImagingadbcMacrophages,%6420<65 <200P = 0.03<300Fibrous cap thickness>300 μNCThThMACFIGURE 12-9. Fibrous cap inﬂammation in ruptured plaques. Thethin ﬁbrous caps of the ruptured or vulnerable plaques aremarkedly inﬂamed with monocyte-macrophage inﬁltration. Ina histologic section of coronary vessel obtained from a suddendeath victim, a huge concentric plaque and cholesterol crys-tal-rich necrotic core (NC) are seen. The thin ﬁbrous cap is dis-rupted and thrombus (Th) occludes the lumen. The areaenclosed by the black square in (a) is magniﬁed in (b); the yel-low boxed area is further magniﬁed and stained for mac-rophages (MAC) (c) . The disrupted site is signiﬁcantlyinﬂamed. Analysis of ﬁbrous caps demonstrates thatmacrophages are the most dominant cellular population inruptured and vulnerable plaques, whereas SMCs are dominantin stable atherosclerotic lesions. Higher numbers of mac-rophages are associated with thinner ﬁbrous caps (d).Macrophages presently are best targeted by employing18F-ﬂuorodeoxyglucose (FDG) for PET molecular imaging.Although multiple targeting strategies have been employed inexperimental disease models and clinically in peripheral vas-culature, FDG-PET/CT imaging of atherosclerotic inﬂammationhas been studied most extensively.
Molecular Imaging of Atherosclerosis 433FIGURE 12-10. (a) Fluorodeoxyglucose accumulation is a mea-sure of the tissues’ glycolytic rate. FDG, which is structurally simi-lar to glucose, enters cells through GLUT transporter proteins.Within cells, FDG is phosphorylated by hexokinase to generateFDG-6-phosphate. However, while glucose-6-phosphate canparticipate in further glycolysis, FDG-6-phosphate cannot.Therefore, it is metabolically trapped and accumulates withinthe tissue in relation to the rate of glycolysis. (b) Macrophageactivation substantially increases the rate of glycolysis. At base-line, prior to stimulation, macrophages produce adenosine-5¢-triphosphate (ATP) at a relatively modest rate. Further, ATPsynthesis in the basal state is relatively evenly distributedbetween glycolytic and mitochondrial ATP syntheses. Afterstimulation with interferon gamma and lipopolysaccharide(LPS), the total ATP synthesis rate increases substantially.Moreover, macrophages accomplish this increased ATP syn-thesis primarily through glycolysis with relatively little mitochon-drial ATP synthesis contributing to this increased metabolicactivity. (c) Upregulation of glycolysis and glycolytic genes inmacrophages. Not all stimuli equally affect macrophage gly-colysis; the classical pathway stimulation leads to an increasein macrophage glycolysis, but alternative stimulation (such aswith IL4/IL13) does not. Classic or innate pathways result in theupregulation of glucose uptake, the start of glycolysis (upperleft) and lactate production, a glycolytic end product (upperright). Macrophage activation via the classic pathway triggersan increase in the expression of glycolysis-associated genes(lower left) and a reduction in the genes associated with thetricarboxylicacidcycleandelectrontransportchain.Moreover,classic stimulation leads to a shift in the expression of the6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2)isoforms (lower right), from the liver type-PFK2 (L-PFK2), whichhas a low net activity, to the more active ubiquitous-PFK2(uPFK2), which maintains higher fructose-2,6-bisphosphate(Fru-2,6-P2) concentrations due to minor bisphosphatase activ-ity and, therefore, potentiates the glycolytic ﬂux. (d) High gly-colytic ﬂux is required to prevent cell death in activatedmacrophages. In classically stimulated macrophages, upregu-lation of glycolysis is important to prevent cell death. In thisexperiment, galactose, which is known to be effectivelymetabolized in mitochondrial but not glycolytic ATP synthesis,was used as a substrate. Although resting macrophages cansurvive using mitochondrial ATP synthesis alone, classically acti-vated macrophages die precipitously (yellow lines) whendeprived of the ability to utilize the glycolytic pathway. CpGcytosine phosphate guanosine, LTA lipoteichoic acid (a –Adapted from Rudd et al. , b – Adapted from Garedewand Moncada , c – Adapted from Rodríguez-Prados et al., d – Adapted from Garedew et al. ).XPlasmaFDGGlucoseTissueGLUTFDGGlucoseHexokinaseG-6-phosphataseHexokinaseG-6-phosphatase Metabolic trappingFDG-6-phosphateGlycolysisG-6-phosphateabTime, h2000600400800642010812ATPsynthesisrate,pmolmiddots-1.10-6cellsTotalcellularATP,nmolmiddot10-6cellsGlycolytic ATP synthesis rateMitochondrial ATP synthesis rateTotal cellular ATP0 3 6IFNγ + LPS9 12***
