Noninvasive Assessment of Myocardial PerfusionMichael Salerno, MD, PhD; George A. Beller, MD
Noninvasive assessment of myocardial perfusion is im-portant in the diagnosis and risk stratification of patients
with known or suspected coronary artery disease (CAD).Although single-photon emission computed tomography(SPECT) is most commonly used, multiple modalities includ-ing myocardial contrast echocardiography (MCE), positronemission tomography (PET), cardiac MRI (CMR), andcardiac computed tomography (CT) have emerged aspromising techniques. This article will critically evaluate thestrengths and weakness of these modalities for evaluatingmyocardial perfusion.
Coronary PhysiologyMyocardial perfusion is a highly regulated process thatincludes epicardial vessels, resistance vessels, and the endo-thelium. Endothelial dysfunction is an early manifestation ofvascular disease and plays a role in the development ofCAD.1 In normal coronaries, sympathetic stimulation causesa flow-mediated endothelium-dependent release of nitricoxide resulting in epicardial and arteriolar vasodilation. Withendothelial dysfunction, vasoconstriction from acetylcholinepredominates, resulting an attenuation or absence of thenormal flow-mediated vasodilation.2 When coronary arteriesare narrowed by atherosclerotic disease, coronary autoregu-lation attempts to normalize myocardial blood flow byreducing the resistance of distal perfusion beds to preserveadequate myocardial oxygen supply.3 A stenosis must exceed85% to 90% of luminal diameter before significant reductionsin resting blood flow occur.4 However, under vasodilatorstimulus, maximal coronary flow has been shown to decreasewith stenosis of �45% (Figure 1).4 This has been demon-strated clinically using quantitative PET myocardial perfu-sion imaging (MPI).5,6 Because perfusion is an early changein the ischemic cascade,7 stress modalities that assess coro-nary perfusion reserve have a higher sensitivity in detectingflow-limiting stenoses than analysis of stress-induced wallmotion abnormalities or ECG changes alone.8 Abnormalcoronary flow reserve with vasodilator stress in the absenceof a significant coronary stenosis occurs and has beenattributed to microvascular and/or endothelial dysfunction.9
Methods for Inducing Coronary VasodilationMPI is based on the ability of stress modalities to induceregional heterogeneity of coronary artery blood flow in the
presence of CAD. Exercise induces coronary vasodilation viaan endothelium-dependent flow-mediated process to meet theincreased oxygen demand.10 During exercise, in the setting ofcoronary disease, perfusion reserve may be reduced fromflow-limiting stenoses, endothelial dysfunction, and adrener-gic stimulation.11 Exercise is typically associated with a 2- to3-fold increase in myocardial blood flow and is the preferredmodality, as exercise capacity has important prognosticvalue.12 Dipyridamole, adenosine, and regadenoson are phar-macological vasodilators that cause arteriolar vasodilation byboth direct and endothelium-mediated mechanisms and areassociated with a 3.5- to 4-fold increase in myocardial bloodflow.13 Dobutamine, a synthetic �1- and �2-receptor agonist,typically produces a 2- to 3-fold increase in myocardial bloodflow similar to exercise.13
The Ideal Perfusion Imaging Techniqueand Agent
Table 1 summarizes the characteristics of an ideal perfusionimaging agent and perfusion imaging modality. An idealagent would have a high first-pass myocardial uptake propor-tional to perfusion, insignificant back-diffusion and recircu-lation, rapid clearance from the blood pool, and kinetics thatare not altered by factors such as metabolism or hypoxia. Forimaging during first pass, there should be a direct andquantifiable relationship between contrast agent concentra-tion and myocardial perfusion. In both cases, the contrastagent concentration should be proportional to perfusion overa large range of coronary flows. The ideal agent would notalter hemodynamics and would be small in volume comparedwith the myocardial blood volume. Finally, the agent shouldbe safe, with minimal side effects. The ideal perfusionimaging modality would have a high sensitivity to smallchanges in coronary blood flow and a quantifiable relation-ship between signal intensity and perfusion. The techniquewould have high spatial resolution so that transmural differ-ences in perfusion could be detected. In the case of techniquesthat image during the first pass of a contrast agent, thereshould be sufficient temporal resolution to adequately samplethe time-intensity curve and provide adequate coverage of theventricular myocardium. The technique should be reproduc-ible and have a high diagnostic utility and should be free ofartifacts that would limit either. Finally, the technique shouldbe widely available, fast and easy to use, and cost-effective.
Our goal will be to critically evaluate each of the perfusionmodalities with respect to these ideals.
SPECT MPIRadiotracersThree radiotracers are commonly used clinically for SPECTMPI. Thallium-201 (Tl-201) is a potassium analog, which istaken up by viable myocytes in proportion to blood flow.However, the low energy of the Tl-201 photon (80 keV) andthe long half-life (�73 hours) are suboptimal for perfusionimaging.14 Tc-99m sestamibi and Tc-99m tetrofosmin bindmitochondrial membranes, show virtually no redistributionafter initial uptake, have a 140-keV photon peak that is nearthe optimal for � cameras, and have a 6-hour half-life,permitting injection of higher activity of tracer.15 The first-
pass extraction of Tl-201, Tc-99m sestamibi, and Tc-99mtetrofosmin are 86%, 64%, and 54%, respectively, at restingflows.14 However, at high flows when extraction is diffusion-limited, the extraction is considerably lower causing thewell-known-roll-off phenomenon (Figure 2). Tl-201 has sig-nificant delayed redistribution so that stress images should beobtained less than 10 to 20 minutes after stress injection.Imaging of the 3- to 4-hour delayed redistribution permitsdistinguishing ischemia from scar.16 The Tc-99m perfusionagents take longer to clear from the hepatobiliary system andgut, which may cause scattering of activity into the inferiorwall of the heart. All of the agents have properties that allowthe stress component and the imaging component to beseparated in time and location, which is a significant advan-tage over other modalities that require imaging during thefirst pass of the contrast agent. Notably, the uptake of allSPECT tracers is dependent on myocardial cellular integrityin addition to blood flow.
