The Vascular Atherosclerosis and Imaging Targets

Peter Libby
1

Biology
1, 3

of

1 ,2

, Marcelo DiCarli

1 , 2,

and Ralph Weissleder

Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School, Boston, Massachusetts; Division, Department of Medicine, Department of Radiology, Brigham and Womens Hospital, Boston, Massachusetts; and for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts

Cardiovascular 3 Center

The growing worldwide health challenge of atherosclerosis, together with advances in imaging technologies, have stimulated interest in novel approaches to gauging this disconsiderable ease. The last several decades have witnessed a burgeoning in understanding of the molecular pathways involved in atherogenesis, lesion progression, and the mechanisms underlying the complications of human atherosclerotic plaques. The imaging of atherosclerosis is reaching beyond anatomy to encompass assessment of aspects of plaque biology related to the pathogenesisandcomplication of the disease. The harnessing of these biologic insights promises to provide a plethora of new targets for molecular imaging of atherosclerosis. The goals for the years to come must include translation of the experimental work to visualization of these appealing biologic targets in humans. Key Words: vascular; atherosclerosis; vascular biology; segmental arterial stenosis J Nucl Med 2010; 51:33S37S DOI: 10.2967/jnumed.109.069633

With respect to current understanding of clinical aspects of atherosclerosis, a new focus on molecular aspects of lesion biology, rather than on the degree of luminal compromise, has emerged. Traditional vascular imaging of atherosclerosis centered on anatomic issues and primarily assessed the degree of segmental arterial stenosis and vascular calcification. Many treatment modalities aim at relieving stenoses. Yet, although revascularization often effectively relieves ischemia, it has proven disappointing in preventing myocardial infarction or prolonging life except in selected patient groups. Most acute coronary syndromes actually result from thrombotic occlusions that often associate with noncritical stenoses (79). On a per-plaque basis, fixed stenoses may cause fewer thrombotic complications than the more numerous noncritically stenoticfound in the same artery (Fig. 1) (9). lesions Pathologic observations shed light on this disparity. remodeling Outward through compensatory enlargement permits the development of a considerable burden of atherosclerosis without luminal encroachment that causes Indeed, a physical disruption of the atherosclestenoses. rotic plaque, rather than preexisting high-degree stenosis, causes most fatal coronary events. Rupture of the plaquescap causes most fatal coronary thrombi (Fig. fibrous 1). Plaques that have provoked fatal coronary thrombosis havefibrous caps, large lipid pools, abundant in ammatory thin cells, and relatively few smooth muscle cells (Fig. 1) (8,10). Laboratory studies substantiate mechanisms that in link ammation to low levels of interstitial collagen, the prime constituent of the plaques protective fibrous cap. ammatory mediators impair interstitial collagen In synthesis by smooth muscle cells and boost production of collagendestroying enzymes, including the matrixmetalloproteinase interstitial collagenases. Moreover, exposure to proin ammatory stimuli heightens monocyte recruitment and macro-production of the potent procoagulant tissue factor. phage Thus, in ammation regulates not only the strength of the plaques extracellular matrix but also its thrombogenicity (5). Aspects of in ammation have therefore surfaced as 1 category of emerging major targets for functional imaging of atherosclerosis (Fig. 2). This vascular biology of atherosclerosis suggests several molecular processes that

he growing worldwide health challenge of atherosclerosis, together with advances in imaging technologies, have stimulated considerable interest in novel approaches to gauging this disease. The last several decades have witnessed a burgeoning in understanding of the molecular involved in atherogenesis, lesion progression, and pathways the mechanisms underlying the complications of human atherosclerotic plaques (16). This progress in our fundamental understanding of the pathogenesis of atherosclerosis has opened up new horizons for imaging. The processes identified by basic science studies offer novel targets for visualizing aspects of atherosclerosis that were unimagined just a decade ago. Appropriate deployment of imaging strategies requires acquaintance with some current of the b asic and clinical biology of this concepts disease.
R ec e i ve d Ma r. 5 , 2 0 10 ; re vi si o n a cc e pte d Mar . 1 2 , 2 0 1 0. F o r c o rr es po n de n c e o r re pri n ts c o nt ac t: Pe te r L ib by, D iv is io n o f Ca rd io v as c u la r M edi c in e , D e pa rtm e n t o f Med ic in e , B ri g h a m a nd W o m e n s Ho sp ita l , Ha r va rd Me di c al Sc h o o l , 77 A ve . L o u is Pa st eu r , B o s to n , MA 0 2 11 5 . E -m a i l: p li bby@ ri c s. bw h. h a rv a rd. e du CO PY RI G HT 2 01 0 by t he So c ie ty o f Nuc l ea r Me dic i n e, In c .

