Newcontrast agents and technologies myocardial contrast ... · demonstrate reliably myocardial perfusion using conventional echocardiographic tech-niques. Therefore, attempts have

Heart (Supplement 1) 1997;78:7-11

New contrast agents and technologies formyocardial contrast echocardiographyDaniele Rovai, Mark J Monaghan

Myocardial contrast echocardiography is anew method for evaluating myocardial perfu-sion. However, it relies on the marriage of twoevolving technologies; ultrasound contrastagents and ultrasound imaging instrumenta-tion. To date, these technologies have onlybeen available to a limited number ofresearchers throughout the world. Within thenext 12 months, both agents and specialisedultrasound instruments will be commerciallyavailable, making this new methodology opento widespread clinical application. Moreover,echocardiographic evaluation of myocardialperfusion should have a major role in the man-agement of both chronic and acute ischaemicsituations, myocardial infarction, and assess-ment of myocardial viability. This reviewexamines the current and likely future status ofboth contrast agents and machines in this con-text. In addition, the probable clinical role ofthe methodology, as a potential replacementfor nuclear techniques, is discussed

In patients with coronary artery disease thestudy of myocardial perfusion is of great clinicalrelevance and is currently investigated bynuclear medicine techniques. Nuclear cardiol-ogy, however, is limited by contaminationrisks, by a limited availability of the equip-ment, and by considerable expense. Further-more, the current role of nuclear medicine incardiology is mainly confined to stablepatients, while acutely ill patients rarely benefitfrom the information regarding myocardialperfusion.An alternative method of studying myocar-

dial perfusion is echocardiography followingthe injection of ultrasound contrast agentsdirectly into the coronary circulation.'2 Thisinvasive approach, however, is limited toapplications within the cardiac catheterisationlaboratory. To overcome this limitation, inves-tigators, pharmaceutical companies, and ultra-sound industries have sought to develop amethod that could achieve myocardialenhancement following peripheral venousinjection of ultrasound contrast agents.Wider use of this methodology might have

an important impact on clinical cardiology, asmyocardial perfusion could be evaluated non-invasively, requiring only the use of widelyavailable ultrasound scanners that have beensuitably adapted. Additionally, the study ofmyocardial perfusion by contrast echocardio-graphy would make information on perfusionavailable to a large population of patients indifferent settings, from the emergency room tothe outpatient clinic. This non-invasiveapproach to myocardial contrast echocardio-

graphy stands on three main pillars: new ultra-sound contrast agents, new equipment, andclinical models for myocardial perfusion stud-ies.

New contrast agentsLeft ventricular cavity opacification can beobtained in the majority of patients aftervenous injection of lung-crossing agents suchas Albunex (MBI, USA)3 and Levovist(Schering AG, Germany).4 However, neitherof these agents is able to opacify themyocardium consistently using conventionalsignal processing and imaging modalities. Inan attempt to visualise myocardial perfusionby intravenous Albunex injection, Villaneuvaet a15 injected dogs with a dose of this agent 10times that previously used for diagnostic pur-poses. They selected microbubbles with adiameter larger than those used for conven-tional imaging and injected the contrast agentdirectly into the right atrial cavity. In addition,the animals were premedicated with dipyri-damole (to increase the ratio between coro-nary blood flow and cardiac output) and,finally, the echocardiographic images weredigitally subtracted and colour coded.Although this approach allowed myocardialperfusion to be visualised in experimental ani-mals, it cannot be used in the clinical setting.

Recently, a new generation of ultrasoundcontrast agents has been produced charac-terised by a prolonged persistence in the circu-lation. This persistence is related to the shellstability and the gases contained in themicrobubbles, which have a higher densitythan air and a low solubility in blood. Asshown in fig 1, the echo contrast effect gener-ated by an agent spontaneously declines overtime. This spontaneous decay in contrastintensity resembles that of radioisotopes and ismainly caused by the diffusion of the gasesfrom the microbubbles in the surroundingmedium. Thus, the microbubbles containinggases with low solubility in blood are charac-terised by a prolonged persistence and in vivostability.A precursor of long persistence contrast

agents is the agent EchoGen (SonusPharmaceutical, USA), which is based ondodecafluoropentane. This gas, in addition tothe high density and low solubility in blood,displays an interesting property, a phase shiftat 28-5°C. Thus, the agent is a fluid at roomtemperature and shifts to a gaseous phase atbody temperature. Both cardiac cavities andthe myocardium show contrast enhancement

CNR, CHnicalPhysiology Institute,Via Savi 8, 56126 Pisa,Italy. email: [email protected] RovaiDepartment ofCardiology, King'sCollege Hospital,Denmark Hill, LondonSE5 9RS, UK. email:monaghanacompuserve.comM J MonaghanCorrespondence to:Dr Monaghan.

