Continuing Medical Education Course for “American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography”Accreditation StatementThe American Society of Echocardiography (ASE) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The ASE designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.The American Registry of Diagnostic Medical Sonographers and Cardiovascular Credentialing International recognize the ASE's certificates and have agreed to honor the credit hours toward their registry requirements for sonographers.The ASE is committed to resolving all conflict-of-interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated.Target AudienceThis activity is designed for all cardiovascular physicians, cardiac sonographers, and nurses with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, sonographers, and other medical professionals having a specific interest in contrast echocardiography may be included.ObjectivesUpon completing this activity, participants will be able to: 1. Demonstrate an increased knowledge of the applications for contrast echocardiography and their impact on cardiac diagnosis. 2. Differentiate the available ultrasound contrast agents and ultrasound equipment imaging features to optimize their use. 3. Recognize the indications, benefits, and safety of ultrasound contrast agents, acknowledging the recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information. 4. Identify specific patient populations that represent potential candidates for the use of contrast agents, to enable cost-effective clinical diagnosis. 5. Incorporate effective teamwork strategies for the implementation of contrast agents in the echocardiography laboratory and establish guidelines for contrast use. 6. Use contrast enhancement for endocardial border delineation and left ventricular opacification in rest and stress echocardiography and unique patient care environments in which echocardiographic image acquisition is frequently challenging, including intensive care units (ICUs) and emergency departments. 7. Effectively use contrast echocardiography for the diagnosis of intracardiac and extracardiac abnormalities, including the identification of complications of acute myocardial infarction. 8. Assess the common pitfalls in contrast imaging and use stepwise, guideline-based contrast equipment setup and contrast agent administration techniques to optimize image acquisition.Author DisclosuresSharon L. Mulvagh: research grant, Lantheus Medical Imaging, GE Healthcare, and Astellas Pharma; consultant/advisory, Acusphere, Point Biomedical. Mani A. Vannan: research grant, other research support, speaker bureau/honoraria, and consultant/advisory board, Lantheus Medical Imaging. Harald Becher: research grant, Philips, Sonosite, and Toshiba; speaker bureau/honoraria, Lantheus Medical Imaging; consultant/advisory board, Point Biomedical, Bracco, Acusphere, ICON, Lantheus Medical Imaging. S. Michelle Bierig: research grant, Lantheus Medical Imaging, Amersham. Peter N. Burns: consultant/advisory board, Philips Ultrasound, Lantheus Medical Imaging. Dalane W. Kitzman: research grant, Lantheus Medical Imaging, IMCOR, Sonus; speakers bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging, Acusphere. Itzhak Kronzon: research grant, GE Healthcare. Arthur J. Labovitz: consultant/advisory board, ICON Medical. Roberto M. Lang: research grant, Acusphere, Point Biomedical; speaker bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging. Julio E. Perez: consultant/advisory board, Biomedical Systems. Thomas R. Porter: research grant, Lantheus Medical Imaging; consultant/advisory board, Acusphere, ImaRx. Judy Rosenbloom: paid consultant with ultrasound equipment manufacturers. Kevin Wei: research grant, Lantheus Medical Imaging, Philips Ultrasound; consultant/advisory board, Acusphere. The following stated no disclosures: Harry Rakowski, Sahar S. Abdelmoneim, Ramon Castello, Patrick D. Coon, Mary E. Hagen, James G. Jollis, Thomas R. Kimball, Joseph Mathew, Stuart Moir, Sherif F. Nagueh, Alan S. Pearlman, G. Monet Strachan, Srihari Thanigaraj, Anna Woo, Eric H. C. Yu, and William A. Zoghbi.Conflicts of Interest: The authors have no conflicts of interest to disclose except as noted above.Estimated Time to Complete This Activity: 1 hour Continuing Medical Education Course for “American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography” The American Society of Echocardiography (ASE) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASE designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. The American Registry of Diagnostic Medical Sonographers and Cardiovascular Credentialing International recognize the ASE's certificates and have agreed to honor the credit hours toward their registry requirements for sonographers. The ASE is committed to resolving all conflict-of-interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated. This activity is designed for all cardiovascular physicians, cardiac sonographers, and nurses with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, sonographers, and other medical professionals having a specific interest in contrast echocardiography may be included. Upon completing this activity, participants will be able to: 1. Demonstrate an increased knowledge of the applications for contrast echocardiography and their impact on cardiac diagnosis. 