Molecular Imaging of Atherosclerosis 4355040302010Macrophage layerNecrosisGranulation tissueTumor cells01a b5 15 30 45 604208610(18F)FDG,%ID/100µgprot.Mac Glioma Panc AdenoCaTime, min0Numberofgrains/100µm2In vitro FDG uptakeFIGURE 12-11. Fluorodeoxyglucose uptake by macrophages isimportant for tumor imaging and suggests that atherosclerosisimaging should be feasible. (a) Several lines of evidence haveshown that FDG uptake of macrophages is important for tumorimaging, such as that demonstrated by a radiomicrographicstudy of intratumor FDG uptake over time in an animal model.Although tumor cells consume an appreciable amount of FDG,more than twice as much FDG localizes within macrophagesand necrotic regions. (b) It has been observed that FDG uptakeby macrophages (Mac) is similar to that seen by glioma andpancreatic adenocarcinoma (Panc AdenoCa) cells. Theseobservations support the notion that at least part of the clinicalutility of FDG positron emission tomography (PET) imaging oftumors can be attributed to FDG uptake by macrophages(a – Adapted from Kubota et al. , b – Adapted fromDeichen et al. ).
436 Atlas of Nuclear Cardiology402008010012060140FDGuptake,%ID/g*103b>5–15 >15Bloodactivity>0–5Vessel inflammation, % RAM-11 stainingP < 0.001, r = 0.79FIGURE 12-12. Distribution of deoxyglucose within atheroscleroticplaques occurs predominantly in macrophages. (a)Deoxyglucose accumulation within plaques co-localizes withfoam cell macrophages. The freshly excised and still live humancarotid atherosclerotic lesions were incubated in tritiateddeoxyglucose, followed by autoradiography and histopatho-logic characterization. The radiolabel was primarily identiﬁedwithin the lipid core of the atheroma, within foamy mac-rophages . (b) It was subsequently observed that FDGuptake within the experimental atherosclerotic lesions corre-lated with the severity of inﬂammation. In this rabbit atheroscle-rotic model developed by balloon deendothelialization andhigh-cholesterol diet; FDG was administered intravenously fol-lowed by the assessment of lesional FDG uptake in comparisonwith macrophage collection deﬁned by RAM-11 staining. Astrong correlation is seen between inﬂammation and FDGuptake in this animal model.
Molecular Imaging of Atherosclerosis 437a c54320 10 20 48 40Inflammation, % CD 68 stainingFDGuptake,T/BbLow uptake1PETTrichromeCD68 High uptaker = 0.70P < 0.001108642r = 0.67P = 0.031 2 3SUVmaxIL-180dFoldexpression6421 2 3SUVmaxCathepsin K0eFoldexpressionr = 0.77P = 0.01FIGURE 12-13. Fluorodeoxyglucose uptake correlates with plaqueinﬂammation in clinical imaging of carotid vascular disease.(a) The hypothesis that arterial FDG uptake correlates withplaque inﬂammation was also tested in patients with signiﬁcantcarotid stenosis who were scheduled for carotid endarterec-tomy. These patients were ﬁrst imaged with FDG-PET, duringwhich FDG uptake within the carotid artery was quantiﬁed asa target-to-background (T/B) ratio (a and b). Shortly afterimaging, the patients underwent carotid endarterectomy, atwhich time carotid atheroma specimens were characterizedfor CD 68 staining for macrophages and quantiﬁed mac-rophage density within the same carotid lesions. A signiﬁcantcorrelation was observed between macrophage staining andFDG uptake (c), conﬁrming the information obtained from theanimal models. Additionally, FDG uptake has been shown tocorrelate with the expression of genes associated withinﬂammation, such as IL-18 (d) and cathepsin K (e). SUV stan-dardized uptake value.
