Cardiovascular Molecular Imaging1

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Note: This copy is for your personal non-commercial use only. To order presentation-readycopies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.REVIEWS AND COMMENTARYCardiovascular MolecularImaging1The goal of this review is to highlight how molecular imaging will impact the management and improved understanding of the major cardiovascular diseases that have substantial clinical impact and research interest. These topicsinclude atherosclerosis, myocardial ischemia, myocardialviability, heart failure, gene therapy, and stem cell transplantation. Traditional methods of evaluation for thesediseases will be presented first, followed by methods thatincorporate conventional and molecular imaging approaches.娀 RSNA, 20071From the Department of Medicine, Division of Cardiology(J.C.W.), Department of Radiology, Molecular ImagingProgram at Stanford (J.C.W., S.S.G.), and Bio-X Program(S.S.G.), Stanford University, 300 Pasteur Dr, EdwardsBldg R354, Stanford, CA 94305-5344; and Department ofNuclear Medicine, Johns Hopkins University, Baltimore,Md (F.M.B.). Received January 25, 2006; revision requested March 24; revision received April 7; final versionaccepted June 1. Address correspondence to J.C.W.(e-mail: joewu@stanford.edu).姝 RSNA, 2007Radiology: Volume 244: Number 2—August 2007337䡲 MOLECULAR IMAGING SERIESJoseph C. Wu, MD, PhDFrank M. Bengel, MDSanjiv S. Gambhir, MD, PhD

MOLECULAR IMAGING SERIES: Cardiovascular Molecular ImagingMolecular imaging is a rapidly advancing biomedical researchand clinical discipline. Compared with traditional in vitro tissue culture and in vivo animal studies, molecular imaging allows noninvasive, quantitative, and repetitive imaging oftargeted biological processes at both thecellular and subcellular levels within aliving organism (1). This kind of imagingprovides an extremely powerful technique with numerous applications, suchas the monitoring of endogenous transcriptional regulation, analysis of genetransfer, tracking of tumor cell survival,screening for transgenic animal phenotypes, and expediting of drug discovery(2). Although the primary focus traditionally has been in the field of cancerbiology, molecular imaging approacheshave now been extended to several cardiovascular-related applications.The goal of this review is to highlighthow molecular imaging will impact themanagement and improved understanding of the major cardiovascular diseasesthat have substantial clinical impact andresearch interest. These topics includeatherosclerosis, myocardial ischemia,myocardial viability, heart failure (HF),gene therapy, and stem cell transplantation. Traditional methods of evaluationfor these diseases will be presentedfirst, followed by methods that incorporate conventional and molecular imaging approaches. Conventional cardiovascular imaging focuses on obtaininganatomic, physiologic, or metabolic information and includes modalities suchas echocardiography, magnetic resonance (MR) imaging, computed tomography (CT), single photon emissioncomputed tomography (SPECT), andpositron emission tomography (PET).Although echocardiography, MRimaging, and CT typically are used toevaluate anatomic structures of theheart, they have limited capabilities inthe assessment or visualization of physiologic and metabolic processes. Conversely, SPECT and PET can be used toevaluate physiologic and metaboliccharacteristics but are limited in theircapability for visualization of anatomicstructures. By using standard anatomicimaging modalities combined with mo338lecular imaging technologies such asSPECT and PET, we now have the potential to detect disease processes at theanatomic, physiologic, metabolic, andmolecular levels and, thereby, allow(a) earlier detection of diseases, (b) objective monitoring of therapies, and(c) better prognostication of diseaseprogression (3).AtherosclerosisAtherosclerosis is a dynamic multifactorial disease of the arterial wall. Although it generally involves the entirevascular system, cardiovascular manifestations are found most frequentlyand ultimately result in clinically overtcoronary artery disease (CAD). A variety of factors contribute to developmentand progression of atherosclerosis.Dysfunction of the endothelium, whichmaintains vascular homeostasis by regulating vascular tone, smooth musclecell proliferation, and thrombogenicity,is thought to be the earliest step in thedevelopment of CAD. The endothelialdysfunction results in the imbalance ofvascular regulatory mechanisms tocause damage to the arterial wall (4).Inflammation, macrophage infiltration,lipid deposition, calcification, extracellular matrix digestion, oxidative stress,cell apoptosis, and thrombosis areamong further molecular mechanismsthat contribute to plaque developmentand progression (5) (Fig 1a, 1b).In the past, invasive coronary angiography has been the only diagnosticprocedure that could be used to identifycoronary