2. Differentiate the available ultrasound contrast agents and ultrasound equipment imaging features to optimize their use. 3. Recognize the indications, benefits, and safety of ultrasound contrast agents, acknowledging the recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information. 4. Identify specific patient populations that represent potential candidates for the use of contrast agents, to enable cost-effective clinical diagnosis. 5. Incorporate effective teamwork strategies for the implementation of contrast agents in the echocardiography laboratory and establish guidelines for contrast use. 6. Use contrast enhancement for endocardial border delineation and left ventricular opacification in rest and stress echocardiography and unique patient care environments in which echocardiographic image acquisition is frequently challenging, including intensive care units (ICUs) and emergency departments. 7. Effectively use contrast echocardiography for the diagnosis of intracardiac and extracardiac abnormalities, including the identification of complications of acute myocardial infarction. 8. Assess the common pitfalls in contrast imaging and use stepwise, guideline-based contrast equipment setup and contrast agent administration techniques to optimize image acquisition. Sharon L. Mulvagh: research grant, Lantheus Medical Imaging, GE Healthcare, and Astellas Pharma; consultant/advisory, Acusphere, Point Biomedical. Mani A. Vannan: research grant, other research support, speaker bureau/honoraria, and consultant/advisory board, Lantheus Medical Imaging. Harald Becher: research grant, Philips, Sonosite, and Toshiba; speaker bureau/honoraria, Lantheus Medical Imaging; consultant/advisory board, Point Biomedical, Bracco, Acusphere, ICON, Lantheus Medical Imaging. S. Michelle Bierig: research grant, Lantheus Medical Imaging, Amersham. Peter N. Burns: consultant/advisory board, Philips Ultrasound, Lantheus Medical Imaging. Dalane W. Kitzman: research grant, Lantheus Medical Imaging, IMCOR, Sonus; speakers bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging, Acusphere. Itzhak Kronzon: research grant, GE Healthcare. Arthur J. Labovitz: consultant/advisory board, ICON Medical. Roberto M. Lang: research grant, Acusphere, Point Biomedical; speaker bureau, Lantheus Medical Imaging; consultant/advisory board, Lantheus Medical Imaging. Julio E. Perez: consultant/advisory board, Biomedical Systems. Thomas R. Porter: research grant, Lantheus Medical Imaging; consultant/advisory board, Acusphere, ImaRx. Judy Rosenbloom: paid consultant with ultrasound equipment manufacturers. Kevin Wei: research grant, Lantheus Medical Imaging, Philips Ultrasound; consultant/advisory board, Acusphere. The following stated no disclosures: Harry Rakowski, Sahar S. Abdelmoneim, Ramon Castello, Patrick D. Coon, Mary E. Hagen, James G. Jollis, Thomas R. Kimball, Joseph Mathew, Stuart Moir, Sherif F. Nagueh, Alan S. Pearlman, G. Monet Strachan, Srihari Thanigaraj, Anna Woo, Eric H. C. Yu, and William A. Zoghbi. Conflicts of Interest: The authors have no conflicts of interest to disclose except as noted above. Estimated Time to Complete This Activity: 1 hour Table of ContentsSynopsis of Suggested Applications for Ultrasound Contrast Agent Use 1180Purpose 1181Introduction 1181Contrast Agents 1181Contrast-Specific Ultrasound Imaging 1182AClinical Applications 1184aAssessment of Cardiac Structure and Function 1184iQuantification of LV Volumes and LVEF 1184iiCardiac Anatomy 1186LV Apical Abnormalities 1186LV Apical Hypertrophy 1186LV Noncompaction 1186LV Apical Thrombus 1186LV Apical Aneurysm 1187Complications of Myocardial Infarction 1187Abnormalities in Other Cardiac Chambers 1187iiiIntracardiac Masses 1187ivExtracardiac Anatomy 1187Vascular Imaging 1187Aortic Dissection and Other Pathology 1187Femoral Arterial Pseudoaneurysms 1187vDoppler Enhancement 1188bContrast Enhancement in Stress Echocardiography 1188cEchocardiography in the Emergency Department 1189dContrast Agent Use in the ICU 1189eContrast Agent Use in Cardiac Interventional Therapy 1191fUse of Contrast