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T A T E - O F - T H E - A R T P A P E R S

yocardial Perfusion Imaging Withontrast Ultrasound

homas R. Porter, MD, Feng Xie, MD

maha, Nebraska

his report reviews the development and clinical application of myocardial perfusion imaging with myocardial

ontrast echocardiography (MCE). This includes the development of microbubble formulations that permit the

etection of left ventricular contrast from venous injection and the imaging techniques that have been in-

ented to detect the transit of these microbubbles through the microcirculation. The methods used to quantify

yocardial perfusion during a continuous infusion of microbubbles are described. A review of the clinical

tudies that have examined the clinical utility of myocardial perfusion imaging with MCE during rest and stress

chocardiography is then presented. The limitations of MCE are also discussed. (J Am Coll Cardiol Img 2010;3:

76–87) © 2010 by the American College of Cardiology Foundation

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series of inventions and scientific break-throughs are responsible for the develop-ment of myocardial perfusion imaging

with myocardial contrast echocardiog-aphy (MCE). First, there was the invention oftable microbubble shells using either electrome-hanical sonication of albumin or lipid emulsions1,2). Second there was the stabilization of theseicrobubbles following venous injection by the

ncorporation of a high molecular weight insolu-le gas within the shell, which permitted consis-ent left ventricular opacification following ve-ous injection (3). Then, it was discovered thathe typical ultrasound imaging techniques at aigh mechanical index (MI) were destroyinghese microbubbles as they transited through theyocardial microcirculation. By either triggering

ltrasound to one frame every cardiac cycle or bytilizing a very low mechanical index and har-onic imaging, myocardial contrast enhance-ent from a venous injection of microbubbles

rom the University of Nebraska Medical Center, Omaha, Nebraskantheus Medical Imaging and Astellas Pharma Inc., significant gra

upport (i.e., equipment, drugs, and software) from Siemens Mediconorarium from Lantheus Medical Imaging and Point BioMed. Sa

anuscript received May 29, 2009; revised manuscript received Augus

as consistently visualized (4). With harmonicriggered imaging, myocardial perfusion abnor-alities were visualized in humans using very

mall intravenous bolus injections of perflouro-arbon containing microbubbles (5). Finally, aeam of investigators headed by Kevin Wei andanjiv Kaul at the University of Virginia madehe landmark discovery that these ultrasoundriggering techniques could be utilized to quantifyyocardial blood flow, and even examine the

omponents responsible for myocardial bloodow (6). This has led to clinical studies demon-trating how MCE can provide important bed-ide information on myocardial blood flow duringtress echocardiography laboratory (7–10), in thecute and chronic assessment of myocardial via-ility (11–14), and in the emergency department15). This paper will review the technical aspectsf myocardial perfusion imaging with MCE, andow it has been utilized to detect coronary arteryisease and guide management.

r. Porter has received modest grant support fromupport from NuVox Pharma Inc., and other grant

aging, and has served as a consultant or receivedKaul, MD, served as Guest Editor for this paper.

t 6, 2009, accepted September 17, 2009.

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Porter and Xie

MPI With Contrast Ultrasound

177

erfusion Imaging Techniques With Myocardialontrast Echocardiography

icrobubbles in an ultrasonic field are strong scat-erers, sending compression and rarefaction wavesack to the scanner. At peak negative pressuresbove 0.1 MPa, the microbubbles respond in aonlinear manner. In general, what nonlinear be-avior means is that the magnitude of compressionnd rarefaction waves are not the same with eachscillation. At these low incident pressures, theicrobubbles exhibit both linear and nonlinear

eturning waves, whereas the myocardium andther structures primarily exhibit linear responses16). The nonlinear responses occur in both theundamental and harmonic frequencies and can beeceived and filtered by the echocardiographic sys-em. Ultrasound imaging software that selectivelyeceives the nonlinear responses produces a muchetter signal-to-noise ratio and more sensitive de-ection of microbubbles than what would be re-eived from conventional imaging software (17).

Microbubbles are destroyed by real-time ultra-ound when it is transmitted at higher intensitiesMIs �0.3). Destruction can be reduced by de-reasing the frame rate to 1 out of every 1 to severalardiac cycles, usually with triggering the frame tohe electrocardiogram. This has been referred to asntermittent imaging, and has been used with botharmonic and power Doppler systems (18–21).hen the intermittent ultrasound impulse is at a

igh intensity (�0.9 MI), there is a strong and briefonlinear echo from the bubble. Interrupting theigh-intensity ultrasound for a short period of timellows for replacement of microbubbles, which serveo produce contrast enhancement for the subse-uent triggered frame. When microbubbles aredministered as a continuous infusion and theltrasound pulsing interval is incrementally varied,he reappearance of bubbles in the myocardiumermits the calculation of mean microbubble veloc-ty and plateau (or peak) myocardial signal intensity5). Multiplying these 2 variables together, one canuantify myocardial blood flow changes. With thesentermittent imaging techniques, it has becomeossible to noninvasively examine myocardial per-usion in animals and humans using a wide varietyf intravenous higher molecular weight micro-ubbles (22,23). Significant achievements haveeen made in low MI real-time visualization ofyocardial function. Pulse inversion Doppler is aultipulse technique that separates linear and non-

inear scattering using the radiofrequency domain. s

hen used at a very low MI, linear scatterers likeyocytes and tissue will have their signals canceled,hereas nonlinear scatterers (like microbubbles)ill produce summated signals (24). Pulse inversionoppler overcomes motion artifacts by sendingultiple pulses of alternating polarity into theyocardium. This allows one to visualize wall

hickening and contrast enhancement simulta-eously at very low MIs (�0.2) while maintainingn excellent signal-to-noise ratio. Because it caneceive only even order harmonics, however, there isignificant attenuation, especially in basal myocar-ial segments in apical windows.Power modulation is another technique that

