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Journal of the American College of Cardiology Vol. 54, No. 1, 2009© 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00P

STATE-OF-THE-ART PAPER

Cardiac Positron Emission Tomography

Frank M. Bengel, MD, Takahiro Higuchi, MD, Mehrbod S. Javadi, MD,Riikka Lautamäki, MD, PHD

Baltimore, Maryland

Positron emission tomography (PET) is a powerful, quantitative imaging modality that has been used for de-cades to noninvasively investigate cardiovascular biology and physiology. Due to limited availability, method-ologic complexity, and high costs, it has long been seen as a research tool and as a reference method for valida-tion of other diagnostic approaches. This perception, fortunately, has changed significantly within recent years.Increasing diversity of therapeutic options for coronary artery disease, and increasing specificity of novel thera-pies for certain biologic pathways, has resulted in a clinical need for more accurate and specific diagnostic tech-niques. At the same time, the number of PET centers continues to grow, stimulated by PET’s success in oncol-ogy. Methodologic advances as well as improved radiotracer availability have further contributed to morewidespread use. Evidence for diagnostic and prognostic usefulness of myocardial perfusion and viability assess-ment by PET is increasing. Some studies suggest overall cost-effectiveness of the technique despite higher costsof a single study, because unnecessary follow-up procedures can be avoided. The advent of hybrid PET-computedtomography (CT), which enables integration of PET-derived biologic information with multislice CT-derived mor-phologic information, and the key role of PET in the development and translation of novel molecular-targetedimaging compounds, have further contributed to more widespread acceptance. Today, PET promises to play aleading diagnostic role on the pathway toward a future of high-powered, comprehensive, personalized, cardiovas-cular medicine. This review summarizes the state-of-the-art in current imaging methodology and clinical applica-tion, and outlines novel developments and future directions. (J Am Coll Cardiol 2009;54:1–15) © 2009 by theAmerican College of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.02.065

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That is gold which is worth gold.

—George Herbert, English poet, 1593 to 1633 (1)

ince the introduction of the first positron emission tomogra-hy (PET) scanner in 1975 (2), PET has been used foroninvasive imaging of the heart (3,4). It has often helpedeveal groundbreaking basic science in the areas of myocardiallood flow regulation (5–9), myocardial substrate metabolism10–14), and cardiac autonomic innervation (15–18).

Due to its inherently quantitative nature, its superior detec-ion sensitivity, and its advantageous spatial and temporalesolution over conventional nuclear techniques, PET has beenonsidered a “gold standard” for noninvasive assessment ofyocardial perfusion and viability. In the past, multiple new

maging techniques have been validated with PET as the goldtandard (19–26). And in the near future, PET imaging isxpected to play a key role in the introduction of novel,olecular-targeted imaging approaches (27,28).

rom the Division of Nuclear Medicine/PET, Russell H. Morgan Department ofadiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.r. Bengel receives research grants from Lantheus Medical Imaging and GEealthcare, and has received speaker honoraria from GE Healthcare, BayerScheringharma, and Siemens Medical Solutions.

iManuscript received November 13, 2008; revised manuscript received January 27,

009, accepted February 23, 2009.

Despite its undisputed value as a high-end diagnosticool, PET has struggled for many years to expand from itsole as a reference standard to broader clinical application.mpeding factors have been the complexity and limitedvailability of PET cameras, the complexity of productionnd delivery of short-lived positron-emitting radiotracers,nd concerns related to the high cost of the test.

Approval of PET radiotracers for clinical cardiac applicationy the U.S. Food and Drug Administration (FDA) in 1989nd 2000, followed by reimbursement of their use for myocar-ial perfusion and viability imaging by the Centers for Medi-are and Medicaid Services (CMS) (Table 1), were importantrst steps toward clinical success (29). In recent years, contin-ous improvement of scanner systems, commercial marketingf the tracers fluorodeoxyglucose (FDG) and rubidium-8282Rb), and increasing availability of the technique, mostly dueo its tremendous success in oncology, have all contributed to aapid growth of PET for clinical cardiac imaging.

Today, many leading nuclear cardiology institutions runigh-throughput PET programs and create further evidenceor its clinical usefulness (30–33). Large sample-size studiesnd randomized trials are underway or have been published34). Industry is introducing novel radiotracers for futureommercialization (35). Technical advances such as hybrid
maging systems (36) and molecular-targeted probes (28)

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2 Bengel et al. JACC Vol. 54, No. 1, 2009Cardiac PET June 30, 2009:1–15

continue to drive the field for-ward. Based on these develop-ments, the notion that PET is“worth gold” to advance cardio-vascular medicine stays strong.

Part 1: State-of-the-Artin Imaging Technology

Strengths of PET methodology.Beta (�) decay of a nucleus re-sults in emission of a positron,which rapidly annihilates with anelectron, giving off two 511-keVphotons, which travel in oppositedirections. The basic principle ofPET is detection of these pho-tons as coincidences in a ringscanner (Fig. 1A). The spatialresolution of reconstructed clini-cal PET images is currently inthe range of 4 to 7 mm (37), andit is superior to conventional nu-

lear imaging techniques. Superior detection sensitivityllows for identification of radiotracer at nano- to picomolaroncentrations. PET also has high temporal resolution,hich allows for creation of dynamic imaging sequences toescribe tracer kinetics. Together with readily availableorrection algorithms for photon attenuation, scatter, andandom events, these characteristics make PET a trulyuantitative imaging tool that measures absolute concentra-ions of radioactivity in the body and allows for kineticodeling of physiologic parameters such as absolute myo-

ardial blood flow or glucose use.In recent years, several technical innovations have con-

ributed to a steady improvement in the performance oflinical PET systems (Figs. 1B to 1D). New detectoraterials have enhanced coincidence detection yield and

educed system dead time (37). Three- rather than-dimensional coincidence detection is being used to max-mize count yield, improve image statistics, and/or reducenjected dose (38,39). Reconstruction algorithms have beenntroduced that decrease noise and correct for geometry-elated loss of resolution with increasing distance from theenter of the field-of-view (40). All of these advances makemplementation of the time-of-flight (the difference be-ween arrivals of coincidence photons on both sides of the

