History of Echocardiographic Contrast Agents

Clin. Cardiol. Vol. 20 (Suppl. I), 1-7-1-1 1 (1997)

NAV~NC. NANDA, M.D. Heart StationfihocardiographyLaboratories, University of Alabama at Birmingham, Birmingham, Alabama, USA

Summary: Since its experimental introduction over 30 years application of contrast echocardiography (CE) is to assess ago, the use of cardiac ultrasound has expanded expeditiously, left-right shunting."' l2 particularly in the last decade. The inception of managed care Commercial development of contrast media began during has fueled this expansion because ultrasound technology has the 1980s. Early agents contained air-tilled microbubbles of the potential to enhance cost-effective diagnosis and medical saline, indocyanine green, sonicated dextrose, or other sub- care. Another important factor driving the growth of cardiac stances. These short-lived agents contained bubbles too large ultrasound has been the recent and rapid development of con- to pass through the pulmonary circulation and did not opacify trast echocardiography (CE). This diagnostic technique, in- the left heart. Later products made use of high-molecular- volving the injection of a contrast agent to enhance ultrasound weight gases, which are less diffusable than air, cross the pul- imaging, provides a safe, noninvasive means of directly as- monary capillary bed, and provide Doppler and gray-scale en- sessing myocardial perfusion and a host of other aspects of hancement.13Newercontrast agent$,eithercurrently available cardiovascular health and integrity. or under development, can traverse the pulmonary capillaries and be seen in the left side of the heart.

Key words: history, contrast agents, perflenapent emulsion, EchoGen", contrast echocardiography,Doppler, imaging First-GenerationAgents Fmt-generationagents include agitated saline, indocyanine Development of Contrast Echocardiography Agents green, sonicated solutions of dextrose, and renogrdfin, among others. These early agents proved less than ideal as contrast The concept of ultrasound contrast agents is widely media, because the microbubbles they generated were too acknowledged to have emerged in 1968, when Gramiak and large to pass through the lungs and opacify the left ventricle Shah observed a "cloud" of echoes from the aortic root after and systemic arteries after aperipheral intravenous injection.I4 injecting saline through an intra-aortic catheter.' Since then, In addition, these agents had half-lives of only a few seconds. many contrast agents have been used to enhance echocardi- As a result, the enhancement they provided was too transient ogmphy. for practical use.15 The first contrast solutions were injected into the venous EchovisC circulation to make gross anatomic abnormalities visible. Ad- ditional applications have included detecting valvular regur- SHU-454, (Echovist@,Schering AG, Berlin, Germany) is a gitation, identifying and distinguishing atrial and venhicular frst-generation contrast agent stabilized with D-galactose, septa1 defects, assessing congenital heart disease, measuring commercially available in Germany and awaiting approval in cardiac output, and evaluating surgical repair of valves or con- the It cannot pass the lung capillary bed and therelore genital abnormalities intraoperatively?-'" The most common cannot opacify the left heart. I 3. I Recent research indicates that Ekhovist is safe and provides adequate clinical information regarding the right heart com- parable to that of first-pass radionuclide ventriculography in healthy subjects, including obese patients.I7 No biological changes in heart rate, blood pressure, or arterial blood gases Address for reprints: have been found with Echovist in dogs.IX Navin C. Nanda, M.D. Director, Heart StatiodEchocardiography Laboratories Albunefl University of Alabama at Birmingham Heart Station SW1102 Sonicated albumin, (Albunex", Molecular Biosystems Inc., Birmingham, AL 35233-6846 San Diego, Calif.) was the first echocardiographic contrast 1-8 Clin. Cardiol. Vol. 20 (Suppl I), October 1997 agent able to pass through the pulmonary capillaries that the were well tolerated and no specific risks were found for pa- FDA approved for general sale to the clinical market. The sub- tients in any disease group. Galactosemia is a contraindication stance is an isotonic dispersion of air-filled microspheres of for the application of galactose contrast agents, however. Ih human serum alb~min.'~Studies have found that Albunex in- Although these first-generation agents are promising, none creases the reflectivity of blood in the left atrium and ventricle, can be considered ideal as a nontoxic, ready-to-use formula- thereby improving the definition of left-ventricular endocar- tion that is injectable intravenously, can cross the pulmonary dial borders and regional wall-motion In addition, capillary bed, is sufficiently stable, and provides both Doppler- venous injection of Albunex opacifies the left-ventricularcav- and gray-scale enhancement.13A major limitation is that these ity in 63%of patients given up to 0.12 mVkg; however, venous agents contain air, which is highly diffusible and rapidly es- injection rarely opacifiesthe myocardium adequatelyand may capes from the bubbles when mixed with blood, resulting in a cause arterial oxygen desaturation at doses of 0.5 mUkg or decrease in backscatter. more.21In addition, Albunex has been found to be pressure- dependent and to last < 30 s in the left ventricle.13 Although Albunex can pass through the pulmonary vascu- lature, resulting in left-sided cavity contrast after intravenous injection, several problems must be resolved before the assessment of myocardial perfusion is attempted intravenously with this agent.22The contrast appearing in the left-side cavi- ties and, even more so, in the myocardium after an intravenous injection is inconsistent. In addition, contrast disap- pears from the left ventricular cavity during systole, possibly limiting the amount of contrast that goes to the myocardium. Like other contrast agents, intravenous Albunex may improve the definition of the Doppler spectral profile of both right- and left-sided regurgitant and stenotic velocities, which may be useful in the diagnosis of valvular heart disease. The demonstrated enhancementof color-flow Doppler signals may improve the evaluation of valvular lesions. Albunex is among the agents that have been used to confirm ventricular anatomy and to characterize blood flow dynamics in patients with congenital heart di~ease.2~Among the clinical uses of Albunex are the evaluation of intracardiac shunts and valvular dysfunction, and the simple opacificationof the cardiac chambers.%

