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.     

Intravenous Optison (FS069) enhances pulmonary vein flow velocity signals: a multicenter study

BACKGROUND: Pulmonary vein spectral Doppler signals to characterize ventricular diastolic and systolic function, though often difficult to obtain, can be enhanced using contrast agents. HYPOTHESIS: The objective of this study was to determine the efficacy of the intravenous contrast agent Optison for enhancement of Doppler signals in patients with poor signals on two-dimensional echocardiographic examinations. METHODS: Enhancement of pulmonary venous flow was evaluated in 191 patients at 0.2, 0.5, 3.0, and 5.0 ml per injection. RESULTS: Greatest contrast enhancement for right and left pulmonary veins was observed at the highest doses. At 0.5 ml, conversion from inadequate to adequate was observed in right and left pulmonary veins in 48.0 and 79.3% of patients, respectively, while any degree of improvement was 54.4 and 65.8%, respectively. The adverse event rate (6.5%) was similar to a first-generation agent. CONCLUSION: The results demonstrate that Optison is a safe and effective contrast agent for improving visualization of pulmonary Doppler signals, especially the left pulmonary vein.     

心腔内三维超声辅助下经导管射频消融治疗心房颤动伴造影剂不相容患者的临床分析

目的:探讨心腔内三维超声辅助下经导管射频消融治疗心房颤动伴造影剂不相容患者的安全性及临床疗效。方法:选择2015年1月至2017年1月期间中国医学科学院阜外医院收治的16例心房颤动伴造影剂不相容的患者。患者均未行左心房、肺静脉CT和造影,在心腔内三维超声辅助下建立左心房及肺静脉三维模型,并指导穿刺房间隔和消融导管在心脏内的操作。结果:15例患者顺利完成心房颤动射频消融,平均手术时间(96.0±14.3)min,透视时间(6.1±1.2)min,X线透视剂量(115.8±49.3)mGy,未发生心脏压塞、脑栓塞、左心房-食道瘘、肺静脉狭窄及动脉瘤等并发症及死亡。1年随访结果显示,9例患者维持窦性心律,其中阵发性心房颤动7例,持续性心房颤动2例。结论:对于心房颤动伴造影剂不相容的患者,心腔内三维超声可以替代经食道超声心动图,避免左心房造影及增强CT检查;心腔内三维超声不延长手术时间,显著减少X线曝光时间及剂量,可避免穿刺房间隔的并发症,提高穿刺准确性。     

Clinical Benefits of Using Second Generation Ultrasound Contrast Agents in Stress Echocardiography

Stress echocardiography is an established and widely used method for the noninvasive detection of myocardial ischemia. However, despite introduction of new echocardiographic technologies, such as harmonic imaging, unsatisfactory image quality limits an accurate interpretation of left ventricular (LV) wall thickening and motion in up to 30% of patients during stress echocardiography. Development and availability of second generation transpulmonary contrast agents, which opacify the LV chamber and have the capability of enhancing endocardial border definition, facilitate high-quality imaging of LV structures even in technically difficult patients. Application of a contrast agent is not associated with significant extra cost of time and manipulations because bolus injections are sufficient in most instances and harmonic imaging capabilities as well as contrast specific presets are implemented and, thus, readily available in most modern ultrasound systems. Numerous studies have demonstrated that contrast echocardiography substantially improves LV cavity visualization at rest as well as at peak stress and, therefore, increases reader confidence and decreases interobserver variability. Moreover, enhanced learning curves for interpreting stress echocardiograms have been reported in novice readers. It has been reported that compared with native stress echocardiography the use of contrast results in identification of more true positive as well as true negative results and helps to avoid unnecessary invasive procedures in a considerable number of patients. Contrast stress echocardiography may, therefore, also prove cost effective in the future. Further refinements of contrast agent properties and new developments in imaging technology will likely continue to extend the spectrum of diagnostic cardiac imaging techniques and further enhance noninvasive assessment of the complex pathophysiology of coronary artery disease. (ECHOCARDIOGRAPHY, Volume 20, Supplement 1, 2003)     

Analysis of Comparative Studies Using Different Contrast Agents for Endoscopic Retrograde Cholangiopancreatography