V ASCULAR BIOLOGY OF ATHEROSCLEROSIS

Libby et al. 33S

FIGURE 1. Simplified schema of versity of lesionsdi- human coronary in atherosclerosis, depicting 2 morphologic extremes of coronary atherosclerotic plaques, to illustrate the challenge of molecular imaging of atherosclerosis. Stenotic lesions, well visualized by traditional angiographic approaches, tend to have smaller lipid cores, more fibrosis, and calcification; thick fibrous caps; and less compensatory enlargement (positive remodeling). They typi- produce ischemia, detectable cally by perfusion scans, that is appropriately managed by combined medical therapy revascularization for symptom and often relief. Thus, traditional imaging modali- well to diagnose and aid ties serve the management of stenotic lesions. Nonstenotic lesions generally outnumber stenotic plaques, and they tend to have large lipid cores and thin fibrous caps, which are susceptible to rupture and thrombosis. These lesions often undergo substantial compensatory enlargement, leading to underestimation of lesion size by angiography. They do not cause perfusion defects on nuclear scans. Nonstenotic plaques may cause no symptoms for many years, but when disrupted, they can suddenly provoke an episode of unstable angina or acute myocardial infarction. Management of nonstenotic lesions should include lifestyle modification (and pharmacotherapy in high-risk individuals). Enlarged segments of this schematic show longitudinal section (left) and cross section (right). Many coronary atherosclerotic lesions may lie between these 2 extremes, produce mixed clinical manifestations, and require multipronged management. Because both types of lesions usually coexist in high-risk individuals, optimum management often requires both revascularization and systemic therapy. PTCA 5 percutaneous transluminal coronary angioplasty; CABG 5 coronary artery bypass graft. (Reprinted with permission of (51).)

could serve as imaging targets (Table 1). The following sections will mention some of these biologic processes and provide examples of how molecular imaging might exploit them .
ENDOTHELIAL ACTIVATION

include intercellular initiation molecule 1 and Pselectin (1517). (CD62P) Microvessels in human atheromata abound, particularly in the plaq ues base (18,19). These neovessels arise by angiogenesis, from the vasa vasorum or perhaps from the macrovascular luminal surface. Molecules involved in angiogenesis thus may also serve as targets for molecular imaging. Integrins expressed by neovessels in atheroscle- such as a rotic arteries, v b 3 , may permit imaging of 1 8 F-labeled affinity angiogenesis in plaques, and several ligands have been described (14). Studies of the ow in plaques, an index of microvascular functions, may also provide a novel imaging target in atherosclerosis (20).
MACROPHAGE ACTIVATION RECRUITMENT AND

The healthy endothelial mono layer in arteries resists prolonged contact with blood leukocytes, produces endogenous vasodilator molecules, combats thrombosis, favors fibrinolysis, and expresses enzymes, such as superoxide dismutase, that can degrade reactive oxygen species. Laminar shear stress, as prevails in normal arteries, fosters these homeostatic endothelial functions (11,12). But endothelial dysfunctional when exposed to disturbed ow, cells become instead of laminar sheer stress, and to proatherogenic factors such as modified lipoprotein or proin ammatory cytokines. Among markers of endothelial dysfunction, leukocyte adhesion molecules have elicited special interest for molecular imaging (Fig. 2). For example, as a target vascular cell adhesion molecule-1 (VCAM-1) serves as a well-validated marker of endothelial activation. The monolayer of endothelial cells on the arterial intima provides a poor imaging target, but human atherosclerotic abundant microvessels rich in VCAMlesions harbor 1. VCAM-1 can internalize ligands and thus cause them to accumulate in activated endothelial cells and perhaps muscle cells. Several VCAM-1directed, peptidesmooth based imaging agents have been developed (13), and at least 1 lead compound is in clinical development (14). Other adhesion molecules implicated in atherogenesis