atherosclerosis. The reduction of the vessel lumen caused by stenosis is used as an indicator of the presence of plaques and allows assessmentof the extent and severity of occlusiveCAD. Advances in CT and MR imagingtechnology have led to the developmentof algorithms for noninvasive contrastmaterial– enhanced angiography by using these techniques (6). These approaches are characterized by high negative predictive values, but their diagnostic accuracy, especially for theassessment of smaller distal parts of thecoronary arterial tree, is still limited atpresent.Wu et alAlthough angiography still serves asa key test in the management of symptomatic CAD, several clinical observations have emphasized the need for amore detailed analysis of the structureand biology of atherosclerotic plaques.First, epidemiologic observations haveshown that a large proportion of peoplewho suffer a sudden cardiac event(acute ischemic syndrome or suddencardiac death) have no prior symptoms(7). Second, it has been found thatacute coronary syndromes often resultfrom plaque rupture at sites with no oronly modest luminal narrowing at angiography (8) (Fig 1a). Vascular remodeling, which consists of atherosclerosisassociated morphologic and biologicchanges of the vessel wall without substantial stenosis, often has occurred atsuch sites (9). Therefore, there is considerable demand for diagnostic procedures that go beyond assessment of thevessel lumen to identify rupture-pronevulnerable plaques as the most frequentcause of sudden cardiac events (5).As a consequence, several methodshave been developed in recent years toprovide detailed information about vessel wall and plaque morphology. Intravascular ultrasonography (US) is an invasive technique that allows assessmentof vessel wall thickness and structure(10). In addition, optical coherence tomography has been introduced as another invasive technique that providesimages of vessel wall morphology at almost histologic quality (11). Finally, MRimaging approaches also have been developed, and these approaches allownoninvasive characterization of the ves-Published online before print10.1148/radiol.2442060136Radiology 2007; 244:337–355Abbreviations:CAD coronary artery diseaseFDG fluorine 18 fluorodeoxyglucoseFHBG 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanineHF heart failureICD implantable cardioverter defibrillatorMI myocardial infarctionMIBG m-iodobenzylguanidineVEGF vascular endothelial growth factorAuthors stated no financial relationship to disclose.Radiology: Volume 244: Number 2—August 2007

MOLECULAR IMAGING SERIES: Cardiovascular Molecular Imagingsel wall (12). Some studies have shownthat CT angiography allows additionalassessment of plaque attenuation (13).The goal of these techniques is to identify vascular remodeling and describeplaques with regard to specific criteriaof vulnerability, such as a thin fibrouscap and a large lipid core.At least as important as its morphology, however, is the biology of a plaque(Fig 1b). Inflammation is a key featureof active, rupture-prone plaques, whichcan be identified invasively by usingthermography (14). Plaque inflammation also may be identified noninvasivelyby using nuclear imaging with fluorine18 (18F) fluorodeoxyglucose (FDG) orother markers of inflammatory activity(15). Further molecular features of unstable plaques, which have been targeted by specific probes, are macrophage infiltration (16,17), proliferatingsmooth muscle cells (18), matrix metalloproteinase activation (19), apoptosisof macrophages and smooth musclecells (20,21), oxidative stress (22), andproangiogenetic factors (23) (Table 1).Most of these biologic imaging techniques are at present still limited to experimental settings, but the increasingnumber of upcoming approaches and ofresearch groups active in the field willhelp for rapid future clinical establishment. Hybrid imaging systems such asPET/CT and SPECT/CT cameras areanticipated to contribute substantiallyto a breakthrough in clinical identification of vulnerable plaques, becausethese systems allow combined assessment of morphology and biology of vascular structures at sufficiently high spatial resolution (Fig 1c).verity of myocardial ischemia, which isclosely correlated to patient outcome.At present, detection of myocardial ischemia thus serves as a gatekeeper tocoronary angiography and guides theclinician to choose interventional orWu et almedical therapy on the basis of individual cardiovascular risk (Fig 2).The clinical usefulness of myocardialperfusion scintigraphy for diagnosticand prognostic evaluation of patientswith suspected or known CAD is sup-Figure 1Myocardial IschemiaAs mentioned previously, atherosclerosis ultimately progresses to clinicallyovert CAD. In the treatment of clinicalCAD, a paradigm change has occurredin recent years. It is increasingly emphasized that the decision for invasivework-up and intervention cannot bebased on symptoms and morphologicdetection of coronary stenoses alone.Functional tests allow accurate identification of the presence, extent, and seRadiology: Volume 244: Number 2—August 2007Figure 1: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis andvascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque ruptureor to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging.Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imagingapproaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology.Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclearand fusion images are simulated).339