Abstract: Pancreatitis induced by ERCP ha been associated with numerous pathogenic factors such as a previous history of pancreatitis, acinarization, mechanical and thermal injury, medications, and lastly the type of contrast agent used. Conventional contrast agents are characterized by both ionicity and high osmolality. These traditional agents have demonstrated deleterious effects upon multiple organ systems. Newer contrast agents have been developed with properties of low osmolality and non-ionicity in efforts to their decrease potential toxic effects, This review analyzes the current literature regarding the role of different contrast agents in the incidence of ERCP related pancreatitis. Nine randomized, double-blind, prospective studies have been published comparing low and high osmolality contrast agents for ERCP. Although five studies have shown lower degrees of amylase/lipase elevation after ERCP for the low osmolality agents, only three studies demonstrated a statistically significant advantage for the reduction of clinical pancreatitis among the low osmolality agent groups. In addition, these studies also varied in terms of specific contrast agents used, inclusion and exclusion criteria, rates of acinarization, and definition of clinical pancreatitis. However, after combining all of the data from these studies, there was a statistically significant advantage in reducing ERCP induced pancreatitis for non-ionic, low osmolality agents (1.44%) compared with the ionic, high osmolality agents (7.39%) [p = 0.007] and the ionic, low osmolality agents (9.67%) [p = 0.0001]. There was no statistical difference between the ionic, high osmolality agents and the ionic, low osmolaltiy agents [p = 0.5481. This data seem to suggest that ionicity rather than osmolality may play a more significant role in the incidence of ERCP induced pancreatitis. The major disadvantage of the use of low osmolality, non-ionic agents is their relatively high cost. Overall, controversy remains about whether these newer agents should be utilized in all patients or be selectively used in only high risk patients. Presently, we utilize these agents routinely.     

Use of contrast enhancement for the assessment of left ventricular function

Endocardial visualization is essential for accurate interpretation of regional wall thickening abnormalities, which constitute the diagnostic hallmark of coronary artery disease, and for reproducible assessment of left ventricular (LV) ejection fraction. Unfortunately, in many cardiac patients, poor image quality does not allow consistent visualization, let alone automated detection, of the endocardial boundary in all segments throughout the cardiac cycle. Continuing efforts directed towards improving endocardial visualization made by both echocardiographic imaging equipment manufacturers and researchers have recently produced new objective, quantitative approaches for the assessment of global and regional LV function. Although these developments have not been integrated into routine clinical practice, they may have a positive impact on endocardial visualization and, thus, eventually improve the ability to accurately and objectively evaluate LV performance. In this review, we discuss some of the latest developments in the use of contrast for the evaluation of LV function.     

Bulls-Eye Display and Quantitation of Myocardial Perfusion Defects Using Three-Dimensional Contrast Echocardiography

Three-dimensional (3-D) myocardial contrast echocardiography (MCE) is able to derive parallel cutting planes of the left ventricle (LV). However, assessment of the site and extent of myocardial perfusion abnormalities has to rely on the reader's 3-D mental reconstruction from the tomograms, and a manual approach has to be employed for quantitative analysis. The objective of this study was to explore the display and quantitative capability of a bulls-eye format from contrast 3-D MCE in the assessment of perfusion abnormalities derived from a canine model of acute myocardial infarction (MI). Three-dimensional MCE data were acquired sequentially in a rotational scanning format during triggered harmonic imaging with an intravenous contrast agent. Reconstructed short-axis views of the LV were aligned in a bulls-eye format with the apex as the inner most ring. The total LV was divided into 120 sectors. The number of sectors with lack of contrast enhancement was used to derive the percent of the LV (%LV) with perfusion defect and was compared with the extent of MI calculated from postmortem triphenyl tetrazolium chloride (TTC) staining. The perfusion defect regions shown on bulls-eye images corresponded correctly with the territories of the occluded coronary arteries. Three-dimensional MCE perfusion defect mass (19.2 +/- 6.0 %LV) correlated well with anatomic MI mass (19.3 +/- 5.6 %LV; r = 0.92, SEE = 2.3%, mean differential = 0.1 +/- 2.4%). We conclude that bulls-eye display of contrast 3-D MCE demonstrates the site and extent of perfusion abnormalities in an easily appreciable manner. It also allows fast and accurate assessment of endangered myocardium.     