SPECT MPI Imaging ProtocolsThere are a number of SPECT MPI protocols available for theassessment of CAD. With the same-day rest-stress protocolusing a Tc99m-labeled perfusion agent, a first injection at restis followed by imaging roughly 30 minutes later. A secondinjection with 2 to 3 times the activity is administered duringpeak stress to overcome the background signal from the restimages, and repeat imaging is performed. A typical Tl-201protocol would involve injection during peak stress, thenimaging roughly 10 minutes later, followed by a redistribu-tion image obtained roughly 4 hours later. A dual-isotopeprotocol in which Tl-201 is used for the rest images and thena Tc-99m perfusion agent is used during stress soon thereafterhas also been used to increase nuclear laboratory through-put.17 However, given the different properties of Tc-99magents and Tl-201, issues may arise from interpreting restimages with one isotope and stress images with a differentisotope. The radiation burden to the patient is higher withdual-isotope imaging (typically 24 mSv) than when using
Figure 1. Relationship between percent diameter stenosis andresting flow (dotted line) and hyperemic flow after intracoronaryinjection of Hypaque (solid line) in 12 dogs demonstrates pre-served resting flow for stenoses �80% but attenuation of hy-peremic flow in the presence of coronary stenoses �45%.Adapted from Gould KL, et al. Am J Cardiol. 1974;33:87–94.
Table 1. Attributes of an Ideal Perfusion Agent and PerfusionImaging Modality
Perfusion Agent Imaging Modality
High first-pass uptake(or intravascular)
High sensitivity
Linear relationship betweenmyocardial concentration andperfusion
Quantifiable relationshipbetween signal intensity andconcentration of agent
Negligible volume High spatial/temporal resolution
No effect on hemodynamics Adequate spatial coverage ofthe ventricle
Stable Reproducible—no operatordependence
Safe High diagnostic utility
Easy to administer Easy to use
Kinetics not altered by metabolism Widely available
Figure 2. Relationship between myocardial blood flow and per-cent activity for both SPECT and PET perfusion agents demon-strates a roll-off phenomenon at high flow rates. This results inreduced sensitivity for less severe coronary stenoses.
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Image AnalysisImages may be analyzed qualitatively using visual analysis orsemiquantitatively using differences in relative counts be-tween rest and stress as compared with normal databases.
Figure 3 demonstrates the utility of semiquantitative analysis.
Advantages and Limitations of SPECTSPECT MPI is widely available and has been extensivelyvalidated. As the stress and imaging components are per-formed separately, SPECT MPI is compatible with multiplestress modalities including exercise, dobutamine, or vasodi-lators. Because the imaging does not occur during first pass ofa contrast agent, there is less demand for high temporalresolution, and signal-to-noise ratio (SNR) can be improvedby collecting data over a longer period of time. SPECT MPIhas multiple limitations, including relatively long acquisitionprotocols and considerably poorer spatial resolution thanother available modalities, limiting detection of subendocar-dial perfusion defects. Furthermore, the roll-off of traceruptake at higher myocardial blood flows limits sensitivity indetecting mild-to-moderate stenoses.15 Additional limitationsinclude motion artifacts related to patient and respiratorymotion, scatter and partial volume artifacts in the inferior wallrelated to gut and biliary activity, and variable attenuationartifacts resulting from breast or subdiaphragmatic attenua-tion. These artifacts can decrease the diagnostic utility of theperfusion images. Motion artifacts can be corrected in post-processing with the use of motion correction algorithms.19
ECG-gated acquisitions, which allow for assessment of re-gional myocardial function, can be used to help distinguishattenuation artifacts from fixed perfusion defects resultingfrom myocardial scar. Attenuation correction algorithms thatuse transmission as well as emission data are available andcan improve the accuracy of SPECT MPI.20 Within the lastfew years, developments in novel imaging hardware anditerative reconstruction are leading to improved spatial reso-lution, contrast, and imaging speed for SPECT MPI.21 Be-cause only relative perfusion is generally assessed, SPECT
MPI has reduced sensitivity for detecting left main disease or3-vessel disease related to balanced ischemia.22–24 Finally, thetracers expose patients to nontrivial radiation doses, typically25 mSv for Thallium-201 and 10 to 16 mSv for Tc99m-basedagents.25
Appraisal of the LiteratureAppropriateness criteria have been published for SPECT MPIand provide guidance for when SPECT MPI should be usedfor evaluation of myocardial perfusion.26 There is an exten-sive literature evaluating the sensitivity and specificity ofSPECT myocardial perfusion imaging for detecting CAD. Ananalysis of 32 studies including 4480 patients with known orsuspected CAD demonstrated mean sensitivity and specificityof 87% and 73%, respectively, for exercise myocardialSPECT for detecting a �50% stenosis.27 An analysis of 16studies of patients with known or suspected CAD including2492 patients demonstrated sensitivity and specificity of 89%and 75%, respectively, for vasodilator stress with dipyridam-ole or adenosine for the detection of a �50% stenosis.27 Inboth of these analyses, the prevalence of CAD was high(�75%) and the effects of referral bias were not considered,which generally results in underestimation of the true- andfalse-negatives and causes an artificial inflation of sensitivityand deflation of specificity. In 12 studies evaluating 721patients with a low likelihood of CAD (�5% to 10%), thenormalcy rate was found to be 91%.27 SPECT MPI providesimportant prognostic information. A meta-analysis, including19 studies of �39 000 patients with an average of 2.3 yearsof follow-up, the event rate with a negative SPECT MPI was0.6%.28 However, other studies demonstrate substantiallyhigher event rates in patients with diabetes and/or severerenal disease.28,29 The diagnostic approach of SPECT MPIguiding selective coronary angiography reduces costs associ-ated with both diagnosis and revascularization.30
PET MPIAlthough PET has been used for MPI for greater than 25years, multiple factors including availability of scanners,increased cost, and reimbursement issues have limited wide-spread clinical application of PET.31 However, the recent
Figure 3. Semiquantitative regional perfusion anal-ysis demonstrates significant reversibility (�2 SDsrelative to a normal database) in all segments atthe apical and midventricular levels. Additionally,the quantification of stress and rest volumes con-firms transient ischemic dilation of the left ventri-cle. This patient was found to have 3-vessel dis-ease at coronary angiography.