438 Atlas of Nuclear CardiologyFIGURE 12-14. Fluorodeoxyglucose uptake and inﬂammationvs. high-risk plaques. Increased FDG uptake observed insymptomatic carotid disease is shown. CT angiographiccharacteristics veriﬁed morphologic features in carotidartery disease that are associated with a high risk of athero-thrombosis, such as low-attenuation plaque (LAP), positiveremodeling (PR), and ulceration. (a) FDG uptake increaseswithin plaques that have high-risk morphologic features.FDG uptake in two patients with signiﬁcant carotid stenosisis compared. The top panel depicts FDG and CT images ofa patient with high-risk morphology, whereas the bottompanel shows images from a patient who had similarly severecarotid stenosis and thus required carotid endarterectomybut did not have any high-risk features. The intense FDGuptake is associated with the high-risk carotid plaque,whereas the patient in the panel below without it showsminimal FDG uptake. (b) The cross-sectional PET-CT imagesin the top row show high-risk CT angiographic features(including positive remodeling, low-attenuation plaques,and ulceration from the lumen into the plaques). The PET-CTimage shows increased FDG uptake in red localizing to thelow-attenuation plaque. Below the PET-CT images aretrichrome and macrophage (CD 68) staining of the samelesion after it was removed during endarterectomy; endar-terectomy shows a complex plaque with multiple lipid-richnecrotic cores associated with intense CD 68 staining formacrophages. The rightmost panels demonstrate thatinﬂammation assessed either by CD 68 staining for mac-rophages or by PET-FDG uptake shows a graded increasein inﬂammation along with an increase in the number ofhigh-risk morphologic features. (c) An FDG uptake study incarotid vessel disease demonstrates intense tracer uptakein the ipsilateral carotid lesions in a patient with recentlysymptomatic disease. In contrast, the contralateral asymp-tomatic carotid lesion has minimal FDG uptake. HRM high-risk morphologic features, TBR target-to-background ratio(a and b – Adapted from Figueroa et al. , c – Adaptedfrom Rudd et al. ).(+)HRM(–)HRMaCT, axial CT, coronal PET-CT, axial PET-CT, coronal
Molecular Imaging of Atherosclerosis 439PET CT Fused imageSymptomaticcarotid stenosisAsymptomaticcarotid stenosisc151050252030Histology,%CD68staining0 1P < 0.001 for trendP < 0.001 for trend2 30 1 2 3Morphologic features210435PET,TBRCTandPET-CTLow-powertrichromeandCD68High-powerCD68imagebFIGURE 12-14. (continued).
440 Atlas of Nuclear CardiologyAorta4320a1657FDGuptake,TBRACS3.30 (2.73–4.00)Stable2.43 (2.00–2.90)P < 0.02100.80.60.40.2Mean TBR<1.7 (n = 306; 91.6 %)≥1.7 (n = 28; 8.4 %)0b10 20 30 40Time, months0Event-freesurvival**P < 0.001Framingham risk score2134MaximumTBR<10 % >20 %10–20 %P = 0.001P = 0.001 P = 0.284cFIGURE 12-15. Direct localization of inﬂammation for the riskstratiﬁcation of acute vascular events. (a) Aortic FDG uptakemay be found to be increased after ACS in the nonculprit vas-culature, including the ascending aorta. It is hypothesized thatthis is caused by the increased cytokine release that is seen afteratherothrombotic injuries such as myocardial infarction. Thisﬁgure demonstrates an increased metabolic activity in the aor-tic root soon after ACS. (b) Elevated arterial FDG uptake identiﬁesan increased systemic risk of future atherothrombosis. In patientsevaluated for oncologic indications for whom subsequent fol-low-up information was available, a relatively lower arterial FDGuptake demonstrated higher event-free survival over the subse-quent 40 months compared with patients with high FDG uptake.These data demonstrate that assessment of arterial inﬂammationin nonculprit arteries may provide prognostic information. (c) TheTBR levels of the arterial FDG signal increases with increasingFramingham risk scores. Stratiﬁed by Framingham risk score,patients with low risk (<10 %) show the lowest TBR and those witha score greater than 20 show relatively higher TBR. Patients withintermediate risk reveal a rather broad range for FDG uptake,with substantial overlap between those with low and highscores. It remains unknown whether the FDG uptake would beuseful for reclassifying patients with an intermediate Framinghamrisk score into truly high- or truly low-risk categories. Carotidplaque inﬂammation on FDG-PET predicts early stroke recur-rence. In a study of 60 patients with recent stroke, a signiﬁcantlyhigher FDG signal was associated with patients who subse-quently experienced a recurrence of stroke within 90 days (seeTable 12.1) (a – Adapted from Rogers et al. , b – Adaptedfrom Rominger et al. , c – Adapted from Kim et al. ).