Rapid Three-Dimensional Myocardial Contrast Echocardiography: Volumetric Quantitation of Nonperfused Myocardium After Intravenous Contrast Administration

Current acquisition methods for quantitative three-dimensional myocardial contrast echocardiography require long acquisition times and therefore require the invasive administration of deposit contrast agents administered intra-arterially or into the left atrium. This study addressed the feasibility of obtaining accurate and precise quantitative volumetric measurements of nonperfused myocardium after an intravenous bolus of echocardiographic contrast agent using a rapid three-dimensional myocardial contrast echocardiographic acquisition technique. An open-chest pig model of acute left anterior descending coronary artery (LAD) occlusion was used. After LAD ligature, an intravenous bolus of contrast agent was given and images were obtained over a 12-second period using a continuously rotating transducer placed at the apical position. There was no significant microbubble destruction during the rotational acquisition period as measured by differences in mean gray scale values of apical, mid, and basal myocardial regions between the first and last image frames of acquisition. Calculated volumes of nonperfused myocardium demonstrated significant agreement and correlation (mean difference ± SD =–0.30 ± 1.71 cm³; r = 0.89; P < 0.01; y = 1.06x – 1.08) with anatomic specimens. When expressed as percent of total LV volume being nonperfused, the mean difference ± SD was 2.1 ± 3.6%, r = 0.94, P < 0.01, and y = 1.33x – 4.08. We conclude that accurate and precise measurements of nonperfused myocardium after an acute LAD coronary artery occlusion can be obtained after the intravenous bolus administration of a contrast material when a rapid 12-second acquisition with a continuously rotating transducer is used.     

Myocardial Contrast Echocardiography: Clinical Benefit and Practical Issues

Real-time bedside evaluation of myocardial perfusion after intravenous application of micro-bubbles is the ultimate goal for contrast echocardiography. Over the past decade rapid evolution has occurred in the development of contrast agents, ultrasound equipment tailored to their detection, and image interpretation. This article offers a review of the basic concepts of the technique's background, contrast agent design, and imaging technology. The major clinical indications of myocardial contrast echocardiography are evaluation of acute ischemic syndromes, diagnosis of viable myocardium following AMI, and the detection of CAD using stress contrast perfusion imaging. Furthermore, the article addresses the most significant practical problems and suggested solutions to master those problems. As major new achievements are realistic expectations for the first decade of the twenty-first century, we conclude that the coupling of a new generation of contrast agents with innovative echocardiographic instrumentation will ultimately enable the full potential of myocardial contrast echocardiography to be realized which may revolutionize modern echocardiography.     

Differences in Myocardial Contrast Produced with Transient Response Imaging When Using Intravenous Microbubbles Containing Gases of Different Molecular Weight

The purpose of this study was to determine the effect of different microbubble gases on the amount of myocardial contrast (MC) produced from intravenously (IV) injected dextrose albuinin microbubbles when using a new imaging modality termed transient response imaging (TRI). In 6 dogs (4 closed chest, 2 open chest) the peak anterior myocardial videointensity (PMVI) and visual degree of MC were determined following IV injections of equivalent doses of perfluorocarbon exposed sonicated dextrose albumin (PESDA), sulfur hexafluoride-exposed sonicated dextrose albumin (SHESDA), and room air exposed sonicated dextrose albumin (RASDA) microbubbles. TRI was performed by triggering ultrasound impulses to 1 point every one to two cardiac cycles. The PMVI produced with TRI was compared to conventional 30 Hz frame rate imaging (CI) for each gas. Visual anterior and posterior MC was evident with TRI in all six dogs using PESDA, but not in any dog with CI. Although RASDA and SHESDA did not produce MC with CI, visually evident anterior MC was seen after 7 of 8 SHESDA and 4 of 9 RASDA injections when using TRI with both gases. PESDA produced the higest peak PMVI of all three microbubbles when using TRI, while SHESDA produced a significantly higher PMVI than RASDA. We conclude that although MC can be produced with TRI using microbubble gases of lower molecular weight, the brightest and most consistent contrast is produced with fluorocarbon containing microbubbles.     