Levovist

SHU-508A (LevovisP, Schering AG, Berlin, Germany), an Echovist derivative, is a suspension of galactose and a small amount of fatty acid that releases small air bubbles when mixed with sterile water. It causes left ventricular opacification after venous injection in all patients with normal pulmonary artery pressures; in patients with pulmonary hypertension, however, this effect is minimal or absentF1 In a European FIG. 1 (A) Transesophageal echocardiographic assessment of multicentertrial of more than 1,200 patients with diagnostical- proximal coronary arteries after contrast enhancement. After con- ly insufficient Doppler signal intensity in routine imaging, trast injection (left),prominent flow signals till the lumen ofthe left Doppler signal enhancement was achieved in > 95% with at main coronary artery and the proximal left anterior descending coronary vessel, which shows hardly any tlow signals at baseline least one dose of Levovist, even in peripheral vessels.16Uses (right). (B) Transesophageal echocardiographic assessment ofprox- include cardiac B-mode and Doppler enhancement (Figs. 1, imal coronary arteries after contrast enhancement. At baseline 2)?5-28Levovist, which is availablein Europe but awaiting ap (right), virtually no flow signals are noted in the left main coronary proval in the U.S.,also allows for left ventricularopacification, artery. After contrast injection (left), prominent flow signals not except in patients with pulmonary hypertension (Fig. 3). only completely fill the lumen but also opacify an additional seg- Levovist and Ekhovist cause no serious or long-lasting side ment of the proximal left anterior descending coronary vessel that was not visualized at baseline. In addition, flow aliasing is noted effects and are considered safe.24 Schlief et al. found that more distally, and its site corresponds to an area of severe stenosis in Levovist caused no changes in heart rate, blood pressure, elec- the left anterior descending artery on the coronary angiogram. trocardiogram, blood chemistry, hematology, or ~rinalysis.~~ CF = the origin of the circumflex vessel. Reproduced from Ref. No. In other studies, repeated intravenous injections of Levovist 25 with permission. N.C. Nanda: Echocardiographic contrast agents

FIG.2 (A) Color Doppler examination of intramyocardial coronary FIG.3 Apical four-chamber view of a patient. Contrast-enhanced arteries. Baseline examination in a canine shows linear flow signals B-mode examination (A) shows incomplete filling of the LV cavity (arrows) within the anterior ventricular septum consistent with the by contrast signals. However, when color Doppler was turned 011 sepval perforator coronary artery. (B) Following injection of (B), complete opacification of the LV cavity occurred. LV = left ven- Levovist through a catheter placed in the left main coronary artery, tricle, RV = right ventricle, RA = right atrium. Reproduced from the perforator artery not only becomes more prominent but also Ref. No.41 withpermission. displays numerous branches (arrow).LV = left ventricle; RV =right ventricle. Reproduced from Ref. No. 27 with permission.

