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ª 2 0 1 7 T H E A U T HO R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

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STATE-OF-THE-ART PAPERS

MR/PET Imaging of theCardiovascular System

Philip M. Robson, PHD,a Damini Dey, PHD,b David E. Newby, MD, PHD,c Daniel Berman, MD,d Debiao Li, PHD,b

Zahi A. Fayad, PHD,a Marc R. Dweck, MD, PHDc

ABSTRACT

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Cardiovascular imaging has largely focused on identifying structural, functional, and metabolic changes in the heart.

The ability to reliably assess disease activity would have major potential clinical advantages, including the identification

of early disease, differentiating active from stable conditions, and monitoring disease progression or response to therapy.

Positron emission tomography (PET) imaging now allows such assessments of disease activity to be acquired in the

heart, whereas magnetic resonance (MR) scanning provides detailed anatomic imaging and tissue characterization. Hybrid

MR/PET scanners therefore combine the strengths of 2 already powerful imaging modalities. Simultaneous acquisition

of the 2 scans also provides added benefits, including improved scanning efficiency, motion correction, and partial

volume correction. Radiation exposure is lower than with hybrid PET/computed tomography scanning, which might be

particularly beneficial in younger patients who may need repeated scans. The present review discusses the expanding

clinical literature investigating MR/PET imaging, highlights its advantages and limitations, and explores future

potential applications. (J Am Coll Cardiol Img 2017;10:1165–79) © 2017 The Authors. Published by Elsevier on

behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

T he ability to measure disease activity in thecardiovascular system accurately and at alow dose of radiation would be a major clin-

ical advance. Indeed, this approach would allowinvestigation of the early stages of disease, permitdisease activity to be tracked over time or in responseto therapy, and allow differentiation of active pathol-ogy from quiescent disease states. The recent adventof hybrid magnetic resonance (MR) and positronemission tomography (PET) scanners has thereforegenerated intense interest, potentially combining

m the aTranslational and Molecular Imaging Institute, Icahn School o

iomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los A

Cardiovascular Science, University of Edinburgh, Edinburgh, United

dicine, Cedars-Sinai Medical Center, Los Angeles, California. This work w

1 HL131478, R01 HL071021, R01 HL128056, R01 HL135878, and R01 EB0096

tish Heart Foundation FS/14/78/31020 (Dr. Dweck). Dr. Newby is support

10/32375, RM/13/2/30158, RE/13/3/30183) and Wellcome Trust (WT103782A

ard for Biomedical Science 15/JTA. All other authors have reported that th

s paper to disclose. Drs. Fayad and Dweck contributed equally as senior an

nuscript received April 10, 2017; revised manuscript received July 26, 20

the strengths of these 2 already powerful imaging mo-dalities. Hybrid MR/PET scanners enable a patient toundergo PET imaging at a lower radiation dosecompared with hybrid PET/computed tomography(CT) scanners, which are most commonly available.

Although radiation dose is not necessarily a signif-icant limitation for routine clinical imaging, thesereductions are likely to be of particular value in theclinical imaging of younger patients in whom concernsabout radiation exposure are greatest and for poten-tially complex research protocols. Moreover, the

f Medicine at Mount Sinai, New York, New York;

ngeles, California; cBritish Heart Foundation Centre

Kingdom; and the dDepartments of Imaging and

as supported by National Institutes of Health grants

38 (Dr. Fayad) and R01 HL124649 (Dr. Li), and by the

ed by the British Heart Foundation (CH/09/002, RG/

IA). Dr. Dweck is the recipient of the Sir Jules Thorn

ey have no relationships relevant to the contents of

d corresponding authors.

17, accepted July 27, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

CT = computed tomography

FDG = fluorodeoxyglucose

LGE = late gadolinium

enhancement

MR = magnetic resonance

PET = positron emission

tomography

SPECT = single-photon

emission computed

tomography

TTR = transthyretin-relate

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simultaneous acquisition of MR and PET datapossible on hybrid scanners provides severaladditional advantages, including accurateco-registration, motion correction, and moreefficient, patient-friendly image acquisition.

Technical challenges remain in applyingthis novel technology to the cardiovascularsystem; however, solutions are rapidlybeing developed, and experience is growingworldwide. Indeed, a maturing body ofliterature has emerged exploring the appli-cation of this technology to a wide range ofcardiovascular disorders. The present review

discusses these recent clinical studies, highlightsboth the strengths and weaknesses of cardiovascularMR/PET imaging, and explores some of its futureapplications.

HYBRID PET/CT IMAGING

PET is a highly sensitive imaging technology thatmeasures the activity of specific disease processes asthey are occurring in the body. Potentially, anypathological process may be studied dependent onthe availability of a targeted radiotracer. After injec-tion into the body, these radiotracers accumulate inareas where the disease process is active, releasingradiation that can be detected by the PET scanner.However, PET imaging is limited by the anatomicinformation that it provides and thus needs to becombined with a second anatomic imaging modality:CT or MR. These allow the PET data to be localized tospecific structures within the body and also permitcorrection for PET signal attenuation by differenttissues in the body (attenuation correction). To date,PET has largely been performed in conjunction withCT scanning, or in standalone PET scanners that use aradioactive source to perform a transmission scan tomeasure attenuation. Although the radiation doseassociated with the transmission scan is negligible,the transmission scan does not provide anatomicreference data and takes many times longer than CTimaging. Moreover, the numbers of standalone PETsystems are declining, being replaced by hybrid PET/CT systems. For this reason, the present reviewfocused on comparing hybrid MR/PET imaging withhybrid PET/CT imaging.