经静脉左心室腔声学造影剂的研究——与Albunex对比分析

目的：用自制１％糖蛋白声学造影剂进行经静脉左心声学造影，观察左心室显影效果，并与国外同类造影剂Ａｌｂｕｎｅｘ对比分析。方法：对６０例经常规超声心动图检查无心内分流、瓣膜反流及明显狭窄的住院病人，从右上肢肘静脉以０．０８ｍｌ／ｋｇ浓度注入１％自制糖蛋白声学造影剂。如左心室显影效果在２＋以下，则于１５分钟后以０．２２ｍｌ／ｋｇ浓度重复造影１次。结果：自制造影剂的微泡浓度为（８．１±１．３）×１０８／ｍｌ，直径：３．８±１．４μｍ，９０％小于１０μｍ，稳定性在１０个月以上（２～８°Ｃ）。与Ａｌｂｕｎｅｘ各项指标相仿，但浓度较高。６０例左心室腔全部显影，成功率１００％，其中达２＋以上者５６例，占９３％；内膜边界增强者５７例，占９５％；心室壁运动可信性增强者５２例，占８７％，高于Ａｌｂｕｎｅｘ临床使用报告的相应结果。结论：用自制的声学造影剂经静脉注射取得良好的左心室显影效果，质量和性能与Ａｌｂｕｎｅｘ相仿，可在临床安全使用。     

Role of Osmolality of Contrast Media in the Development of Post-ERCP Pancreatitis: A Metanalysis

The role of osmolality of contrast media (CM) in the development of post-ERCP pancreatitis (PEP) is debated. We therefore performed a metanalysis to determine whether osmolality affects the incidence of PEP. A literature search of English-language studies was performed using computerized databases and manual searching of abstracts and article bibliographies. Randomized controlled trials comparing the incidence of PEP associated with high- and low-osmolality contrast media (HOCM, LOCM) were considered. The outcome assessed was clinical pancreatitis as evidenced by both elevation of pancreatic enzymes and pain. Data were analyzed using logistic regression with terms for study and osmolality. Fisher's exact test was done to compare PEP rates. Homogeneity between studies was indicated by the nonsignificance of the study effect in the logistic regression model. Logistic regression also indicated no difference in PEP rates between LOCM and HOCM (P = 0.399). Comparison of PEP rates in both groups using Fisher's exact test did not indicate a difference in any individual study (all P values > 0.05). Due to the large variation of study sample sizes, we repeated the analysis by creating three study groups. The effect of osmolality was invariant to how the data were combined. The results of this metanalysis indicate that there is no significant difference between HOCM and LOCM with respect to clinical PEP.     

Harmonic imaging: echocardiographic enhanced contrast intensity and duration

The intensity and duration of contrast effect within the left ventricular cavity after an intravenous bolus of Levovist Injection were observed with both harmonic and fundamental imaging in nine patients with known or suspected coronary artery disease. Contrast intensity was assessed by a qualitative grading system (0, none; 1, weak; 2, moderate; 3, good) and by videodensitometric analysis of pixel intensity. Duration of left ventricular contrast effect was determined by measuring time from the initial visual appearance of contrast agent to its disappearance. The mean increase in pixel intensity within the left ventricular cavity from precontrast to peak contrast was significantly greater for second harmonic than for fundamental imaging (25.5 vs 7.1; P < 0.012). The mean contrast intensity qualitative score with harmonic imaging was higher (2.6 ± 0.73 vs 1.2 ± 0.44; P < 0.01) and the duration of contrast effect was longer (242 ± 131 s vs 53 ± 33 s; P < 0.004). Second harmonic imaging significantly enhanced contrast intensity and prolonged visible duration of contrast effect after a peripheral venous injection of Levovist.     