Agents in Pediatric Echocardiography 1191BSafety of Echocardiographic Contrast Agents 1192CEchocardiography Laboratory Implementation of Contrast Agent Use: A Team Approach 1193aRole of the Physician 1193bRole of the Sonographer 1194cRole of the Nurse 1194dTraining Issues 1194eCost-Effectiveness 1194DSummary of Recommendations for Ultrasonic Contrast Agent Use for Echocardiography 1195ESpecial Considerations 1195Synopsis of Suggested Applications for Ultrasound Contrast Agent Use•In difficult-to-image patients presenting for rest echocardiography with reduced image quality○To enable improved endocardial visualization and assessment of left ventricular (LV) structure and function when ≥2 contiguous segments are not seen on noncontrast images○To reduce variability and increase accuracy in LV volume and LV ejection fraction (LVEF) measurements by 2-dimensional (2D) echocardiography○To increase the confidence of the interpreting physician in LV functional, structure, and volume assessments•In difficult-to-image patients presenting for stress echocardiography with reduced image quality○To obtain diagnostic assessment of segmental wall motion and thickening at rest and stress○To increase the proportion of diagnostic studies○To increase reader confidence in interpretation•In all patients presenting for rest echocardiographic assessment of LV systolic function (not solely difficult-to-image patients)○To reduce variability in LV volume measurements through 2D echocardiography ○To increase the confidence of the interpreting physician in LV volume measurement•To confirm or exclude the echocardiographic diagnosis of the following LV structural abnormalities, when nonenhanced images are suboptimal for definitive diagnosis○Apical variant of hypertrophic cardiomyopathy○Ventricular noncompaction○Apical thrombus○Complications of myocardial infarction, such as LV aneurysm, pseudoaneurysm, and myocardial rupture•To assist in the detection and correct classification of intracardiac masses, including tumors and thrombi•For echocardiographic imaging in the intensive care unit (ICU) when standard tissue harmonic imaging does not provide adequate cardiac structural definition○For accurate assessment of LV volumes and LVEF○For exclusion of complications of myocardial infarction, such as LV aneurysm, pseudoaneurysm, and myocardial rupture•To enhance Doppler signals when a clearly defined spectral profile is not visible and is necessary to the evaluation of diastolic and/or valvular functionPurposeUltrasound contrast agents, used with contrast-specific imaging techniques, have an established role for diagnostic cardiovascular imaging in the echocardiography laboratory. This document focuses on when and how contrast agents are used to enhance the diagnostic capability of echocardiography. It also reviews the role of physicians, sonographers, and nurses, as well as ways to integrate the use of contrast agents into the echocardiography laboratory most efficiently. These recommendations are based on a critical review of the existing medical literature, including prospective clinical trials. Where no significant study data are available, recommendations are based on expert consensus opinion. Updating a previous publication,aMulvagh S.L. DeMaria A.N. Feinstein S.B. Burns P.N. Kaul S. Miller J.G. et al.Contrast echocardiography: current and future applications.J Am Soc Echocardiogr. 2000; 13: 331-342Abstract Full Text Full Text PDF PubMed Google Scholar this document describes the evidence-based use of contrast echocardiography in clinical practice while acknowledging recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information, as described in section B.IntroductionRadiographic and paramagnetic contrast agents have an important role in current noninvasive imaging techniques. They are essential for delineating vascular structures with computed tomography (CP) and for perfusion and viability studies with magnetic resonance imaging, and they are an integral part of all nuclear cardiac imaging techniques. Historically, contrast agents have not been an integral component of the echocardiography imaging laboratory. However, a unique class of contrast agents composed of microbubbles, rather than dyes, chemical compounds, or radioisotopes, has been developed, along with new ultrasound imaging techniques that optimize their detection.Contrast AgentsUltrasound contrast agents have an established role in clinical diagnosis, patient management, and clinical research. The contrast agents that are approved by regulatory agencies for echocardiographic use throughout the world (Table 1) share the common indications, as approved by the FDA, of LV opacification (LVO) and LV endocardial border definition (EBD) in patients with technically suboptimal echocardiograms under rest conditions.bCohen J.L. Cheirif J. Segar D.S. Gillam L.D. Gottdiener J.S. Hausnerova E. et al.Improved left ventricular endocardial border delineation and opacification with Optison (FS069), a new echocardiographic contrast agent: results of a phase III multicenter trial.J Am Coll Cardiol. 