Hybrid PET/CT imaging is widely used to study theheart and large arteries. Currently, the principalclinical applications are myocardial perfusion andviability assessments in patients with ischemic heartdisease (1). PET perfusion offers several key advan-tages compared with single-photon emissioncomputed tomography (SPECT), including the ability

d

to quantify perfusion and the ability to detectbalanced ischemia and microvascular disease.11C-labeled fatty acids can be used to assess cardiacmetabolism (2), whereas 18F-fluorodeoxyglucose(18F-FDG) is used to investigate myocardial viability.18F-FDG is a glucose analogue, the uptake ofwhich reflects cellular glucose uptake and phosphor-ylation. Given that glucose is a major energy substrateof the myocardium, 18F-FDG uptake can identifyareas of viable myocardium, including areas ofhibernation with impaired systolic function, and canbe used to predict recovery of function after revas-cularization (3).

An alternative use of 18F-FDG–PET imaging is in theassessment of cardiovascular inflammation. Thisapproach relies on a different mechanism, relatedto the high uptake of glucose by macrophages andother inflammatory cells. In the heart, high-fat-no-carbohydrate dietary preparation can help switchmyocardial metabolism away from glucose to freefatty acids, suppressing physiological 18F-FDG uptakeby myocytes and allowing regions of inflammation tobe observed. This method has been used to investi-gate the inflammation associated with myocardialsarcoidosis (4–6), valve endocarditis (7), and cardiacdevice infection. Although these uses are supportedby recent clinical guidelines (8), myocardial sup-pression of physiological glucose utilization isunsuccessful in approximately one-quarter of pa-tients, leading to the potential for false-positivemyocardial 18F-FDG uptake (9).

Coronary 18F-FDG–PET/CT imaging is also limitedby myocardial 18F-FDG uptake (9,10); however, thisscenario is not a problem for larger arteries remotefrom the heart. Indeed, carotid and aortic 18F-FDG–PET/CT imaging correlates well with macrophageburden and is used to investigate inflammationrelated to atherosclerosis and vasculitis (11,12).Because the scan–rescan reproducibility is also verygood, demonstration of change in the 18F-FDG signalrequires only modest group sizes (11). As a conse-quence, vascular 18F-FDG–PET/CT scanning isincreasingly being used in clinical trials to assess theanti-inflammatory effects of novel atherosclerosistreatments, demonstrating close agreement withthe results of larger clinical outcome studies exam-ining clinical outcomes (13).

NOVEL IMAGING TRACERS

Multiple new PET radiotracers are in developmentand increasingly being used to investigate differentaspects of cardiovascular disease in the researchsetting (Table 1). Most notably, 18F-fluoride–PET/CT

TABLE 1 Novel PET Tracers for Cardiovascular Applications

Target Disease Ref. #

PET tracer18F-Fluciclatide avb3 and avb5

integrinsAngiogenesis/functional

recovery post–myocardial infarction

(84)

11C-hydroxyephedrine Denervation in themyocardium

Ischemic heartdisease/heart failure

(85)

11C-PiB Amyloid Cardiac amyloidosis (1)18F-florbetapir18F-flutemetamol18F-florbetaben64Cu-DOTATATE Macrophages Vascular inflammation in

atherosclerosis(86)

68Ga-DOTATATE18F-sodium fluoride Micro-calcification Atherosclerotic plaque and

aortic stenosis(10,14,19)

Amyloid Cardiac amyloidosis (54)18F-MISO Tissue hypoxia Atherosclerotic plaque (87)68Ga-NOTA-RGD Angiogenesis Atherosclerotic plaque (88)18F-galacto-RGD11C-PK11195 Translocator protein Atherosclerotic plaque (89)11C-choline Macrophages Vascular inflammation in

atherosclerosis(90,91)

18F-choline

MR tracer

Ultra-smallparamagnetic ironoxide particles

Macrophages Atherosclerotic plaque (36,62)

Gadolinium-labeledliposomes

Monocytes Atherosclerotic plaque (92)

Paramagneticquantum dots

Targeted cellinternalization

Various targets:atheroscleroticplaque/tumors

(93)

Gadolinium-labeledliposomes

Infarctedmyocardium

Ischemic myocardium (94)

MR ¼ magnetic resonance; PET ¼ positron emission tomography.

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imaging has been used to study microcalcification incoronary and carotid atheroma (9,10,14) and as amarker of valve disease activity in patients withaortic stenosis (15,16). Large prospective studiesare underway assessing whether 18F-fluoride canimprove risk prediction and assess response to ther-apy in these conditions. Novel MR imaging tracers arealso being developed, such as ultra-small particles ofiron oxide, dual-modality probes, and other nano-particles, which could be used to image multipledisease processes together with PET imaging.

MR/PET IMAGING

As with CT imaging, MR imaging provides accurateanatomic detail but also advanced soft tissuecontrast, allowing improved discrimination of lesionsand pathological changes. MR methods are thereforemore naturally suited to imaging many differentstructures in the cardiovascular system than CTscanning, including the myocardium and carotid ar-teries. These factors have led many researchers toexplore the potential benefits of the newly availablehybrid MR/PET imaging technology. However,combining MR and PET into a single scanner hasproved a major technological challenge, primarily dueto difficulties in developing PET detectors that willoperate effectively within a strong magnetic field(standard PET photo-multiplier tubes do not). EarlyMR/PET systems involved separate PET and MRscanners with a movable patient table (Ingenuity TFPET/MR, Philips Healthcare, Best, the Netherlands).