MOLECULAR IMAGING SERIES: Cardiovascular Molecular Imagingported by a large body of evidence. Anormal myocardial perfusion scan canbe used to rule out myocardial ischemiaand is associated with a low cardiovascular event rate of less than 1% per year(24). Cardiac risk, and thus the benefitfrom invasive therapeutic strategies, increases in relation to the severity ofmyocardial ischemia and perfusion abnormalities (25,26). Noninvasive ischemia-guided strategies for diagnostic andtherapeutic work-up of patients withCAD were shown to be cost effective ingeneral (27). In addition, the importance of perfusion imaging for decisionmaking has been demonstrated in specific situations, such as in acute coronary syndromes (28), after myocardialinfarction (MI) (29), prior to noncardiac surgery, or in high-risk subgroupssuch as diabetic patients (30).Nonnuclear imaging techniques fordetection of myocardial ischemia arebecoming increasingly available. Thesetechniques have the advantage of no radiation exposure, but their diagnosticand prognostic usefulness is still lesswell established compared with perfusion scintigraphy. Echocardiographycan be applied for detection of wall motion abnormalities during physical exercise (31) or dobutamine stimulation(32). Furthermore, contrast-enhancedechocardiography has been establishedfor measuring perfusion with echogenicmicrobubbles (33). A promising approach to detection of ischemia is MRimaging. This technique is thought to beless dependent on patient conditionsand observer experience. MR imagingcan be effectively used for detection ofWu et alischemia-associated wall motion abnormalities during dobutamine stimulation(34) or for direct assessment of myocardial perfusion after a bolus injection of agadolinium-based contrast agent at restand during pharmacologic vasodilation(35). Although these nonnuclear methods are likely to grow in the future, it isthought that nuclear imaging will bepushed by the hybrid PET/CT andSPECT/CT cameras, which allow further refinement of functional cardiac assessment with measurement of myocardial perfusion, geometry, function, andcoronary morphology within a singleimaging session.Assessment of ischemia by usingmeasurement of perfusion and functionwill remain the method for stratificationof patients with known CAD. Identification of ischemia-associated molecularalterations, however, may find a role incertain situations that are not yet possible through conventional assessment ofperfusion and/or contractile function.Specific identification of myocardiumthat has previously been exposed to ischemia, but is now normally perfused,would be of considerable interest. Anischemic memory marker would allowidentification of myocardium at risk inpatients with acute coronary syndromesor extensive CAD. It may also provideinsights into the clinical role of ischemicpreconditioning, a cellular mechanismby which short episodes of ischemia andreperfusion result in an improved tolerance of prolonged ischemic episodes(36).Annexin V is a protein that can beradiolabeled and that binds to phospha-Table 1Visualization of Biologic Features of Vulnerable PlaquesMolecular MechanismPlaque inflammationMacrophageinfiltrationApoptosisMatrix degradationAngiogenesisThrombosisSmooth muscle cellproliferation340ProbeImaging MethodThermography, FDGSuperparamagnetic iron oxide–labeled macrophages,radiolabeled monocyte chemoattractant protein 1Radiolabeled annexin VRadiolabeled matrix metalloproteinase inhibitorsLabeled integrin ligandsLabeled fibrin-binding peptidesRadiolabeled Z2D3 antibodiesInvasive, nuclearMR imaging, nuclearNuclearNuclearNuclear, MR imagingNuclear, MR imagingNucleartidylserine, a molecule expressed on thecell surface during the early phase ofapoptosis (programmed cell death). Recent studies have shown that annexin Vuptake occurs not only in irreversiblydamaged infarcted myocardium (37)but also temporarily in myocardium after reversible severe ischemia (38,39).These observations suggest that earlyphases of apoptosis are reversible andthat annexin V may be used as a molecular marker to identify areas that havepreviously suffered severe ischemia buthave not yet transformed to scar. Another approach for molecular imaging ofischemic memory is the application ofthe radiolabeled fatty acid analogue iodine 123 (123I) -methyl-p-iodophenylpentadecanoic acid. After episodes ofischemia, which result in a metabolicshift from fatty acids to