1998; 32: 746-752Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, cCrouse L.J. Cheirif J. Hanly D.E. Kisslo J.A. Labovitz A.J. Raichlen J.S. et al.Opacification and border delineation improvement in patients with suboptimal endocardial border definition in routine echocardiography: results of the phase III Albunex multicenter trial.J Am Coll Cardiol. 1993; 22: 1494-1500Abstract Full Text PDF PubMed Google Scholar, dLindner J.R. Dent J.M. Moos S.P. Jayaweera A.R. Kaul S. Enhancement of left ventricular cavity opacification by harmonic imaging after venous injection of Albunex.Am J Cardiol. 1997; 79: 1657-1662Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, eAllen M.R. Pellikka P.A. Villarraga H.R. Klarich K.W. Foley D.A. Mulvagh S.L. et al.Harmonic imaging: echocardiographic enhanced contrast intensity and duration.Int J Card Imaging. 1999; 15: 215-220Crossref PubMed Scopus (15) Google Scholar, fKitzman D.W. Goldman M.E. Gillam L.D. Cohen J.L. Aurigemma G.P. Gottdiener J.S. Efficacy and safety of the novel ultrasound contrast agent perflutren (Definity) in patients with suboptimal baseline left ventricular echocardiographic images.Am J Cardiol. 2000; 86: 669-674Abstract Full Text Full Text PDF PubMed Scopus (78) Google ScholarTable 1Echocardiographic contrast agentsAgentBubble size (μm), mean (range)GasShell compositionIndicationLevovist⁎Approved in Canada, Europe, and some Latin American and Asian countries.,†Bayer Schering Pharma AG (Berlin, Germany).2.0-3.0 (2.0-8.0)AirLipid (palmitic acid)LVO and DopplerOptison‡Approved by the FDA. Optison and Definity are also approved in Canada, and Definity is approved in Europe under the name Luminity.,§GE Healthcare (Princeton, NJ).4.7 (1.0-10.0)PerfluoropropaneHuman albuminLVO, EBD, and DopplerDefinity‡Approved by the FDA. Optison and Definity are also approved in Canada, and Definity is approved in Europe under the name Luminity.,∥Lantheus Medical Imaging (North Billerica, MA).1.5 (1.0-10.0)PerfluoropropanePhospholipidLVO, EBD, and DopplerSonoVue⁎Approved in Canada, Europe, and some Latin American and Asian countries.,#Bracco Diagnostics (Milan, Italy).2.5 (1.0-10.0)Sulfur hexafluoridePhospholipidLVO and DopplerCARDIOsphere⁎⁎Not yet FDA approved.,POINT Biomedical Corporation (San Carlos, CA).4.0 (3.0-5.0)NitrogenBiodegradable polymer bilayerMCEImagify⁎⁎Not yet FDA approved.,Acusphere (Watertown, MA).2.0DecafluorobutaneSynthetic polymerLVO and MCELVO, Left ventricular opacification; EBD, endocardial border definition; MCE, myocardial contrast echocardiography (perfusion). Approved in Canada, Europe, and some Latin American and Asian countries.† Bayer Schering Pharma AG (Berlin, Germany).‡ Approved by the FDA. Optison and Definity are also approved in Canada, and Definity is approved in Europe under the name Luminity.§ GE Healthcare (Princeton, NJ).∥ Lantheus Medical Imaging (North Billerica, MA).# Bracco Diagnostics (Milan, Italy). Not yet FDA approved.†† POINT Biomedical Corporation (San Carlos, CA).‡‡ Acusphere (Watertown, MA). Open table in a new tab The microbubbles have thin and relatively permeable shells and typically are filled with a high-molecular-weight gas (eg, perfluorocarbon [PFC]) that slows diffusion and dissolution within the bloodstream. After intravenous (IV) injection, the microbubbles transit rapidly through the lungs, cardiac chambers, and myocardium, without any clinical effect on LV function, coronary or systemic hemodynamics, ischemic markers, or pulmonary gas exchange. Optison (GE Healthcare, Princeton, NJ), with a shell derived from human serum albumin, was the first PFC-containing IV ultrasonographic contrast agent approved for LVO and EBD use in humans. Definity (Lantheus Medical Imaging, North Billerica, MA) has also received FDA approval for LVO and EBD. Definity is a lipid-coated microbubble formed from 2 components, a long-chain lipid and an emulsifier, that are combined by agitation in a vial pressurized with PFC gas. This mixture is activated (Vialmix; Lantheus Medical Imaging) before use. The design characteristics of these agents are intended to preserve gas within the bubble to increase the duration of opacification.None of these agents is yet approved by the FDA for assessment of myocardial perfusion. However, 2 additional agents, CARDIOsphere (POINT Biomedical Corporation, San Carlos, CA) and Imagify (Acusphere, Watertown, MA), have been evaluated in phase 3 pivotal studies for their indication in the diagnosis of coronary artery disease (CAD) by evaluation of myocardial perfusion, and both have been found to be noninferior to nuclear single photon-emission computed tomographic imaging.gWei K. Crouse L. Weiss J. Villanueva F. Schiller N. Naqvi T. et al.Comparison of usefulness of dipyridamole stress myocardial contrast echocardiography to technetium-99m sestamibi single-photon emission computed tomography for detection of coronary artery disease (PB127 multicenter phase 2 trial results).Am J Cardiol. 