However, a major breakthrough came with thedevelopment of avalanche photodiode and siliconphotomultiplier detectors that were capable ofworking within the MR scanner (17,18). These pavedthe way for the development of truly hybrid systemsthat housed the MR and PET scanners within thesame gantry (Biograph mMR, Siemens Healthcare,Erlangen, Germany; Signa PET/MR, GE Systems,Waukesha, Wisconsin). Hybrid MR/PET scannersnow offer simultaneous, spatially co-registered im-aging, precisely combining the molecular specificityof PET imaging with the anatomy, tissue character-ization, and functional information provided by MRimaging. This new generation of MR/PET scannerspotentially provide some advantages compared withPET/CT options and versus performing PET/CT andMR imaging individually. Despite the current draw-backs of cost and complexity (Table 2), a singleMR/PET scan maintains the advantages of the 2individual imaging approaches while providingadditional potential advantages, discussed in thefollowing text (Central Illustration).

REDUCED RADIATION EXPOSURE. Levels of radia-tion exposure in current clinical PET/CT protocols donot pose a significant health risk to general patientgroups. Nevertheless, reduced radiation exposure is akey goal in cardiovascular imaging according to theALARA (as low as reasonably achievable) principle.This approach is particularly true in younger patients,who are most likely to undergo repeated imaging andare most susceptible to the risks of radiation. In theclinical arena, MR/PET imaging is therefore mostlikely to prove useful in this patient group.

In the research setting, advanced cardiovascularPET/CT protocols increasingly use detailed contrast-enhanced CT angiograms and CT calcium scoring inaddition to attenuation correction scans (9,19). Theradiation doses from CT in these protocols aretherefore high. Moreover, with the recent develop-ment of multiple novel PET tracers, there is interestin measuring the activity of multiple processes. Thisuse of more than 1 PET tracer would result in furtherincreases in PET-related radiation. The potential

TABLE 2 Summary of the Characteristics of CT, MR, and PET Imaging and the

Combined Modalities

CT MR PET PET/CT MR/PET

Anatomic imaging

Spatial resolution Strong Strong Weak Strong Strong

Soft tissue contrast Weak Strong NP Weak Strong

Molecular and functional imaging

Molecular imaging NP NP Strong Strong Strong

Exogenous contrast tissue imaging Moderate Strong NP Moderate Strong

Tissue characteristics Weak Strong NP Weak Strong

Temporal resolution Moderate Strong Moderate Moderate Strong

Other

Complexity Strong Moderate Moderate Moderate Weak

Scan time Strong Weak Moderate Moderate Weak

Cost Strong Moderate Weak Moderate Weak

Robustness of imaging Strong Moderate Moderate Moderate Weak

Potential

Research potential Moderate Strong Weak Moderate Strong

Translatability Strong Moderate Weak Strong Moderate

CT ¼ computed tomography; FDG ¼ fluorodeoxyglucose; NP ¼ not possible; other abbreviations as in Table 1.

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advantages of lower radiation MR/PET imaging aretherefore being considered. There is particular inter-est in longitudinal studies involving multiple com-plex MR/PET scans to investigate the activity ofchronic disease processes over time (e.g., athero-sclerosis, valve disease) or before and after anexperimental intervention (e.g., administration of anovel therapy). Alternatively, multiple cardiovascularscans using different radiotracers could be per-formed, allowing the activity of several differentdisease processes to be investigated. As noted earlier,these MR/PET research protocols would hold greatestvalue in the imaging of younger patients and theearlier stages of disease.

MOTION AND PARTIAL VOLUME CORRECTION. Thecombined effect of both cardiac contraction and res-piratory displacement leads to a complex pattern ofmotion, causing artifact and blurring in the cardiacPET data. Motion correction is therefore an importantgoal for researchers working in the field and poten-tially a major strength of hybrid MR/PET comparedwith PET/CT systems. Motion compensation typicallyrelies on using electrocardiogram gating to acceptonly PET data acquired during diastole. Although thistechnique has improved visualization of coronary andvalvular PET activity (9,19), it does not account forrespiratory variation and discards the majority of PETdata acquired. More efficient and sophisticated ap-proaches are, however, feasible. Although cardiacmotion can be estimated using the PET data itself(20), an alternative approach is to use anatomic MRimaging to track the motion of the heart directly.

The resulting motion information can then be appliedto the PET data, correcting for motion artifact.Respiratory motion correction with MR/PET imaginghas been successfully applied to liver and lungimaging (21,22). Although cardiac motion is morecomplex, the basic feasibility has been demonstratedin phantoms and preclinical and clinical studies(23–25), with further research ongoing (26,27).

Partial volume errors arise when tracer uptakebleeds into neighboring voxels causing blurring,inaccuracies in PET quantification, and impaireddiagnostic evaluation. Correction of partial volumeerrors uses sophisticated techniques that incorporatehigh-resolution anatomic information into the PETreconstruction (28). These may be further improvedwith the superior soft tissue discrimination providedby hybrid MR/PET imaging. In addition, simultaneousacquisition will avoid the errors associated with theretrospective co-registration of 2 independent scans,leading to further improvements in partial volumeerrors and motion correction.