Effect of a Stabilized Microbubble Echo Contrast Agent on Hemolysis of Human Erythrocytes Exposed to High Intensity Pulsed Ultrasound

Microbubble contrast agents have been shown to enhance ultrasonic cell lysis in vitro when exposed to continuous-wave ultrasound having spatial peak temporal average (SPTA) intensities of a few W/cm². The response is strongly dependent upon the hematocrit (HCT) of the cell sample; detectable cell lysis essentially disappears as the HCT approaches 5%-10%. This study was conducted to determine whether high intensity pulsedsound is an effective lytic agent in the presence of preexisting potential cavitation nuclei (Albunex® contrast agent). Human erythrocytes weresuspended in autologous plasma to HCTs ranging from 1%–40%. Suspensions were exposed or sham exposed for 60 seconds to focused, pulsed ultrasound. The pulse duration was 1 msec, and the pulse repetition frequency was 20 Hz. The pressure amplitudes, spatial peak pulse average (SPPA) intensity, and SPTA intensity were 4.7 MPa peak positive pressure, -2.7 MPa peak negative pressure, 420 W/cm², and 8.5 /cm², respectively. Samples were exposed to ultrasound in a dialysis membrane exposure vessel rotating at 200 rpm. When included in the erythrocyte samples, the Albunex concentration was 35 μL/mL suspension. Significant ultrasound-induced hemolysis in the absence of Albunex was observed only at the lowest HCT value tested (1%). In the presence of Albunex significant cell lysis was observed at all tested HCT values. The relative fraction of cells lysed by the combination of ultrasound exposure and Albunex diminished with increasing HCT, but the number of cells lysed per sample was nearly constant over the range of 5%–40% HCT. The ultrasound exposure parameters used in this study differ substantially from those associated with diagnostic imaging equipment; it is not valid to infer from the present results that the use of Albunex in diagnostic applications will induce or enhance hemolysis in vivo.     

Problems with Evaluation of Micro-Pore Size in Silicon Carbide Using Synchrotron X-ray Phase Contrast Imaging

We report near- and far-field computer simulations of synchrotron X-ray phase-contrast images using a micropipe in a SiC crystal as a model system. Experimental images illustrate the theoretical results. The properties of nearly perfect single crystals of silicon carbide are strongly affected by μm-sized pores even if their distribution in a crystal bulk is sparse. A non-destructive technique to reveal the pores is in-line phase-contrast imaging with synchrotron radiation. A quantitative approach to evaluating pore sizes is the use of computer simulations of phase-contrast images. It was found that near-field phase-contrast images are formed at very short distances behind a sample. We estimated these distances for tiny pores. The Fresnel zones did not provide any information on the pore size in the far-field, but a contrast value within the first Fresnel zone could be used for simulations. Finally, general problems in evaluating a micro-pore size via image analysis are discussed.     

Contrast echocardiography for myocardial perfusion imaging using intravenous agents: progress and promises.

AIMS: This article is a convenient overview to assist the interested echocardiographist towards acquiring his own experience in the field of myocardial perfusion imaging using intravenous contrast agents. This goal is now pursued in many centres, since contrast echo holds the advantages of cardiac ultrasound (non-invasiveness, high spatial and temporal resolution, wide availability, use of non-ionizing radiation), and because a variety of transpulmonary agents-together with a spectrum of imaging modalities-are becoming available. METHODS AND RESULTS: Many technical considerations need to be addressed for optimal myocardial perfusion imaging: characteristics of the contrast medium (air-filled or perfluorocarbon filled and/or encapsulated agents), modality of administration (bolus injection or continuous infusion) and interaction between microbubbles and ultrasound (dependency on power output). Moreover, intermittent harmonic imaging, intermittent harmonic power Doppler, pulse inversion and amplitude modulation imaging have all been developed to enhance microbubble detection over myocardial tissue. These new acquisition modalities also yield specific artifacts impacting on myocardial perfusion assessment. Finally, acute myocardial infarction and chronic ischaemic heart disease (at baseline and during stress) are the most studied clinical models for perfusion imaging with contrast echo, and are reviewed in this article. CONCLUSION: Perfusion imaging with intravenous contrast agents has never been as close to widespread clinical use as it is today, but many methodological issues remain unsettled before the wish of the contrast echocardiographist comes true: that is, a cheap, user-friendly and widely available technology that would disclose new information in echocardiography.