After adhering to the endothelium via adhesion molecules such as VCAM-1, leukocytes can enter into the intima, drawn in by chemoattractant cytokines overex- in plaque. Mononuclear phagocy tes, the pressed most abundant leukocytes recruited to atheromata, enter the arterial wall as monocytes and mature into macrophages. phagocytes exhibit several functions Mononuclear that could serve as targets for molecular imaging. For example, simply monitor accumulation of these one might cells within the artery wall. Expression of activation markers, function, or structures that identify subtypes phagocytic of monocytes might go beyond mere accumulation of leuko- to reveal their functional capacities as well cytes (21,22). Phagocytosis provides an attractive target for molecular imaging of macrophages, because it could lead to the capture

34S T

HE

JOURNAL OF NUCLEAR MEDICINE Vol. 51 No. 5 (Suppl) May 2010

FIGURE 2. Potential molecular imaging targets in atherosclerosis. White boxes show putative targets for molecular imaging atherosclerosis. of Atherogenesis involves recruitment of in ammatory cells from blood, represented by the monocyte in the upper-left-hand corner of this diagram. Monocytes are the most numerous leukocytes in atherosclerotic plaque. Recruitment depends on expression of adhesion molecules on macrovascular endothelium, as shown, and on plaque microvessels. Once resident in the arterial intima, activated macrophages become phagocytically active, a process that provides another potential plaque imaging. Oxidatively modified low-density lipoprotein (mLDL)associated epitopes that accumulate in target for plaques serve as targets for molecular imaging. Foam cells may exhibit increased metabolic activity, augmenting their may also 18 F-FDG uptake. Activated phagocytes can also elaborate proteinuptake of glucose, a process already measurable in the clinic by degrading enzymes that can catabolize collagen in the plaques fibrous cap, weakening it, and rendering it susceptible to rupture and hence thrombosis. Mononuclear phagocytes dying by apoptosis in plaques display augmented levels of phosphatidylserine on their surface. Probes for apoptosis such as annexin V may also visualize complicated atheromata. Microvessels themselves can express not only leukocyte adhesion molecules (shown in green) but also integrins such as a Proof-of-principle experiments in animals support each process or molecule in white boxes as target for molecular imaging agents.

b3 .

and concentration of imaging agents. Imaging initiatives have advantage of several aspects of phagocytosis. Activated taken macrophages can internalize and concentrate nanoparticles example, those coated with dextran (23). Activated for macrophages also express scavenger receptors, members of the broad pattern recognition receptor family. Oxidativelylow-density lipoprotein can bind to certain modified scavenger and thus undergo update and accumulation receptors within macrophages (2,24). Epitopes associated with such modified lipoproteins may also serve as imaging targets (2527).

Activated macrophages may use glycolysis more than 1 8 F-FDG other cells within can measure glucose plaques. as an example of a metabolic marker, associated uptake and serves with in ammatory cells, that may also disclose functional regarding plaques (Fig. 2) (28,29). information Macrophages within atheromata produce matrixdegrading proteinases implicated in weakening the fibrous cap and rendering plaques liable to rupture and thrombosis. The cat- property of enzymes should amplify signals. alytic Thus, proteinases represent promising targets for molecular imaging,

V ASCULAR BIOLOGY OF ATHEROSCLEROSIS

Libby et al. 35S

TABLE 1. Functional Atherosclerosis

Target Examples

Imaging

Targets

in

Endothelial activation Adhesion molecules, class histocompatibility molecules Accumulation and activation of cells Visualization of in ammatory mediators Metabolic cells within activity of monocytes), smooth muscle cells Fractalkine, chemokine receptors Glucose transport II