SUPERIOR SOFT TISSUE CONTRAST. MR scanningprovides improved soft tissue characterizationcompared with CT scanning, particularly when im-aging the myocardium and atherosclerotic plaque.The ability to easily and accurately co-register thisinformation with disease activity is a major potentialadvantage of hybrid MR/PET imaging. Cardiac MRcine imaging provides high contrast between theblood pool and myocardium and excellent temporalresolution, allowing accurate evaluation of cardiacvolumes, mass, wall motion, and ejection fraction. Inthe myocardium, the late gadolinium enhancement(LGE) approach is used clinically to identify areas ofmyocardial injury and cardiac infiltration in a range ofcardiac conditions. More sophisticated techniques areemerging, including T1-mapping for diffuse myocar-dial fibrosis; T2-mapping for myocardial edema; andT2*-mapping for myocardial iron deposition (29).

MR scanning offers powerful assessment ofatherosclerotic plaque composition, particularly inthe carotid arteries (30,31). High in-plane resolutionimaging with multicontrast T1, T2, and proton-density weighting has become the gold standardapproach to identifying positive remodeling andlipid-rich necrotic core. Prospective studies haveconfirmed that T1-weighted MR imaging of acuteplaque hemorrhage or intraluminal thrombus forma-tion accurately identifies culprit and high-risk plaquein the carotids and coronary arteries, as well as pa-tients with an increased risk of future cardiovascularevents (31–33). Finally, administration of gadoliniumcontrast allows identification of thin or ruptured

CENTRAL ILLUSTRATION Hybrid MR/PET Imaging: The Whole Is Greater Than the Sum of its Parts

Robson, P.M. et al. J Am Coll Cardiol Img. 2017;10(10):1165–79.

Not only can the strengths of each modality shown at the base of the pyramid be achieved in a single scan, but hybrid imaging provides additional advantages,

including perfect co-registration, improved motion correction, and low-radiation imaging compared with positron emission tomography (PET)/computed tomography

(CT) imaging. This combination has the potential to improve the characterization of cardiovascular disease with advantages for patient diagnosis and treatment

monitoring. Lower radiation is likely to be of particular value in the clinical imaging of younger patients but may also allow more complex research protocols

investigating cardiovascular disease at multiple different time points with several different tracers. Magnetic resonance (MR)/PET is already being applied to the

investigation of atherosclerosis and myocardial disease, although further research is required to demonstrate its repeatability, precision, and cost-effectiveness.18F-FDG ¼ 18F-fluorodeoxyglucose; LGE ¼ late gadolinium enhancement.

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fibrous caps (34) and plaque angiogenesis (35),whereas ultra-small paramagnetic iron oxide nano-particles can be used to assess plaque macrophageinfiltration (36).

MULTIPARAMETRIC MULTIORGAN ASSESSMENTS. Theabsence of radiation allows for complex MR protocolsto be performed, collecting a wide spectrum ofinformation about the cardiovascular system andbeyond. This collection might include anatomic as-sessments of multiple vascular beds, including thecoronary arteries, carotid arteries, and aorta, but alsoradiation-free investigation of cardiac function andflow hemodynamic parameters, as well as theadvanced soft tissue characterization describedearlier. In addition, noncardiac structures can beimaged to investigate the systemic influences andconsequences of cardiovascular disease. Potentialareas of study include the association of emotionalstress with cardiovascular inflammation (37),vascular disease with neurocognitive disorders (38),and vascular calcification with skeletal bonemetabolism (39).

RECENT APPLICATIONS OF

CARDIOVASCULAR MR/PET IMAGING

This section describes the recent exploratory andfeasibility studies that have investigated the poten-tial clinical utility of MR/PET imaging across a rangeof cardiovascular disorders. These studies havegenerally involved relatively small numbers of pa-tients, and confirmation in larger multicenter studiesis therefore required.

AGREEMENT BETWEEN MR/PET AND PET/CT IMAGING.

Two recent studies including a total of 40 patients(40,41) compared quantification of carotid 18F-FDGactivity using MR/PET versus PET/CT imaging. Stan-dard uptake values were well correlated but indicateda small but significant underestimation by MR/PETscans, likely due to differences in attenuationcorrection. Another study investigated myocardial18F-FDG uptake values using MR/PET and PET/CTimaging (42). Twenty-seven patients underwent the 2scans within 1 h of each other after a single injection.Importantly, only minor differences in the normal-ized standard uptake values were observed, indi-cating that myocardial PET tracer quantification onthe 2 scans is broadly similar. Further research isrequired to assess the impact of different methods forMR attenuation correction and whether uptake valuesare similar in different disease states.

MYOCARDIAL DISEASE. Ischemic heart disease. 18F-FDG–PET and MR scanners are widely used to assess

myocardial viability in patients with ischemic heartdisease. Both techniques have shown excellent diag-nostic accuracy and provide important prognosticinformation. In a recent study, 21 patients post–myocardial infarction were imaged with hybridMR/PET scanners (43) to correlate cardiac function,area-at-risk, glucose metabolism, and infarct size.The investigators demonstrated close agreementbetween the area-at-risk, delineated by 18F-FDG–PET,and MR T2-mapping, both of which were larger thanthat observed with LGE. LGE transmurality and18F-FDG uptake performed equally well in predictingmyocardial functional recovery. In another study of28 post–myocardial infarction patients (44), moderateagreement between MR and PET assessments ofviability was shown (kappa ¼ 0.65), with bothmodalities again accurately predicting recovery inregional wall motion after 6 months. Although thesestudies have demonstrated the feasibility of hybridMR/PET imaging in patients after myocardial infarc-tion, the incremental value of MR/PET versus existingtechniques remains to be demonstrated. The same istrue of myocardial perfusion imaging. Further studiesare required in these areas, particularly in youngerpatients.Cardiac sarcoidosis. One of the most exciting potentialclinical applications of MR/PET imaging is in theassessment of cardiac sarcoidosis. MR imaging in-forms about myocardial structure, function, and thepattern of injury on LGE, whereas 18F-FDG–PETinforms about myocardial and extra-cardiac inflam-mation. Moreover, the ability to easily and accuratelyfuse MR/LGE and FDG/PET images facilitates cross-referencing of the image findings, aiding in theinterpretation of both scans. Finally, both MR andPET scans are recommended in current clinicalguidelines for the investigation of suspected cardiacsarcoidosis (45). When both assessments arerequired, their completion within a single scanstreamlines the patient pathway and improves cost-effectiveness.