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proliferation of hybrid PET-CT scanners may lead to anincreasingly important clinical role.
PET RadiotracersN-13ammonia, Rubidium-82 (Rb-82), and O-15 water are thePET tracers typically used for myocardial perfusion. O-15water is freely diffusible and has a high first-pass extraction.15
The uptake is proportional to flow over the largest range ofmyocardial flows without significant roll-off (Figure 2). O-15water has a very short half-life of 123 seconds, which makesthe agent only compatible with pharmacological stress butenables serial imaging and results in a low overall patientdose (typically �2 mSv).25 Additionally, the rapid equilib-rium between the blood pool and left ventricular cavityrequires subtraction techniques for analysis.15 O-15 is cur-rently not Food and Drug Administration (FDA) approved forMPI.32 N-13 ammonia has high myocardial retention and fastwashout of the blood pool, which make it a good perfusionagent. The increased half-life enables the potential for exer-cise to be used as the stress modality. Unfortunately, N-13ammonia still has roll-off of uptake at high coronary bloodflow. Both of these agents require an on-site cyclotron forsynthesis. The radiation dose from for N-13 ammonia studiesare typically 2 mSv.18 Rb-82 can be eluted from a generatorand thus does not require an on-site cyclotron. The disadvan-tage is that Rb-82 has the most roll-off in uptake of theaforementioned PET tracers and a higher radiation dose(typically 13 mSv).18 The short half-life makes is mostcompatible with pharmacological stress but allows for re-peated measurements. Recently, new agents based onfluorine-18 (F-18) have been developed that have highcardiac uptake proportional to flow without significant roll-off and good myocardial retention without significant redis-tribution.33,34 Furthermore, the long half-life of F-18 (110minutes) makes it compatible with multiple stress imagingprotocols, and it does not require onsite cyclotron. Clinicalstudies with this promising tracer are in progress.
Imaging ProtocolTypically a resting perfusion image is acquired using eitherRb-82 or N-13 ammonia. A bolus of the tracer is given andimaging usually commences between 90 to 120 secondsthereafter. ECG-gated PET acquisition is usually performedfor 3 to 6 minutes for Rb-82 and 5 to 15 minutes for N-13ammonia, owing to their different half-lives. Given theserelatively short half-lives, stress imaging can be performedsoon after rest imaging. Images at both rest and stress requireseparate transmission images for attenuation correction. Toquantify absolute myocardial perfusion in milliliters perminute per gram, dynamic scanning during first pass of thecontrast agent is performed.
Image AnalysisImages may be analyzed qualitatively and semiquantitatively,as described above for SPECT imaging. Quantitative analysiscan also be performed using data from dynamic acquisitionsduring first pass of the contrast agent. These methods consistof deriving the arterial input function (AIF) from the bloodpool and tissue-activity curves from the myocardium. After
correction for partial volume effects, these curves are fit to a2-compartment kinetic model from which absolute perfusioncan be determined.35 This has been shown to be highlycorrelated with myocardial blood flow from microspheres inanimal models.35 Figure 4 demonstrates the utility of absolutequantification of perfusion using Rb-82 PET in detecting3-vessel disease.36
Advantages and LimitationsPET has improved spatial resolution as compared withSPECT, with spatial resolution of 2 to 3 mm as comparedwith the 6- to 8-mm resolution of conventional SPECTimaging.32 PET tracers have significantly less roll-off ofextraction at high flows as compared with Tc-99m–basedSPECT agents. Unfortunately, Rb-82, which does not requirea cyclotron, has the most significant roll-off of the PETperfusion agents. Furthermore, Rb-82 has high positronemission energy and a mean range of 5.5 mm, resulting in ahigher dose and lower spatial resolution than N-15 ammo-nia.37 Because PET perfusion images are corrected for atten-uation as an inherent component of the technology, attenua-tion artifacts are less of an issue for PET. Furthermore, thetracers used in PET are more easily applied in dynamicscanning to be used for absolute quantification of perfusion.With the recent advances in PET/CT technology, multimo-dality functional imaging of perfusion with PET combinedwith anatomic imaging of computed tomographic angiogra-
Figure 4. Stress-rest Rb-82 PET images demonstrate an obvi-ous fixed perfusion defect in the inferior and inferior lateralwalls, but there are no visual defects in the left anteriordescending coronary artery (LAD) territory. Quantitative analysis,however, demonstrates severe impairment of the vasodilator-induced blood flow in all perfusion territories, with nearlyexhausted perfusion reserve. Coronary angiography demon-strated occluded right coronary artery (RCA) and left circumflex(LCX) arteries, with a severe lesion in the LAD. MBF indicatesmyocardial blood flow; CFR, coronary flow reserve. Adaptedfrom Di Carli. J Nucl Med. 2007;48:783–793.