2003; 91: 1293-1298Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar One of these manufacturers(Acusphere) is seeking FDA approval for this indication at the time of this publication. Both agents are synthetic polymer-coated microspheres. CARDIOsphere has an albumin and polylactide shell, which has sufficient thickness to be stable in the bloodstream even though the encapsulated gas is nitrogen, which has high solubility in blood. CARDIOsphere's particular structure, with a relatively stiff, brittle shell and rapidly diffusing gas, makes it suitable for intermittent harmonic power Doppler imaging at higher levels of mechanical index (MI). Imagify has both a synthetic, biodegradable polymer shell and a slowly diffusing encapsulated gas (decafluorobutane) that improves microbubble persistence within the bloodstream and renders it suitable for low-MI insonation. The requirements of myocardial perfusion by echocardiography are different from those of LVO. This perfusion technique requires the ability to deplete a myocardial region of microspheres by a pulse of ultrasound and then assess the rapidity of replenishment as a surrogate for myocardial blood flow, akin to a negative indicator dilution bolus. In this way, semiquantitative and quantitative image interpretation can be performed.Contrast-Specific Ultrasound ImagingAlthough PFC gases and improved microbubble shell designs made ultrasound contrast agents more stable in the bloodstream, the ability of conventional echocardiographic imaging systems to detect them within the cardiac cavities and myocardial tissue was limited. The development of harmonic imaging, intermittent imaging, harmonic power Doppler, and, more recently, low-MI pulsing schemes has dramatically enhanced the ability to detect intravenously injected microbubbles in echocardiographic studies and to improve the duration of opacification. These methods all have in common the aim to detect the echo from bubbles and suppress the echo from tissue; they rely on the unique nonlinear behavior of a bubble in an acoustic field, the understanding of which is a prerequisite to a successful contrast study in the echocardiography laboratory.aMulvagh S.L. DeMaria A.N. Feinstein S.B. Burns P.N. Kaul S. Miller J.G. et al.Contrast echocardiography: current and future applications.J Am Soc Echocardiogr. 2000; 13: 331-342Abstract Full Text Full Text PDF PubMed Google Scholar Current commercially available ultrasound scanners have prespecified vendor presets that are generally suitable to yield good LVO.Microbubbles in an ultrasound beam undergo resonant oscillation in response to the variations in acoustic pressure transmitted by the transducer. While the bubble oscillates, it is more stiff when compressed and less stiff when expanded. As a result, the radius of the bubble changes asymmetrically, and the reflected sound waves contain nonlinear components at multiples of the insonifying frequency. The creation of these microbubble “higher harmonics” yielded the first and most simple of the imaging methods, harmonic imaging.hBurns P.N. Harmonic imaging with ultrasound contrast agents.Clin Radiol. 1996; 51: 50-55PubMed Google Scholar Currently, harmonic imaging with contrast is rarely used in isolation because it is confounded by the tissue harmonic, which is created by nonlinear propagation of sound in tissue and results in incomplete suppression of the tissue echo. Indeed, the strength of the nonlinear components depends on the acoustic intensity, or MI, of the sound field.iMeltzer R.S. Food and Drug Administration ultrasound device regulation: the output display standard, the “mechanical index,” and ultrasound safety.J Am Soc Echocardiogr. 