mproves the signal-to-noise ratio at very low me-hanical indices. This technique, developed byhilips (Andover, Massachusetts), is also a multi-ulse cancellation technique; however, with powerodulation, the power of each pulse is varied.ontrast pulse sequencing (Siemens Acuson Se-uoia; Mountain View, California) ex-ends these multipulse techniques by in-erpulse phase and amplitude modulation25). Both power modulation and contrastulse sequencing can be used at a very lowI to assess myocardial contrast in real

ime with excellent spatial resolution atigher bandwidths (Fig. 1). In these ex-mples, note that background signals fromhe myocardium are virtually absent.ualitative and quantitative methods ofyocardial perfusion analysis. Regardlessf the route of microbubble injection, anccurate definition of microbubble con-entration in the myocardium requires that theelationship between concentration and signal in-ensity be linear. This precondition is fulfilled atow intramyocardial microbubble concentrations.t a certain microbubble concentration, however,

chocardiographic systems normally reach a satura-ion point, where videointensity is no longer pro-ortional to the microbubble concentration (26).his becomes a factor with bolus injections oficrobubbles, in which transient high concentra-

ions can be reached even in regions with reducedyocardial blood flow, leading to a brief period

uring which contrast enhancement falsely appearsormal in these regions. It is not until microbubbleoncentration falls during the washout period thatifferences in microbubble concentration are visu-lly evident. It is during this time period that theres a linear relationship between concentration and

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f microbubbles, the myocardial contrast intensityuring this washout period is a reflection of myo-ardial blood volume. Estimates of myocardiallood flow cannot be ascertained from bolus injec-ions, because mean transit times cannot be ob-ained from time intensity curves due to dispersionf the bolus by intrapulmonary filtering.The difficulties arising with thresholding effect and

aturation point of echocardiography systems canartly be avoided by using a continuous peripheralenous infusion for microbubbles instead of a bolusnjection. This method assumes that the input of

icrobubbles into the myocardium is constant. Theractical advantage of a continuous infusion is that at-enuation artifacts due to high contrast intensity in theeft ventricular cavity can be reduced (27–29). More-ver, the contrast dosage administered can easily bedjusted on the basis of what is seen during imaging (29).

The ultrasound beam destroys these microbubbleshen a high MI is used, so that insonation at highIs results in almost complete bubble destruction

ith every pulse. Triggering ultrasound to 1 frameimed to end systole in the cardiac cycle at a sequencef incrementally longer cardiac cycles allows a replen-shment of contrast agent corresponding to flow to theiven region during that time sequence. The longerhe triggering intervals are set, the more microbubbleseplenish the capillaries and the higher the signalntensity to be registered in the tissue, until finally alateau phase is reached. Alternatively, if one ismaging at a low MI in real time, brief high-MImpulses can be applied to the imaging plane, afterhich replenishment can be visualized in real time at

he low MI (Fig. 2). Regardless of the technique, thelateau background-subtracted myocardial contrastntensity of a respective myocardial region is related tohe capillary cross-sectional area. The initial slope athich this plateau stage is achieved is proportional to

Figure 1. An Example of the Excellent Background Subtraction

The images are achieved with low–mechanical index pulse sequenc4-chamber view, note that there are virtually no signals from the mtricular cavity opacification (B) and eventual myocardial contrast (Cbasal segments is most likely due to a high initial concentration of

he blood flow velocity in that region. The slope times c

eak or plateau myocardial videointensity, therefore,epresents a measure of myocardial blood flow (6).

Factors such as attenuation, underlying tissueignals, incomplete microbubble destruction withigh MI impulses, and difficulties with softwareuantification techniques have prevented the wide-pread use of quantification during myocardial con-rast echocardiography (MCE). Models have beenroposed and validated that correct for attenuationn the plateau myocardial signal intensity by divid-ng it by the adjacent left ventricular cavity inten-ity. These normalized plateau intensities, whenultiplied by the rate of contrast replenishment and

ivided by tissue density, can be used to computeyocardial blood flow (30). Continuous infusion

echniques can be done with infusion pumps orand-held infusions. With either of the commer-ially available contrast agents, one can mix them athe bedside with saline and infuse them either as aontinuous drip or as a hand-held infusion.

linical Application of Ultrasonographic Contrastor Perfusion Imaging

ith Vasodilator Stress Perfusion Imagingetection of coronary artery disease. Radionuclide

cintigraphy is still considered by the majority ofardiologists as the diagnostic tool to assess myocardialerfusion during stress testing. This method, whenerformed with technetium-99m (99mTc) or 201Tl,as been reported to detect coronary artery diseaseCAD) with high sensitivity during exercise or vaso-ilator stress imaging. Despite its widespread use,owever, both radionuclide single-photon emissionomputed tomography (SPECT) and positron emis-ion tomography (PET) are limited by poor spatialesolution. SPECT is also limited by frequent atten-ation artifacts. With intravenous perfluorocarbon

hemes designed to assess myocardial perfusion. In this apicalardium before contrast administration (A), but excellent left ven-er venous infusion of ultrasound contrast. The attenuation in therobubbles in the left ventricular cavity.

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ng techniques, detection of underperfused myocardialegments during stress echocardiography has becomefeasible alternative. Initial studies deployed intermit-

ent harmonic or power Doppler imaging techniqueso detect coronary stenoses during vasodilator stress.sing intravenous Optison and intermittent high MIarmonic imaging, Kaul et al. (7) described a 92%oncordance between segmental perfusion scores by

CE and 99mTc-sestamibi SPECT at rest anduring dipyridamole stress. Heinle et al. (9) used an

ntravenous Optison infusion and harmonic poweroppler imaging at long pulsing intervals during

denosine stress testing to compare perfusion with9mTc-sestamibi SPECT in 123 patients with sus-ected CAD. There was an overall concordance be-ween both techniques of 83%; concordance wasigher in patients with no or multivessel CAD.Real-time perfusion and other lower MI imaging

echniques have been applied to vasodilator stress asell (Table 1) (10,31–43). Recently, the first multi-

enter studies compared MCE (triggered replenish-ent imaging) with radionuclide SPECT. These