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phy (CTA) is now possible. The short half-lives of the PETagents result in lower radiation doses than SPECT agents.The major limitations to PET include higher costs andlimitations imposed by the need for a cyclotron for all butRb-82 imaging or imaging agents labeled with F-18. Artifactsfrom motion during the scan are frequently less apparent,making it harder to evaluate their effects on images. Further-more, registration artifacts between perfusion images andattenuation maps can result in artifacts. Additionally, whenPET is combined with CTA, patients probably will beexposed to even higher radiation doses.
Appraisal of the LiteraturePET MPI has been extensively evaluated and has been shownto be both sensitive and specific for the diagnosis of CAD. Arecent meta-analysis including 14 studies (840 patients)demonstrated a sensitivity of 0.92 (95% CI, 0.90 to 0.94) andspecificity of 0.85 (95% CI, 0.79 to 0.90) for the detection ofCAD. The average prevalence of CAD in these data sets was77%, and the studies included both N-13 ammonia and Rb-82as the perfusion agents.38 There are multiple studies directlycomparing the diagnostic utility of PET as compared withSPECT that have demonstrated similar or superior diagnosticaccuracy for PET.39,40 A recent article studied 112 patientswho underwent Rb-82 PET and 112 patients who underwentSPECT and compared their diagnostic utility, using angiog-raphy as the gold standard. The patients were matched fortheir baseline characteristics, and the cohorts included asubset of patients with low likelihood of coronary disease. Ona per-patient basis, PET had a higher diagnostic accuracy(91% versus 76%) and higher specificity (100% versus 66%)for detection of a 50% or greater coronary artery stenosis.37
The summed stress score (SSS) from dipyridamole Rb-82PET MPI has been shown to have prognostic value in patientswith known or suspected coronary disease. In a study of 367patients who were followed for an average of 3.1 years, therewas an incremental prediction of death and nonfatal myocar-dial infarction with annual events of 0.4%, 2.3%, and 7% inthe normal (SSS �4), mild (SSS, 4 to 7), and moderate tosevere (SSS, 8 to 11).41 In another study of 685 patients witha higher prevalence of known CAD (70%), Rb-82 dipyridam-ole stress demonstrated incremental prognostic value toclinical history and angiographic data. Patients with normalscans had a 90% event-free survival, compared with 87% inpatients with small, 75% with moderate, and 76% withextensive defects at 70 months of total follow-up. A normalstudy was associated with a 0.9% annual event rate, whereasa positive study was associated with a 4.3% annual eventrate.42 Additionally, PET has been found to be cost-effectivecompared with angiography, exercise ECG, and SPECT interms of quality-adjusted life-years, for a prevalence of CAD�70%.43 Initial studies have begun to assess the potential ofhybrid PET-CT imaging protocols.44
Myocardial Contrast Echo PerfusionAlthough echocardiography for evaluation of exercise- ordobutamine-induced wall motion analysis is commonly usedclinically, limitations of the sensitivity of wall motion anal-ysis have led to the development of MCE techniques for
assessing perfusion. Unfortunately, the lack of an FDA-approved MCE contrast agent for perfusion has currently putlimitations on its widespread clinical application.
Contrast AgentsMCE contrast agents are small, gas-filled microbubbles (�10um) that compress and expand when exposed to an acousticfield and generate strong acoustic backscattering.45 At certainacoustic pressures they undergo nonlinear oscillations thatresult in generation of harmonic frequencies that can be usedto distinguish the signal of the microbubbles from thesurrounding tissue. This forms the basis for multiple MCEperfusion techniques.46 The ultrasonic characteristics of thebubbles are related to both the composition of the shell andthe encapsulated gas. The microbubbles remain intravascularas they transit the myocardial capillary bed and do not affectcardiac hemodynamics and thus directly reflect myocardialblood flow.47 The intravascular nature of these contrast agentsis different from the first-pass cellular uptake of SPECTradionuclide tracers and extravascular diffusion of CT andmost MRI contrast agents. The microbubbles must be stableenough to resist destruction from normal ultrasound poweroutputs to ensure adequate concentrations for imaging butmay need to have the ability to rupture with high mechanicalindex ultrasound for some techniques to measure myocardialperfusion.48
Although ultrasound contrast agents are generally consid-ered safe,49 the FDA issued a black-box warning for Definityand Optison, which, after a 2008 revision, recommendsintensive monitoring for patients with pulmonary hyperten-sion or unstable cardiopulmonary conditions and close obser-vation of patients without these conditions. Currently thereare no ultrasound contrast agents approved for MCE perfu-sion imaging, and the FDA considers it to be an experimentalprocedure.50
Contrast Echocardiography Perfusion TechniquesMyocardial perfusion can be assessed with continuous infu-sion of microbubbles.
When the microbubbles have reached steady-state concen-trations, a high mechanical index pulse is used to destroy thebubbles in the imaging plane. The subsequent replenishmentof microbubbles is related to myocardial perfusion. Areas thatare hypoperfused will have a slower return of microbubbles,whereas areas that are well perfused will have a more rapidreturn of microbubbles. After the high mechanical indexpulse, images can be obtained in a gated intermittent modewith high mechanical index pulses48 or in a real-time modewith low mechanical index pulses.51 Figure 5 shows MCEperfusion images in a patient with inducible ischemia in boththe left circumflex and right coronary artery territories.52
These areas of reduced perfusion agree with the results ofcoronary angiography. The advantage of the intermittentmode is a higher SNR, but destruction of contrast preventscontinuous imaging and thus wall motion cannot be assessedsimultaneously. The real-time technique allows simultaneousassessment of both perfusion and wall motion but has a lowersensitivity for microbubble detection.52 Myocardial contrast
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perfusion echocardiography has been performed with bothvasodilator and inotropic pharmacological stress.