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Cq

0 20 40 60 80 100 120 140

Time (s)

Figure 1 Spontaneous decay in echo contrast intensity. In this experiment the contrastagent SHU 454 (Echovist) was injected in a recirculatingflow model. After theequilibrium was reached, signal intensity declined because of the diffusion ofgasesfrom themicrobubbles in the surrounding medium. The decay half time ofEchovist in salinecorresponded to 68 seconds. IB2D, 3D integrated backscatter index.

Figure 2 The myocardium perfused by the left anterior descending and the right coronatyartery shows a contrast enhancement one minute after intravenous administration of theecho contrast agent BRI (left panel). The myocardium perfused by the left circumflexcoronary artery show a contrast effect three minutes later (right panel).

soon after venous administration. Later on,the contrast is washed out from the cardiaccavities whereas the myocardium maintainscontrast enhancement, which can persist forseveral minutes. Recently, Grayburn et al 6

administered EchoGen intravenously in a

canine model of acute coronary occlusion.Myocardial contrast echocardiography accu-

rately defined the extent of the area ofmyocardium at risk and the infarct size. Themain limitation of this agent is its potentialtoxicity; pulmonary artery pressure and pul-monary vascular resistance increase at highdoses of contrast, while arterial oxygen satura-

tion and cardiac output decrease. A new for-mulation of this agent that allows a densemyocardial opacification without negativehaemodynamic effects is under investigation.7

Other new generation contrast agents are

also characterised by an elevated in vivo stabil-ity but show the ability freely to cross themicrocirculation in the absence of any tissuedeposit. Compared with Albunex andLevovist, the behaviour of these agents iscloser to that of intravascular free flowing trac-ers. These agents include perfluorocarbonexposed sonicated dextrose albumin,8 FS069(MBI),9 BR1 (Bracco Research,Switzerland),'0 Imagent(r)US (AlliancePharmaceutical Corp, USA)," andAerosomes."2 There are several others underinvestigation. The table illustrates many of theultrasound contrast agents that are currentlyunder development or available.The intravenous injection of these agents

results in an enhancement of the ultrasoundsignal in the ventricular cavities, which can lastup to several minutes. During peak contrastenhancement of the left ventricular cavity,myocardial opacification has been observedwith all agents. Myocardial contrast echoeffect obtained by intravenous contrastechocardiography is expected to reflect thepresence of microbubbles in the coronary cir-culation and thus myocardial perfusion.However, contrast enhancement of themyocardium could also be ascribed to a

blooming effect induced by the huge numberof microbubbles in the left ventricular cavity.Figure 2 shows that myocardial contrast effectdoes reflect true myocardial perfusion. In thisdog, the left circumflex coronary artery was

cannulated and perfused via a bypass withblood taken from the femoral artery (fig 3); a

reservoir filled with blood was present in seriesin the bypassing circuit and delayed the arrivalof blood in the circumflex perfusion territory.After intravenous contrast administration, themyocardium perfused by the left anteriordescending and the right coronary artery earlyshowed contrast enhancement (fig 2, leftpanel), while the myocardium perfused by thecircumflex coronary artery showed a late con-trast effect (fig 2, right panel). Furthermore,several experiments have been carried out indifferent laboratories that support the conceptthat myocardial echo enhancement aftervenous administration of the most recent gen-eration of contrast agents reflects myocardialperfusion and may permit quantitative assess-

ment of perfusion deficits.