1996; 9: 216-220Abstract Full Text PDF PubMed Google Scholar Ultrasound imaging systems are required to provide a continuous display of the estimated MI used for imaging. The MI is a standardized estimate of the peak acoustic intensity, defined as the peak negative pressure [in megapascals] divided by the square root of the transmit frequency [in megahertz]. It should be noted that although a single MI value is estimated for a whole image, in reality it varies with depth and lateral location within the field of view. With use of a standard cardiac transducer at an MI > 0.1, most contrast microbubbles produce an echo with strong nonlinear components (Figure 1A). The role of the different contrast imaging modes is to create and detect these nonlinear components and display an image formed from them while suppressing the linear echoes from tissue and tissue motion.Different techniques may be used to create bubble-specific images. High-MI methods rely on the fact that ultrasound, when applied at intensities commonly used in conventional imaging, disrupts and eliminates most microbubble contrast agents. Indeed, continuous imaging in harmonic mode at high MI results in destruction of microbubbles and creates a “swirling” artifact (Figure 1B, and Supplementary Figure 1 and Supplementary Movies 1 and 2). This feature can be used to the sonographer's advantage, however, with intermittent imaging, because the destruction effect is rapid (normally within a few microseconds). A technique such as power Doppler, designed to detect changes due to blood flow, interprets the change that occurs when bubbles are disrupted as a Doppler shift by displaying a bright signal in the echocardiographic image at the location of bubble disruptionjBurns P.N. Powers J.E. Simpson D.H. Brezina A. Kolin A. Chin C.T. et al.Harmonic power mode Doppler using microbubble contrast agents: an improved method for small vessel flow imaging.in: Levy M. Schneider S.C. McAvoy B.R. 1994 IEEE Ultrasonics Symposium proceedings: an international symposium. Vol 3. Institute of Electrical and Electronics Engineers, New York1994: 1547-1550Google Scholar (Figure 1C). Another approach uses harmonic imaging and subtraction of the predisruption image from the postdisruption image, and yet another approach detects the ultraharmonics (at 1.5 times the transmitted frequency) scattered by a disrupting bubble.The advantage of higher MI methods is that they are sensitive to bubbles and thus effective for myocardial perfusion imaging.kPorter T.R. Xie F. Transient myocardial contrast after initial exposure to diagnostic ultrasound pressures with minute doses of intravenously injected microbubbles: demonstration and potential mechanisms.Circulation. 1995; 92: 2391-2395Crossref PubMed Google Scholar They yield a high signal-to-noise ratio, reduce artifact, and facilitate strict image interpretation criteria for perfusion assessment that is based on duration of time required for replenishment. The disadvantage for LVO and EBD is that immediately after the image is made, the tracer has disappeared in the tissue, and a replenishment time of ≥1 cardiac cycle must elapse before another image can be made. Image acquisition is generally triggered to the electrocardiogram, and the mode is referred to as intermittent triggered imaging.lPowers J.E. Burns P.N. Souquet J. Imaging instrumentation for ultrasound contrast agents.in: Nanda N.C. Schlief R. Goldberg B.B. Advances in echo imaging using contrast enhancement. 2nd ed. Kluwer Academic, Dordrecht, the Netherlands1997: 139-170Crossref Google Scholar Clearly, the wall motion information from the echocardiographic image cannot be gleaned when in intermittent triggered imaging mode, because the frame rate is extremely low.Real-time imaging of wall motion with LVO can only be achieved with methods that can detect bubbles without disrupting them, as occurs with low-MI imaging (Figure 1D, and Supplementary Figure 2 and Supplementary Movies 2 and 3). Thus, only the low-MI modes described below are relevant to the FDA-approved indication of LVO and EBD. The MI is held below 0.2, and a sequence of pulses is sent along each scan line, with each pulse differing in phase or amplitude, or both. The resulting stream of echoes is then processed so that when added together, the echoes from linear scatterers, such as tissue, cancel out completely, leaving only those from nonlinear scatterers, such as the bubbles. These pulse inversion or amplitude modulation techniques can be extended to include filters that eliminate tissue motion, so that bubbles can be detected in real time, even in the moving myocardium.mSimpson D.H. Chin C.T. Burns P.N. Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents.IEEE Trans Ultrason Ferroelectr Freq Control. 1999; 46: 372-382Crossref PubMed Scopus (387) Google Scholar The disadvantage of low-MI modes is only relevant to the assessment of myocardial perfusion. These low-MI modes are less sensitive to bubbles than high-MI imaging. The advantage of low-MI perfusion imaging is that it can be used in a continuum of evaluation of wall motion and perfusion assessme