Image AnalysisMyocardial contrast echo studies can be analyzed qualita-tively or quantitatively. Qualitative analysis is performed bylooking for abnormalities in the rate or amount of contrastreplenishment after a high mechanical index pulse.52 Quan-titative analysis involves fitting parameters to the time-intensity curves of microbubble replenishment. The reappear-ance rate of microbubbles is related to myocardial blood flowvelocity, and the plateau value is related to the microvascularcross-sectional area. An index of myocardial blood flow is theproduct of these 2 parameters.48 Absolute myocardial bloodflow can also be determined with knowledge of the myocar-dial blood volume, which can be assessed as the ratio of thesignal intensity of the myocardium to the left ventricularcavity. This has been shown to correlate well with PET-derived blood flow.53
Advantages and LimitationsMCE has a number of potential advantages over othermodalities. MCE has an advantage over SPECT, PET, andCT perfusion imaging because it does not involve ionizingradiation. Compared with SPECT, MCE has improved spatialresolution, enabling detection of subendocardial ischemia.MCE also has the ability to perform absolute quantification ofmyocardial blood flow. Imaging can be performed duringpharmacological stress with inotropes or vasodilators or withexercise.54 Practical advantages of echocardiography includeits wide availability and its relatively low cost. The techniquehas some limitations. Suboptimal images are obtained in asignificant number of patients as the result of respiratorymotion, body habitus, or lung disease.50 Attenuation from themicrobubbles may result in artifacts in the basal segments ofthe left ventricle. These factors can limit image quality andadequate spatial coverage of the ventricle, resulting in in-creased variability and decreased reproducibility. Further-more, there are some operator-dependent factors such asmaintaining a constant image plane during replenishment ofmicrobubbles. Finally, there are no FDA-approved contrastagents for MCE perfusion.
Appraisal of LiteratureA number of studies have demonstrated a high concordanceof stress perfusion echocardiography and SPECT.55,56 Ameta-analysis of 9 studies including 588 patients comparingSPECT with perfusion stress echocardiography demonstratedan average concordance of 81%.46 Multiple studies have alsodemonstrated comparable accuracy to SPECT for diagnosingCAD. The overall sensitivity and specificity of MCE from ameta-analysis of 18 studies including 1088 patients demon-strated a sensitivity of 82% and specificity of 80%.46 In aretrospective study of 788 patients, MCE was shown to haveprognostic value that was incremental to left ventricularejection fraction.57
CMR Perfusion ImagingOver the last few years, improvements in hardware, pulsesequence development, and image reconstruction algorithmshave enabled high-resolution imaging of first-pass myocar-dial perfusion with CMR.
Contrast AgentsMost CMR studies of myocardial perfusion are based on thefirst-pass of a bolus of gadolinium-DTPA contrast agents.Interactions between the unpaired electrons of paramagneticgadolinium and water protons in close proximity result inmore rapid relaxation of these water protons. Thus, thegadolinium is being detected indirectly via its effect on therelaxation of protons. The T1 and T2 relaxation times of waterprotons are inversely proportional to the local gadoliniumconcentration.58 Therefore, areas that are well perfused willhave a shorter T1 and appear bright on heavily T1-weightedimages, whereas regions that are hypoperfused will havelonger T1 and will appear hypointense. The T1 of themyocardium is affected by multiple factors, including theextraction fraction of the contrast agent as well as waterexchange between the intravascular, extravascular, and extra-cellular spaces. The extraction fraction is typically 0.5 to 0.6for extracellular, extravascular contrast agents, which aresmall molecules that freely diffuse out of the vascular space.59
Quantification of myocardial perfusion is possible by meth-ods that take these factors into account. Intravascular contrastagents exist and have been applied to MPI.60 These agents areusually confined to the intravascular space because of their
Figure 5. Dobutamine stress perfusioncontrast echocardiography demonstratesinducible ischemia in the posterior/apicaland inferoapical regions that correlate tothe significant stenoses seen in the leftcircumflex and right coronary arteries.Adapted from Dijkmans PA, et al. J AmColl Cardiol. 2006;48:11:2168–2177.
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large size and have higher relaxivity.61 Recently, the firstgadolinium-based intravascular agent was approved for mag-netic resonance angiography.
Data Acquisition Pulse SequencesRequirements of a first-pass CMR perfusion imaging pulsesequence include strong T1 weighting to impart contrastrelated to the contrast agent concentration, rapid data acqui-sition to obtain images at multiple slice locations per R-Rinterval, adequate spatial resolution to detect subendocardialperfusion abnormalities, and minimal artifacts to maximizediagnostic utility. The relationship between signal intensityand underlying blood flow is affected by the choice of pulsesequence parameters. Recent studies have used nonselectivesaturation recovery (SR) pulse sequences, which are wellsuited for multislice imaging, insensitive to variations in heartrate, and enable shorter preparation times than inversionrecovery (IR)-prepared pulse sequences.62 The disadvantagesof SR are its reduced dynamic range as compared with IRpreparation. The saturation time is an important determinantof the linearity of T1 to signal intensity. At shorter saturationtimes, the signal intensity is more linearly related to T1 butthe SNR is generally lower. At longer saturation times theSNR is higher, but there is a loss of linearity, especially athigher contrast agent concentrations.