Ultrasound contrast agents available or under development

Agent Manufacturer Type Encapsulated Gas

Albunex/Infoson Mallinckrodt (USA) Albumin microsphere AirNC100,100 Nycomed (Norway) Confidential ConfidentialLevovist Schering (Germany) Galactose palmitic acid AirAerosomes/MRX1 15 ImaRx (USA) Lipid microbubble PerfluoropropaneQuantison (Depot) Andaris (UK) Albumin microsphere AirEchogen Sonus (USA) Phase-shift DodecofluoropentaneBY 963 Byk-Gulden (Germany) Phospholipid AirFS069 MBI (USA) Albumin microsphere PentafluoropentaneBRl/Sonovue Bracco (Switzerland) Lyophilisate SF6Imagent/AFO150 Alliance (USA) Buffered surfactant PerfluorohexaneSonovist/SHU 563A Schering Cyanocrylate particle AirEchovist Schering Galactose Air

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New contrast agents and technologies for myocardial contrast echocardiography

Figure 3 Experimental animal model. The left circumflex coronary artery is perfused viaa bypass with blood taken from thefemoral artery; a reservoir is present in series in thebypassing circuit.

100% _Tissue + contrastbackscatter Tissue

backscatter<,75%

. ^ \/ ~~~~~~~~effectE 50%

C / | ~~~~~~~~~2ndharmonic

U)25%

0%0 1.0 2.0 3.0 4.0 5.0

Backscattered frequency (MHz)

Figure 4 Diagrammatic representation of the principle behind 2nd harmonic contrastimaging. A graph of backscattered ultrasound signal amplitude againstfrequency isillustratedfor tissue alone and tissue plus contrast. The tissue signal is centred around thetransmittedfundamentalfrequency of2 MHz. However, when a contrast agent isintroduced into the tissues, it causes a small increment in signal amplitude at thefundamental (used in conventional imaging), an absorption of energy around the resonantfrequency (2 5 MHz), and an increase in signal at the 2nd harmonic. The latter twoeffects may be detected by frequency specific imaging technology and allow better contrastfor tissue discrimination than conventional imaging methods.

New technologiesDespite the development of new contrastagents, which have improved stability and invivo persistence, it has been difficult todemonstrate reliably myocardial perfusionusing conventional echocardiographic tech-niques. Therefore, attempts have been madeto explore other imaging technologies, whichmay offer improved sensitivity for detection ofthe small quantities of contrast agent withinthe myocardium.Many of these new technologies have

utilised the fact that some ultrasound contrastmicrospheres have resonant properties."3 14

This means that, when exposed to an ultra-sound field where the resonance frequency ofthe contrast microspheres lies within the band-width of transmitted ultrasound, the charac-teristics of the backscattered signal will bealtered in some way. Contrast microspheresabsorb energy at their resonant frequency andthat absorbed energy is re-emitted at harmonicsof the resonant frequency" (fig 4). While con-

trast agents do cause an increase in backscat-tered ultrasound intensity at the fundamentalfrequency (centre frequency of the trans-ducer), the increment in intensity over the sig-nal reflected from myocardial tissue isrelatively small. This can make it difficult toevaluate the presence of the agent within thetissue. However, by examining specifically thesignal content at the resonant frequency or itsharmonic (especially the 2nd harmonic), thereis much greater difference in signal levelbetween tissue alone and tissue plus contrast.This makes detection of the presence of thecontrast agent and its distribution much easierto appreciate.

While the tissue signal at the 2nd harmonic,which is achieved by transmitting at one fre-quency and then selectively receiving at dou-ble that frequency, is relatively low, thecontrast agent generates a high amplitude sig-nal, which is easier to detect. This technology isrelatively easy to implement, either by modifi-cation to transducer design or by using broad-band width transducers and digital inputfiltering. It has been shown to demonstratemyocardial perfusion as well as perfusion inother organs such as liver and kidney followinglow volume intravenous injections.'5 It isunlikely that 2nd harmonic imaging is the finalstage in the development of contrast agentimaging technology.