White blood cells (especially

2). Monitoring oxidative stress in plaques could provide an additional window on cellular functions that go beyond anatomy to reveal features of atheromata that in uence clinical importance their (48). The imaging of atherosclerosis is reaching beyond anatomy to encompass the assessment of aspects of plaque biology related to the pathogenesis and complication of the disease. Laboratory investigations that suggest the operation of in ammatory pathways from the inception through the complication of this disease have received considerable observations on human tissues and in support from human populations. Several pilot observations and experimental studies of atherosclerosis have served as proof of the principle that in ammatory processes durin g atherogenesis a new window for imaging. Other can provide recent biologic insights into atherosclerosis suggest imaging in addition to in ammatory processes. For targets example, epitopes of modified lipoprotein may permit targeting assessment of one of the triggering pathways thought to operate in the initiation of atherosclerosis. Indeed, constit- oxidatively modified low-density lipoprotein may uents of serve as a proximal inciting stimulus to the in ammatory under way in the atheromatous plaque. response Angio- within plaques, another emerging target for atherogenesis sclerosis imaging, may result from in ammatory activation but can also amplify in ammation by providing a large surface area for ongoing leukocyte recruitment. Once resident in the plaque, activated phagocytic leukocytes can elaborate effector molecules of innate immunity, including and reactive oxygen speciesaspects of atheroproteinases genesis also susceptible to molecular imaging. The harnessing of these biologic processes promises to provide a plethora of new targets for molecular imaging of atherosclerosis. The goals for the years to come must include of translation the experimental work to the visualization of these appealing biologic targets in humans. This enterprise will require multidisciplinary teams and resources that extend those available to most individual laboratories. beyond In particular, molecular imaging probes will require scalable using good manufacturing processes for syntheses human approval for human use of new imaging probes use. The will necessitate toxicology studies. Bridging the gap between the animal laboratory and the clinic thus presents considerable challenges (49). The dividends of realizing the promise of the molecular imaging of atherosclerosis should reward this investment. of novel therapies and hence drug Evaluation development in the atherosclerosis arena desperately need biomarkers that re ect biologic aspects of the disease. Molecular imaging strategies may well help to identify doses of new agents most likely to succeed in large clinical endpoint trials. Finally, molecular imaging of aspects of atheroscle- prove to be a valuable clinical tool in rosis may selected Like any imaging modality, however, the patients. clinical molecu lar imaging will require rigorous use of evaluationclinical benefit and cost-effectiveness (50). for added

atherosclerotic plaque Apoptosis within atherosclerotic plaque Plaque procoagulant activity Proteolytic enzymes Cathepsin K, matrix-metalloproteinases: gelatinases and collagenases Reactive oxygen species Superoxide anion (O hypochlorous acid Angiogenesis markers Integrin a
V 3 22

Phosphatidyl serine Tissue factor, factor XIII

),

and several active site binders and imaging prodrugs have described (3035). Because proin ammatory been mediators boost the expression of these matrix-degrading enzymes in cells that elaborate them in atheromata, imaging proteinases may not only enable interrogation of a specific pathobiologic process (extracellular matrix digestion) but may provide a window on in ammation in also general. advanced atherosclerotic plaque contains a lipid The core rich in cholesteryl esters, cholesterol monohydrate crystals, and cellular debris. Some refer to this compartment of the plaque as the necrotic core. Indeed, cells in atheromata can dieoncosis, by apoptosis (programmed cell death) (3639). by Smooth muscle cell apoptosis may disrupt repair mechanisms in the plaque that maintain the extracellular matrix required for structural integrity (40,41). Macrophage apoptosis may help generate the lipid core and, by the production of tissuefactorrich apoptotic bodies, may generate thrombogenic microparticles whose release on plaque disruption can propagate thrombosis. Cells undergoing apoptosis exteriorize phosphatidylserine, a target for molecular imaging of dying cells and potentially for reporting on the biology associated with cell death in atheromata. Annexin V binds to phospha- providing a ligand for imaging cell death (42,43). tidylserine, Activated macrophages, smooth muscle cells, and endothelial cells heighten the production of reactive oxygen that promote cellular damage or death and also species serve as both a monitor of in ammation and a pathophysiologic mediator. Nicotinamide adenine dinucleotide phos- hydrogen oxidases that produce superoxide anion, phate and myeloperoxidase that generates hypochlorous acid, received considerable interest in the context have of atherosclerosis (4447). These 2 reactive oxygen species may represent attractive targets for molecular imaging (Fig.

