Contrast echocardiography

Myocardial contrast echocardiography (MCE) is a noninvasive imaging technique that relies on the ultrasound detection of microbubble contrast agents. These agents are confined to the intravascular space thereby producing signal enhancement from the blood pool. This review encompasses many of the key concepts regarding the clinical application of MCE. The first section focuses on the composition, safety, and biokinetics of ultrasound contrast agents. Then we discuss new ultrasound imaging methodology that has been developed to enhance detection of contrast agent and to assess perfusion at the tissue level. Next, the clinical applications of contrast ultrasound are reviewed. These include enhancement of the cardiac chambers for better assessment of cardiac function and masses, myocardial perfusion imaging for the detection of coronary artery disease, and the assessment of myocardial viability and microvascular reflow. Finally, we discuss some of the future applications for MCE, which include molecular imaging of disease and drug/gene delivery. The overall aim of the review is to update the clinician on state-of-the-art MCE and how it can be applied in patients with cardiovascular disease.     

Real-Time Contrast Echo Assessment of Myocardial Perfusion at Low Emission Power: First Experimental and Clinical Results Using Power Pulse Inversion Imaging

Power pulse inversion (PPI) has been developed for echocontrast specific imaging in order to reduce destruction of microbubbles. The purpose of this study was to evaluate PPI for real-time contrast echocardiography. Therefore, in vitro studies in a physiological flow-phantom and clinical examinations in patients with coronary artery disease were performed. The in vitro rersults of this study indicate that PPI allows real-time imaging at low emission power and is almost nondestructive to contrast microbubbles of Definity. At this low emission power a strong linear relationship between the dosage of the contrast agent and the resulting PPI signal intensity was found (R = 0.998, p < 0.001). In the clinical examinations real-time imaging using low mechanical index PPI resulted in strong myocardial signals and a complete filling of the cavities indicating absence of bubble destruction. Most striking was the ability of PPI to display myocardial thickening and wall motion simultaneously with the assessment of myocardial contrast replenishment following ultrasound induced bubble destruction by high power frames. We conclude that PPI allows nondestructive contrast imaging both in experimental and clinical settings. Therefore, real-time imaging of myocardial perfusion and real-time assessment of contrast replenishment following ultrasound induced destruction of microbubbles is feasible. Moreover, PPI allows simultaneous assessment of perfusion and myocardial function.     

Contrast Ultrasound,Sonothrombolysis and Sonoperfusion in Cardiovascular Disease: Shifting to Theragnostic Clinical Trials

Contrast ultrasound has a variety of applications in cardiovascular medicine, both in diagnosing cardiovascular disease as well as providing prognostic information. Visualization of intravascular contrast microbubbles is based on acoustic cavitation, the characteristic oscillation that results in changes in the reflected ultrasound waves. At high power, this acoustic response generates sufficient shear that is capable of enhancing endothelium-dependent perfusion in atherothrombotic cardiovascular disease (sonoperfusion). The oscillation and collapse of microbubbles in response to ultrasound also induces microstreaming and jetting that can fragment thrombus (sonothrombolysis). Several preclinical studies have focused on identifying optimal diagnostic ultrasound settings and treatment regimens. Clinical trials have been performed in acute myocardial infarction, stroke, and peripheral arterial disease often with improved outcome. In the coming years, results of ongoing clinical trials along with innovation and improvements in sonothrombolysis and sonoperfusion will determine whether this theragnostic technique will become a valuable addition to reperfusion therapy.     

Real-time perfusion imaging: a new echocardiographic technique for simultaneous evaluation of myocardial perfusion and contraction

Myocardial contrast echocardiography (MCE) with high acoustic energy and triggered harmonic imaging is the best established ultrasound technique to date for the assessment of myocardial perfusion. With this technique, however, the ultimate goal of MCE (noninvasive real-time simultaneous assessment of myocardial perfusion and function after an intravenous injection of microbubbles) is not met. Recently, technologic advances have enabled myocardial opacification to be visualized during low-energy real-time imaging. During real-time perfusion imaging, wall motion and myocardial perfusion may be assessed simultaneously, obviating the need of the presently time-consuming combination of different imaging modalities. When high-energy ultrasound bursts are periodically transmitted to produce bubble destruction during low-power imaging, the consecutive frames after destruction delineate the restoration of contrast intensity. Microbubble replenishment rate and peak intensity may be determined subsequently, and provide reliable quantitative parameters of regional microcirculatory flow. This review will introduce the modalities used for real-time perfusion imaging with focus on power pulse inversion imaging and quantitative analysis. Furthermore, we will describe the clinical role the technique may have in the identification of coronary artery disease, quantification of coronary stenosis severity, assessment of myocardial viability, determination of infarction size, and evaluation of reflow and no- or low-reflow after acute myocardial infarction.     