Figure 2. An Example of Normal Myocardial Replenishment (Ap

With real-time perfusion image, the myocardial replenishment is afttions (A) that normal replenishment occurs within 4 s of the high Mreplenishment normally occurs within 2 s (B).

emonstrated a similar sensitivity and specificity be- i

ween the 2 techniques, regardless of stenosis severity31). Quantitative measurements of myocardial bloodow reserve have yielded sensitivities and specificitiesor the detection of CAD that exceeded both visualnd quantitative assessments of dipyridamole stressith radionuclide SPECT (32). The better spatial

esolution of MCE has been shown to improve theetection of subendocardial perfusion defects thatould otherwise go undetected with lower-resolutionPECT imaging. An example of this is shown inigure 3, where an anteroseptal and apical perfusionefect during adenosine stress is evident during theeplenishment phase of contrast with real-time MCE.he corresponding radionuclide image appeared nor-al, despite the presence of a significant left anterior

escending lesion at quantitative angiography (33). Inhe majority of these studies, the analysis of perfusionith MCE was performed independent of wall mo-

ion analysis. As might be expected with vasodilatortress, myocardial perfusion analysis consistently hasad higher sensitivity for detecting CAD than wallotion analysis. Proposed protocols for perfusion

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re displayed in Figure 4. Note that due to the beamidth elevation and capillary blood flow, normal myo-

ardial blood flow under resting conditions should beithin 5 s of a high-MI impulse, whereas during vaso-ilator or exercise stress replenishment, it should beithin 2 s (Fig. 2).

uring Dobutamine Stress Echocardiography

nimal studies have shown that perfusion defectsppear before wall-thickening abnormalities duringobutamine infusion and better delineate the area atisk (44). Clinical MCE studies comparing myocar-ial perfusion with wall motion during dobutaminetress have confirmed this better sensitivity (Table 2)44–52). In predominately single-center studies, real-

Figure 3. An Example of a Subendocardial Perfusion Defect

The defect is evident in the anteroseptal and apical segments of the lemechanical index impulse during adenosine stress imaging. Note thatthere was no evident defect noted on the lower-resolution radionuclid

yocardial Perfusion Stress Imaging Studies Performed With Intr

Year Test N Sensitivity Specificity

2004 Dipy 35 — —

2004 Dipy 73 73% 86%

2004 Dipy 46 — —

2004 Dipy�EX 70 91% 70%

2005 Dipy or Adeno 36 — —

2006 Dipy 123 80% 63%

2006 Dipy or Adeno 89 83% 72%

2006 Adeno 43 77% 69%

2007 Adeno 40 73% 90%

2008 Adeno 24 67% 67%

2008 Dipy 103 67% 86%

2008 Adeno 48 71% 94%

2008 Dipy 63 92% 95%

2009 Dipy 285* 61% 74%

377* 71% 64%

ivity,racy)

1,455 76% 78%

gio � angiography; CI � continuous infusion; Dipy � dipyridamole; EX � exerciseed.

the presence of significant coronary artery disease at angiography (Angio)

ime perfusion echocardiography has been shown toncrease the sensitivity of the dobutamine stress testhen compared with wall motion analysis (44–46,53)

nd improve the ability of the test to predict death oronfatal myocardial infarction (4). Dolan et al. (54)ecently published multicenter data confirming therognostic value of perfusion imaging during dobut-mine stress echocardiography. In their study, annducible perfusion defect, even in the absence of aall motion abnormality, was an independent predic-

or of risk for subsequent death or nonfatal myocardialnfarction (54).

Newer clinical studies have suggested that real-timeerfusion imaging may assist in the detection ofubendocardial ischemia during dobutamine stress. In

ntricle during the replenishment phase of contrast after a high–use the defect was confined to the subendocardium (black arrows),gle-photon emission computed tomography (SPECT) image despite

nous Ultrasound Contrast During Stress Echocardiography

Accuracy Bolus or CI Mode Gold Standard

97% for stenosis82% for normal

— Low MI Angio

— CI Angio

83% TRI SPECT

— CI RT Angio

TRI 81% RT 85% Bolus TRI and RT SPECT

— CI TRI Angio

— CI RT Angio

73% CI RT Angio

84% CI RT Angio

— Bolus RT Angio

70% Bolus RT Angio

90% CI RT Angio

— CI RT Angio

68% CI RT Angio

69% CI RT Angio

78%

mechanical index; RT � real time; SPECT � single-photon emission computed

ft vebecae sin

Table 1. Vasodilator M avein the Last 5 Years

Author (Ref #)

Peltier (32)

Janardhanan (10)

Yu (35)

Moir (36)

Tsutsui (37)

Jeetley (38)

Korosoglou (39)

Malm (40)

Xie (33)

Wasmeier (41)

Lipiec (42)

Mor-Avi (43)

Hayat (34)

Senior (31)

Pooled (average sensitspecificity, and accu

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(red arrows). Reprinted, with permission, from Xie et al. (33).

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atients with significant left anterior descendingAD, subendocardial wall-thickening abnormalitiesere detected in 35 of 45 patients with subendocardialerfusion defects despite the presence of normal trans-ural wall thickening (55). Because dobutamine will

ecruit the subepicardial layers to contract, theseall-thickening abnormalities would have gone un-etected if contrast were only used to enhancendocardial borders. An example of this is demon-trated in Figure 5, where the presence of a suben-ocardial perfusion defect in the apex and apical

0 1 2 3 Time line (min)

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Protocol of Dipyridamole

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B

Figure 4. Proposed Protocols for Dipyridamole or Adenosine St

The images shown are not intended for analysis of perfusion, but techocardiography.