glucose as thepreferred substrate for energy production, regional uptake of this tracerseems to be reduced for a longer periodof time (40).Coronary Artery DiseaseAnother area of interest for targetedmolecular imaging is to identify patientswith CAD who have a high likelihood forischemia-induced remodeling, a phenomenon that results in transition toHF. Early identification of such patientswould allow prevention of the development of remodeling-associated ventricular dilatation and reduction of contractile function. Alterations of the cardiacsympathetic nervous system seem to playa critical role in left ventricular remodeling. Integrity of presynaptic sympatheticnerve endings can be identified by usingradiolabeled catecholamines such as123I–m-iodobenzylguanidine (MIBG). Researchers in several studies have identified innervation defects larger than perfusion defects in patients with CAD andafter MI; these findings suggest thatsympathetic neurons are more sensitiveto ischemia than are myocytes (41,42).An imbalance of autonomic signaltransduction may contribute to the maladaptive process of postischemic remodeling. This idea has been suggestedby investigators who observed accelerRadiology: Volume 244: Number 2—August 2007

MOLECULAR IMAGING SERIES: Cardiovascular Molecular Imagingated ventricular dilatation in patientswith larger innervation defects thatwere indicated by reduced myocardialMIBG uptake (43). In addition to presynaptic innervation, postsynaptic receptor density can be evaluated by usingPET and radiolabeled adrenergic receptor antagonists. Findings in a studyshowed that reduction of -adrenergicdensity early after MI can be used topredict ventricular volumes at 6 monthsafter the event (44); such results suggest that receptor-targeted imaging maybe another approach to identify candidates for remodeling. Other moleculartargets in the ischemic myocardium include integrins, a group of adhesionmolecules that play a central role in angiogenesis. These can be identified withspecific v 3-integrin–targeted radiotracers in vivo (45) and may allow assessment of postischemic recovery andangiogenesis therapy in the future (46).Finally, myocyte apoptosis is thought tobe another relevant feature of remodeling that may be targeted by noninvasivemolecular imaging although no detailedtrials have been performed up to now.Wu et alFigure 2Myocardial ViabilityIt has been extensively documented thatpatients with poor left ventricular function and advanced multivessel CADshow improved clinical outcome aftersurgical revascularization (47–50). Thesepatients may benefit most from revascularization, but the decision to proceedwith interventional therapy is not an inconsequential one. Patients with severeventricular dysfunction undergo coronary artery bypass graft surgery or percutaneous coronary intervention with aconsiderable risk of procedure-relatedmorbidity and mortality (50). Hence,accurate methods to identify patientswho will benefit most are required tojustify the potential risks.There has been increasing clinicalawareness that contractile dysfunctionin patients with CAD does not necessarily reflect the presence of scar tissue(51). In investigations of contractile reserve in the catheterization laboratoryin the 1970s, reversibility of left ventricRadiology: Volume 244: Number 2—August 2007Figure 2: Imaging in myocardial ischemia. (a) Imaging markers in CAD. (b) Examples of morphologic,functional, and molecular images. LAD left anterior descending artery, LCA left coronary artery, LCX left circumflex artery, RCA right coronary artery.ular dysfunction was described (52,53).Since then, several noninvasive imagingtechniques have been developed toidentify tissue viability in dysfunctionalmyocardium and to thereby determinewhich patients with ventricular dysfunction are the most appropriate candidates for revascularization (54).Two major pathogenetic mechanisms, which coexist in most clinical situations, contribute to development ofdysfunctional but still viable myocardium. First, “myocardial stunning” describes a state of persistent postischemic contractile dysfunction despite restoration of near-normal blood flow. Inaddition to “acute stunning” that occursas a consequence of a single episode ofischemia, the definition of myocardialstunning has been extended to chronicleft ventricular dysfunction associatedwith repetitive episodes of ischemia,which is then referred to as “repetitivestunning” (55). Molecular mechanismsfor stunning include intracellular calcium overload caused by ischemia,which results in desensitization and lysisof myofilaments (56), and generation ofoxygen-derived free radicals, which inhibit ionic pumps and mitochondrialfunction, at reperfusion (57).Second, “myocardial hibernation”has been described as a consequence ofreduced resting perfusion caused by severe coronary stenosis that leads to anadaptive downregulation of contractilefunction, which is reversible after reestablishment of normal perfusion (51,58).341

