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Contrast Echocardiography 4MEDICAL REVIEW Contrast Echocardiography Mark A. Friedman Echocardiography Laboratory Barnes-Jewish Hospital Washington University School of Medicine St. Louis, MO 53110 ABSTRACT CONTRAST AGENTS Ultrasound contrast agents are widely used in clinical The ability to opacify vascular structures on echocardio- practice for left ventricle opacification in sub-optimal grams by injecting agitated saline solution has been well echocardiograms. Recently, significant research has recognized for more than thirty years (Gramiak and Shah, focused on the use of contrast echocardiography as a 1968). Early contrast agents were produced by manually non-invasive means to evaluate myocardial perfusion. agitating solutions such as saline, yielding bubbles that Advances in contrast agents as well as ultrasound tech- provided brief ultrasound contrast by scattering the nology have enabled investigations into myocardial con- incoming ultrasound energy before dissolving rapidly in trast echocardiography as a possible alternative to blood. These hand-agitated intravenous solutions have nuclear imaging studies. This review will focus on the been shown to be safe and are still used clinically to pro- development and current uses of contrast echocardiog- vide brief contrast during echocardiograms for evaluating raphy, as well as future indications, including myocardial cardiac shunts and patent foramen ovale (Bommer et al., perfusion and risk stratification following myocardial 1984). Hand-agitated intravenous solutions, however, infarction. cannot be used to evaluate left-sided cardiac chambers because the bubbles have neither a small enough size nor the stability to cross the pulmonary vasculature. (Table 1) INTRODUCTION Echocardiography has become a standard tool in the TABLE 1 PROPERTIES OF AN IDEAL ECHOCARDIOGRAPHIC CONTRAST AGENT evaluation and diagnosis of a wide range of cardiac con- ditions. In addition to the determination of cardiac size • High echogenicity (scattering) and function, echocardiography is widely used for the • Minimal diffusion of gas outside the microbubble assessment of left ventricular wall motion, systolic and diastolic function, valvular structure and function, as well • Small size to transverse pulmonary circulation as imaging of the great vessels. The use of agitated saline • Stability during pulmonary passage as an intravenous ultrasound contrast agent to enhance images has been well described and is currently in use for • Confinement to the intravascular compartment evaluating right to left shunts. However, the large size and short half-life of saline bubbles prevent their pas- sage through the pulmonary circulation and thus pre- Sonication, or the exposure of a solution to ultrasound cludes their use as an intravenous agent for enhance- energy leading to the formation of stable microbubbles, ment of the left ventricle. Recent advances in microbub- was originally described by Feinstein (Feinstein et al., ble technology, along with improved ultrasound trans- 1984). The first commercially available contrast agent, ducer technology, have enabled the wide-spread use of Albunex, consisted of sonicated albumin microbubbles intravenous contrast for left ventricular opacification. containing air, and was approved by the Food and Drug However, it has not historically been possible to assess Administration (FDA) in 1992 as an intravenous injection myocardial perfusion, that is, the functional state of the for left ventricular opacification in sub-optimal echocar- coronary vasculature, using echocardiography. Expand- diograms. The air within Albunex bubbles diffused rap- ing on the technology of ventricular opacification, much idly into the circulation following peripheral injection, research has focused on the use of echocardiography causing the bubbles to become progressively smaller. with intravenous contrast to evaluate myocardial perfu- Because the ability to detect a microbubble by ultra- sion. Numerous phase III clinical trials are presently sound is a function of the sixth power of the radius of underway investigating transthoracic ultrasound as an the bubble, these first-generation microbubbles such as alternative to nuclear imaging studies currently used in Albunex began to lose their echogenicity in a relatively assessing myocardial perfusion. This review of contrast short time as air diffused out into the circulation (Cheng, echocardiography will discuss the development and cur- et al., 1998). In low output states, with increased contact rent indications for contrast echocardiography, as well as time between the microbubbles and blood, Albunex did possible future uses of the technology. not reliably lead to cavity opacification. Gandhok et 2 Einstein J. Biol. Med. (2004) 21:2-8. 