Table 2. Dobutamine or Exercise Myocardial Perfusion Stress Im

Author (Ref #) Year Test N Se

Porter (45) 2001 Dob 40

Shimoni (47) 2001 EX 100

Olszowska (49) 2003 Dob 44

Tsutsui (46) 2005 Dob

Elhendy (50) 2005 Dob 128

Xie (51) 2005 Dob 27

Miszalski-Jamka (48) 2007 EX 42

Hacker (52) 2008 Dob 32

Lønnebakken (44) 2009 Dob 37

Pooled (average sensitivity,specificity, and accuracy)

526

Dob � dobutamine; other abbreviations as in Table 1.

ateral segments permitted the detection of a wall-hickening abnormality when transmural wallhickening appeared normal.eal-time MCE during exercise stress echocardio-raphy. There are greater challenges when attempt-ng to use real-time perfusion imaging during tread-

ill or bicycle exercise stress echocardiography. Thesenclude increased frequency of respiratory artifacts andhe brief period of time when a patient can bexamined at peak stress. Nonetheless, multicentertudies using treadmill and supine bicycle stress have

5 6 7 8 9 10 11 12


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Stress 4C, 3C, 2Cwith Contrast

3 4 5 6


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rve as reminders when to examine myocardial contrast

ng Studies Performed With Intravenous Ultrasound Contrast Dur

tivity Specificity Accuracy Bolus or CI Mode

— 83% Bolus RT

— 76% Bolus RT

% 93% — Bolus RT

— 84% Bolus RT

% 53% 81% Bolus RT

% 50% 65% Bolus RT

% 88% — CI RT

% 91% — CI RT

% 87% — CI RT

% 77% 78%

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— Angio

89 Angio

66 Angio

88 Angio

86 Angio

70 Angio

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emonstrated the incremental value of myocardialerfusion assessment using low-MI imaging duringxercise testing (47). Indeed, recent data have sug-ested that real-time perfusion imaging, by delineat-ng subendocardial wall-thickening abnormalities,

ay further improve the sensitivity of wall motionnalysis during treadmill exercise stress (56). Supineicycle exercise studies during a continuous infusion ofltrasound contrast have shown that replenishmentelays in contrast enhancement after high-MI im-ulses have 88% sensitivity and accuracy for theetection of significant CAD (48). An example of areadmill exercise-induced perfusion defect is delin-ated in Figure 6. Figure 7 illustrates proposed pro-ocols for real-time perfusion imaging during dobut-mine or exercise stress.ssessment of myocardial viability in the acute andhronic setting. MCE has proven useful in evaluatingatients after interventional or thrombolytic treatmentn acute myocardial infarction. Identification of pa-

Figure 5. An Example of a Subendocardial Wall-Thickening Abn

The abnormality is delineated by real-time perfusion imaging durinmechanical index (MI) impulse. If only transmural wall thickening wthe wall thickening would have appeared normal. Reprinted, with preplenishment.

Figure 6. An Example of an Inferior Wall Perfusion Defect

The defect was confined to the subendocardium after treadmill exealso observed (blue arrows). Note also the end-systolic shape chanan area of rib shadowing that prevented delineation of perfusion in
ber view can be used to delineate perfusion in these segments.
ients with the “no-reflow” phenomenon has proveno be an important clinical application for MCE57–59). This phenomenon, described first in annimal setting by Kloner et al. in 1974 (57), isharacterized by a lack of recovery in microvascularerfusion, although the occluded coronary artery isuccessfully reopened by percutaneous intervention orhrombolysis. Ito et al. (58) were the first to system-tically examine myocardial microvascular perfusionith intracoronary microbubbles in patients with

cute anteroseptal myocardial infarction immediatelyfter restoration of antegrade flow in the left anteriorescending artery. Several investigators have suc-eeded in detecting the no-reflow phenomenon fromntravenous administration of microbubbles (Table 3)13,60–68). In patients undergoing primary coronarytenting, homogenous myocardial contrast enhance-ent within the infarct zone by continuous-infusion

ntravenous MCE has been shown to be highlyredictive of regional recovery of function (10). Res-

ality

e replenishment phase of contrast (During MCR) after the high–examined in this patient (Pre-MCR after High MI Impulse images),ission, from Xie et al. (55). MCR � myocardial contrast

stress, where a subendocardial wall-thickening abnormality washat accompanies the perfusion defect. The open arrows indicatebasal to mid-anterior segments. A foreshortened apical 2-cham-

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oration of microvascular perfusion was most likely toccur if patients demonstrated at least partial perfu-ion to the risk area before primary stenting. MCEerformed during dipyridamole infusion 1 week after

Dobutamine Stress

0 5 Time (min)5u 1

InterE

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Low dose MCEif resting WMA

3% DInf

Protocol of Exercise

0 3 6 9 Time line (min)

1.7

10

2.5

12

3.4

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3% DefinityInfusion

Speed (mph

B

B

A

Figure 7. Proposed Protocols for Dobutamine or Treadmill/Bicy

The images shown are not intended for analysis of perfusion, but tography (MCE).

Table 3. Viability Studies Examining the Predictive Value of MCPredicting Outcome (Both Recovery of Regional Function and C

Author (Ref #) N FU (months)

Swinburn (13) 96 3–6

Main (60) 34 2

Hillis (61) 37 2

Janardhanan (62) 50 3

Korosoglou (63) 32 1

Huang (64) 34 4

Sbano (65) 50 6

Abe (66) 21 6

Dwivedi (67) 95 46

Galiuto (68) 110 6

CO � clinical outcome (death or nonfatal myocardial infarction); FU � follow-up; R

cute myocardial infarction in patients receiving pri-ary fibrinolytic therapy has been shown to be useful

n detecting both a significant residual stenosis withinhe infarct vessel and predicting when multivessel

ho Echocardiography

10 13 16 19

20u30u

Dobutamine

Atropine

40u

iate

2C

Peak StressEcho

4C, 3C, 2C

nityon

ress Echocardiography

12 15 18

5.0

18

5.5

20Stress Echo4C, 3C, 2C

Restart 3% DefinityInfusion 30 sec Prior toTreadmill Terminationor Peak Bicycle Stress

eline Protocolncline (%)

xercise Stress

rve as reminders when to examine myocardial contrast echocardi-

amined Within 7 Days of Acute Myocardial Infarction inal Outcome)