Abbreviationsand Acronyms

CAD � coronary arterydisease

CFR � coronary flowreserve

CMS � Centers forMedicare and MedicaidServices

CT � computedtomography

FDA � Food and DrugAdministration

FDG � fluorodeoxyglucose

MBF � myocardial bloodflow

PET � positron emissiontomography

SPECT � single-photonemission computedtomography

DA-Approved Cardiac PET Tracers

Table 1 FDA-Approved Cardiac PET Tracers

Tracer Half-LifeTissue Positron

Range (mm) Myocardi82Rb 78 s 2.6 Na/K-ATPase13NH3 10 min 0.7 Diffusion/met18F-FDG 110 min 0.2 Glucose transp

MS � Centers for Medicare and Medicaid Services; FDA � Food and Drug Administration; FDG � fluorodb � rubidium.

etector ring, which is in the range of picoseconds) close toecoming a clinical reality. This will increase spatial infor-ation and improve the signal/noise ratio (37).On the acquisition side, collection of data in list mode has

ecome available for routine use, allowing for multiplemage reconstructions from a single dataset, including static,ated, and dynamic images (Fig. 2). This increases flexibilitynd provides various options for advanced image processing.lectrocardiogram-gated datasets can be created for com-lementary functional analysis (41). The addition of respi-atory gating may allow for creation of “motion-frozen”mages, which will reduce distortion and facilitate correctionor respiratory misalignment (42).

These advantages may be combined with creation of dy-amic imaging sequences for routine measurement of tracerinetics and noninvasive absolute quantification of biologicalnd physiological processes by compartmental modeling (43).ositron-emitting radiotracers for cardiac imaging.able 1 lists current FDA-approved tracers for cardiac PET,

nd Table 2 lists other cardiac tracers that are not FDApproved but have been successfully applied in humans.

ET PERFUSION TRACERS. FDA-approved 82Rb and 13N-mmonia (13NH3) allow for short imaging protocols andame-day repeated studies due to their short half-lives. A PETerfusion study can be readily accomplished in a fraction of theime necessary for single-photon emission tomographySPECT) myocardial perfusion imaging (29,44). 13NH3 has arst-pass extraction of 80% and requires energy for myocardialetention. The images are of high quality and resolution, andptake is linear over a wide range of myocardial blood flowxcept at very high flow rates (45). Imaging with 13NH3

equires either an on-site cyclotron or close proximity to aegional radiopharmaceutical production center.

82Rb is a potassium analog that has a first-pass extractionf 65% and also requires energy for myocardial uptake viaa/K-ATPase. With 82Rb, the extraction fraction decreases

n a nonlinear manner with increasing blood flow, and thisffect is more pronounced when compared with ammonia,lthough still superior when compared with technetium-9m (99mTc)-labeled SPECT compounds (46,47). Imageesolution and quality are somewhat compromised due tohe high energy of positrons emitted during the decay of2Rb and due to lower count rates as a result of theltrashort half-life (Fig. 3). A major advantage of 82Rb over3NH3 is that it is produced by an 82Sr/82Rb generator

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ion) December 1989 March 1995

trapping (perfusion) March 2000 October 2003

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3JACC Vol. 54, No. 1, 2009 Bengel et al.June 30, 2009:1–15 Cardiac PET

ithout the need for a cyclotron. Commercial availability of2Rb generators in the U.S. has been considered a keylement for more widespread application of clinical myo-ardial perfusion PET.

Another well-established perfusion tracer, H215O, is

otentially superior to 82Rb and 13NH3 because it is

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Figure 1 Advances in PET Technology

(A) Basic positron emission tomography (PET) principle: a positron (e�) isemitted from the atomic nucleus together with a neutrino. The positron movesrandomly through the surrounding matter, where it hits electrons (e�) until itfinally loses enough energy to interact with a single electron. This process,called “annihilation,” results in 2 diametrically emitted photons with an energyof 511 keV each. These photons are detected as coincidences in the detectorring of the PET camera. (B) Traditional 2-dimensional imaging (left) uses onlycoincidences that occur within the same axial detector ring. Adjacent detectorrings are separated by septa. Advanced 3-dimensional imaging (right) usescoincidences from all possible detector pairs. This increases sensitivity andcount density but is demanding and requires correction for the higher amountof scatter and inhomogeneity at the axial edge of the field of view. (C) Inhomo-geneity of in-plane spatial resolution is a function of a broader line of responsefor detector pairs toward the edge of the field of view (pink line vs. blue line).System matrix resolution modeling has been developed to correct for thiseffect and increase resolution. (D) Time-of-flight (TOF) PET increases the signal-to-noise ratio. This has become a reality since the introduction of novel detec-tors with high time resolution of 500 picoseconds or less. In traditional non-TOF PET, the only spatial information is derived from the line of response ofthe detector pair (green). The system has to assume that the annihilation mayhave occurred anywhere along this line of response. However, if TOF informa-tion is available, location of annihilation can be narrowed to several centime-ters along the line of response (red), by taking into account the time differencebetween arrivals of coincidence photons at opposite detectors (t1–t2).

etabolically inert and freely diffusible across cell mem- h

ranes. However, the tracer is not accumulated in myocar-ium and instead reaches equilibrium between extra- andntravascular compartments. Images of regional myocardialerfusion are not readily obtained, and processing for bloodool subtraction is needed (6). The lack of FDA approvalas limited this compound to research applications in the U.S.