MOLECULAR IMAGING SERIES: Cardiovascular Molecular ImagingUncoupling of contractile work andmyocardial blood flow is thought to bepart of this adaptation. Since approximately 60% of oxygen consumption islinked to contractile performance, energy can be saved and the tolerance toischemia can be increased at the expense of regional dysfunction. It hasbeen shown that this adaptive process isassociated with molecular alterations,such as dedifferentiation of myocytes,decreased expression of contractile proteins, accumulation of glycogen, loss ofsarcoplasmic reticulum, small mitochondria, and increasing interstitial fibrosis (59–61).The prediction of functional recovery by using detection of myocardial viability has emerged as a clinical application for molecular imaging. Reversibleleft ventricular dysfunction is generallyassociated with maintained or even increased tissue uptake of the glucosemetabolic marker FDG (62–64). Hibernating and repetitively stunned myocardia are characterized by a perfusionmetabolism mismatch pattern with reduced regional uptake of a perfusiontracer but preserved uptake of FDGmetabolic tracer. Scar tissue, on theother hand, is characterized by amatched reduction of perfusion andWu et alFDG uptake (Fig 3). Studies of myocardial metabolism by using FDG and PEThave provided important informationfor a better understanding of thepathophysiologic interrelations amongmyocardial blood flow, substrate metabolism, and contractile function in ischemically compromised myocardium.These studies have also played a fundamental role in the clinical emergence ofnoninvasive viability imaging and are regarded as an imaging reference standard (65,66). An extensive body of literature exists that documents the diagnostic accuracy of FDG PET for prediction offunctional recovery after revascularization. In addition, the prognostic value ofPET has been described (67,68), and theperfusion-metabolism mismatch has beenidentified as an unstable state associatedwith a high risk and poor outcome if nottreated immediately (69,70).Other techniques have been introduced for prediction of functional recovery and were validated compared withPET metabolic imaging (71,72). Studiesof the contractile response to low-dosedobutamine by using echocardiographyor MR imaging were shown to be diagnostically useful. Measurements of contractile reserve have a marginally higherspecificity but somewhat lower sensitiv-ity for prediction of functional recoverywhen compared with FDG metabolicimaging (71). This has been explainedby the fact that FDG may be used todetect residual viable tissue in some areas where extensive fibrosis already coexists. These areas of advanced hibernation may show only slow functionalimprovement but may still be importantto revascularize because of an association with poor outcome (73).Further, MR imaging has been usedto identify scar tissue by means of theretention of gadolinium-based contrastagent. Imaging of gadolinium-basedcontrast agent late enhancement allowsaccurate detection of the regional andtransmural extent of irreversibly damaged myocardium. It has been shownthat the transmural extent of gadolinium-based contrast agent enhancement is correlated with the likelihood ofregional functional recovery (74). Thediagnostic and prognostic accuracy ofthis test, however, needs to be definedin detail. Findings in other studies havesuggested that functional measures ofregional viability may be superior to thestatic measurement of the extent of necrotic tissue for prediction of recovery(75) and, thus, that biologic and molecular mechanisms other than scar devel-Figure 3Figure 3: Examples of patterns of myocardial viability from perfusion-metabolism PETimaging. Representative left ventricular (LV) short- and long-axis sections from two patientswith severe ventricular dysfunction are depicted in “hot metal” color scale (brighter color indicates higher radioactivity concentration). In top two rows, an anteroseptal perfusion defect ispresent in [13N]ONH3 perfusion images, with concomitant matched reduction of uptake ofthe metabolic tracer FDG. This pattern indicates the presence of scar tissue, which will notbenefit from revascularization. In bottom two rows, a perfusion defect is shown in the anteriorand apical wall. Enhanced FDG uptake is found in the metabolic study, indicating the presenceof ischemically compromised hibernating myoardium, which will benefit from revascularization. Note that relatively reduced uptake of FDG in normally perfused inferior wall is consistentwith use of fatty acids as substrate in this area of normally perfused myocardium. LA leftatrium, RA right atrium, RV right ventricle.342Radiology: Volume 244: Number 2—August 2007