Sensitivity Specificity Outcome

59% 76% RF

77% 83% RF

80% 67% RF

87% 78% RF

81% 88% RF

83% 82% RF

95% 52% RF

98% 32% RF

80% 76% CO

70% 74% RF

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oronary disease is present (67). The extent andeverity of myocardial contrast defect size, determinedith real-time perfusion, has been shown to be an

ndependent predictor of both death and recurrentyocardial infarction at a mean of nearly 4 years

ost-infarction (11). Multicenter studies have recentlyemonstrated that the extent of microvascular dam-ge, assessed on day 1 after reperfusion therapy incute myocardial infarction, is the most powerfulndependent predictor of whether left ventricular re-

odeling will occur (68).In patients with chronic CAD and left ventricu-

ar dysfunction, both the visual and quantitativessessment of MCE during a continuous infusion ofntravenous microbubbles has provided significantndependent data on the effects of revascularizationo that segment. In this setting, the product of thelope of myocardial replenishment and plateau myo-ardial contrast intensity (an index of myocardiallood flow) in dysfunctional segments correlated withontractile reserve by low-dose dobutamine, as well as60% thallium uptake with radionuclide SPECT.ore importantly, this index of myocardial blood flow

y MCE was able to identify viable myocardium inegments that did not exhibit contractile reserve byobutamine stress (69,70). However, these studiesere small (n � 20 patients) and have yet to beerified in multicenter studies.

Figure 8. An Example of a Patient With Left Bundle Branch Bloc

An example of a patient with left bundle branch block who exhibited norfusion in the septum during radionuclide single-photon emission compute
details. Reprinted, with permission, from Hayat et al. (34).
eal-timeMCE to detect CAD in clinical scenarios whereadionuclide imaging and wall motion are limited. Pa-ients with left bundle branch block (LBBB) oracemaker-dependent patients represent clinical sce-arios where both the assessment of wall thickeningnd conventional myocardial perfusion imaging withadionuclide SPECT are not helpful in the detectionf CAD (47). In these patients, there are difficultiesith interpretation of wall thickening in the septum

in LBBB) or, in pacemaker-dependent patients, inhe septum and entire apex. In LBBB patients, per-usion defects in the interventricular septum are seenn radionuclide SPECT despite normal myocardiallood flow with real-time perfusion and no significantAD by angiography (Fig. 8). The reason for this

ppears to be the partial volume effect, as the false-ositive perfusion defects seen with radionuclidePECT had a normal perfusion appearance withigher-resolution real-time MCE and were indepen-ently associated with smaller septal systolic wall-hickness measurements (34). Similar wall-thicknessbnormalities encompassing a larger territory (theeptum and apex) are seen in pacemaker-dependentatients. Although real-time MCE may be useful foruling in or ruling out significant CAD in theseatients, it has yet to be determined in publishedlinical studies.

perfusion with myocardial contrast echocardiography but abnormal per-mography despite no significant coronary artery disease. See text for

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rtifacts in myocardial perfusion assessments. Oneust be able to differentiate potential artifacts that

reate the appearance of perfusion defects. The mostommon source of artifacts is attenuation. This typi-ally occurs in basal segments and is differentiatedrom true defects by its location. Attenuation typicallyasks not only the myocardium, but adjacent epicar-

ial and endocardial borders as well. Attenuation issually present both at rest and during stress, whereasnducible defects are present only during stress andypically involve just the subendocardium. Other po-ential artifacts are lung shadows, which will oftenask an entire region (e.g., the anterior wall in the

pical 2-chamber view) (Fig. 6). A second locationhere artifacts tend to occur is in the apical region. If

he near-field gains (time gain compensation) are setoo low, the apex will appear hypoperfused. Unlikerue defects, this can be corrected by increasing theear-field potentiometer settings. Near-field destruc-ion of microbubbles can also cause the false appear-nce of perfusion defects in the apex. This can beorrected by moving the focus to the near field, whichecreases the scan-line density in this region andeduces destruction.

onclusions

CE is a bedside imaging technique that has very

bruster RW. Detection of myocardial 139:675– 83.

eed of ionizing radiation. The use of intravenousicrobubbles for perfusion imaging is now a reality.nfortunately, the U.S. Food and Drug Administra-

ion still has not approved the use of ultrasoundontrast for myocardial perfusion imaging. Nonethe-ess, the real-time methods used to achieve optimaleft ventricular opacification (the approved U.S. Foodnd Drug Administration indication) often result inyocardial opacification, which permits the simulta-

eous analysis of perfusion. Consensus documentsrom both the U.S. and Europe have also clearlyummarized the incremental value of myocardial per-usion imaging in detecting CAD both during restnd stress echocardiography (71,72). Clinical studiesave demonstrated the potential for this technique inhe emergency department, during stress echocardiog-aphy, and in the detection of viability, and prospec-ive studies are underway to examine the prognosticalue of real-time perfusion imaging during stresschocardiography as compared with conventionalchocardiographic imaging.

eprint requests and correspondence: Dr. Thomas R. Por-er, University of Nebraska Medical Center, Cardiology,81165 Nebraska Medical Center, Omaha, Nebraska

igh resolution and can be performed without the 68198-1165. E-mail: [email protected].

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E F E R E N C E S

1. Keller MW, Feinstein SB, WatsonDD. Successful left ventricular opaci-fication following peripheral venousinjection of sonicated contrast agent:an experimental evaluation. AmHeart J 1987;114:570–5.

2. Unger EC, Lund PJ, Shen DK, FritzTA, Yellowhair D, New TE.Nitrogen-filled liposomes as a vascularUS contrast agent. Radiology 1992;185:453–6.

3. Porter TR, Xie F. Visually discerniblemyocardial echocardiographic contrastfollowing intravenous injection ofsonicated dextrose albumin micro-bubbles containing high molecularweight less soluble gases. J Am CollCardiol 1995;25:509–15.

4. Tsutsui JM, Elhendy A, Anderson JR,Xie F, McGrain AC, Porter TR.Prognostic value of dobutamine stressmyocardial contrast perfusion echo-cardiography. Circulation 2005;112:1444–50.