ET VIABILITY TRACERS. 18F-FDG is an FDA-approvedlucose analogue that is widely available due to its success asmetabolic imaging tracer in clinical oncology. The tracer isell established to determine myocardial glucose use as an

ndicator of myocardial viability. Increased FDG uptake cane observed in ischemic tissue; markedly reduced or absentptake indicates scar formation (11,48).FDG uptake is heterogeneous in normal myocardium in

he fasting state, so oral glucose loading, nicotinic aciderivatives, or infusion of insulin and glucose have beensed to enhance myocardial FDG uptake (44,49). Imagesbtained in nondiabetic patients and in patients withoninsulin-dependent diabetes are of higher quality afterdditional insulin infusion than those obtained after orallucose loading alone. Bolus injections of insulin have beenuggested (44,50). When such protocols for patient prepa-ation are followed, cardiac FDG images are generally ofigh diagnostic quality.adiation exposure. Radiation exposure from cardiac im-

ging procedures has increasingly become a matter ofiscussion (51). An in-depth review of this topic is beyondhe scope of this article, and the interested reader is referredo dedicated literature (51). It should be noted, however,hat positron emitting tracers typically provide less radiationurden to the patient when compared with SPECT tracerssed for the same diagnostic purpose, which is, in part, dueo their much shorter half-lives. Also, the radiation burdeno staff involved in cardiac PET imaging has been investi-ated, and due to differences in radiotracer administration,can acquisition, and stress-testing tasks, doses with PETeem to be lower for staff (as for patients) when comparedith single-photon emitting tracers (52).

art 2: State-of-the-Art in Clinical Application

yocardial perfusion. DIAGNOSIS OF CORONARY ARTERY

ISEASE (CAD). In a 2005 review, 8 studies that comparederfusion PET with coronary angiography, representing aotal of nearly 800 patients, were summarized, and a meanensitivity of 93% and specificity of 92% for detection ofignificant CAD were observed (29). A more recent review,eporting a weighted sensitivity of 90% and specificity of9% from 9 studies including 877 patients, scanned mostlyith 82Rb PET, confirmed these results (36). For detectionf myocardial ischemia, myocardial perfusion PET is con-idered to have superior diagnostic accuracy when comparedith the more widely available and more frequently usedPECT technique (Fig. 4).Available published reports comparing PET and SPECT

ave also been recently reviewed (36). The robust methods

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or attenuation correction with PET reduce the number ofalse-positive scans due to attenuation artefacts, and speci-city is increased. This is of particular importance in obeseopulations and women, where attenuation artefacts arerequent. Perfusion PET also tends to be more sensitivehan SPECT, which can be explained by better spatialesolution and better tracer extraction at high flow, allowingor detection of more subtle perfusion abnormalities. How-ver, the existing literature comparing SPECT and PETas either been published before 1992 or compared bothechniques in different, retrospectively matched groups. Arospective head-to-head comparison or randomized studysing current state-of-the-art for both techniques is missingnd would be desirable to further support the superiorityf PET.

ROGNOSTIC VALUE. Although meta-analyses confirm a veryigh diagnostic accuracy, it should be emphasized that thereatest value of perfusion imaging is considered to be itsotential to predict adverse cardiac events (53). This incre-ental outcome information has been shown to be useful asgatekeeper for invasive procedures and as a guide to

ppropriate therapy based on individual risk. Studies in veryarge patient groups have supported the incremental prog-ostic value for SPECT perfusion imaging, and confirma-

Time after injection

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Figure 2 Multidimensional List-Mode PET Acquisition

Scanner coincidences are continuously recorded along with information about thebreathing position (optional). Data can then be resampled in multiple formats at aall information after a pre-defined pre-scan delay (delay time after tracer injection).times after injection. This is used for tracer kinetic analysis. (C) Electrocardiograpventricular function. (D) Respiratory gated images can be obtained at different phatole; ES � end systole; EXSP � expiratory phase; INSP � inspiratory phase; PET �

ory data for myocardial perfusion PET are also available. In p

ne study, 685 patients were scanned with dipyridamole2Rb PET and follow-up was obtained over a mean of 41onths. The annual mortality rate for a normal scan was

.9%; it was 4.3% for an abnormal scan. After a multivariatenalysis, PET results had an independent and incrementalrognostic value (54). In a more recent study in 367atients, 3 groups with different stress perfusion abnormal-ties (normal, mild, moderate to severe) had annual rates ofard event of 0.4%, 2.3%, and 7%, respectively, and PETata were the strongest predictors of total cardiac events. Inbese patients, a preferred target group for PET imagingnd a group of individuals at higher risk, the annual totalvent rate was 11% with an abnormal scan and 1.5% with aormal scan (32). Another very recent study confirmed therognostic value of dipyridamole 82Rb PET in 1,441 pa-ients with suspected or known CAD, and it demonstratedn incremental value of stress left ventricular ejectionraction from gated PET (55).

