Local drug and gene delivery through microbubbles.

Ultrasound contrast agents (microbubbles) lower the threshold for cavitation by ultrasound energy. Ultrasound microbubbles may be used as cavitation nuclei for drug and gene delivery. By tailoring the physical properties of microbubbles and coating materials, drugs and genetic drugs can be incorporated into ultrasound contrast agents. As the microbubbles enter the region of insonation, the microbubbles cavitate, locally releasing the therapeutic agents. Cavitation also causes a local shockwave that improves cellular uptake of the therapeutic agent. As a result of the human genome project and continuing advances in molecular biology, many therapeutic genes have been discovered. In the cardiovascular system, gene therapy has the potential to improve myocardial vascularization and ameliorate congestive heart failure. For successful development of clinical gene therapy, however, effective gene delivery vectors are needed. Ultrasound contrast agents can be used to develop new, more effective vectors for gene delivery. Transthoracic ultrasound can be focused on the heart so that an intravenous injection of gene-bearing microbubbles will deliver genes relatively selectively to the myocardium. Using this technique, we have produced high levels of transgene expression in the insonated region of the myocardium. This new technology, using microbubbles and ultrasound for drug and gene delivery, merits further study and development.

Power Doppler dual-frame triggering of myocardial contrast echocardiography: a quantitative video intensity analysis.

AIM: The purpose of this study was to define the pattern of myocardial contrast observed during triggered dual-frame power Doppler imaging. METHODS AND RESULTS: Ten patients with no previous history of myocardial infarction underwent a continuous intravenous infusion of Optison at 0.5 ml/min. Triggered, sequential dual-frame power Doppler imaging was performed from an apical four-chamber view using a prototype Acuson Sequoia imaging system. The average triggering interval was once every four cardiac cycles, and the average interval between sequential frames was 50 msec. Video intensity analysis was performed in five myocardial regions of interest, and the percent decrease in video intensity of the destruction frames in each region of interest was determined by subtracting the destruction frame video intensity from the fill frame video intensity. The percent decrease in video intensity varied significantly by myocardial location (P < 0.001), with greater destruction seen in the apical than in the basal regions. CONCLUSION: This preliminary study demonstrates that power Doppler dual-frame triggering produces nonuniform decreases in video intensity, which likely represent nonuniform microbubble destruction. These results have important implications for the interpretation of myocardial perfusion patterns using this technique.

Ultraharmonic myocardial contrast imaging: in vivo experimental and clinical data from a novel technique.

Myocardial contrast echocardiography (MCE) with high-mechanical-index (MI), triggered harmonic imaging is the best-established technique to date for the assessment of myocardial perfusion. A high signal-to-noise ratio, which is significantly influenced by precontrast tissue signals, is an important prerequisite. Our goal was to evaluate the efficacy of ultraharmonic MCE, a technique that rejects tissue signals by receiving signals beyond the second but below the third harmonic. Imaging was performed in 6 closed-chest dogs and in 15 healthy volunteers (11 of whom also had dipyridamole stress). Analyses of videointensity (VI) confirmed uniformly low precontrast tissue VI, a significant increase of postcontrast VI (before and after dipyridamole), and a significant decrease in VI after microbubble destruction. We conclude that ultraharmonic MCE produces low precontrast tissue signals, thus optimizing postcontrast myocardial opacification, and exhibits efficient microbubble destruction with use of multiple-frame triggering. Thus this new technique opens up a new possibility of further optimizing coronary microcirculation imaging with microbubbles.

Real-time myocardial blood flow imaging in normal human beings with the use of myocardial contrast echocardiography.

Triggered myocardial contrast echocardiography (MCE) has been used successfully to quantify myocardial blood flow and assess coronary stenosis in animal models, but practical considerations have limited its broad clinical use. Real-time MCE may have practical advantages to assess perfusion and real time myocardial blood flow in human beings. We compared real-time MCE with triggered imaging in 23 normal human volunteers by using an investigational ultrasound contrast agent (DMP-115) and a commercially available ultrasound platform (Acuson Sequoia). Peak myocardial opacification (reflecting myocardial blood volume) after contrast infusion was quantified digitally in gray scale units (GU). In 13 subjects, myocardial blood flow reserve was assessed during dipyridamole infusion with the use of intermittent destruction-replenishment techniques. Real-time MCE resulted in a 30- to 45-GU increase from baseline compared with a 20- to 70-GU increase with triggered imaging. Real-time MCE showed no statistical difference in opacification (P = .131 by analysis of variance) among any of the myocardial regions of interest. Triggered imaging resulted in heterogeneous opacification among the regions of interest (P < .05 by analysis of variance). Dipyridamole did not significantly change peak myocardial opacification (myocardial blood volume) for either technique. Quantification of flow reserve revealed that myocardial blood flow reserve for the dipyridamole group was 3.6 +/- 0.4 (mean +/- 1 standard error of the mean). Real-time MCE is feasible in normal human volunteers and provides homogenous opacification of the myocardium. Furthermore, quantification of myocardial blood flow with real-time MCE in normal human beings produces results that are consistent with the known physiology of the coronary microcirculation.