Recent studies have indicated that exposureof contrast microbubbles to diagnostic ultra-sound fields results in their destruction. Thisclearly limits the potential effectiveness ofultrasound detection of perfusion. Methods tolimit this phenomenon have been investigatedincluding reducing the transducer outputpower, thereby decreasing spatial ultrasoundintensity. Reductions in temporal ultrasoundexposure may also be achieved by reconfigur-ing the echocardiography system so that inter-mittent rather than continuous imaging isperformed.816 This means that only one frameof an echocardiographic image is generatedevery cardiac cycle (or every other cardiaccycle) rather than the normal imaging modewhen approximately 30 frames per second aregenerated. By employing intermittent imaging,significant improvements in detection ofmyocardial perfusion have been demon-strated,'7 as destruction of contrast micro-spheres is considerably reduced and micro-spheres that are destroyed are usually replen-ished before the next frame is created. Onelimitation of this technique is that a real timeimage is no longer displayed, which may havelimitations for temporal analysis and visualappreciation of contrast appearance and disap-pearance. Improvements in image processingand display technology are likely to beemployed to overcome these limitations.

However, it is also possible that the phe-nomenon of contrast microbubble destructioncould be turned to advantage in the future, ascontrast microbubbles could be used for drugdelivery, using localised higher intensity ultra-sound to destroy the microspheres and release adrug at desired sites. In addition, it may bepossible to adjust ultrasound output power

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Figure S Colour codedfunctional images of myocardial perfusion. The time from contrastinjection into the aortic root up to myocardial contrast appearance is displayed in a colourscale (left, baseline; right, ischaemia). In the presence of a severe stenosis of the leftcircumflex coronary artery myocardial contrast appearance is delayed and the ischaemicmyocardium shows up as yellow.

levels, so that contrast microspheres are

destroyed at exactly the same rate that they are

replenished, within a given myocardial bed.Myocardial perfusion, which was occurring ata rate higher than the destruction rate, wouldresult in a gradual increase in segment inten-sity, whereas lower levels of perfusion wouldmean that more microbubbles were beingdestroyed than being replenished and so inten-sity would decrease. In theory, this wouldallow this phenomenon to be used for measur-ing myocardial perfusion.

These technologies are still very much intheir infancy, however, many ultrasoundinstrument manufacturers are introducing har-monic imaging as a facility on their systems. Inaddition, quantitative software is now available

Figure 6 Contrast echo images obtained by the injection ofAlbunex into the left coronatyartery ofa patient, both at baseline and after low dose dipyridamole infusion.

that allows analysis of the changes in 2nd har-monic (or other frequency characteristic)amplitudes before, during, and after contrastadministration. Software that performs digitalsubtraction and colour coding on harmonicimages is also, being generated and this shouldcreate colour coded perfusion images, similarto those obtained by nuclear medicine studies.Pseudo-colour maps are often used to enhancethe detection of spontaneous echo contrast inthe left atrial cavity or appendage and suchspecific display modalities might favour thedetection of low concentrations of contrastagent. Although no studies have so far com-pared grey scale with colour images in thedetection of myocardial perfusion abnormali-ties, it is expected that colour coded imagescould allow a better detection of myocardialcontrast enhancement.A further advancement might be the use of

so called functional images,18 where the colourrepresents the value of a functional parameter(fig 5). Each of these two images derives fromthe analysis of a series of frames and thecolours represent the time from contrast injec-tion into the aortic root up to myocardial con-trast appearance. Under baseline conditions,the myocardium appears homogeneously red,while it turns toward yellow in the area per-fused by a stenotic left circumflex coronaryartery because of a delay in myocardial con-trast appearance. Although these imagingmodalities may favour the detection and local-isation of myocardial perfusion abnormalities,it is not clear what the best parameter will beto study myocardial perfusion by intravenouscontrast echocardiography.

Clinical modelsExperimental studies have shown that myocar-dial contrast echocardiography can differenti-ate normal from severely hypoperfusedmyocardium; however, the absolute measure-ment of coronary blood flow by this techniqueis still limited by several factors.

It is foreseeable that the categories ofpatients who might benefit more from newechocardiographic contrast agents and tech-nologies are those in whom a semiquantitativeassessment of myocardial perfusion is suffi-cient for clinical decision making. Thesepatients should ideally present a normal perfu-sion pattern in certain areas of themyocardium and a severe hypoperfusion inother areas. Examples are with either acute orchronic myocardial infarction.

In patients with acute infarction, the endpoints of contrast echocardiography should beto detect myocardial perfusion abnormalities,to quantify the spatial extent of these abnor-malities, to establish the occurrence ofmyocardial reperfusion, and thus to predictthe late recovery of left ventricular function.