BSOLUTE FLOW QUANTIFICATION. The ability to quantifyyocardial blood flow (MBF) and coronary flow reserve

CFR) in absolute terms is another powerful feature ofET. This is achieved by compartmental modeling ofultiframe dynamic acquisitions (47,56–60), and it has

nitially been limited to research applications in selected

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or multiple risk factors such as hyperlipidemia, diabetes, ormoking and supported the beneficial effects of risk-factorodifications and novel medical therapies (61–73). These

tudies have contributed to a paradigm shift in the percep-ion of CAD, away from a pure macroscopic view of luminaltenoses and toward an emphasis on microcirculation and

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Figure 3 PET Perfusion Tracers

Tomographic positron emission tomography (PET) images of myocardial perfusionafter administration of adenosine using 3 different tracers, the Food and DrugAdministration-approved agents 82rubidium (82Rb) (top) and 13N-ammonia (13NH3)(middle), and the novel compound 18F-fluorobenzyl-triphenylphosphonium (18F-FBnTP) (bottom). All images were obtained in a dog model of hemodynamicallyrelevant left circumflex coronary artery stenosis, resulting in reduced perfusion ofinferolateral myocardium, as shown by all 3 tracers. Since the canine cardiac anat-omy is different from human anatomy, the septum is displayed more superiorly inshort axis (SA) images. HLA � horizontal long axis; VLA � vertical long axis.

ther Cardiac PET Tracersith Reported Human Application

Table 2 Other Cardiac PET TracersWith Reported Human Application

Tracer Half-Life, min Myocardial Uptake Mechanism

H215O 2 Free diffusion (perfusion)

62Cu-PTSM 9.7 Intracellular binding (perfusion)18F-BMS747158 110 Mitochondrial binding (perfusion)11C-acetate 20 Krebs cycle flux, oxidative metabolism11C-palmitate 20 Fatty acid metabolism11C-glucose 20 Glucose metabolism18F-FTHA 110 Fatty acid uptake11C-hydroxyephedrine 20 Sympathetic neuronal catecholamine

uptake11C-epinephrine 20 Sympathetic neuronal catecholamine

storage11C-phenylephrine 20 Sympathetic neuronal catecholamine

turnover18F-fluorodopamine 110 Sympathetic neuronal uptake and

function11C-CGP12177 20 �-adrenergic receptor density11C-CGP12388 20 �-adrenergic receptor density11C-GB67 20 �1-adrenergic receptor density11C-MQNB 20 Muscarinic receptor density

THA � fluorothiaheptadecanoic acid; MQNB � methylquinuclidinyl benzilate; PET � positronmission tomography; PTSM � pyruvaldehyde bis(N4-methylthiosemicarbazone).

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ndothelial function. These are both determinants of CFRnd MBF and are key mediators of disease progression andisk. Several studies have suggested the prognostic value ofuantitative PET measurements of MBF and CFR forrogression toward clinically overt CAD (74) and in idio-athic and hypertropic cardiomyopathies (75,76).The growing use of myocardial perfusion PET for the

linical workup of CAD has resulted in stronger efforts tonclude absolute flow quantification in the analysis oflinical studies. Technical improvements (i.e., more rapidnd robust processing and analysis of dynamic data) havexpedited these efforts. Algorithms for the most frequentlysed clinical cardiac PET tracer, 82Rb, are increasinglyeing validated and used (43,47,60). Quantitative floweasurements may be useful and complementary to the

urrent standard of visual/semiquantitative analysis. Theireproducibility has been demonstrated repeatedly (77–79).hey may be useful for detection and evaluation of extensiveultivessel CAD with balanced ischemia on qualitative

mages (80) (Fig. 5), evaluation of the significance of a givenesion (81), evaluation of collateral flow (82), identificationf endothelial dysfunction in pre-clinical disease, as well aseliable monitoring of therapeutic strategies.

UMMARY. Table 3 summarizes the evidence and potentiallinical role of PET myocardial perfusion imaging.

yocardial viability. CLINICAL VALUE. Therapeutic deci-ion making is difficult in patients with advanced CAD and

99mTc-MIBI SPECT 82Rb PET

Stress

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Figure 4 Comparison of PET and SPECT Perfusion Imaging

Shown are matched, representative short-axis slices for single-photon emissioncomputed tomography (SPECT) (left) and positron emission tomography (PET)(right) in 2 subjects with suspected coronary artery disease. Panel A illus-trates improved specificity with PET. A fixed defect in the inferior wall on SPECTis absent on PET, suggesting the presence of a SPECT attenuation artefact.Panel B illustrates improved sensitivity with PET. Stress-induced perfusiondefects in the anterior and inferolateral walls (arrows) are more clearly shownwith PET versus SPECT.

evere left ventricular dysfunction because revascularization has

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high procedure-related risk. Viability testing has been devel-ped to serve as a guide to the most appropriate therapy.nitially, PET techniques played a key role in understandinghe myocardial response to severe ischemic damage and instablishing the identification of myocardial viability as aiagnostic target. Metabolic imaging has been used to supporthe notion that assessment of perfusion alone may not benough to predict functional recovery after revascularization.he pathophysiology of hibernating myocardium has been

haracterized by PET imaging as resting hypoperfusion andysfunction with preserved glucose metabolism (11) (Fig. 6).It is now well known that PET, using the metabolic

racer FDG, is accurate to predict improvement of regionalall motion and global left ventricular ejection fraction after

evascularization. When comparing PET with alternativeiability imaging techniques such as low-dose dobutaminechocardiography, SPECT imaging with perfusion tracers,r delayed enhancement magnetic resonance imaging, dif-

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Qualitative and quantitative assessment of myocardial perfusion by rest/dipyridamand (B) in a subject with angiographically proven triple-vessel disease and balanceual left ventricular (LV) maximum and show no significant regional perfusion heterodynamic images (right), are all normalized to the same flow range of 0 to 3 ml/mreserve. Abbreviations as in Figure 3.

erences exist that are mostly related to the pathophysiolog- w

cal target of each imaging test. A detailed comparisonetween techniques is beyond the scope of this article, andeaders are referred to dedicated reviews (83–85).