5. Porter TR, Li S, Kricsfeld D, Arm-

perfusion in multiple echocardio-graphic windows with one intravenousinjection of microbubbles using tran-sient response second harmonic imag-ing. J Am Coll Cardiol 1997;29:791–9.

6. Wei K, Jayaweera AR, Firoozan S,Linka A, Skyba DM, Kaul S. Quan-tification of myocardial blood flowwith ultrasound-induced destructionof microbubbles administered as aconstant venous infusion. Circulation1998;97:473–83.

7. Kaul S, Senior R, Dittrich H, Raval U,Khattar R, Lahiri A. Detection of coro-nary artery disease with myocardial con-trast echocardiography: comparison with99mTc-sestamibi single-photon emissioncomputed tomography. Circulation 1997;96:785–92.

8. Cwajg J, Xie F, O’Leary E, KricsfeldD, Dittrich H, Porter TR. Detectionof angiographically significant coro-nary artery disease with acceleratedintermittent imaging after intrave-nous administration of ultrasoundcontrast material. Am Heart J 2000;

9. Heinle SK, Noblin J, Goree-Best P, etal. Assessment of myocardial perfu-sion by harmonic power Doppler im-aging at rest and during adenosinestress: comparison with (99m) Tc-sestamibi SPECT imaging. Circula-tion 2000;102:55–60.

0. Janardhanan R, Senior R. Accuracy ofdipyridamole myocardial contrastechocardiography for the detection ofresidual stenosis of the infarct-relatedartery and multivessel disease earlyafter acute myocardial infarction.J Am Coll Cardiol 2004;43:2247–52.

1. Balcells E, Powers ER, Lepper W, etal. Detection of myocardial viability bycontrast echocardiography in acute in-farction predicts recovery of restingfunction and contractile reserve. J AmColl Cardiol 2003;41:827–33.

2. Main ML, Magalski A, Morris BA,Coen MM, Skolnick DG, Good TH.Combined assessment of microvascu-lar integrity and contractile reserveimproves differentiation of stunningand necrosis after acute anterior wallmyocardial infarction. J Am Coll Car-
diol 2002;40:1079–84.
mailto:[email protected]

1

1

1

1

1

1

1

2

2

2

2

3

3

3

3

3

4

4

4

4

4


F E B R U A R Y 2 0 1 0 : 1 7 6 – 8 7

Porter and Xie


186

3. Swinburn JM, Lahiri A, Senior R.Intravenous myocardial contrast echo-cardiography predicts recovery of dys-synergic myocardium early after acutemyocardial infarction. J Am Coll Car-diol 2001;38:19–25.

4. Shimoni S, Frangrogiannis NG, AggeliCJ, et al. Identification of hibernatingmyocardium with quantitative intrave-nous myocardial contrast echocardiog-raphy: comparison with dobutamineechocardiography and thallium-201scintigraphy. Circulation 2003;107:538–44.

5. Tong KL, Kaul S, Wang XQ, et al.Myocardial contrast echocardiographyversus thrombolysis in myocardial infarc-tion score in patients presenting to theemergency department with chest painand a nondiagnostic electrocardiogram.J Am Coll Cardiol 2005;46:920–7.

6. de Jong N, Ten Cate FJ, Lancee CT,Roelandt JR, Bom N. Principles andrecent developments in ultrasoundcontrast agents. Ultrasonics 1991;29:324–30.

7. Burns P, Becher H. Handbook ofContrast Echocardiography LV Func-tion and Myocardial Perfusion. NewYork, NY: Springer Verlag, 2000.

8. Macsweeny JE, Cosgrove DO, ArensonJ. Colour Doppler energy (power)mode ultrasound. Clin Radiol 1996;51:387–90.

9. Powers JE, Burns PN, Souquet J.Imaging instrumentation for ultra-sound contrast agents. In: Nanda NC,Schlief R, Goldberg BB, editors. Ad-vances in Echo Imaging Using Con-trast Enhancement. 2nd edition. Dor-drecht, the Netherlands: KluwerAcademic Publishers, 1997:139.

0. Broillet A, Puginier J, Ventrone R,Schneider M. Assessment of myocar-dial perfusion by intermittent har-monic power Doppler using SonoVue,a new ultrasound contrast agent. In-vest Radiol 1998;33:209–15.

1. Senior R, Kaul S, Soman P, Lahiri A.Power Doppler harmonic imaging: afeasibility study of a new technique forthe assessment of myocardial perfu-sion. Am Heart J 2000;139:245–51.

2. Binder T, Assayag P, Baer F, et al.NC100100, a new echo contrast agentfor the assessment of myocardial per-fusion: safety and comparison withtechnetium-99m sestamibi single-photon emission computed tomogra-phy in a randomized multicenterstudy. Clin Cardiol 1999;22:273–82.

3. Main ML, Escobar JF, Hall SA, KillamAL, Grayburn PA. Detection of myocar-dial perfusion defects by contrast echocar-diography in the setting of acute myocar-dial ischemia with residual antegrade flow.
J Am Soc Echocard 1998;11:228–35.
24. Simpson DH, Burns PN. Pulse inver-sion Doppler: a new method for de-tecting nonlinear echoes from micro-bubble contrast agents. Proc IEEEUltrason Symp 1997;2:1597–1600.

25. Rafter P, Phillips P, Vannan MA.Imaging technologies and techniques.Cardiol Clin 2004;22:181–97.

26. Skyba DM, Jayaweera AR, GoodmanNC, Ismail S, Camarano G, Kaul S.Quantification of myocardial perfusionwith myocardial contrast echocardiogra-phy during left atrial injection of contrast:implication for venous injection. Circula-tion 1994;90:1513–21.

27. Lindner JR, Villanueva FS, Dent JM,Wei K, Sklenar J, Kaul S. Assessmentof resting perfusion with myocardialcontrast echocardiography: theoreticaland practical considerations. AmHeart J 2000;139:231–40.

28. Weissman NJ, Mylan CC, Hack TC,et al. Infusion versus bolus contrastechocardiography: a multicenter,open-label, crossover trial. Am Heart J2000;139:399–404.