4MEDICAL REVIEW Contrast Echocardiography TABLE 2 INTRAVENOUS CONTRAST AGENTS (partial list) *approved by FDA Name ManufacturerShell Composition Gas Albunex * Molecular BiosystemsAlbumin Air (no longer available) Optison * Mallinckrodt MedicalAlbumin Octafluoropropane Definity * Dupont PharmaceuticalsLipid Octafluoropropane Levovist ScheringGalactose/Palmitate Air (approved in Europe) Imagent ScheringSurfactant/powder Perflexane SonoVue Bracco ImagingPhospholipid Sulfur-hexafluoride PB-127 Point-BiomedicalAlbumin/Polylactide Nitrogen al.,(1997) found that only 44% of selected patients with signal generates a maximal signal from the microbubble ≥1 of the following conditions (moderate-to-severe sys- (Kaul, 2001). The goal in using contrast agents is to tolic dysfunction, moderate-to-severe mitral or tricuspid increase the signal from the tissue or cavity that contains regurgitation, pulmonary hypertension, or atrial fibrilla- the contrast while simultaneously minimizing the signal tion) achieved significant left ventricular opacification from surrounding tissues. In opacifying the left ventricle, with Albunex, compared to 88% of patients without blood within the cavity contains maximum amount of these conditions. In view of the large percentage of contrast, which generates a more intense signal com- patients referred for echocardiography with these condi- pared to the myocardium which contains comparatively tions, Albunex achieved less than ideal opacification in a few microbubbles. Soft tissues scatter the incoming ultra- significant number of patients. sound wave in a linear fashion, while microbubbles have the ability to scatter a given frequency at multiples of Recently, second-generation contrast agents have been the original frequency, termed harmonics (Porter et al., developed using poorly soluble gases such as high-molec- 1996). By filtering out the fundamental frequency and ular-weight perfluorcarbons. The resulting microbubbles processing only the harmonics, the technology described have an increased longevity compared to first-genera- as harmonic imaging has enhanced the differentiation tion agents, and maintain their echogenicity for several between contrast and surrounding tissue. minutes following peripheral injection, providing suffi- cient time to obtain the desired opacification (Skyba and In numerous clinical trials, harmonic imaging echocardio- Kaul, 2001). Several second-generation agents have been graphy with intravenous contrast has improved the qual- granted FDA approval for ventricular opacification in ity and diagnostic yield compared to echocardiograms sub-optimal studies and are now widely used in clinical without contrast. The impaired transmission of ultra- practice for left ventricular opacification (Table 2). sound energy caused by body habitus, lung disease, hyperventilation, or tachycardia can result in non-diag- nostic images in up to 30% of patients referred for ULTRASOUND TECHNOLOGY echocardiogram (Marwick et al., 1992). Contrast offers the potential to convert many of these non-diagnostic Along with advances in microbubble technology, signifi- studies into diagnostic images by improving the ability to cant progress has been made in ultrasound imaging. The visualize the endocardial border and myocardial thicken- ability of an ultrasound wave to detect microbubbles ing (Figures 1 & 2). Cohen et al. (1998) studied 203 depends on the degree of physical change that the bub- patients with initial sub-optimal non-contrast echocar- ble undergoes. At progressively higher diagnostic ultra- diograms and found that the use of Optison, a second- sound intensity, which can be monitored by the mechan- generation contrast agent consisting of an albumen shell ical index, the bubbles oscillate with increasing intensity, filled with octafluoropropane, achieved 100% left ven- eventually breaking apart and yielding a maximum sig- tricular opacification in 89 out of 102 (87%) patients. In nal. Mechanical index is directly proportional to the addition, Optison increased the amount of well-visual- power output of the ultrasound transducer and inverse- ized left ventricular endocardium by as much as 7.6 cm at ly proportional to the square root of the transducer fre- the highest dose used. This study by Cohen et al. (1998) quency. This means that a high intensity, low frequency compared Optison to Albunex, a first-generation, air- The Einstein Journal of Biology and Medicine 3 4MEDICAL REVIEW Contrast Echocardiography FIGURE 1 Sub-Optimal Echocardiogram (without contrast) In this apical four-chamber view, the apex of the left ventricle is not visualized adequately, which prevents an accurate assessment of wall motion or wall thickening and making the evaluation of ejection fraction impossible. filled contrast agent and found
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