PET is most predictive of improvement of function afterevascularization when blood flow is reduced by �50%, withelatively high glucose uptake. A recent pooled analysis of4 studies in 756 patients, demonstrated a weighted meanensitivity and specificity of 92% and 63%, respectively, foregional functional recovery, with positive and negativeredictive values of 74% and 87%, respectively (85).It has been shown that it is critical to revascularize patients

ith PET-defined hibernating myocardium as soon as possibleecause improvement is less likely to occur when surgery iselayed after documentation of dysfunctional but viable myo-ardium (86). This has recently been confirmed in a large studynalyzing more than 700 patients who all underwent 18F-FDGET. Patients with rapid intervention had significantly betterutcomes when compared with a propensity-matched group

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Other studies have shown that PET can also be used toredict improvement of heart failure symptoms and im-rovement of exercise capacity (87). Several retrospectivetudies have focused on the outcome of patients withschemic heart disease and ventricular dysfunction relative toheir PET results and their treatment strategy. A recenteta-analysis summarized 10 studies in 1,046 patients and

ound annualized mortality rates of 4% for those with viableyocardium who underwent revascularization versus 17%

or those with viability who did not undergo revasculariza-ion. The mortality was 6% for those without viabilityndergoing revascularization versus 8% for those withoutiability not undergoing revascularization (85).

ANDOMIZED TRIALS. Assessment of myocardial viability byET is one of the few diagnostic approaches that have beenxplored in randomized diagnostic studies. Such studies areifficult to design because therapeutic decision makingwhich will influence outcome) is difficult to control. Theeld should be commended for having conducted suchtudies. Despite the strength of randomization, results ofhese studies must be interpreted with caution. Inclusionriteria as well as management algorithms need to be taken

linical Myocardial Perfusion PET:ummary of Evidence and Potential Clinical Role

Table 3 Clinical Myocardial Perfusion PET:Summary of Evidence and Potential Clinical Role

Imaging technique High temporal resolution enables dynamic imagingand absolute blood flow quantification.

Spatial resolution superior to SPECT.Well-established attenuation correction increases

specificity.

Radiotracers Extraction fraction superior to SPECT tracers (44–46).Short half-life enables shorter imaging protocols and

lower radiation exposure, but complicates use ofexercise stress (vasodilator stress preferred) (28).

Diagnostic accuracy Meta-analyses suggest sensitivity and specificity fordetection of coronary artery stenosis is around90% (28,35).

Comparison to SPECT suggests superiority (35), butrecent prospective head-to-head comparison is notavailable.

Prognostic value Predictive of risk for cardiac events, supported bysome studies (30,31,54,55). Less evidence tosupport PET when compared with SPECT.

Cost-effectiveness Some older studies support cost savings despite highsingle-test costs (93,94); more recent analyses arenot available.

Superior accuracy helps avoid unnecessarysubsequent procedures (95).

Randomized trials None available.

Suggestions forcurrent clinical use

Second-line test after equivocal SPECT or otherequivocal perfusion studies.

First-line test in groups where SPECT is frequentlyequivocal (obese patients).

First-line test in situations where quantification andreproducibility are important (suspected balancedischemia, longitudinal follow up studies) (76–78).

Potential future use May be used as first-line test in all cases if diagnosticsuperiority to SPECT is confirmed in head-to-heador randomized trials and if cost-effectiveness isproven in the present health care environment.

ET � positron emission tomography; SPECT � single-photon emission computed tomography.

nto consideration. One early randomized study assigned

atients to either SPECT or PET and found no differencen accuracy between techniques for viability assessment (88).

owever, the study included patients with relatively pre-erved ejection fractions, where differences between tech-iques may be minimal.The benefits of PET are expected to be greater in a target

opulation with severe heart failure and an ejection fractionelow 35%. A group of patients fulfilling these criteria wastudied in another recent randomized trial that assigned 430atients to either management assisted by FDG PET ortandard care. The study overall showed only a nonsignifi-ant trend toward reduction in cardiac events for FDGET-assisted management versus standard care. But iteeds to be emphasized that alternative viability testing wasllowed in the control arm and that nonadherence toET-based recommendations was found in a significantubfraction of patients in the PET arm. Importantly, inhose who adhered to PET recommendations regardingherapy, significant survival benefits were observed (34).lthough PET has been used in large and powerful viability

tudies, the results of these studies are still controversial andt is difficult to find a unifying conclusion. The evidence inupport of the usefulness of PET is growing, but the use ofiability imaging at a given center is still defined mostly byocal expertise and availability.

UMMARY. Table 4 summarizes the evidence and potentiallinical role of PET myocardial viability imaging.

Match

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Perfusion(82Rb, Rest)

Metabolism(18F-FDG)

Figure 6 PET Perfusion/Metabolism Imagingfor Assessment of Myocardial Viability

(Top) A mismatch with reduced rest perfusion (measured by 82Rb) and pre-served/increased metabolism (measured by 18F-FDG) is shown in the inferolat-eral wall, indicating ischemically compromised but viable “hibernating”myocardium. (Bottom) A matched perfusion/metabolism defect is shown inthe inferior wall, indicating nonviable scar. FDG � 18F-deoxyglucose; otherabbreviations as in Figure 3.