29. Wei K, Jayaweera AR, Firoozan S,Linka A, Skyba DM, Kaul S. Basis fordetection of stenosis using venous ad-ministration of microbubbles duringmyocardial contrast echocardiography:bolus or continuous infusion? Circu-lation 1998;32:252–60.

30. Vogel R, Indermuhle A, Reinhardt J,et al. The quantification of absolutemyocardial perfusion in humans bycontrast echocardiography. J Am CollCardiol 2005;45:754–62.

31. Senior R, Monaghan M, Main ML,et al. Detection of coronary arterydisease with perfusion stress echocar-diography using a novel ultrasoundimaging agent: two phase 3 interna-tional trials in comparison with radi-onuclide perfusion imaging. Eur JEchocardiogr 2009;10:26–35.

32. Peltier M, Vancraeynest D, Pasquet A,et al. Assessment of the physiologicsignificance of coronary disease withdipyridamole real-time myocardial con-trast echocardiography. Comparisonwith technetium-99m sestamibi single-photon emission computed tomographyand quantitative coronary angiography.J Am Coll Cardiol 2004;43:257–64.

33. Xie F, Hankins J, Mahrous HA, PorterTR. Detection of coronary artery dis-ease with a continuous infusion ofdefinity ultrasound contrast duringadenosine stress real time perfusionechocardiography. Echocardiography2007;24:1044–50.

34. Hayat SA, Dwivedi G, Jacobsen A,Lim TK, Kinsey C, Senior R. Effectsof left bundle branch block on cardiacstructure, function, perfusion, and per-fusion reserve: implications for myocar-
dial contrast echocardiography versusradionuclide perfusion imaging for the
detection of coronary artery disease.Circulation 2008;117:1832–41.

5. Yu EH, Skyba DM, Leong-Poi H, etal. Incremental value of parametricquantitative assessment of myocardialperfusion by triggered Low-Powermyocardial contrast echocardiography.J Am Coll Cardiol 2004;43:1807–13.

6. Moir S, Jaluska BA, Jenkins C, FathiR, Marwick TH. Incremental benefitof myocardial contrast to combineddipyridamole-exercise stress echocar-diography for the assessment of coro-nary artery disease. Circulation 2004;110:1108–13.

7. Tsutsui JM, Xie F, McGrain AC, etal. Comparison of low-mechanical in-dex pulse sequence schemes for de-tecting myocardial perfusion abnor-malities during vasodilator stressechocardiography. Am J Cardiol2005;95:565–70.

8. Jeetley P, Hickman M, Kamp O, et al.Myocardial contrast echocardiography forthe detection of coronary artery stenosis.J Am Coll Cardiol 2005:47:141–5.

9. Korosoglou G, Dubart AE, DaSilvaKG Jr., et al. Real time myocardialperfusion imaging for pharmacologicstress testing: added value to singlephoton emission computed tomogra-phy. Am Heart J 2006;151:131–8.

0. Malm S, Frigstad S, Torp H, WisethR, Skjarpe T. Quantitative adenosinereal-time myocardial contrast echo-cardiography for detection of angio-graphically significant coronary arterydisease. J Am Soc Echocardiogr 2006;19:365–72.

1. Wasmeier GH, Asmussen S, VoigtJU, Flachskampf FA, Daniel WG,Nixdorff U. Real-time myocardialcontrast stress echocardiography usingbolus application. Ultrasound MedBiol 2008;34:1724–31.

2. Lipiec P, Wejner-Mik P, Krzeminska-Pakuła M, et al. Accelerated stressreal-time myocardial contrast echo-cardiography for the detection of cor-onary artery disease: comparison with99mTc single photon emission com-puted tomography. J Am Soc Echo-cardiogr 2008;21:941–7.

3. Mor-Avi V, Koch R, Holper EM, etal. Value of vasodilator stress myo-cardial contrast echocardiographyand magnetic resonance imaging forthe differential diagnosis of ischemicversus nonischemic cardiomyopathy.J Am Soc Echocardiogr 2008;21:425–32.

4. Lønnebakken MT, Bleie O, Strand E,Staal EM, Nygard OK, Gerdts E.Myocardial contrast echocardiographyin assessment of stable coronary arterydisease at intermediate dobutamine-
induced stress level. Echocardiogra-phy 2009;26:52–60.

4

4

4

4

4

5

5

5

5

5

6

6

6

6

6

7

7

7

Ke


F E B R U A R Y 2 0 1 0 : 1 7 6 – 8 7

Porter and Xie


187

5. Porter TR, Xie F, Silver M, KricsfeldD, O’Leary E. Real-time perfusionimaging with low mechanical indexpulse inversion Doppler imaging.J Am Coll Cardiol 2001;37:748–53.

6. Tsutsui JM, Elhendy A, Xie F, O’LearyEL, McGrain AC, Porter TR. Safety ofdobutamine stress real-time myocardialcontrast echocardiography. J Am CollCardiol 2005;45:1235–42.

7. Shimoni S, Zoghbi WA, Xie F, et al.Real-time assessment of myocardialperfusion and wall motion during bi-cycle and treadmill exercise echocardi-ography: comparison with single pho-ton emission computed tomography.J Am Coll Cardiol 2001;37:741–7.

8. Miszalski-Jamka T, Kuntz- Hehner, S,Schmidt H, et al. Real time myocardialcontrast echocardiography during supinebicycle stress and continuous infusion ofcontrast agent. Cutoff values for myocar-dial contrast replenishment discriminatingabnormal myocardial perfusion. Echocar-diography 2007;24:638–48.

9. Olszowska M, Kostkiewicz M, TraczW, Przewlocki T. Assessment ofmyocardial perfusion in patients withcoronary artery disease. Comparisonof myocardial contrast echocardiogra-phy and 99mTc MiBI single photonemission computed tomography. IntJ Cardiol 2003;90:49–55.

0. Elhendy A, Tsutsui JM, O’Leary EL,Xie F, Porter TR. Noninvasive diag-nosis of coronary artery disease inpatients with diabetes by dobutaminestress real-time myocardial contrastperfusion imaging. Diabetes Care2005;28:1662–7.