Several groups have now investigated the feasi-bility of MR/PET imaging in cardiac sarcoidosis.Initial studies investigated the benefits of co-registering scans acquired on separate MR and PETscanners (46,47), demonstrating improved scaninterpretation compared with side-by-side evaluationof the independent scans.

Hybrid 18F-FDG–MR/PET imaging in patients withsuspected cardiac sarcoidosis was first described incase report format, providing early illustration of theadvantages of simultaneous scanning (48,49). First,accurate co-registration was achieved rapidly in3 orthogonal planes between the PET data and

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contrast-enhanced 3-dimensional MR angiograms ofthe heart. Subsequently, LGE images were fusedwith the PET data, demonstrating accurate co-localization of increased 18F-FDG activity withareas of myocardial injury observed on LGE. In alarger cohort of 25 patients with suspected activecardiac sarcoidosis, patients were categorized into 4groups (50). MRþPETþ patients demonstratedincreased 18F-FDG uptake co-localizing with regionsof LGE and were considered to have imaging evi-dence of active cardiac sarcoidosis (Figure 1).MRþPET– patients had characteristic LGE appear-ances but no increase in 18F-FDG activity, suggestingchronic scarring secondary to “burnt-out” sarcoid-osis, whereas MR–PET– patients had no evidence ofcardiac sarcoidosis involvement. The most chal-lenging group to interpret were the 8 MR–PETþ pa-tients, 6 of whom had diffuse uptake throughout themyocardium. This finding is not consistent with thepatchy nature of cardiac sarcoidosis involvement,and the myocardial uptake also showed a dynamicPET profile different from that of patients in theMRþPETþ group. These patients were thereforebelieved to have false-positive 18F-FDG uptakerelated to failed myocardial suppression. However, 2of the MR–PETþ patients had focal increases in18F-FDG activity localizing to the inferolateral wallin the absence of any LGE changes. Although suchpatterns could relate to myocardial inflammationvisible on PET but not MR imaging, in theseparticular subjects, the magnitude and dynamicprofile of the 18F-FDG uptake was the same asthat observed in patients with physiological false-positive uptake.

Considerable caution is therefore required wheninterpreting the results of myocardial 18F-FDG–PETimaging alone. However, MR/PET imaging seems tobe helpful in this regard, allowing cross-referencingwith MR-LGE images and the dynamic profile of theuptake to be assessed during the longer bed times.Additional studies are now required to investigatethese initial findings and to assess whether hybridMR/PET scanners improve the diagnostic accuracyand prediction of adverse outcomes compared withthe current standard of care. Importantly, in both ofthe aforementioned studies, 18F-FDG–PET scanningappeared to outperform T2-mapping in the identifi-cation of active myocardial disease, supporting theguidelines and the requirement for an additional PETscan.Myocarditis. Patients with myocarditis commonlypresent with troponin-positive chest pain but anormal coronary angiogram. MR scanning is alreadywidely used to confirm the diagnosis and rule out

myocardial infarction based on the characteristicpattern of mid-wall LGE. In certain cases, addition of18F-FDG–PET scanning might prove complementary,indicating whether the underlying disease process isactive (Figure 2) (48). In a study of 65 patients withsuspected myocarditis, hybrid 18F-FDG–MR/PETscanning was performed, including LGE andT2-weighted imaging (51). Eight patients had failedmyocardial suppression despite dietary restrictions,and 2 were unable to complete imaging due toclaustrophobia. In the remainder, agreement between18F-FDG–PET and cardiac MR was good (kappa ¼ 0.73)with the closest association observed between PETand T2-mapping values. Further studies in this con-dition are required.

Cardiac amyloidosis. MR scanning is a well-establishedtool in the diagnosis of cardiac amyloidosis. How-ever, MR scanning is unable to differentiate betweenthe 2 predominant forms of amyloid: acquiredmonoclonal immunoglobulin light-chain and trans-thyretin related (TTR). This clinical distinction isbecoming increasingly important given their differentprognoses and emerging treatments. Recently, SPECTimaging has been used to address this problem, basedon the increased binding of bisphosphonate bonetracers to TTR amyloid (52,53). Trivieri et al. (54)recently showed that, similar to SPECT, patients withTTR amyloid exhibited increased myocardial activityof the PET bone tracer 18F-fluoride than patients withacquired monoclonal immunoglobulin light-chainamyloid and matched control patients. Moreover,increased PET activity was observed to co-localizewith the pattern of injury observed on LGE(Figure 3). An important advantage of using PETscanning compared with SPECT is that it allowsquantification of uptake, with a tissue-to-backgrounduptake value of 0.85 appearing to provide cleardistinction between groups. Similar results were alsorecently observed in a small 18F-fluoride PET/CTstudy (55) and although confirmation is required inlarger patient cohorts, cardiac amyloidosis remains anexciting area in which MR/PET imaging might rapidlyfind a clinical role.