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ther clinical applications. Apart from its use in CAD,ET has also been used for less frequent diseases involving

he heart and cardiovascular system. Low radiation exposurend short imaging protocols make it attractive for assess-ent of perfusion and metabolism in selected pediatric

ardiac patients (89,90). Also, the ability to do whole bodymaging in addition to dedicated cardiac imaging makes itttractive for evaluation of systemic inflammatory diseaseuch as sarcoidosis, in which cardiac involvement is prog-

linical Use of PET Imaging for Assessment ofyocardial Viability: Summary of Evidence andotential Clinical Role

Table 4Clinical Use of PET Imaging for Assessment ofMyocardial Viability: Summary of Evidence andPotential Clinical Role

Imaging technique Spatial resolution superior to SPECT but inferior toMRI or echocardiography.

Well-established attenuation correction increasesspecificity.

Radiotracers Metabolic tracer 18F-FDG indicates preservedglucose use in ischemically compromised butviable myocardium.

Should be combined with a perfusion study.Metabolic preconditioning required (glucose

and/or insulin).

Diagnostic accuracy Meta-analyses suggest sensitivity around 90% andspecificity of 60% to 70% for prediction ofregional functional recovery afterrevascularization (83–85).

Targeted biomechanism needs to be consideredfor comparison with other techniques(metabolism may be preserved whencontractile reserve is already absent, explaininglower specificity but higher sensitivity whencompared with functional techniques usinglow-dose dobutamine) (83).

Prognostic value Supported by many retrospective studies (85).Predictive of functional and symptomatic

improvement.Better overall outcome for revascularized vs.

nonrevascularized when PET used to determineviable myocardium.

Cost-effectiveness Limited evidence (guidance to appropriate therapymay improve medical care and costs).

Randomized trials Randomized comparison to SPECT failed to showsuperiority, probably due to inclusion ofpatients with higher ejection fraction (88).

PARR2 trial: No significant difference betweenPET-assisted and standard care in general, butsignificant benefit when PET recommendationswere followed (33).

Suggestions for currentclinical use

Type of viability testing still depends on localexpertise and availability.

First-line test in severely impaired ischemicLV dysfunction (LVEF �35%); most beneficialwhen adherence to results is achieved.

Second-line test if therapeutic decision remainsdifficult after a first test.

Potential future use May be used more broadly if cost-effectivenessis proven.

May be integrated into diagnostic algorithms withother tests such as MRI or echocardiography,but requires prospective validation.

DG � fluorine-18-fluoro-deoxyglucose; LV � left ventricular; LVEF � left ventricular ejectionraction; MRI � magnetic resonance imaging; PARR � PET and Recovery Following Revascular-zation; PET � positron emission tomography; SPECT � single-photon emission computedomography.

ostically very relevant (91,92). m

ost-effectiveness considerations. In cardiology, imagingptions are extensive and often redundant. Because financialesources in health care are increasingly limited, the ques-ion of cost-effectiveness is crucial. The value of PET as aesearch tool and as a gold standard for other diagnosticmaging techniques is not in question, but reimbursementnd general clinical application of the technique is underore scrutiny because a PET procedure is more expensive

han other noninvasive procedures.Looking only at the costs of a single test is a short-

ighted, incomplete approach. Estimation of the total costf diagnostic tests for CAD requires consideration ofndirect and induced costs of management algorithms basedn the test. False positives may result in unnecessaryubsequent diagnostic or therapeutic procedures, whicharry additional costs and risks. A missed diagnosis due to aalse-negative test, on the other hand, may result in pre-entable adverse events that could impair life duration anduality. A comprehensive analysis of utility has to accountor the impact of medical care on quality as well as quantityf life.Patterson et al. (93) used a mathematical model to

ompare cost-effectiveness of exercise electrocardiography,PECT, PET, and invasive angiography to diagnose CAD.heir model accounted for costs per effect or cost per utilitynit (including cost of diagnostic and therapeutic measures,hich included those that yield false-positive results as well

s those that yield false-negative results). They observedhat PET, despite the high cost of a single test, shows theowest cost per effect in patients with a pre-test likelihood ofAD below 70%. This was attributed to its superioriagnostic accuracy and avoidance of false-positive andalse-negative studies. Only when the pre-test likelihoodas above 70% was direct angiography the most cost-

ffective approach. Gould et al. (94), using a somewhat lessomplex model, had earlier come to similar conclusions, butoth studies were published more than 13 years ago.Merhige et al. (95) more recently compared the frequency

f diagnostic arteriography, revascularization, costs, and-year clinical outcomes in 2,159 patients studied with PETith an internal and an external SPECT control group.hey showed reduced use of downstream invasive proce-ures when using perfusion PET versus SPECT, whichesulted in lower costs with comparable outcomes.