Molecular Imaging of Atherosclerosis 441a1.11.00.90.80.70 7 14 222.214.171.124.126.96.36.199.42MeanTBRScan 1Scan 2L-GCGCAscendingaortaArch ofaortaDescendingaorta*AbdaortaLeftcarotidRightcarotidbTime, days0.6Mean TBR in scan 1 and scan 2 by regionRelative SUV10864975321No Rx Atorvastatin Simvastatin Mevastatinc0P < 0.001P < 0.001P < 0.001RelativeSPECTsignalFIGURE 12-16. Reproducibility of vascular 18F-ﬂuorodeoxyglucoseuptake and feasibility of demonstrating the efﬁcacy of phar-maceutical interventions. (a) The arterial FDG uptake signal isrelatively stable over a 1-month period in clinically stablepatients with atherosclerosis. The excellent reproducibility ofthe signal was observed across several different vascular beds.(b) Moreover, animal studies show that the arterial inﬂammatorysignal is rapidly modiﬁable using anti-inﬂammatory treatment.In this particular case, the encapsulated glucocorticoid formu-lation is associated with a substantial and rapid reduction ininﬂammation (within 2 days after drug administration). (c)Similarly, rapid modulation of atherosclerotic lesions has beendemonstrated using other targeting strategies. In this experi-ment, radiolabeled monocytes are employed to targetinﬂamed atherosclerotic lesions. Pretreatment with any of threestatins results in a signiﬁcant reduction in tracking of the radio-labeled monocytes to the lesions, and such rapid tracking tothe aortic lesions is observed over 5–7 days. These data dem-onstrate that atherosclerotic lesions are rapidly modiﬁed usinganti-atherosclerotic therapies. Abd abdominal, GC glucocorti-coid, L-GC nanomedicinal formulation of glucocorticoid, Rxtreatment, SPECT single-photon emission CT (a – Adapted fromRudd et al. , b – Adapted from Lobatto et al. , c –Adapted from Kircher et al. ).
442 Atlas of Nuclear CardiologyFIGURE 12-17. (a) The efﬁcacy of statin therapy was ﬁrst observedin a single-center open-label study of simvastatin therapy vs.dietary modiﬁcation in patients undergoing FDG-PET imaging.Over a 3-month period, the FDG uptake, measured as an SUV,remained stable in patients who were randomly assigned todiet alone, whereas a 10 % signal reduction was observed inpatients treated with low to moderate doses of simvastatin. (b) Similarly, pioglitazone therapy for 4 months resulted ina signiﬁcant reduction in the FDG signal, measured here as theTBR. In contrast, glimepiride did not result in a reduction in PETsignal. Care was taken to keep fasting glucose levels similarbetween patients randomly assigned to glimepiride and thoseassigned to pioglitazone. A correlation also was observedbetween changes in both high-density lipoprotein (HDL) andC-reactive protein and the reduction in TBR signal . (c) AP38 mitogen-activated protein (MAP) kinase inhibitor similarlyreduced arterial inﬂammation in patients with atherosclerosis.Patients with stable atherosclerosis were randomized to pla-cebo vs. one of two doses of P38 MAP kinase inhibitors. Atbaseline, patients were relatively well treated for the athero-sclerosis, manifesting in low-density lipoprotein of 70 mg/dLand baseline C-reactive protein of 1 mg/L. After 3 months oftreatment, there was a substantial but comparable reductionin the arterial inﬂammatory signal with both inhibitorscompared with the placebo . Interestingly, the same studyreported a substantial reduction in the FDG signal within vis-ceral fat in patients treated with the higher dose of the P38MAP kinase antagonist; there was no signiﬁcant change in thesignal within subcutaneous