ATHEROSCLEROTIC PLAQUE. MR/PET imaging isparticularly well suited to atherosclerotic plaqueimaging in the large arteries (carotid, aorta, andfemorals) (56–59). In a study of 16 patients, multi-spectral MR and CT imaging were used to classifycarotid and femoral atherosclerotic plaques as lipid-necrotic, collagen-rich, or calcified. Of these, thelipid-necrotic plaques demonstrated the highest18F-FDG uptake (58). In another study of 25 patientsundergoing carotid endarterectomy, 18F-FDG–PET

FIGURE 1 MR/PET Imaging in Cardiac Sarcoidosis

A B

C D

E F

G H

Magnetic resonance (MR) and positron emission tomography (PET) images from 4 patients with active cardiac sarcoidosis in whom

characteristic patterns of myocardial late gadolinium enhancement (left column) co-localize with increased 18F-fluorodeoxyglucose uptake

(fused images, right column) (50).

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FIGURE 2 MR/PET Imaging in Patients With Acute Chest Pain

A D

E

F

B

C

MR/PET imaging of a 25-year-old woman with pericarditic chest pain. (A) The late gadolinium enhancement (LGE) images demonstrate linear

mid-wall LGE consistent with myocarditis. (B) Increased 18F-fluorodeoxyglucose (18F-FDG)–PET uptake co-localized with LGE on fusion image

indicating active disease, whereas (C) T2-mapping could not clearly differentiate regions of myocardial inflammation. (D) MR/PET image of a

50-year-old woman presenting with heart failure demonstrating transmural LGE in the anterior wall. (E) No increase in 18F-FDG uptake was

observed in this region, consistent with an old, previously unrecognized myocardial infarction. (F) Again, T2-mapping was inconclusive (48).

Abbreviations as in Figure 1.

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scanning correctly identified all the lesions with alarge necrotic core on histology, whereas T1-weightedMR scanning demonstrated good accuracy in thedetection of large intra-plaque hemorrhage

(specificity 100%; sensitivity 70%) (59). Severalstudies have compared 18F-FDG–PET/CT imaging withMR assessments of vascular inflammation, includingdynamic contrast-enhanced MR imaging (60,61) and

FIGURE 3 MR/PET Imaging in Cardiac Amyloidosis

0.6 ATTR AL Control

0.7

0.8

0.9

1

1.5TBRmax

p < 0.05p = 0.001

1.3

1.4

1.1

1.2

Blood Pool Activity

BA

Patient with transthyretin-related amyloidosis (ATTR). (A) Short-axis fused MR/PET image demonstrating increased myocardial 18F-sodium

fluoride uptake co-localizing to areas of LGE (white arrows) in the inferolateral wall. (B) PET uptake in patients with ATTR was 48%

higher than in subjects with acquired monoclonal immunoglobulin light-chain (AL) amyloid and 68% higher than in control subjects (54).

TBRmax ¼ maximum tissue-to-background; other abbreviations as in Figures 1 and 2.

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ultra-small paramagnetic iron oxide nanoparticleimaging in both carotid atheroma (62) and abdominalaortic aneurysms (63).

Coronary artery imaging using MR/PET scanners ischallenging due to both the small caliber of thesevessels and their complex motion. Although MR angi-ography techniques are able to reliably image theproximal coronary arteries, CT scans remain thepreferred modality (29); thus, coronary PET imaginghas almost exclusively been performed using PET/CTscanning. Nevertheless, research interest in coronaryMR/PET imaging persists because of the benefitsrelated to motion correction and radiation exposureand because MR angiography achieves sufficientspatial resolution to allow PET activity to bemapped tothe coronary vessels. Recently, in a study of 23 pa-tients, Robson et al. (64) reported the feasibility ofcoronary MR/PET imaging using 18F-fluoride. Thisstudy highlighted extensive PET artifact at the heart–lung and lung–diaphragm borders when using stan-dard breath-held, attenuation correction maps thatfrequently rendered PET activity in the coronary ar-teries uninterpretable. However, this artifact wascorrected using a free-breathing, motion-insensitiveMR attenuation correction map (3-dimensionalgolden-angle radial, spoiled-gradient-echo), enablingidentification of 18F-fluoride hotspots within the cor-onary arteries in 7 patients (Figure 4). Increasing the

number of iterations of the PET reconstruction furtherimproved image quality.CARDIAC MASSES. Cardiac masses were one of thefirst cardiovascular conditions to be investigated withMR/PET scanners. MR imaging provides anatomicand functional information, as well as detailed softtissue characterization. In some cases, MR imagingcan accurately diagnose specific masses with no needfor further investigation (e.g., cardiac fibroma, ven-tricular thrombus); however, findings are frequentlynonspecific, and it often remains unclear evenwhether a mass is benign or malignant. 18F-FDG–PETimaging has been widely used in oncological practiceto make this distinction, suggesting that MR/PET im-aging might prove of incremental value. Yaddanapudiet al. (65) fused separately acquired MR and PET dataand found that the complementary information fromthe 2 scans aided in the diagnosis of 6 patients withcardiac masses, in particular distinguishing benignfrom malignant lesions. In a study of 20 patients whounderwent hybrid MR/PET scanning, 18F-FDG–PETscanning had a sensitivity of 100% and specificity of92% for the differentiation of malignant versus benigncardiac masses (66). MR scans, including functionalcine and T2-weighted imaging, revealed very similarresults, but when the data from the 2 modalities werecombined, 100% sensitivity and specificity wereachieved.