To maximize temporal resolution and spatial coverage, SRpreparations are combined with a variety of rapid readouttechniques including fast low-angle shot (FLASH),63 echo-planar imaging,64 or steady-state free precession (SSFP).65
The advantages of FLASH include reduced susceptibility-induced image artifacts; disadvantages include lower achiev-able SNR and longer readout duration. The advantage ofSSFP sequences is higher SNR, but at the cost of increasedsusceptibility artifacts. Echoplanar imaging techniques havethe highest temporal resolution but may have ghosting arti-facts resulting from periodic fluctuations of the k-spacesignal. Multiple studies have compared these techniques, but,regarding the optimal protocol, there has been no clearconsensus in the field. To further improve temporal resolu-tion, all of the above techniques have been combined withparallel imaging techniques.66 Parallel imaging with acceler-ation factors of 2 is now routinely used in clinical practice,and multiple highly accelerated techniques have begun to beapplied in human studies.
Many investigators have performed perfusion studies at 3T and have demonstrated improved SNR and CNR.67 Re-cently, 3D encoding methods have been combined withparallel imaging to improve spatial coverage using either 3DSSFP or 3D FLASH.68
Imaging ProtocolStress perfusion CMR is generally applied as part of acomprehensive study that evaluates ventricular function,stress and rest perfusion, and viability/myocardial infarction.Cine images to assess ventricular function are obtainedgenerally in �10 minutes. Stress perfusion images are thenobtained during infusion of 140 �g/kg/min of adenosine for 2to 4 minutes. Typically, 3 to 4 short-axis perfusion images areacquired each heart beat during the injection of 0.05 to
0.1 mmol/kg gadolinium contrast at a rate of 3 to 4 mL/s viaa power injector during first pass of the contrast agent. Fortyto 60 image frames are usually obtained. After a 10-minutecontrast washout period, perfusion images are obtained at restusing the same imaging protocol. Finally, late gadolinium-enhanced images are obtained covering the heart. The studytypically takes approximately 45 to 60 minutes in experi-enced centers.
To perform quantitative perfusion, the AIF at rest andstress must also be determined. Accurate determination of theAIF requires a low contrast dose to avoid T2* saturationeffects. Three approaches have been used: using a lower doseof contrast (0.05 mmol/L) for the whole perfusion study,performing separate injections during stress and rest withvery low contrast doses (0.0025 mmol/kg), or using a hybridperfusion sequence that obtains a separate image for the AIFon each heartbeat.
Image AnalysisImages can be evaluated qualitatively using visual analysis.Klem et al69 reported an algorithm with high sensitivity andspecificity for detecting CAD. First late gadolinium-enhancedimages are reviewed for evidence of prior myocardial infarc-tion, then the stress images are evaluated for inducibleischemia, and finally the rest images are reviewed to assessfor artifacts. This technique has an overall sensitivity andspecificity of 89% and 87%, respectively, for detectingCAD.69 The high spatial resolution of CMR enables thedetection of subendocardial ischemia. In a patient with3-vessel disease, the subendocardial ischemia is clearly seenon the CMR study, whereas it is not evident on the SPECTMPI study (Figure 6). Images can also be analyzed using asemiquantitative approach using the time-intensity curvesduring the first pass of signal through the myocardium.Parameters such as the upslope, time to peak, and peakmyocardial enhancement have been used to evaluate for areaswith reduced perfusion. Absolute quantification of myocar-dial perfusion can be obtained from the time-intensity curvesof the myocardium AIF using deconvolution (Figure 7).70
Advantages and LimitationsCardiac MRI has significant advantages for perfusion stresstesting, including its high spatial resolution, the ability toperform absolute quantification of perfusion, and the addi-tional information provided in a comprehensive CMR study.Furthermore, the study can be performed rapidly, has limitedoperator dependence, and the signal characteristics are largelyindependent of the patient’s body habitus. CMR perfusionstudies have adequate spatial coverage and temporal resolu-tion that continue to improve with further advances in parallelimaging techniques. Current pulse sequences suffer from a“dark-rim” artifact that can be mistaken for a true perfusionabnormality.62 The origin of this artifact probably is multi-factorial, including myocardial motion during data acquisi-tion, Gibbs ringing caused by resolution limitations, orsusceptibility artifacts from the passage of the contrastagents.65,71,72 As compared with a true perfusion abnormality,this artifact tends to be present transiently at peak ventricularcavity enhancement. Because imaging occurs during first
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pass of a contrast agent, CMR perfusion imaging is mostcompatible with vasodilator stress. For multiple reasons,gadolinium-DTPA is not an ideal contrast agent. It hasintermediate extraction fraction during first-pass imaging andhas nonlinearity in the relationship between signal intensityand perfusion. In regions of infarction, gadolinium has a slowwashout that changes the baseline signal intensity for the restperfusion study; however, the combination of perfusion withdelayed enhancement imaging enables accurate detection ofmyocardial infarction. Recently, gadolinium contrast agentshave been associated with a rare but serious condition callednephrogenic systemic fibrosis, which primarily occurs inpatients with significant reductions in creatinine clearance.73
The FDA has issued a black-box warning for gadolinium-based contrast agents in patients with a creatinine clearance�30 mg/dL.