fat (see Tables 12.2 and 12.3).Visceral fat is known to be inﬁltrated by macrophages. (d)Recently, the effect of the cholesteryl ester transport protein-antagonist dalcetrapib was evaluated on arterial inﬂammationas assessed by FDG-PET imaging. Although no signiﬁcant treat-ment effect on the overall arterial inﬂammatory signal wasobserved, there was a signiﬁcant relationship betweenincreases in HDL across all patients vs. changes in theinﬂammatory signal . (e) Further, the change in the PET sig-nal at 6 months is associated with future changes in structuralmeasurements of the same arterial lesions at 24 months. Thepatients who experienced an increase in their inﬂammatorysignal at 6 months tended to show a substantial progression oftotal vessel area on MRI at 2 years, whereas patients who hada decrease in the PET signal at 6 months revealed substantiallyless remodeling on MRI at 24 months. These data provide pre-liminary insights into a relationship between early inﬂammatorychanges and later structural changes within the same vessels.BD twice a day, MDS most diseased segment, NS not signiﬁcant,OD once a day.Diet SimvastatinSUVBaselineFollow-up2.01.51.02.01.51.0Baseline Post-treatmentNSBaseline Post-treatmentP < 0.01PET/CTa
Molecular Imaging of Atherosclerosis 443Pioglitazone Glimepiride Change in mean TBR from baselineTBR2.52.01.51.00.502.52.01.51.00.50Baseline Post-treatmentP < 0.01Baseline Post-treatmentNS P < 0.02b0–0.1–0.2–0.3–0.40.20.10.3ΔTBRPioglitazone Glimepiride–0.1–0.200.05–0.15–0.25–0.05Changeinatherosclerosisinflammation,ΔTBRPlacebo BDODP = 0.01P = 0.02c–2020400–40ChangeinMDSTBR,%increasefrombaselineTertile 1(<1)Tertile 3(>12)Tertile 2(1–12)R = –0.30, P = 0.04Slope = 4.3%de PET: change in MDS TBR at 6 months0.060.040.0200.100.080.12MRI:changeinvesselareaat24monthsDecrease IncreaseFIGURE 12.17 (continued).
444 Atlas of Nuclear CardiologyGroup102345FDGuptakeCoronaryPET-CTACS:new stentStable syndrome:new stentStable syndrome:old stentACS:new stentStable syndrome:old stentStable syndrome:new stentP = 0.02P = 0.006FIGURE 12-18. Imaging of coronary artery inﬂammation. The fea-sibility of molecular imaging has ﬁnally been demonstrated forthe assessment of inﬂammation in coronary vasculature. In arecent study, patients presenting with ACS underwent an FDG-PET imaging study and were compared with patients with sta-ble coronary syndromes. CT imaging was obtained to identifythe culprit lesion in ACS or the target lesion in stable disease,which was indicated by virtue of stent placement. As can beappreciated here, the group of patients with recent ACS hadrelatively high FDG uptake in association with the location ofthe culprit lesion detected by the recently deployed stent. Incontrast, lower FDG signals were observed in association withstents deployed for stable syndromes (Adapted from Rogerset al. ).Maximum SUV (SD) Day 84 vs. baseline Placebo and baseline correctedGroup Baseline Day 84 Difference 95 % CI P value Difference 95 % CI P valueHD (n=33) 0.32 (0.085) 0.30 (0.095) −0.02 −0.05, 0.00 0.060 −0.00 −0.04, 0.03 0.815LD (n=32) 0.34 (0.084) 0.31 (0.079) −0.03 −0.05, 0.00 0.020 −0.01 −0.05, 0.03 0.636Placebo (n=30) 0.34 (0.112) 0.32 (0.108) −0.02 −0.05, 0.01 0.168 NA NA NATABLE 12-2. The FDG signal in subcutaneous fat. HD high dose, LD low dose, NA not applicable.Maximum SUV (SD) Day 84 vs. baseline Placebo and baseline correctedGroup Baseline Day 84 Difference 95 % CI P value Difference 95 % CI P valueHD (n=33) 0.59 (0.110) 0.53 (0.120) −0.06 −0.09, –0.02 