36S T

HE

JOURNAL OF NUCLEAR MEDICINE Vol. 51 No. 5 (Suppl) May 2010

ACKNOWLEDGMENTS

26 . Tor zews ki M, S ha w P X, Han KR, et al . Red uc ed i n vi vo ao rt i c up t ak e o f r adi o l abel ed ox id at i on -s p eci fi c a nt i bo di es re ect s chan ge s i n p l aqu e c omp os i t i o n co ns i s t ent wi t h pl aq ue st ab i l i zat i o n. Ar t er i os cl er T hr omb Va sc Bi ol . 2 00 4; 2 4: 2 30 7 23 12 . 27 . B ri l ey -S aeb o KC, S haw P X, M ul de r WJ , et al . Targe t ed mo l ecul a r pro be s fo r i m agi n g at h eros cl er ot i c l es i on s wi t h mag net i c re so nan ce us i n g an ti b od i es t h at r ecog ni ze ox i dat i o n- sp eci fi c ep i t op es . Ci r cul a t i on . 20 08 ; 11 7: 3 20 6 32 15 . 28 . R ud d J H, Warb ur t on EA, Fr yer TD, et al . Ima gi n g at h ero scl er ot i c p l aqu e i n amm at i on wi t h [
18

We thank our many colleagues affiliated with the W.Donald Reynolds Clinical Cardiovascular Research Center at Harvard Medical School who contributed to our efforts to develop molecular imaging of atherosclerosis. We also acknowledge the National Institutes of Health and the American Heart Association for their support.
REFERENCES
1. Lus i s AJ . At her os cl er os i s. N a t ure . 20 00 ; 40 7: 23 3 24 1. 2. Gl ass C K, W i t zt um JL . At h ero scl er os i s : th e ro ad ah ead . C el l . 20 01 ; 10 4: 5 03 51 6. 3. Li bb y P. In amm at i on i n at her os cl er os i s. N a t ure . 20 02 ; 420 : 86 8 87 4. 4. Li bb y P. T he p at ho gen esi s of at h ero scl e ros i s . In : Ka sp er DL, Br aun wal d E, Fau ci S, Haus er S L, Lo ng o D L, J ames on J L, ed s . Har r i so ns P ri n ci pl es o f M ed i ci ne. 16 t h ed . New York , NY: McGraw- Hi l l Co mp ani e s, I nc. ; 2 00 5: 1 42 5 14 30 . 5. Li bb y P. T he mo l ecul ar m ech ani s ms o f t he t hr om bo t i c co mp l i cat i on s o f at her os cl ero si s . J In t ern M ed . 20 08 ; 26 3: 5 17 52 7. 6. Hart v ig s en K, C ho u M -Y, Hans en LF, et a l. T he r ol e o f i nn at e i m mu ni t y i n at her og enes i s . J L i p i d R es. 20 09; 5 0( su pp l ): S 3 88 S 39 3. 7. Li bb y P. Les i on v ers us l u men . Na t M ed . 19 95 ; 1: 1 71 8 . 8. Fal k E, Sh ah P, F us t er V. C oro nar y p l aqu e di s ru pt i on . Ci r cul a t i on . 1 99 5; 9 2: 65 7 67 1. 9. Li bb y P . T he m ol ecu l ar b as es of t he acu t e co ro nar y s yn dr om es. C i rcu l at i o n. 19 95 ; 91 :2 84 4 28 50 . 10 . Dav i es MJ . S t ab i l i ty and i n st ab i l i t y: t he t wo face s of co ro nar y at her os cl ero s i s. Th e P au l Du dl ey W hi t e L ect ur e, 19 95 . C i rcu l at i o n. 1 99 6; 9 4: 20 1 32 02 0. 11 . P arm ar KM, Lar man HB, Dai G, et al . I nt eg rat i on of o w-d epen den t end ot h el i al p hen ot y pes b y Krup pe l -l i ke fact o r 2 . J C l i n Inv est . 2 00 6; 1 16 : 49 5 8. 12 . Dai G, Vau gh n S , Zh ang Y, Wan g ET, Garci a -Ca rd ena G, Gi mb ro ne M A Jr. B i om echa ni cal fo rces i n at h ero scl e ros i s -res i s t ant v ascu l ar re gi o ns r egu l at e en do t hel i al red ox bal an ce vi a p ho sp ho i no si t o l 3-k i nas e/ Ak t -de pen den t act i vat i on o f Nr f2. Ci r c Res . 2 00 7; 1 01 : 72 3 73 3. 13 . Nah ren do rf M, Jaf fer FA, Kel l y KA, et al . No ni nv as iv e v as cul ar ce ll ad hes i on m ol ecu l e-1 i m agi n g i d ent i fi es i n amm at or y act i va t i on o f cel l s i n at her os cl ero s i s. C i rcu l at i o n. 2 00 6; 1 14 : 15 04 1 51 1. 14 . La it i n en I , S ara st e A, Wei dl E, et al . E val ua t io n o f a
v