Gene delivery using ultrasound contrast agents.

With the human genome product and continuing advances in molecular biology many therapeutic genes have been discovered. In the cardiovascular system, gene therapy has the potential to improve myocardial vascularization and ameliorate congestive heart failure. For successful development of clinical gene therapy, however, effective gene delivery vectors are needed. Ultrasound contrast agents can be used to develop new, more effective vectors for gene delivery. Ultrasound contrast agents lower the threshold for cavitation by ultrasound energy. Using physical properties of microbubbles and coating materials, genetic drugs have been incorporated into ultrasound contrast agents. Gene-bearing microbubbles can be injected IV and ultrasound energy applied to the target region. As the microbubbles enter the region of insonation, the microbubbles cavitate, locally releasing DNA. Cavitation also likely causes a local shockwave that improves cellular uptake of DNA. With transthoracic ultrasound, using commercially available diagnostic ultrasound system and an IV injection of gene-bearing microbubbles, high levels of transgene expression are observed in the insonated region of the myocardium. This new technology using microbubbles and ultrasound for gene delivery merits further study and development.

Power Doppler myocardial contrast echocardiography using an improved multiple frame triggered Harmonic Angio technique.

Although B-mode harmonic, intermittent-triggered myocardial contrast echocardiography (MCE) is a well-established technique, a variety of MCE techniques have been introduced recently to improve myocardial opacification. One such technique uses a power Doppler method in conjunction with multiple frame triggering (MFT), but has been limited by nonuniform microbubble destruction and blooming as well as motion artifacts. Utilizing two different contrast agents, Definity and Optison, we tested the feasibility of an improved version of Harmonic Angio MFT that utilizes a lower transmit frequency, reduced packet size, and more stringent wall filter in normal volunteers and in patients with known perfusion defects. The results showed that Harmonic Angio MFT produced fill frames with readily visible opacification and destruction frames with little visible opacification. The patterns of opacification also correlated with the expected perfusion patterns in both groups of subjects. Thus, Harmonic Angio MFT appears to be a promising new MCE technique.

Balloon atrial septostomy in end-stage pulmonary hypertension guided by a novel intracardiac echocardiographic transducer.

Blade and balloon atrial septostomy has been used to reduce cardiopulmonary symptoms and as a bridge to lung or heart lung transplant in primary pulmonary hypertension. Due to severe right atrial dilatation and resultant loss of anatomical landmarks, the procedure is technically difficult, and the reported postprocedure mortality rate varies between 5% and 50%. Among others, marked systemic desaturation and systemic hypotension presumably secondary to an excessively large atrial septal defect have been reported as causes of postprocedure death. We report a case where a novel intracardiac catheter-based phased-array 5.5--10 MHz transducer with spectral and color-flow Doppler capabilities was used to assist a balloon atrial septostomy and to obtain hemodynamic data in a patient with end-stage pulmonary hypertension.

Three-dimensional echocardiography of left atrial appendage thrombus.

Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) in evaluating the left atrial appendage (LAA) as a potential cardiac source of embolus in patients with stroke. We describe two such patients in whom a TEE and subsequently a three-dimensional (3-D) reconstruction of the LAA were performed. These case reports show that 3-D echocardiography provides better visualization of LAA anatomy, and that a 3-D description of LAA morphology may be the basis of describing normal and abnormal LAA.

Imaging techniques for the myocardial contrast echocardiography.

Myocardial contrast echocardiography (MCE) has seen a significant evolution of its clinical application with the advent of newer microbubbles suitable for intravenous administration and development of ultrasound imaging technologies. These new technologies, which are specifically aimed to improve our ability to visualize these microbubbles in the myocardial circulation, require the user to have an understanding of the basis for optimal use in the clinical setting. The discussion below aims to provide a summary of these new microbubble technologies.

Echocardiographic analysis of regional and global left ventricular shape in Chagas' cardiomyopathy.