0.002 −0.05 −0.09, –0.01 0.018LD (n=32) 0.58 (0.133) 0.56 (0.140) −0.02 −0.06, 0.02 0.274 −0.02 −0.06, 0.03 0.502Placebo (n=30) 0.57 (0.130) 0.57 (0.081) −0.01 −0.03, 0.02 0.654 NA NA NATABLE 12-3. The FDG signal in visceral fat. HD high dose, LD low dose, NA not applicable.TABLE 12-1. Carotid plaque inﬂammation to predict early stroke recurrence. CCA common carotid artery, ICA internalcarotid artery (Adapted from Marnane et al. )Maximum SUV, g/mL (SD)Site of FDG uptake Stroke recurrence, n=13 No stroke recurrence, n=47 P valueSymptomatic ICA 2.87 (0.81) 2.37 (0.52) 0.01Asymptomatic ICA 2.63 (0.62) 2.26 (0.41) 0.01Symptomatic CCA 3.1 (0.56) 2.58 (0.52) 0.003
Molecular Imaging of Atherosclerosis 445Arterial lumenBlood monocyteMCP-1CCR2Monocyte adheredto epitheliumMonocyte migratinginto intimaDyingmacrophageApoptoticbodiesMacrophagefoam cellTissuefactorLipiddropletsModifiedlipoproteinparticleScavengerreceptorAdhesionmoleculeVCAM-1Arterial intimaM-CSFROSMMPCytokinesMonocyte becomingintimal macrophageFIGURE 12-19. Strategies for targeting of inﬂammation in athero-sclerosis. Newer techniques will evolve that target the upregu-lation of surface molecules or secreted products that areuniquely expressed by the inﬂammatory cells associated withunstable plaques. This road map identiﬁes important targets formolecular imaging. It will be important to identify atherosclero-sis burden, based on the results of the PROSPECT (ProvidingRegional Observations to Study Predictors of Events in theCoronary Tree) trial published in the New England Journal ofMedicine in 2011. In addition, inﬂammation is a destabilizingcomponent of high-risk atherosclerotic lesions and therefore isa high-reward molecular imaging target (see Table 12.4).Although FDG is an attractive targeting tracer and offers globalinformation about vascular inﬂammation, newer radiotracers,such as 18F-4V or 11C-PK11195, are emerging as promising tools.A positron emission tomography tracer (18F-4V) that reports onvascular cell adhesion molecule (VCAM)-1, an adhesion mol-ecule upregulated early in atherogenesis, may allow noninva-sive detection of the system-wide burden of inﬂammatoryatherosclerosis . Speciﬁc localization of high-risk coronaryplaques will greatly improve the efﬁciency of clinical trials test-ing local therapies. For example, the recently described SECRITT(Shield Evaluated at Cardiac Hospital in Rotterdam forInvestigation and Treatment of TCFA) trial employed multi-modal structural imaging prior to prophylactic stent implanta-tion . For high-resolution molecular imaging of coronarylesion inﬂammation, a near-infrared ﬂuorescence (NIRF) molec-ular imaging agent for coronary high-risk plaque detection isthe US Food and Drug Administration–approved agent indo-cyanine green (ICG). Using intravascular NIRF sensing, ICG wasrecently shown to target macrophages and lipids within exper-imental and human plaques . Further advances in molecu-lar imaging of coronary lesions are expected with newintegrated NIRF-OCT catheters that allow simultaneous high-resolution structural and molecular imaging . CCR2chemokine (CC motif) receptor 2, MCP monocyte chemoat-tractant protein, M-CSF monocyte colony-stimulating factor,MMP matrix metalloproteinase, ROS reactive oxygen species(Adapted from Libby ).Future ConsiderationsTargetsModality VCAM Monocyte Lipid Protease MPO, ROS Apoptosis AngiogenesisMRI + + + + + + +PET/SPECT + + + + + + +NIRF + + + + + + +US + +TABLE 12-4. Imaging agents for targets and imaging modalities.