FIGURE 4 MR/PET Imaging of Coronary Atherosclerosis

A

*

*

B

C

D

E

F

Patient with breathlessness underwent 18F-sodium fluoride-MR/PET imaging. (A) Standard breath-held attenuation correction leads to artifacts at the diaphragm (*),

heart–lung boundary (white arrowhead), and bronchus (white arrow). (B) These artifacts were corrected with a free-breathing MR sequence for attenuation

correction, (C,D,F) allowing an area of increased 18F-fluoride uptake to be visualized overlying an obstructive plaque (black arrowhead) in the left anterior descending

artery. Additional uptake was observed in the aortic wall and mitral valve annulus (black arrows). (E) Transmural LGE was observed in the perfusion territory of this

lesion, suggesting recent plaque rupture and myocardial infarction (64). Abbreviations as in Figures 1 and 2.

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FUTURE POTENTIAL APPLICATIONS

There are a number of other cardiovascular applica-tions in which hybrid MR/PET technology is antici-pated to be advantageous, although theseapplications have yet to be investigated. Multipledifferent cardiomyopathies are under investigationwith existing radiotracers (67), while the develop-ment of new PET and MR tracers, targeting differentpathological processes, seem set to rapidly expandour ability to measure disease activity in themyocardium (Table 1).

Both MR and PET scans are increasingly beingapplied in research studies to patients with heartvalve disease. In aortic stenosis, MR imaging canprovide assessments of both the valve (peak aorticvalve jet velocity and planimetered aortic valve area)and the remodeling response of the left ventricle(hypertrophy, function, and myocardial fibrosis)(68,69). Cardiac MR imaging is also used to quantifyaortic and mitral regurgitation, particularly eccentricjets and paraprosthetic lesions, which are difficult toassess with echocardiography. PET imaging has been

explored in valvular heart disease using 2 tracers:18F-fluoride PET/CT scanning as a marker of calcifi-cation activity (15,70) and 18F-FDG to investigatepatients with endocarditis. The feasibility of MR/PETimaging in aortic stenosis has recently beenshown (71).

Similarly, there is research interest in usingMR/PET imaging in patients with congenital heartdisease, in whom cardiac MR is considered thegold standard anatomic imaging technique. PETmight be useful in detecting calcific degenerationand endocarditis of the implanted valves andconduits.

The wide spectrum of available MR measurementswill also spur more novel MR/PET applications. Forexample, Gullberg et al. (72) used MR/PET imaging toinvestigate cardiac efficiency in heart failure byrelating total mechanical work (measured with func-tional MR scans) to chemical energy consumption(measured by using 11C-acetate PET scans). Similarly,dynamic PET and MR spectroscopy could be used toimage cellular metabolism (73) or metabolite synthe-sis. Moreover, advanced hyperpolarized 13C MR

TABLE 3 Summary of Potential Cardiovascular Uses of MR/PET

MR Assessment PET Assessment Potential Clinical Use Ref. #

Myocardial perfusion Contrast-enhanced stress perfusion 82Rb chloride, 13N ammonia, 15O water(stress perfusion)

Cross-validationYounger patients

(1)

Myocardial viability LGE (myocardial tissue characterization) 18F-FDG (viability) Cross-validationYounger patients

(43,44)

Cardiac sarcoidosis Cine imaging (LV structure and function)LGE and T1/T2 mapping (myocardial

tissue characterization)

18F-FDG, 68Ga-dotatate (inflammation) Assess disease activityMonitor response to therapy

(46–50)

Cardiac amyloid Cine imaging (LV structure and function)LGE and T1 mapping (myocardial tissue

characterization)

18F-fluordide (TTR vs. AL amyloid)18F-fluorbetapan (amyloid deposition)18F-FDG (inflammation)

Differentiate AL from TTR amyloidMonitor response to therapy

(54)

Other cardiomyopathies Cine imaging (LV structure and function)LGE and T1/T2 mapping (myocardial

tissue characterization)

18F-FDG, 68Ga-dotatate (inflammation)18F-fluciclatide (angiogenesis)Novel tracers for fibrosis activity

Improve diagnostic accuracyAssess disease activityMonitor response to therapy

(48,51,67)

Atherosclerotic plaque MR angiography (anatomy and stenosis)Multispectral black blood and T1-

weighted plaque imaging (plaqueburden and plaque characterization)

18F-FDG, 68Ga-dotatate (inflammation)18F-fluoride (microcalcification)18F-fluciclatide (angiogenesis)

Assess disease activityMonitor response to therapyImprove risk prediction

(57–64)

Heart valve disease Flow mapping (severity ofregurgitation/stenosis)

Cine imaging (LV remodeling andfunction)

LGE and T1 mapping (myocardial tissuecharacterization)

18F-FDG, 68Ga-dotatate (inflammation)18F-fluoride (microcalcification)

Simultaneous assessment of diseaseactivity in the valve and LVremodeling

Improve risk stratificationAssessment of endocarditis

(15,68–70)

Congenital heart disease Cine imaging (LV structure and function)Flow mapping (severity of regurgitation/

stenosis)

18F-FDG, 68Ga-dotatate (inflammation)18F-fluoride (microcalcification)

Assess degeneration of prosthesesEndocarditis

(7)

Aortic aneurysm disease MR angiography (anatomy)USPIO imaging (inflammation)4D flow mapping (shear stress

mechanical stress)

18F-FDG, 68Ga-dotatate (inflammation)18F-fluoride (microcalcification)

Measure disease activityImprove risk prediction

(63)

4D ¼ four-dimensional; AL ¼ acquired monoclonal immunoglobulin light-chain; FDG ¼ fluorodeoxyglucose; LGE¼ late gadolinium enhancement; LV ¼ left ventricular; USPIO ¼ ultra-small paramagnetic ironoxide; other abbreviations as in Tables 1 and 2.