Similar issues need to be considered for PET imaging ofyocardial viability. The costs of a single test are high, but

he costs and risk of avoidable surgical or interventionalreatment may be even higher. Avoidance of an unnecessaryypass operation, or even of an unnecessary cardiac trans-lantation, may justify conducting numerous noninvasiveests if they are appropriate for guidance of clinical decisionaking. It has clearly been shown that PET assessment of

iability influences decision making (96), and if PETecommendations are followed, outcomes will improve (34).ne study in the United Kingdom applied an economic
odel and compared 3 strategies (bypass for all patients,

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edical therapy for all patients, and PET-guided decisionor bypass or medical therapy). It was concluded that PETay be cost-effective to select patients with poor left

entricular function for coronary artery bypass grafting (97).Hence, there is some evidence for cost-effectiveness of

ardiac PET in the clinical setting. Factors such as higheratient throughput and patient comfort due to shortermaging protocols for PET versus SPECT have not eveneen considered in the above analyses. But cost-effectivenessemains complex and difficult to generalize. Further studiessing updated clinical algorithms and updated values forccuracy and procedure costs are necessary to support these of PET in the actual health care environment.Target populations in which perfusion PET may be

specially cost-effective are obese patients and women,lthough it should be noted that computed tomographyCT) angiography may emerge as a competitor to PET inuch situations (98). For viability imaging, end-stage isch-mic cardiomyopathy may be the most useful situation.tudying cost-effectiveness in these specific groups in moreetail might further support an efficient clinical use of theigh-end technique.

art 3: New Developments and Future Directions

ybrid PET-CT: the merging of morphology, functionnd biology. Due to their success in oncology, all currentlyffered PET imaging systems are hybrid PET-CT scanners.his has brought challenges for cardiac imaging that are

elated mainly to the use of a separate CT for attenuationorrection of subsequently acquired PET data. Respiratoryr patient motion may result in misalignment of CT andET and artificial heterogeneity in CT-attenuation–orrected cardiac PET images (99). Corrective algorithmsave been proposed to address this issue (99–101).More importantly, the advent of hybrid PET-CT has

esulted in the unique opportunity to combine CT-derivedorphologic information with PET-derived functional,

hysiological and biological information. Most PET-CTcanners are now equipped with multislice CT, allowing forT measurement of coronary calcium and/or CT coronary

ngiography in addition to PET imaging procedures.Schenker et al. (31) measured myocardial perfusion and

oronary calcium in a single cardiac PET-CT study in 695atients with an intermediate pre-test likelihood of CAD.hey observed an increasing prevalence of abnormal PETith increasing coronary calcium scores. In about 50% of

ases with very high calcium, myocardial perfusion wasbnormal. But interestingly, abnormal perfusion was alsoound in 16% of patients with absent calcium.

Risk-adjusted survival analysis demonstrated a stepwisencrease in cardiac events with increasing calcium scores inatients with and without ischemia on PET. Amongatients with normal PET myocardial perfusion imaging,he annualized event rate in patients with no calcium was
ower than in those with high calcium (2.6% vs. 12.3%, t
espectively). In patients with ischemia demonstrated onET, the annualized event rate in those with no calciumas also lower than in those with high calcium (8.2% vs.2.1%). These data suggest that CT calcium scoring andET perfusion imaging are complementary for the assess-ent of cardiovascular risk. Both can be integrated to

tratify patients into different risk-based categories.There is less evidence at the moment for the integrated

se of CT coronary angiography and perfusion PET,lthough initial studies suggest that both tests may also beomplementary rather than competitive. Not all patientsith obstructive atherosclerosis on CT show ischemia onET and, vice versa, not all patients with nonobstructiveAD have no perfusion abnormalities (102).Contrast-enhanced CT angiography enables the detec-

ion of noncalcified plaque and, if imaging is repeatedeveral minutes after injection, it may allow for detection ofnfarcts by delayed contrast enhancement (103,104). Howhis information is best combined with PET for maximiza-ion of diagnostic and prognostic accuracy will be a matterf further research in the future. It is likely, however, thatncreasing availability of 64-slice CT in PET-CT systems,long with new prospectively gated CT acquisition tech-iques, which lower radiation exposure for CT angiographyy more than 70% (105), will contribute to a more wide-pread use in hybrid PET-CT protocols (Fig. 7). Innovativentegrated imaging protocols may include CT for morpho-ogic assessment of coronary arteries and PET for functionalssessment of myocardial blood flow. A CT delayed en-ancement study may be done after CT angiography to

dentify the presence or absence of scar (104). This maybviate the need for a rest perfusion study.ovel myocardial perfusion tracers. All established PET

erfusion tracers have half-lives that are very short. Thisimits their applicability for exercise stress, so clinical pro-ocols usually use pharmacologic stress with the patient onhe camera table, followed by immediate imaging. Anotheronsequence of the short half-lives is the limited availabilityf tracers because they require an on-site cyclotron or aignificant financial commitment to a strontium/rubidiumenerator, which needs to be replaced every month andequires high-throughput imaging to be cost-effective. Thisas generated interest in fluorine-18-labeled perfusion trac-rs, which may overcome both problems due to a longer,10-min half-life. Like FDG, which has already beenuccessfully commercialized, these tracers can be producedn regional centers for dose-by-dose delivery to multipleET sites. Also, they may be injected during exercise stressith enough time to move the patient to the camera after

ompletion of the stress protocol.Currently, data are available on 2 18F-labeled perfusion

ompounds. 18F-BMS747158 is a pyridazinone derivativehat avidly binds to mitochondrial complex-1 (106). Itsrst-pass extraction fraction is very high at 94% (107), and

t yields high and stable myocardial uptake that is propor-
ional to myocardial blood flow. Myocardial uptake is

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reater than that of the SPECT tracers thallium-201 and9mTc-sestamibi (35). The compound is very promising foryocardial perfusion PET imaging and it is currently being

ested in clinical phase 1 and 2 studies (Fig. 8).18F-fluorobenzyl triphenyl phosphonium (FBnTP) is an-

ther compound that is taken up rapidly by myocardium inroportion to myocardial blood flow (108), with highontrast that is superior to the SPECT tracer 99mTc-etrofosmin. It also targets mitochondria (109) and seems toe promising for myocardial perfusion imaging (Fig. 3),lthough, unlike BMS747158, it has not entered clinicalrials yet.