446 Atlas of Nuclear CardiologyReferences1. Jaffer FA, Weissleder R. Molecular imaging in the clinical arena.JAMA. 2005;293:855–62.2. Jaffer FA, Libby P, Weissleder R. Molecular imaging of cardio-vascular disease. Circulation. 2007;116:1052–61.3. Narula J, Garg P, Achenbach S, et al. Arithmetic of vulnerableplaques for noninvasive imaging. Nat Clin Pract CardiovascMed. 2008;5:S2–10.4. Shapiro E, Bush D, Motoyama S, et al. Imaging atheroscleroticplaques vulnerable to rupture. In: Budoff MJ, Achenbach S,Narula J, editors. Atlas of cardiovascular computed tomogra-phy. Philadelphia: Current Medicine Group; 2007. p. 119–38.5. Hansson GK. Inﬂammation, atherosclerosis, and coronaryartery disease. N Engl J Med. 2005;352:1685–95.6. Kwon HM, Sangiorgi G, Ritman EL, et al. Enhanced coronaryvasa vasorum neovascularization in experimental hypercho-lesterolemia. J Clin Invest. 1998;101:1551–6.7. Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhageand progression of coronary atheroma. N Engl J Med.2003;349:2316–25.8. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaqueprogression and vulnerability to rupture: angiogenesis as asource of intraplaque hemorrhage. Arterioscler Thromb VascBiol. 2005;25:2054–61.9. Kolodgie FD, Narula J, Yuan C, et al. Elimination of neoangio-genesis for plaque stabilization: is there a role for local drugtherapy? J Am Coll Cardiol. 2007;49:2093–101.10. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, MintzGS, et al. A prospective natural-history study of coronary ath-erosclerosis. N Engl J Med. 2011;364(3):226–35.11. Motoyama S, Kondo T, Anno H, et al. Multi-slice computetomographic characteristics of coronary lesions in acute coro-nary syndromes. J Am Coll Cardiol. 2007;50:319–26.12. Motoyama S, Sarai M, Harigaya H, et al. Computed tomogra-phy characteristics of atherosclerotic plaques subsequentlyresulting in acute coronary syndrome. J Am Coll Cardiol.2009;54(1):49–57.13. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterizationof coronary atherosclerotic plaque by use of optical coher-ence tomography. Circulation. 2005;111:1551–5.14. Takaya N, Yuan C, Chu B, et al. Presence of intraplaque hem-orrhage stimulates progression of carotid atheroscleroticplaques: a high-resolution magnetic resonance imaging study.Circulation. 2005;111:2768–75.15. Raman SV, Winner MW, Tran T, et al. In vivo atheroscleroticplaque characterization using magnetic susceptibility distin-guishes symptom-producing plaques. JACC CardiovascImaging. 2008;1:49–57.16. Feinstein SB. Contrast ultrasound imaging of the carotid arteryvasa vasorum and atherosclerotic plaque neovascularization.J Am Coll Cardiol. 2006;48:236–43.17. Yonetsu T, Kakuta T, Lee T, Takahashi K, Kawaguchi N,Yamamoto G, et al. In vivo critical ﬁbrous cap thickness forrupture-prone coronary plaques assessed by optical coher-ence tomography. Eur Heart J. 2011;32:1251–9.18. Rudd JH, Narula J, Strauss HW, Virmani R, Machac J, Klimas M,et al. Imaging atherosclerotic plaque inﬂammation byﬂuorodeoxyglucose with positron emission tomography: readyfor prime time? J Am Coll Cardiol. 2010;55(23):2527–35.19. Garedew A, Moncada S. Mitochondrial dysfunction andHIF1alpha stabilization in inﬂammation. J Cell Sci. 2008;121(20):3468–75.20. Rodríguez-Prados JC, Través PG, Cuenca J, Rico D, AragonésJ, Martín-Sanz P, et al. Substrate fate in activated mac-rophages: a comparison between innate, classic, and alterna-tive activation. J Immunol. 2010;185(1):605–14.21. Garedew A, Henderson SO, Moncada S. Activated mac-rophages utilize glycolytic ATP to maintain mitochondrial mem-brane potential and prevent apoptotic cell death. Cell DeathDiffer. 2010;17(10):1540–50.22. Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N.Microautoradiographic study for the differentiation of intratu-moral macrophages, granulation tissues and cancer cells bythe dynamics of ﬂuorine-18-ﬂuorodeoxyglucose uptake. J NuclMed. 1994;35:104–12.23. Deichen JT, Prante O, Gack M, Schmiedehausen K, Kuwert T.Uptake of [18F]ﬂuorodeoxyglucose in human monocyte-mac-rophages in vitro. Eur J Nucl Med Mol Imaging. 