F ]- u oro de oxy gl u co se po s i t ron e mi s si o n t om og rap hy.

C i rcu l at i o n. 2 00 2; 1 05 : 27 08 2 71 1. 29 . R ud d JHF , Hyafi l F , F ayad ZA . In am mat i o n i mag i ng i n at her os cl ero s i s. Ar t er i os cl er T h ro mb Vas c Bi ol . 2 00 9; 2 9: 1 00 9 10 16 . 30 . S u H, S pi n al e F G, Dob ru cki LW, et al . Non i nvas i ve t arg et ed i m agi n g of mat r i x m et al l op ro t ei nas e act i v at i on i n a mu ri ne mo del o f p os t i nf arct i o n r emo del i n g. C i rcu l at i o n. 2 00 5; 1 12 : 31 57 3 16 7. 31 . Deg uch i J , Ai kawa M, Tun g C -H, e t al . In a mm at i on i n a t hero s cl ero si s : v i su al i zi ng mat r i x m et al l op rot e i nas e act i o n i n m acro ph age s i n v i vo . C i rcu l at i o n. 2 00 6; 1 14 : 55 62 . 32 . J aff er FA, Ki m DE, Qui n t i L, et al . Opt i c al vi s ual i z at i on of c at hep s in K act i v i t y i n at he ros cl er os i s wi t h a no vel , p ro t eas e-act i va t abl e u or es cence se ns or. C i rcu l at i o n. 2 00 7; 1 15 : 22 92 2 29 8. 33 . Zh an g J, Ni e L, R azav i an M, et al . Mo l ecu l ar i m agi n g of act i v at ed mat r i x m et al l op ro t ei nas es i n vas cul a r r emo del i n g. C i rcu l at i o n. 2 00 8; 1 18 : 19 53 1 96 0. 34 . J aff er FA, Li b by P , Wei s s l eder R. Opt i ca l a nd m ul t i m od al i t y m ol ecu l ar i ma gi n g: i n si g ht s i nt o a t hero s cl ero si s . Ar t eri o sc l er T h romb Va s c B i ol . 20 09 ; 29 : 10 17 1 02 4. 35 . Oh sh i ma S , P et r ov A, F uj i m ot o S , et a l. Mo l ecul ar i m agi n g o f mat r i x m et al l op ro t ei nas e exp res s i on i n at her os cl ero t i c pl aq ues of m i ce defi ci en t i n ap ol i p op rot e i n e or lo w-d ens i t y- l i po pro t ei n recep t or. J N u cl M ed. 2 00 9; 5 0: 6 12 6 17 . 36 . Gen g Y- J, Li b by P . Ev i den ce fo r ap opt o s i s i n ad van ced h um an at h ero ma: co l o cal i zat i on wi t h i nt erl e uk i n-1 b- conv ert i n g en zy me. Am J Pa t ho l . 19 95 ; 14 7: 2 51 2 66 . 37 . Gen g YJ , Li b by P. P rog res s i on o f at her om a: a s t ru ggl e b et ween d eat h an d p ro creat i o n. Ar t er i os cl er T h ro mb Vas c Bi ol . 2 00 2; 2 2: 1 37 0 13 80 . 38 . Li t t l ewo od TD, B enn et t MR . Apo pt o t i c cel l d eat h i n at h ero scl er os i s . C u rr Op i n L i p id ol . 2 00 3; 1 4: 4 69 4 75 . 39 . C l ark e MC , B en net t MR. Cau s e o r co ns eq uen ce: what do es macr op hag e ap op t os i s d o i n a t hero s cl ero si s ? Ar t er i os cl er T hro mb Vas c Bi o l . 2 00 9; 2 9: 1 53 1 55 . 40 . Gen g Y-J , W u Q, Mu szy ns k i M, Ha ns so n G, Li b by P. Apo pt o si s o f vas cu l ar s mo ot h mu scl e cel l s i n du ced by i n vi t ro s t im ul at i o n wi t h i nt er fero n- g , t u mo r n ecro si s f act or -a, an d i nt erl eu ki n -1 -b. A rt er i o scl er T h ro mb Vas c Bi ol . 