olecular imaging. Cardiovascular molecular imaging is aapidly emerging discipline that aims toward visualization ofpecific molecular targets and pathways that precede ornderlie changes in morphology, physiology, and function.ue to its high detection sensitivity, PET is considered a

ey player in the development and introduction of novelolecular-targeted imaging approaches. The introduction

f dedicated small animal imaging systems, which allow for

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Figure 7 Hybrid PET-CT Imaging

Integrated assessment of vascular anatomy and myocardial perfusion using hybridonset of chest pain after 4� coronary artery bypass grafting. Anterior and lateral vthe left internal mammary artery graft (only clips, indicated by white arrows, are vises). The most severe native coronary lesion is found in a ramus intermedius, whsoft plaque in the proximal segment). Fusion images of CT anatomy and stress pehighlight a mild perfusion defect in the territory of the ramus intermedius as the p

erial in vivo imaging in rodents and facilitate translation of e

ew diagnostic compounds from experimental to clinicalractice (Fig. 9), has further contributed to increasingecognition of the future potential of molecular imaging inardiovascular research and patient care (110–113).

Due to the wide spectrum of novel approaches, a detailedeview of PET-based molecular imaging is beyond the scopef this article, and the reader is referred to dedicated articles27,28,114,115). Some key principles and some examplesre highlighted below. First, molecular imaging places anmphasis on the diagnosis (and subsequent treatment) ofrecursors or the earliest stages of the disease, as opposed tots sequelae. Examples are the use of neuronal imaging todentify subjects at risk for ventricular arrhythmia (116), theevelopment of compounds targeting plaque vulnerability be-ore rupture and subsequent myocardial infarction (117,118),nd the targeting of biomechanisms that precede left ventric-lar remodeling and development of heart failure (119,120).

Second, molecular imaging has great potential to facili-ate discovery and development of novel therapies throughmproved target identification and implementation of more

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measured by dipyridamole 82Rb PET are shown on the right. Green arrowse correlate of the patient’s symptoms.

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Figure 9 Translational Molecular Cardiac PET Imaging

Shown are representative midventricular short-axis slices of myocardial sympathetFor size comparison, images are shown at the same scale (A) and after zoomingner and the rat heart with a dedicated small animal scanner.

Third, visualization of cellular and subcellular targettructures has contributed to advances in fundamentalardiac research such as cell trafficking, myocardial regen-

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ration, and heart failure-specific functional genomics androteomics. Examples are the development of reporter genemaging techniques (28) and the implementation of cellabeling for imaging of engraftment after transplantation28,124).

And fourth, the need to visualize small amounts ofolecular-targeted compounds in small target areas drives

dvances in the imaging sciences such as instrumentation,econstruction algorithms, and probe design to improve theetection sensitivity, molecular specificity, and translationalotential of molecular imaging.The vision is that novel molecular-targeted approaches

ill guide early disease detection and therapeutic/preventiveecision making based on an individual’s biology. PET as aey modality may thereby contribute to further personaliza-ion of cardiovascular medicine.ynergies between oncologic and cardiovascular PET.lthough PET is on the move in cardiovascular medicine

nd new developments are likely to increase its applicationnd impact in clinical practice, some similarities and inter-elationships between its cardiac applications and applica-ions for tumor imaging should be noted. First, the successf PET as a key modality in tumor staging and evaluation ofnti-tumor therapy has resulted in dissemination of theechnique and in improved availability for cardiac imaging.econd, expensive equipment, such as scanners, radiochem-

stry laboratories, and cyclotrons, is most effectively usedhen it serves multiple areas of PET imaging applications.nd finally, many existing and novel biologic targets forET imaging are important not only in heart and vessels,ut also in tumors (Table 5). This is highly relevant not onlyecause advances in tumor biology may help advance car-iovascular biology via improved understanding of relatediomechanisms, but also because multiple applications ineart, vessels, and tumors will be helpful to stimulate

nterest in commercialization of compounds with a broaderpectrum of target groups.

ummary and Conclusions

ardiac PET is a powerful, quantitative, noninvasive imag-ng technique that is increasingly penetrating the clinicalrena. For clinical assessment of myocardial perfusion andiability, evidence for diagnostic and prognostic usefulness isncreasing and cost-effectiveness due to high accuracy de-pite high single-test costs is suggested. The advent ofybrid imaging enables routine combination of PET with

Examples of Common Imaging Targets in Myoca

Table 5 Examples of Common Imaging Targ

Biologic target Myocardium

Glucose use 1 (when dama

Apoptosis 1 (when dama

Integrin expression/angiogenesis 1 (when dama

Matrix metalloproteinase expression 1 (when dama

T-derived morphologic parameters. New molecular imag-

ng compounds will be key elements in the emergingaradigm of personalized medicine.

cknowledgmenthe authors would like to thank Mrs. Judy Buchanan,ivision of Nuclear Medicine, Johns Hopkins University,

or her valuable editorial support.

eprint requests and correspondence: Dr. Frank M. Bengel,irector of Cardiovascular Nuclear Medicine, Russell H. Morganepartment of Radiology and Radiological Science, Johns Hop-

ins University, 601 North Caroline Street/JHOC 3225, Balti-ore, Maryland 21287. E-mail: [email protected].

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ey Words: positron emission tomography y myocardial perfusion y
yocardial viability y hybrid imaging y molecular imaging.

Cardiac Positron Emission Tomography Positron Emission Tomography Frank M. Bengel, MD, Takahiro...

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