1. Xie F, Tsutsui JM, McGrain AC, etal. Comparison of dobutamine stressechocardiography with and withoutreal-time perfusion imaging for detec-tion of coronary artery disease. Am JCardiol 2005;96:506–11.

2. Hacker M, Hoyer HX, Uebleis C, etal. Quantitative assessment of cardiacallograft vasculopathy by real-timemyocardial contrast echocardiography:a comparison with conventional echo-cardiographic analyses and [Tc99m]-sestamibi SPECT. Eur J Echocar-diogr 2008;9:494–500.

3. Elhendy A, O’Leary EL, Xie F, McGrainAC, Anderson JR, Porter TR. Compar-ative accuracy of real-time myocardialcontrast perfusion imaging and wall mo-tion analysis during dobutamine stressechocardiography for the diagnosis of cor-onary artery disease. J Am Coll Cardiol2004;44:2185–91.

4. Dolan M, Gala SS, Dodla S, et al.Safety and efficacy of commerciallyavailable ultrasound contrast agents
for rest and stress echocardiography: a
multicenter experience. J Am CollCardiol 2009;53:32–8.

55. Xie F, Dodla S, O’Leary E, Porter TR.Detection of subendocardial ischemia inthe left anterior descending coronaryartery territory with real-time myocar-dial contrast echocardiography duringdobutamine stress echocardiography.J Am Coll Cardiol Img 2008;1:271–8.

56. Dodla S, Xie, F, O’Leary E, Smith M,Porter T. Detection of CAD with realtime perfusion imaging during exer-cise and dobutamine stress echocardi-ography. Circulation 2008;118S:850.

57. Kloner RA, Ganote CE, Jennings RB.The “no-reflow” phenomenon aftertemporary coronary occlusion in thedog. Clin Invest 1974;54:1496–1508.

58. Ito H, Tomooka T, Sakaii N, et al. Lackof myocardial perfusion immediately aftersuccessful thrombolysis: a predictor ofpoor recovery of left ventricular function inanterior myocardial infarction. Circulation1992;85:1699–1705.

59. Lepper W, Hoffmann R, Kamp O, etal. Assessment of myocardial reperfu-sion by intravenous myocardial con-trast echocardiography and coronaryflow reserve after primary percutane-ous transluminal coronary angiographyin patients with acute myocardial infarc-tion. Circulation 2000;101:2368–74.

60. Main ML, Magalski A, Chee NK, etal. Full-motion pulse inversion powerDoppler contrast echocardiographydifferentiates stunning from necrosisand predicts recovery of left ventricu-lar function after acute myocardial in-farction. J Am Coll Cardiol 2001;38:1390–4.

61. Hillis GS, Mulvagh SL, Gunda M, etal. Contrast echocardiography usingintravenous octafluoropropane andreal-time perfusion imaging predictsfunction recovery after acute myocar-dial infarction. J Am Soc Echocar-diogr 2003;16:638–45.

62. Janardhanan R, Swinburn JM, GreavesK, et al. Usefulness of myocardial con-trast echocardiography using low-powercontinuous imaging early after acutemyocardial infarction to predict latefunctional left ventricular recovery.Am J Cardiol 2003;92:493–7.

63. Korosoglou G, Labadze N, Giannitsis E,et al. Usefulness of real-time myocardialperfusion imaging to evaluate tissue levelreperfusion in patients with non ST-elevation myocardial infarction. Am JCardiol 2005;95:1033–8.

64. Huang WC, Chiou KR, Liu CP, et al.Comparison of real-time contrastechocardiography and low-dose do-butamine stress echocardiography inpredicting the left ventricular func-
tional recovery in patients after acute c
myocardial infarction under differenttherapeutic intervention. Int J Cardiol2005;104:81–91.

5. Sbano JC, Tsutsui JM, Andrade JL, etal. Detection of functional recoveryusing low-dose dobutamine and myo-cardial contrast echocardiography af-ter acute myocardial infarction treatedwith successful thrombolytic therapy.Echocardiography 2005;22:496–502.

6. Abe Y, Muro T, Sakanoue Y, et al.Intravenous myocardial contrast echo-cardiography predicts regional andglobal left ventricular remodeling afteracute myocardial infarction: compari-son with low dose dobutamine stressechocardiography. Heart 2005;91:1578–83.

7. Dwivedi G, Janardhanan R, HayatSA, Swinburn JM, Senior R. Prog-nostic value of myocardial viabilitydetected by myocardial contrast echo-cardiography early after acute myocar-dial infarction. J Am Coll Cardiol2007;50:327–34.

8. Galiuto L, Garramone B, Scara A, etal. The extent of microvascular dam-age during myocardial contrast echo-cardiography is superior to otherknown indexes of post-infarct reper-fusion in predicting left ventricularremodeling. J Am Coll Cardiol 2008;51:552–9.

9. Shimoni S, Frangogiannis NG, AggeliCJ, et al. Microvascular structural cor-relates of myocardial contrast echocar-diography in patients with coronaryartery disease and left ventricular dys-function: implications for the assess-ment of myocardial hibernation. Circu-lation 2002;106:950–6.

0. Shimoni S, Frangogiannis NG, AggeliCJ, et al. Identification of hibernatingmyocardium with quantitative intrave-nous myocardial contrast echocardiog-raphy: comparison with dobutamineechocardiography and thallium-201scintigraphy. Circulation 2003;107:538–44.

1. Senior R, Becher H, Monaghan M, et al.Constrast echocardiography: evidence-based recommendations by European As-sociation of Echocardiography. Eur JEchocardiogr 2009;10:194–212.

2. Mulvagh SL, Rakowski H, VannanMA, et al. American society of echo-cardiography consensus statement onthe clinical applications of ultrasoniccontrast agents in echocardiography.J Am Soc Echocardiogr 2008:21:1179–201.

ey Words: myocardial contrastchocardiography y ultrasound
ontrast.

myocardial perfusion imaging with contrast...

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