Chagas' heart disease is a common form of cardiomyopathy in Latin America and an important cause of cardiac morbidity and mortality there. Left ventricular (LV) apical aneurysm and LV dysfunction are frequent findings in Chagas' cardiomyopathy. Because cardiac shape has important implications for LV function, we sought to characterize regional and global changes in LV geometry in Chagas' heart disease. Quantitative shape analysis was performed on 2-dimensional echocardiograms from 43 patients with Chagas' cardiomyopathy. Regional shape was quantitated by measuring endocardial curvature and global shape was evaluated by Fourier shape analysis of the endocardial contour. Data from 22 age- and sex-matched normal test subjects were used for comparison. Regional shape analysis demonstrated decreased apical curvature (consistent with blunting of normal apical shape) in the group with Chagas' disease compared with controls (apical 2-chamber view: 19 +/- 1 vs 24 +/- 1 [p = 0.0039] at end-diastole and 20 +/- 2 vs 29 +/- 3 [p = 0.0019] at end-systole). Fourier shape power index was decreased in the Chagas' group, consistent with a more spherical ventricle (apical 2-chamber view: 9 +/- 1 vs 17 +/- 2 [p <0.0001] at end-diastole and 12 +/- 1 vs 35 +/- 3 [p <0.0001] at end-systole). Shape changes among the population with Chagas' disease were further evaluated in those with end-diastolic volumes equal to or greater than the median for the group (104 ml) and those < 104 ml. Global shape did not differ between patients with dilated ventricles and those with relatively nondilated ventricles. Diastolic Fourier shape power index = 8 +/- 2 in dilated ventricles compared with 9 +/- 5 in nondilated ventricles (p = 0.53); systolic Fourier shape power index = 10 +/- 2 in dilated versus 14 +/- 2 in nondilated ventricles (p = 0.15) (apical 2-chamber view). In Chagas' cardiomyopathy, LV apical deformation results in disruption of the optimal global prolate-ellipsoid shape, even in patients with relatively preserved LV volumes.

Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms.

OBJECTIVES: This study was performed to compare the safety and efficacy of intravenous 2% dodecafluoropentane (DDFP) emulsion (EchoGen) with that of active control (sonicated human albumin [Albunex]) for left ventricular (LV) cavity opacification in adult patients with a suboptimal echocardiogram. BACKGROUND: The development of new fluorocarbon-based echocardiographic contrast agents such as DDFP has allowed opacification of the left ventricle after peripheral venous injection. We hypothesized that DDFP was clinically superior to the Food and Drug Administration-approved active control. METHODS: This was a Phase III, multicenter, single-blind, active controlled trial. Sequential intravenous injections of active control and DDFP were given 30 min apart to 254 patients with a suboptimal echocardiogram, defined as one in which the endocardial borders were not visible in at least two segments in either the apical two- or four-chamber views. Studies were interpreted in blinded manner by two readers and the investigators. RESULTS: Full or intermediate LV cavity opacification was more frequently observed after DDFP than after active control (78% vs. 31% for reader A; 69% vs. 34% for reader B; 83% vs. 55% for the investigators, p < 0.0001). LV cavity opacification scores were higher with DDFP (2.0 to 2.5 vs. 1.1 to 1.5, p < 0.0001). Endocardial border delineation was improved by DDFP in 88% of patients versus 45% with active control (p < 0.001). Similar improvement was seen for duration of contrast effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to affect patient management. There was no difference between agents in the number of patients with adverse events attributed to the test agent (9% for DDFP vs. 6% for active control, p = 0.92). CONCLUSIONS: This Phase III multicenter trial demonstrates that DDFP is superior to sonicated human albumin for LV cavity opacification, endocardial border definition, duration of effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to influence patient management. The two agents had similar safety profiles.

Ruptured sinus of Valsalva aneurysm simulating endocarditis.

A previously healthy, 31-year-old man was evaluated in the emergency department after being violently assaulted. A harsh, continuous murmur was noted on physical examination. Transthoracic and transesophageal echocardiograms were interpreted as showing a ruptured sinus of Valsalva aneurysm with a shunt into the right atrium and a tricuspid valve vegetation. The patient was treated with antibiotics for presumed endocarditis. Subsequent echocardiographic and surgical evaluation showed no evidence of past or present endocarditis. Rather, the sinus of Valsalva aneurysm and rupture gave the appearance of a valvular mass. This report shows some of the potential pitfalls in the delineation of abnormalities related to sinus of Valsalva aneurysms and rupture.

Three-dimensional echocardiographic evaluation of aortic disorders with rotational multiplanar imaging: experimental and clinical studies.