1 99 6; 1 6: 1 9 27 . 41 . C l ark e MC, F i gg N, Mag ui r e J J , et al . Apo pt o si s of v asc ul ar s mo ot h mus cl e cel l s i n du ces f eat ur es o f pl aq ue v ul n erab i l i t y i n at h ero scl e ros i s . N at M ed . 2 00 6; 1 2: 1 07 5 10 80 . 42 . I so be S , Ts i mi k as S , Z ho u J, et al . Non in vas i ve i mag i ng o f at her os cl ero t i c l es i on s i n apo l i po pr ot ei n E -d efic i ent an d l ow- den si t y -l i p op rot e in recep t or d efi ci ent mi ce wit h an ne xi n A5. J Nu cl M ed . 20 06 ; 47 : 14 97 1 50 5. 43 . La ufe r E M, Wi n ken s MHM, Narul a J , Hof st r a L. Mol ecu l ar i mag i ng o f m acro ph age cel l de at h fo r t he as se ss men t of p l aqu e v ul n erab i l i t y. A rt er i os cl er T h romb Vas c B i ol . 2 00 9; 2 9: 1 03 1 10 38 . 44 . S u gi ya ma S , Oka da Y, S u kh ova GK, Vi r man i R, Hei n eck e JW , L i bb y P. Ma crop ha ge mye l op erox i da se reg ul at i o n b y gr anu l ocy t e m acro ph age col o ny s t i mu l at i ng f act or i n h um an at her os cl er os i s an d i mpl i ca t i on s i n acu te co ro nar y s yn dr om es. Am J Pa t ho l . 20 01 ; 15 8: 8 79 8 91 . 45 . Hei n eck e J W. Oxi d at i ve s tr es s: new ap pr oach es t o di ag no si s and pr ogn os i s i n at h ero sc le ros i s . Am J C ar di o l. 20 03 ; 91( 3A) : 12 A1 6A. 46 . Haze n S L. My el op ero xi d ase and pl aq ue v ul n erab i l i t y. Ar t eri o sc l er T h ro mb Vas c Bi o l . 20 04 ; 24 : 11 43 1 14 6. 47 . Gr i end l i ng KK. ATVB i n fo cus : r edo x m echan i s ms i n b l oo d v ess el s . A rt er i os cl er T h romb Vas c B i ol . 2 00 5; 2 5: 2 72 2 73 . 48 . S h eph erd J, Hi l de rb rand S A, Wat erm an P , Hei n eck e J W, We is s l ed er R , L i bb y P. A uo res cen t pro be f or t h e det ec t i on o f m yel o per oxi d as e act i vi t y i n at h ero sc le ros i s -as s oci at ed m acro ph age s. C he m Bi o l . 20 07 ; 14 : 12 21 12 3 1. 49 . Nat i o nal Hear t L un g an d Bl o od Ins t i t u t e. NHLB I Wo rk i ng Gr ou p. Tr an s l at i on of C ar di o vas cu l ar M o l ecul a r I mag in g Exe cut i ve S umma ry. Avai l ab l e at : h t t p: / / www. nhl b i . ni h .g ov / fu nd i ng /i n i t s /c ard i o-i m agi n g. h t m. Acces sed March 29 , 2 01 0. 50 . Li b by P. At h eros cl er os i s i m agi n g: a bi o l ogi cal an d cl i n i cal pers p ect i ve. In: Di C arl i M F, Kwon g RY, ed s. T echn i qu es f or Ima gi n g t he H ear t : C ar di a c M R an d C T. Ho bo ken , NJ : Wi l ey -B l ack wel l ; 20 08 : 25 9 27 7. 51 . Li b by P, Th erou x P . P at h op hy si o l og y o f co ron ary art er y d i sea se. C i rcu l at i o n. 2 00 5; 1 11 : 34 81 3 48 8.