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imaging and spectroscopy could be considered forimaging metabolites in the heart (74). The currentand future cardiovascular applications of MR/PETscanning are summarized in Table 3.

Future avenues for development in MR/PET im-aging are 2-fold. First, technical developments areunderway to solve remaining problems (see thefollowing discussion) and to investigate the leverageof the advantages of motion correction and partialvolume correction. Second, clinical studies areneeded to explore the potential applications dis-cussed here and to evaluate their clinical roletogether with existing MR and PET/CT protocols.

DISADVANTAGES OF MR/PET IMAGING AND

BARRIERS TO FUTURE ADOPTION

Despite the numerous potential advantages ofMR/PET imaging, substantial obstacles remain to itswidespread adoption in both the clinical and researcharenas (Table 2).

TECHNICAL OBSTACLES. The primary technicalchallenge for MR/PET imaging is attenuation correc-tion, which is the process by which the collected PETdata are corrected for attenuation by the tissues of

the body and the components of the MR scanner. TheMR receiver coils sit between the PET detectors andthe body, potentially attenuating the PET signal andintroducing artifact. However, research has shownthat the impact of this effect on cardiovascular uptakeis in practice minimal because of the low absorptioncross-section of the coils and their distance fromcardiovascular tissue (75). In contrast, accurateattenuation correction for surrounding tissues in thebody is essential. CT scanning offers accurate atten-uation correction because the Hounsfield unit ofX-ray attenuation is readily transformed into theequivalent linear attenuation coefficient for PETphotons.

The approach for MR/PET imaging is more com-plex. An MR image must first be segmented intodifferent tissue classes, which are then assigned anattenuation coefficient based on their known CTcharacteristics. Typically, 4 tissue classes (air, lung,fat, and soft tissue) are assigned on images acquiredusing multi-echo gradient-echo MR imaging (76).Bone is not included in these attenuation correctionmaps because it is effectively invisible on conven-tional MR imaging. This issue is a potential problemwhen examining tissue in close proximity to bony

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structures given their strong attenuation of PETphotons. The development of advanced ultra-shortand zero-echo time MR techniques to image bonemay solve this significant problem (77).

Estimation of attenuation correction at the edge ofthe field of view is another issue because the mag-netic field becomes inhomogeneous in these areas.Image fidelity and attenuation estimates of the armsare therefore degraded, particularly in obese patients.Advanced PET reconstruction algorithms that simul-taneously estimate attenuation and activity based onthe nonattenuated PET signal might solve this prob-lem (78) as might MR-based techniques (79).

Metallic implants, including coronary stents andprosthetic valves, cause more severe artifact in MRimaging than in CT imaging. These affect attenuationcorrection as well as anatomic and functional imag-ing. Although MR sequences are available to mitigatesome of these effects (80), this factor may prove amajor limitation for MR/PET imaging in patients withadvanced cardiovascular disease and previouspercutaneous or surgical intervention.

OPERATIONAL OBSTACLES. MR/PET imaging isassociated with several operational obstacles,including the small bore size of MR/PET scanners,which might increase the likelihood of patient claus-trophobia. Moreover, MR/PET systems are currentlynot widely available, and there is a lack of cardiolo-gists, radiologists, and technologists with training inboth modalities. There are also important financialconsiderations: MR/PET scanners are both expensiveto purchase and run while uncertainty persists aboutthe level of reimbursement that insurance companieswill offer for hybrid MR/PET examinations. Thesesystems are therefore unlikely to generate clinical

revenue from cardiac imaging in the short term.However, MR/PET scanners can also be used to imageother organ systems, demonstrating particularpromise in the investigation of neurodegenerativedisorders (81) and common cancers such as head,neck, and prostate cancer (82,83). This potentiallybroad application has encouraged an expandingnumber of health care providers to invest in thiscutting edge, yet expensive, imaging technology.

CONCLUSIONS

MR/PET scanning is an exciting novel imagingmodality that can assess disease activity togetherwith assessments of cardiac anatomy, function, andtissue composition during a single scan. The lowerassociated radiation doses may be particularlyimportant for the clinical imaging of younger pa-tients. In the research arena, beyond the ability toeasily combine and co-register already establishedMR and PET imaging techniques into a single scan,many researchers are seeking novel complex appli-cations that may further advance the state-of-the-art.Although technological and operational obstaclespersist, these are rapidly being overcome, positioningMR/PET scans as a useful new imaging modality forthe investigation of cardiovascular disease. Furtherclinical trials are now required to explore the poten-tial of this technique.

ADDRESS FOR CORRESPONDENCE: Dr. Marc R.Dweck, Centre for Cardiovascular Sciences, Univer-sity of Edinburgh, The Chancellor’s Building, LittleFrance Crescent, Edinburgh, Midlothian EH26 0NL,United Kingdom. E-mail: marc.dweck@ed.ac.uk.

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KEY WORDS atherosclerosis,cardiomyopathy, hybrid imaging, MR, PET