Appraisal of the LiteratureAppropriateness criteria have been established for CMR thatprovide guidance to the appropriate use of CMR perfusionimaging and stress testing.74 Adenosine stress cardiac MRIhas been shown to be both sensitive and specific for detectionof CAD. A recent meta-analysis including 1516 patients withintermediate likelihood of disease (prevalence 57.4%) under-going adenosine stress perfusion MRI demonstrated a sensi-tivity of 0.91 (95% CI, 0.88 to 0.94) and specificity of 0.81(95% CI, 0.77 to 0.85).75 As CMR perfusion is still arelatively new modality, there is less prognostic data ascompared with other modalities. In a study of 420 patientswith known or suspected CAD, the presence of abnormalperfusion was associated with a 17% event rate, whereas anormal perfusion study was associated with a 5% event rate.76
In a study of 135 patients presenting to the emergency
Figure 6. SPECT MPI (left) and CMR first-pass perfusion images (right) at stress and rest in a patient with suspected coronary disease.The superior spatial resolution of the CMR study enables clear visualization of subendocardial ischemia in this patient who was foundto have 3-vessel disease at coronary angiography.
Figure 7. First-pass CMR perfusion image demonstrates a large perfusion defect in the inferolateral wall (yellow arrow). This is seen onthe time-intensity curves from the region of the perfusion abnormality and remote myocardium (purple arrow). By deconvolution of thetissue functions from the AIF (green curve) absolute myocardial blood flow can be determined. Adapted from Patel A, et al. J Nucl Car-diol. 2008;15,5:698–708.
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department with chest pain and negative troponin-I, therewere no events in 107 patients without CMR perfusionabnormalities at 1 year, and the presence of an abnormalstress CMR was significantly predictive of MACE.77 Abso-lute perfusion reserve by CMR perfusion is highly correlatedwith values obtained by PET in human subjects.78 CMRperfusion has also been shown to correlate with fractionalflow reserve by cardiac catheterization.79 A multicenterdose-ranging trial of 234 patients randomly assigned subjectsto receive 1 of 5 gadolinium contrast doses and directlycompared CMR stress perfusion and SPECT MPI usingcoronary angiography as the gold standard. Perfusion CMR atthe optimal CM dose (0.1 mmol/kg) had a performancesimilar to SPECT, if only the SPECT studies of the 42patients with this dose were considered; however, the diag-nostic performance of perfusion CMR was superior as com-pared with the entire SPECT population (N�212), whichrequires further evaluation in larger prospective trials withstandardized methodology.80
CTA Perfusion ImagingWith the recent advances in multidetector CT (MDCT) andCT coronary angiography, there has been renewed interest inusing CT to evaluate myocardial perfusion.
Contrast AgentsMyocardial perfusion imaging with CT is based on theintravenous injection of iodinated contrast agents that in-crease the absorption of x-rays in proportion to the concen-tration of iodine.81 Most of the agents used clinically arenonionic contrast agents with a high iodine concentration.82
Iodinated contrast agents are not hemodynamically inert andhave an influence on coronary blood flow, inducing areduction in coronary flow followed by a hyperemic re-sponse.83 This effect is less significant, however, for lowosmolarity nonionic contrast agents.84 During first pass, thereis also significant diffusion of the contrast agents into theinterstitial space, particularly for nonionic and low-molecular-weight compounds.85 The first-pass extraction ofcontrast is around 33% with maximal vasodilation and issubstantially higher at lower flow rates.85 Thus, for accurate
assessment of perfusion, the extravascular diffusion of theagent must be taken into account. Methods for correcting forthis effect have been applied.86 In terms of safety, the majorconcern is contrast-induced nephropathy, especially in patientswith reduced renal function (creatinine clearance �60).87
Imaging TechniquesMultiple studies have evaluated perfusion in myocardialinfarction, but to date there are only a few published studiesthat have evaluated myocardial perfusion to detect inducibleischemia with vasodilator stress. Kurata et al88 performedECG-gated contrast-enhanced coronary CTA protocols dur-ing adenosine stress and 20 minutes later at rest and visuallyassessed for areas of inducible ischemia in 12 patientswithout known CAD and demonstrated high concordance(0.83) with conventional SPECT in localizing territories ofinducible ischemia. A comparison between CTA perfusion,SPECT, and angiography is shown in Figure 8. Kido et al89
performed dynamic cine 16-detector MDCT during adeno-sine infusion in 14 patients with intermediate risk of CAD.Images were obtained continuously for 20 seconds at amidventricular level, and myocardial blood flow was quanti-fied. Coronary angiograms and SPECT stress studies werealso obtained. In territories with significant coronary stenosisby angiography, there was significantly reduced myocardialblood flow. Their study had a 72% sensitivity and 80%specificity for detecting a significant coronary stenosis with amyocardial blood flow cutoff of 1.5 mL/min/g.89 George etal90 performed adenosine stress coronary CTA using a 64-detector MDCT in an animal model of left anterior descend-ing coronary artery stenosis. They detected a significantreduction in signal density of the myocardium in the leftanterior descending coronary artery territory as comparedwith remote regions. Furthermore, they demonstrated a non-linear correlation of the ratio of the signal density in themyocardium normalized to the left ventricular cavity signaldensity. George et al91 also evaluated the use of dynamicperfusion imaging in a dog model of left anterior descendingcoronary artery stenosis using 64-detector MDCT. Afteradenosine infusion, dynamic CT images covering 32 mm ofthe left ventricle were obtained continuously for 70 seconds.
Figure 8. Adenosine stress (A)/rest (B)SPECT MPI images demonstrate a partiallyreversible perfusion abnormality in the in-ferior and anterior walls. The CT perfusionstress (C)/rest (D) study demonstrates atransmural hypoperfused area in the inferi-or wall and a subendocardial perfusiondefect in the anterior wall at stress that areconcordant with SPECT. Coronary CTAdemonstrates stenoses in the right coro-nary artery (E) and diagonal branch (G),which were confirmed by coronary angiog-raphy (F and H). Despite severe calcifica-tion in the left anterior descending coro-nary artery territory, the combination of CTstress perfusion and CTA demonstratesonly a small area of ischemia in the leftanterior descending coronary artery terri-tory. Adapted from Kurata et al. Circ J.2005;69:550–557.