perfluorocarbons, which perfuse less readily. These agents have, in fact, been awarded a number of U.S. patents.24These Second+eneration Agents newer, second-generationproducts, which are in development in the U.S., are less diffusiblethan air.3s The substantially high- Research on second-generation agents (e.g., EchoGen", er reflectivity provided by them permits enhancement to be de- Optison", and BR-1) has focused on the size and stabilization tected in the peripheral circulation on the gray scale as well as of microbubbles, since these properties determine their effec- with Doppler imaging.15 tiveness.") Various forms of stabilization have been added to increase longevity. These agents are detectable on B-mode as Optison@ far as the left side of the heart, but once they have been diluted in the general systemic circulation, adequate visualization re- FS069 (Optison@,Molecular Biosystems Inc, San Diego, quires a more sensitive technique, such as Doppler imaging.I5 Calif.) provides persistent contrast effect. Unlike Albunex, Some second-generation contrast agents employ colloidal however, it gives no information about myocardial blood flow suspensionsand emulsions, including collagen microspheres, when injected into a coronary artery.3s perfluoro-octylbromide (Imagenf, Alliance Pharmaceutical In one study, FS069 produced higher levels of harmonic Corp., San Diego, Calif.),"' lipid emulsions?* and particles of signals than Albunex. The researchers meamred RMS ampli- iodipamide ethyl ester.33 tudes of the Doppler-shift spectra as a function of the concen- Major limitations of the first-generation agents have been tration of the agents, frequency, and transmitted acoustic pres- overcome by the use of high-molecular-weightgases, such as sure.36Optison is awaiting FDA approval. 1-10 Clin. Cardiol. Vol. 20 (Suppl I), October 1997

Overall, this agent provides persistent contrast with longer NUS (NycomedMallinckrodt, Oslo, Norway) and SHU half-life than earlier agents. The agent has no effect on hemo- 563A (Schering AG, Berlin, Germany) consist of polymer- dynamics, myocardial blood flow, left ventricular wall thick- encapsulated micro bubble^.^^ ening, or pulmonary gas exchanges. In addition, FS069 pro- duces higher levels of first and second harmonic signals than Alb~nex.~~ Future Developments

BR-1 In the future, CE will likely play a number of important roles in diagnostic and clinical pathways, such as serving as a BR-1 (Brdcco Research SA, Geneva, Switzerland) is an "diagnostic gatekeeper" to other tests and procedures, improv- aqueous suspension of stabilized sulfur hexduoride micro- ing patient care, reducing costs, and allowing earlier diagnosis bubbles. Its developers identify BR-1 as a promising agent and fewer invasive procedures:" Potential applications of CE with high echogenicity, stability, and resistance to pressure include post-thrombolytic and post-percutaneous translumi- changes. BR- 1 injections in animals resulted in homogeneous, nal coronary angioplasty assessment; definitive testing for dose-dependentopacification of the left heart. The agent, now CAD; postdirect angioplasty detection of reocclusion; post- in the early stages of FDA review, was highly echogenic in an elective angioplasty detection of re-stenosis; assessment of almost constant pattern over the entire medical frequency valvular disease and coronary flow reserve: salvage of subop- range of 1 to I0 MHz.~' timal echocardiograms; enhanced color and spectral Doppler signals; left ventricular wall-motion visualization in real time; EchoGen@' Emulsion simplified detection of atrial and septa1 shunts; calculation of Perflenapent emulsion (EchoGen@,SONUS Pharmaceuti- ejection fractiodCAD presence, location, and extent; and vi- cals, Bothell, Wash.) was the first fluorocarbon microbubble sualization and localization of myocardial perfusion deficits. contrast agent to be developed and taken into clinical trials and The use of transient imaging, harmonic imaging, harmonic is expected to receive FDA approval in the near future. After power Doppler imaging, and stimulated acoustic emission hypobaric activation, perfluorocarbon liquid droplets undergo will further increase the future applications of CE."' 43 a phase conversion to become microbubbles. Potential indi- cations include enhancement of ventricular chambers, improvement of endocardial border delineation in adults with References suboptimal echoes undergoing ventricular function studies, I. Gramiak R, Shah PM: Echocardiography ofthe aortic root. Irnwt improved assessment of ejection fraction measurements, and RudiolI968;3:35&366 wall-motion studies. EchoGen@emulsion may also be used in 2. Aronson S, Han LK Stress echocardiography,contrast echtrardio- assessing myocardial perfusion in adult patients by providing graphy and tissue characterization.Crir Cure Cliri 1996: 12:429450 myocardial tissue enhancement within the left ventricular 3. Gramiak R, Nanda NC: Contrast techniques in echocxdiography. wall. 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