b 3 i n t egr i n-t a rget e d

p os i t ro n emi s si o n t om og rap hy t r 1 8 F -g al act o -R GD f or i mag i ng o f vas cu l ar acera mma t i on i n a t hero s cl ero t i c mi c e. Ci r c C ar di o vas c I mag i ng . 20 09 ; 2: 3 31 in 3 38 . 15 . Dav i es MJ , Go rd on J L, Ge ari ng AJ, et al . The ex pr ess i o n of t he ad hes i on m ol ecu l es IC AM-1 , VC AM-1 , P EC AM, an d E-s el ect i n i n hu man a t hero s cl ero s i s. J Pat h ol . 1 99 3; 1 71 : 22 3 22 9. 16 . Le y K, R eut er sh an J . Leu co cyt e-e nd ot h el i al i n t eract i o ns i n heal t h an d di s eas e. Ha nd b E xp Pha r maco l . 20 06 (1 76 pt 2) :9 7 13 3. 17 . Mes t as J , L ey K. Mon oc yt e-e ndo t he l ia l cel l i nt era ct i on s i n t he dev el op men t o f at h ero scl e ros i s . Tr end s C ar di ov as c M ed . 20 08 ; 18 : 22 8 23 2. 18 . B arg er A, B eeuwk es R III , Lai n ey L, Si l v erm an K. Hy po t hes i s : v asa va so ru m an d n eova scu l ari za t io n o f h uma n co ron ary art er i es. N E ng l J Me d. 19 84 ; 31 0: 1 75 1 77 . 19 . Mo ul t o n KS . An gi o gen es i s i n at h ero s cl ero si s : gat h eri n g evi d enc e b ey on d s pec ul at i o n. C ur r Opi n L i p i do l . 20 06 ;1 7: 5 48 5 55 . 20 . Kerwi n W, Ho ok er A, S p i l ker M , et al . Qu an t i t at iv e mag net i c r eso nan ce i ma gi ng an al ys i s of n eov asc ul at u re vo l um e i n car ot i d at her os cl ero t i c pl aq ue. C i rcu l at i o n. 2 00 3; 1 07: 851 8 56 . 21 . S wi rs k i F K, Li b by P , Ai kawa E, et al . Ly-6 C
hi

m on ocy t es do mi n at e

h yp erch ol es t ero l emi a- as so ci at ed mon oc yt os i s and gi ve r i se t o macr op hag es i n h ero mat a. J C li n I nves t . 20 07 ; 11 7: 1 95 2 05 . at 22 . S wi rs k i F K, Nah ren do rf M, W il d gr ub er M, et al . Id ent i fi cat i o n o f s pl en i c re ser vo i r mo no cy te s a nd t hei r dep l oy men t t o i n amm at or y s i t es . Sci en ce. 2 00 9; 3 25 : 61 26 1 6. 23 . Koo i ME , Ca pp end i j k VC , C l eut je ns KB , et a l. Accum ul at i o n of ul t r asm al l s up erp aram agn et i c p art i cl es o f i r on ox i de i n hu man at h ero scl er ot i c pl aq ues can b e d et ect ed b y i n v i vo m agn et i c r es on ance i ma gi n g. C i rcu l at i o n. 20 03 ; 10 7: 2 45 3 24 58 . 24 . Ts i mi k as S , Br i l aki s ES , Mi l l er ER , e t al . Oxi d iz ed p ho s ph ol i pi d s , L p(a ) l i p opr ot ei n , an d c oro nar y art ery d i se ase. N Eng l J Me d. 2 00 5; 3 53 :4 6 57 . 25 . Ts i mi k as S, S haw P X. No n- i nva si v e i m agi n g o f vu l ner abl e pl a qu es b y mo l ecu l ar t ar get i n g of ox i di zed LDL wi t h t agg ed ox i dat i o n- sp eci fi c ant i b od i es. J C el l Bi o che m Su pp l . 20 02 ; 39 : 13 8 14 6.

V ASCULAR BIOLOGY OF ATHEROSCLEROSIS

Libby et al. 37S