In patients with previous infarction, con-trast echocardiography should provide indicesof myocardial viability, based on the hypothesisthat myocardial echo contrast effect reflectsmicrovascular integrity and thus viability.'9Finally, contrast echocardiography should be

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New contrast agents and technologies for myocardial contrast echocardiography

compared with stress echocardiography withthe end point of detecting myocardialischaemia or viability.20 An example of com-bined stress and contrast echocardiography isshown in fig 6, where Albunex was injectedinto the left coronary artery of a patient withprevious infarction both at baseline and afterintravenous dipyridamole infusion.

ConclusionAfter the initial observation that it was possibleto study myocardial perfusion by echocardio-graphy, following injection of contrast agentsinto the coronary circulation, different investi-gators, pharmaceutical, and instrument com-panies have contributed towards a progressiveadvancement of knowledge in this field. Oncethe new generation of echo contrast agentsand scanners are available, an acceleration inthis process can be expected. The combina-tion of these efforts will provide a non-inva-sive, non-nuclear assessment of myocardialperfusion, preserving the high spatial and tem-poral resolution of ultrasound, in addition,being available in real time in a number of dif-ferent clinical arena.

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2 Monaghan MJ, Quigley PJ, Metcalfe JM, Thomas SD,Jewitt DE. Digital subtraction contrast echocardiogra-phy: a new method for the evaluation of regional myocar-dial perfusion. BrHeartJ 1988;59:12-19.

3 Feinstein SB, Cheirif J, Ten Cate FJ, Silverman PR,Heidenreich PA, Dick C, et al. Safety and efficacy of anew transpulmonary contrast agent: initial multicenterclinical results. JAm Coll Cardiol 1990;16:316-24.

4 Schlief R, Staks T, Mahler M, Rufer M, Fritzsch T, SeifertW. Successful opacification of the left heart chamberson echocardiographic examination after intravenousinjection of a new saccharide based contrast agent.Echocardiography 1990;7: 161-4.

5 Villaneuva FS, Glasheen WP, Sklenar J, Jayaweera AR,Kaul S. Successful and reproducible myocardial opacifi-cation during two-dimensional echocardiography fromright atrial injection of contrast. Circulation 1992;85:1557-64.

6 Grayburn PA, Erickson JM, Escobar J, Womack L, VelascoCE. Peripheral intravenous myocardial contrast echocar-diography using a 2% dodecafluoropentane emulsion:

identification of myocardial risk area and infarct size inthe canine model of ischemia. J Am Coll Cardiol 1995;26:1340-7.

7 Main ML, Escobar JF, Hall SA, Grayburn PA. Safety andefficacy of QW7437, a new fluorocarbon-based echocar-diographic contrast agent [abstract]. J Am Coil Cardiol1997;29(Suppl 2):299A.

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9 Dittrich HC, Bales GL, Kuvelas T, Hunt RM, McFerranBA, Greener Y. Myocardial contrast echocardiographyin experimental coronary artery occlusion with a newintravenously administered contrast agent. J Am SocEchocardiogr 1995;8:465-74.

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13 de Jong N, Hoff L, Skotiand T, Bom N. Absorption andscatter of encapsulated gas filled microspheres: theoreti-cal considerations and some measurements. Ultrasonics1992;2:95-103.

14 Monaghan MJ, Metcalfe JM, Odunlami S, Thomas SD,Waaler A, Jewitt DE. Digital radiofrequency echocardiog-raphy in the detection of myocardial contrast followingintravenous administration of Albunex. Eur Heart J1993;14: 1200-19.

15 Mulvagh SL, Foley DA, Aeschbacher BC, Klarich KK,Seward JB. Second harmonic imaging of an intravenouslyadministered echocardiographic contrast agent: visualisa-tion of coronary arteries and measurement of coronaryblood flow. JAm Coll Cardiol 1996;27:1519-25.

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20 Rovai D, Zanchi M, Lombardi M, Magagnini E, Chella P,Pieroni A, et al. Residual myocardial perfusion inreversibly damaged myocardium by dipyridamole con-trast echocardiography. Eur HeartJ 1996;17:296-301.

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