Transesophageal echocardiography has become a highly valuable method to assess aortic disorders. With this method, however, aortic disease has been visualized only in two-dimensional views. Advances in computer technology have introduced three-dimensional (3D) echocardiography as a developing modality in cardiac imaging. Previous efforts to obtain 3D reconstructions of the aorta, by various techniques, had limited clinical applicability. In this study we attempted to explore the feasibility and potential of 3D reconstructions of the aorta employing a widely used multiplane transesophageal imaging technique in an experimental setting and in patients. In the in vitro study, we created 35 lesions in 28 pig aortic trees (15 aortic dissections, five saccular aneurysms, five coarctations, five atheromas, and five clots within dissections). Suspending these specimens in a water bath, sequential two-dimensional images were acquired over a 180-degree rotation with a commercially available multiplane transesophageal probe and ultrasound system with a 3D software package. Data processing (digital reformation, interpolation, and segmentation) and 3D display were accomplished on an off-line computer system. 3D reconstructions were achieved and displayed in wire-frame, surface-rendered, and volume-rendered images. These 3D reconstructions corresponded well with the actual anatomic specimens in delineating the various pathologic findings. In patient studies, we collected a total of 36 studies in both adults and children with a mean age of 44.5 years (range 1 month to 82 years). In addition to normal aortas (n = 13), the spectrum of abnormalities studied included six atheromatous lesions, four aortic dissections, 10 coarctations, one aneurysm with a thrombus, and one dilated aortic root. We were able to accomplish volume-rendered 3D images depicting the aortic lesions in their true form that could be viewed in many different perspectives in all patients. We conclude that 3D echocardiography is able to display the aorta and aortic disease in a realistic manner. Although this modality still has limitations, further improvements in computer and ultrasound technology would strengthen 3D echocardiography as a clinically viable diagnostic tool, in the evaluation of aortic disorders.

Automatic backscatter analysis of regional left ventricular systolic function using color kinesis.

Assessment of regional wall motion by 2-dimensional echocardiography can be performed by either semiquantitative wall motion scoring or by quantitative analysis. The former is subjective and requires expertise. Quantitative methods are too time-consuming for routine use in a busy clinical laboratory. Color kinesis is a new algorithm utilizing acoustic backscatter analysis. It provides a color encoded map of endocardial motion in real time. In each frame a new color layer is added; the thickness of the color beam represents endocardial motion during that frame. The end-systolic image has multiple color layers, representing regional and temporal heterogeneity of segmental motion. The purpose of this study was to validate the use of color kinesis for semiquantitative analysis of regional left ventricular systolic function and quantitatively in measurement of endocardial excursion. Semiquantitative wall motion scoring was performed in 18 patients using both 2-dimensional echo and color kinesis. Scoring was identical in 74% of segments; there was 84% agreement in definition of normal vs. abnormal. There was less interobserver variability in wall motion scoring using color kinesis. Endocardial excursion was quantified in 21 patients. 70% of the imaged segments were suitable for analysis. Correlation between 2-dimensional echocardiographic measurements and color kinesis was excellent, r = 0.87. The mean difference in excursion as measured by the 2 methods was -0.05 +/- 2.0 mm. In conclusion, color kinesis is a useful method for assessing regional contraction by displaying a color map of systolic endocardial excursion. This algorithm may improve the confidence and accuracy of assessment of segmental ventricular function by echocardiographic methods.

Volumetric multiplexed transmission holography of the heart with echocardiographic data.

Three-dimensional imaging enhances delineation of cardiac anatomy and function. Currently, three-dimensional echocardiography involves complex rendering techniques to imply depth in a given image. Also, display of the final images on a video monitor neutralizes the volume information of the object. A hologram is a true, three-dimensional replica of the original object and does not entail complex data processing. Holography has not been used previously in cardiovascular imaging. In this experiment, 11 excised mammalian whole hearts and five isolated left ventricles were imaged in a water bath. Parallel, tomographic, echocardiographic images comprised the data source from which holograms were obtained by the technique of multiplexed holography. Holograms were mounted on a holographic film and viewed in a special viewing box. High-quality holograms were obtained from every data set. Excellent gray-scale discrimination allowed crisp visualization of cardiac structures and simulated diseases. Electronic sectioning and various projections optimized viewing of the three-dimensional anatomy in surgical orientations. Thus holograms can be produced from tomographic cardiac ultrasound data and could open a new avenue in three-dimensional echocardiography.

Biplane and multiplane transesophageal echocardiography: methodology and echo-anatomic correlations.

Transesophageal echocardiography (TEE) is one of the most significant developments in cardiology and cardiac imaging in the last decade. While monoplane TEE clearly showed the advantages of imaging from the esophagus, biplane TEE was the next important step forward. The combination of transverse and longitudinal axis images served to provide incremental information about various cardiac pathologies. Multiplane TEE is a further advancement that allows continuous visualization of cardiac anatomy by electronic or manual steering of the ultrasound beam through 180 degrees. The intermediate views obtained by beam steering provides an unlimited perspective of normal and abnormal cardiac anatomy. This ability to view cardiac structures in multiple planes aids the understanding of the spatial arrangement of normal cardiac structures and complex disorders of cardiac anatomy. Multiplane TEE technology also eases the examination by reducing the need for probe manipulation. The ability to obtain multiplane images in a sequential manner lays the foundation for three-dimensional imaging of the heart. Ongoing developments in transducer technology should further strengthen the clinical role of TEE.