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They demonstrated a strong correlation between absoluteperfusion by MDCT and microspheres. Nagao et al92 per-formed cardiac MDCT at rest and SPECT MPI at rest andstress in 34 patients with suspected coronary disease. Theyfound that systolic endocardial signal density in regions withinducible ischemia by SPECT MPI was significantly lowerthan in nonischemic regions. Recently, George et al per-formed adenosine stress CT perfusion imaging in 40 patientsusing 64- or 256-detector MDCT. They demonstrated that thecombination of CT perfusion and angiography detected per-fusion abnormalities with a sensitivity and specificity of 86%and 92%, respectively, as compared with a combination ofcoronary angiography and SPECT MPI.93 In their study, theradiation dose for 64-detector MDCT was 16.8 mSv (stressonly) and 21.6 mSv with 256-detector MDCT (stress andrest); however, doses may be lower with 320-detector, pro-spectively gated acquisitions.
There has also been a recent report of using dual-energyCT (DECT) on a dual-source MDCT scanner to determineregional myocardial perfusion. DECT relies on the fact thatiodinated contrast agents have unique absorption of x-rays ofdifferent energy levels that enables mapping of the iodineconcentration.94 Ruzsics et al95 performed dual-energy CTAin 35 patients with known or suspected CAD. Iodine distri-bution maps were determined from the image sets withdifferent x-ray energies. In 16 patients, stress/rest SPECT wasalso performed. In the 5 patients with fixed defects, DECTcorrectly identified 90% of the perfusion defects, and in the11 patients with reversible defects, DECT correctly identified88% of the defects on a per-defect basis. It is interesting thatDECT imaging at rest correlated with inducible ischemia bystress/rest SPECT; however, the physiology underlying thisobservation requires further investigation.
Advantages and LimitationsThe advantages of MDCT include its high spatial resolution,rapid data acquisition, and the ability to potentially combineinformation of coronary anatomy, ventricular function, andperfusion in one study. Furthermore, with the growth of CTA,MDCT scanners are becoming widely available. Absolutequantification of CT perfusion has been demonstrated fordynamic studies but requires modeling of the effects ofcontrast diffusion into the extravascular space. Furthermore,advancement of MDCT with 256 or 320 detectors may enabledynamic analysis of perfusion with high temporal resolution.However, the use of MDCT for perfusion analysis hasmultiple limitations. Because image quality is inverselyrelated to heart rate, the increase in heart rate with vasodilatorstress may compromise image quality. Furthermore, artifactssuch as beam-hardening result in variations of signal intensity
within the myocardium, limiting the ability of quantitativeassessment of perfusion. The contrast agent doses typicallyused preclude evaluation of patients with significant renalinsufficiency. The main disadvantage of assessing perfusionwith MDCT is the potentially high doses of ionizing radia-tion. Protocols that involve obtaining CTA studies at rest andstress would potentially double the current coronary CTAradiation dose. Dynamic perfusion analysis probably wouldhave an even higher radiation dose. As MDCT continues toevolve, further studies of perfusion using this technique arewarranted.
SummaryThere has been significant progress in the noninvasive eval-uation of myocardial perfusion over the last 30 years. Thecurrently available modalities each have their advantages andlimitations, as described in this article, but no technique hasdemonstrated unequivocal superiority (Table 2). Advances inquantitative methods are continuing to improve diagnosticaccuracy in patients with left main and 3-vessel disease whoare most likely to benefit in revascularization over medicaltherapy. It is vitally important to develop methodologies thatpermit measurement of absolute flow in milliliters per minuteper gram or flow reserve from rest to stress states. Presently,the radionuclide techniques as used clinically only assessrelative flow differences between regions of myocardium.Integration of anatomic and functional information from 1 ormultiple modalities in the form of multimodality imagingwith fusion of 2 disparate images (eg, CMR with PET) isbecoming increasingly important as well. Future studiesshould adopt a functional gold standard, such as fractionalflow reserve, in addition to the anatomic gold standard ofcoronary stenosis severity. This is especially relevant to ourunderstanding of microvascular dysfunction, resulting inreductions in perfusion reserve without angiographicallysignificant coronary stenoses. Additionally, in the era ofescalating medical costs, we must determine the value of theaccurate noninvasive assessment of perfusion, as a means ofcontrolling costs for expensive and invasive procedures suchas coronary angiography and unnecessary revascularization.Appropriateness criteria for perfusion stress testing have beenestablished for SPECT26 and CMR74 and should be estab-lished for PET, contrast echocardiography, and CT perfusion,as well as other new imaging techniques as they becomeestablished into clinical practice. Cost-effectiveness of thenew technologies must be evaluated. It is no longer sufficientto provide test performance only as compared with estab-lished techniques but rather to determine whether they sig-nificantly affect patient treatment and ultimately patientoutcomes. Outcomes studies demonstrating the worth of
Table 2. Pooled Diagnostic Performance of Perfusion Imaging Techniques
imaging of myocardial perfusion are being demanded. Ad-vances in technology are continuing to improve the diagnos-tic and prognostic utility of noninvasive assessment of myo-cardial perfusion and are enhancing the ability to risk-stratifypatients for targeted personalized therapy.
DisclosuresNone.
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KEY WORDS: echocardiography � imaging � magnetic resonance imaging� nuclear medicine � perfusion
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