2003;30:267–73.24. Figueroa AL, Subramanian SS, Cury RC, Truong QA, GardeckiJA, Tearney GJ, et al. Distribution of inﬂammation within carotidatherosclerotic plaques with high-risk morphological features:a comparison between positron emission tomography activity,plaque morphology, and histopathology. Circ CardiovascImaging. 2012;5(1):69–77.25. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, AntounN, et al. Imaging atherosclerotic plaque inﬂammation with[18F]-ﬂuorodeoxyglucose positron emission tomography.Circulation. 2002;105(23):2708–11.26. Rogers IS, Nasir K, Figueroa AL, Cury RC, Hoffmann U, VermylenDA, et al. Feasibility of FDG imaging of the coronary arteries:comparison between acute coronary syndrome and stableangina. JACC Cardiovasc Imaging. 2010;3(4):388–97.27. Rominger A, Saam T, Wolpers S, et al. 18F-FDG PET/CT identiﬁespatients at risk for future vascular events in an otherwise asymp-tomatic cohort with neoplastic disease. J Nucl Med. 2009;50:1611–20.28. Kim TN, Kim S, Yang SJ, et al. Vascular inﬂammation in patientswith impaired glucose tolerance and type 2 diabetes: analysiswith 18F-ﬂuorodeoxyglucose positron emission tomography.Circ Cardiovasc Imaging. 2010;3:142–8.29. Lobatto ME, Fayad ZA, Silvera S, Vucic E, Calcagno C, Mani V,et al. Multimodal clinical imaging to longitudinally assess ananomedical anti-inﬂammatory treatment in experimentalatherosclerosis. Mol Pharm. 2010;7(6):2020–9.30. Kircher MF, Grimm J, Swirski FK, Libby P, Gerszten RE, Allport JR,Weissleder R. Noninvasive in vivo imaging of monocytetrafﬁcking to atherosclerotic lesions. Circulation. 2008;117(3):388–95.31. Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuatesplaque inﬂammation: evaluation by ﬂuorodeoxyglucose posi-tron emission tomography. J Am Coll Cardiol. 2006;48:1825–31.32. Mizoguchi M, Tahara N, Tahara A, et al. Pioglitazone attenu-ates atherosclerotic plaque inﬂammation in patients withimpaired glucose tolerance or diabetes: a prospective, ran-domized, comparator-controlled study using serial FDG PET/CTimaging study of carotid artery and ascending aorta. JACCCardiovasc Imaging. 2011;4:1110–8.33. Maysoon Elkhawad, James H.F. Rudd, Lea Sarov-Blat,Gengqian Cai, Richard Wells, L. Ceri Davies, David J. Collier,Michael S. Marber, Robin P. Choudhury, Zahi A. Fayad,Ahmed Tawakol Fergus V. Gleeson, John J. Lepore, Bill Davis,Robert N. Willette, Ian B. Wilkinson, Dennis L. Sprecher, andJoseph Cheriyan. Effects of p38 mitogen-activated proteinkinase inhibition on vascular and systemic inﬂammation inpatients with atherosclerosis: results from a randomizedcontrolled study. JACC Cardiovascular Imaging 2012;5(9):911–922.34. Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T,et al. Safety and efﬁcacy of dalcetrapib on atheroscleroticdisease using novel non-invasive multimodality imaging(dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378(9802):1547–59.
Molecular Imaging of Atherosclerosis 44735. Marnane M, Merwick A, Sheehan OC, Hannon N, Foran P, Grant T,et al. Carotid plaque inﬂammation on 18F-ﬂuorodeoxyglucosepositron emission tomography predicts early stroke recurrence.Ann Neurol. 2012;71(5):709–18.36. Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S,Figueiredo JL, et al. 18F-4V for PET-CT imaging of VCAM-1expression in atherosclerosis. JACC Cardiovasc Imaging.2009;2(10):1213–22.37. Ramcharitar S, Gonzalo N, van Geuns RJ, Garcia-Garcia HM,Wykrzykowska JJ, Ligthart JM, et al. First case of stenting of avulnerable plaque in the SECRITT I trial-the dawn of a new era?Nat Rev Cardiol. 2009;6(5):374–8.38. Vinegoni C, Botnaru I, Aikawa E, Calfon MA, Iwamoto Y, FolcoEJ, et al. Indocyanine green enables near-infrared ﬂuorescenceimaging of lipid-rich, inﬂamed atherosclerotic plaques. SciTransl Med. 2011;3(84):84ra45.39. Yoo H, Kim JW, Shishkov M, Namati E, Morse T, Shubochkin R,et al. Intra-arterial catheter for simultaneous microstructuraland molecular imaging in vivo. Nat Med. 2011;17(12):1680–4.40. Libby P. Inﬂammation in atherosclerosis. Nature. 2002;420:868–74.