MOLECULAR IMAGING SERIES: Cardiovascular Molecular Imagingopment are important in chronic ischemic ventricular dysfunction.Innovations in molecular imagingmay allow refinement of the characterization of jeopardized myocardium and,thus, further improvement of diagnosticand prognostic assessment of myocardial viability in the future. The extent ofapoptotic cell death in hibernating myocardium may be identified by using tracers such as radiolabeled annexin V. Thismay allow one to identify the severity ofischemic damage and the transitionfrom programmed cell survival to programmed cell death. Other biologic targets for molecular imaging in chronicdysfunctional myocardium may be extracellular matrix activation, collagendeposition, or inflammation. Finally,multimodality imaging may be of specialvalue in chronic left ventricular dysfunction by providing a combination of morphologic, functional, and metabolic information (Fig 4).Heart FailureIn the United States, approximately 5million patients have HF, with an estimated 500 000 new cases diagnosedeach year (76). HF is the leading causeof morbidity, mortality, and hospitalization in patients older than 60 years andis the most common Medicare diagnosis-related group (77). The direct andindirect cost of HF was estimated at 23.2 billion in 2002 (78). Clearly, thisdisease exerts major societal burdenand costs. Yet, despite recent advancesin medical therapy, nearly 300 000 patients will die of HF as a primary orsecondary cause each year (79). Therefore, other treatment approaches, suchas implantable cardioverter defibrillator(ICD), cardiac resynchronization therapy, cardiac gene therapy, and cardiacstem cell transplantation, have been advocated. The last two subjects will bediscussed in subsequent sections of thisarticle.It is known that approximately 50%of all HF deaths are caused by ventricular tachycardia and approximately 80%of patients with symptomatic systolicdysfunction have ventricular tachycardia (80). Results of the Multicenter AuRadiology: Volume 244: Number 2—August 2007Wu et alFigure 4Figure 4: Multimodality imaging of myocardial viability. Short-axis MR images show late enhancement ofgadopentetate dimeglumine (in gray scale) and PET images show glucose metabolism (using FDG) and perfusion (using [13N]ONH3[NH3]). PET images are displayed in a hot metal color scale where brighter colorindicates higher radioactivity concentration. Nontransmural late enhancement, indicating subendocardialscar tissue, is shown on MR images. PET scans show reduced perfusion in the same area (bottom middle), butFDG uptake is less reduced and higher compared with perfusion (top middle). This perfusion-metabolismmismatch indicates residual viability in the subepicardial portion of the area with subendocardial scar. IRTrueFISP Gd inversion-recovery true fast imaging with steady-state precession and gadolinium-basedcontrast agent.tomatic Defibrillator Implantation Trial(also known as MADIT-II) showed thatroutine implantation of ICDs in patientswith a prior MI and an ejection fractionof less than 30% led to reduction ofmortality rates from 19.8% (conventional therapy group) to 14.2% (ICDgroup) (hazard ratio 0.69, P .16)(81). Findings in this study suggestedthat ICD implantation should be considered routinely in all patients with reduced ventricular ejection fraction afterMI (82). Besides risk of sudden cardiacdeath, patients with HF can have intraventricular dyssynchrony (or left bundlebranch block), which causes the twoventricles to beat in an asynchronousfashion, reduces systolic function, andincreases systolic volume.Intraventricular dyssynchrony isseen in approximately 15%–30% of patients with HF (83). Cardiac resynchronization therapy paces both the rightand left ventricle, which can synchronize the activation of the heart and,thus, improve left ventricular systolicfunction (84). This differs from the typical pacemaker, which paces only theright ventricle. In the Multicenter InSync Randomized Clinical Evaluation(also called MIRACLE), results indicated that cardiac resynchronizationtherapy improved symptoms, exercisetolerance, and quality of life substantially (84). However, the estimated costof cardiac resynchronization therapyand/or ICD and hospitalization for implantation is between 40 000 and 50 000 per patient (78). Applying thisexpense to the estimated 400 000 to 1.5million patients with HF who may benefit from ICD poses an astronomic burden to health care costs. In addition, anestimated 20%–30% of patients do notrespond to cardiac resynchronizationtherapy (85). Thus, these issues empha343

MOLECULAR IMAGING SERIES: Cardiovascular Molecular Imagingsize the need for additional measuresthat can be used to selectively identifywhich patients will benefit the mostfrom ICD and cardiac resynchronizationtherapy.Traditio

plantation. Traditional methods of evaluation for these diseases will be presented first, followed by methods that incorporate conventional and molecular imaging ap-proaches. RSNA, 2007 1 From the Department of Medicine, Division of Cardiology (J.C.W.), Department of Radiology, Molecular Imaging Program at Stanford (J.C.W., S.S.G.), and Bio-X .

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