Instrumentation for contrast echocardiography

A number of new imaging methods have been developed specifically for use with ultrasound contrast agents. These methods rely on the peculiar behavior of microbubbles in an ultrasound field. At low incident acoustic pressures (reflected by the mechanical index, MI) microbubbles emit harmonics. These can be detected using harmonic or pulse inversion imaging. At higher MI, bubbles are disrupted, emitting a strong, nonlinear echo. Harmonic power Doppler methods are able to detect this echo, offering the most sensitive method for the detection of microbubble at the perfusion level. Although the first images of myocardial perfusion were made using this disruption method, it requires intermittent imaging with interframe intervals of up to 6 heart beats. Pulse inversion Doppler imaging is a newer method that is able to detect the nonlinear component of bubble echoes at a very low MI, thereby making possible real-time myocardial perfusion imaging. An understanding of the behavior of bubbles during an imaging examination is an essential prerequisite to its success in clinical practice.     

Detection and quantification of coronary stenosis severity with myocardial contrast echocardiography

The development of microbubble contrast agents and new imaging modalities now allows the assessment of myocardial perfusion during echocardiography. These microbubbles are excellent tracers of red blood cell kinetics. Apart from providing a spatial assessment of myocardial perfusion, myocardial contrast echocardiography (MCE) can also be used to quantify the 2 specific components of myocardial blood flow-flow velocity and myocardial blood volume. The method to quantify myocardial blood flow velocity is based on rapid destruction of microbubbles by ultrasound, and subsequent assessment of the rate of replenishment of microbubbles into the myocardial microcirculation within the ultrasound beam elevation. Assessment of steady state myocardial video intensity (VI) provides a measure of myocardial or capillary blood volume. Perfusion defects that develop distal to a stenosis during hyperemia are therefore due to capillary derecruitment. We have shown that the degree of derecruitment (and therefore the severity of a perfusion defect) is proportional to stenosis severity. Because the capillary bed also provides the greatest resistance to hyperemic flow, decreases in capillary blood volume distal to a stenosis during hyperemia result in increases in microvascular resistance, which is the mechanism underlying the progressive decrease in flow reserve in the presence of a stenosis. Consequently, both the severity of a perfusion defect and quantification of abnormal myocardial blood flow reserve on MCE can be used to determine stenosis severity. As imaging methods with MCE continue to be refined, the optimal imaging algorithms for clinical practice still need to be determined. MCE, however, holds promise as a noninvasive, instantaneous, on-line method for the detection and quantification of coronary artery disease.     

Imaging of Myocardial Perfusion with SonoVue™ in Patients with a Prior Myocardial Infarction

Myocardial contrast echocardiography (MCE) is an evolving noninvasive imaging technique that can be used to assess regional myocardial perfusion. MCE relies upon the detection of nonlinear ultrasound signal from gas-filled microbubbles during their microvascular transit, resulting in tissue opacification. Provided that the relation between myocardial microbubble concentration and video intensity (VI) is within the linear range, VI measured from any myocardial region reflects the relative tissue concentration of microbubbles, which is influenced by three factors: (1) microbubble concentration in blood; (2) the myocardial blood volume fraction; and (3) microbubble destruction that occurs within the ultrasound beam. In this article, we discuss how these three factors may influence myocardial perfusion information provided by MCE and highlight the importance of image processing. In order to illustrate these concepts, we examine data obtained during perfusion imaging in patients with prior myocardial infarction using intermittent harmonic imaging at various ultrasound pulsing intervals (PIs) during bolus and continuous venous infusions of a second-generation microbubble agent (SonoVue™). Our results suggest that evaluation of resting perfusion is most accurate when both myocardial blood volume and blood velocity are assessed. This information is provided only with continuous infusions of microbubbles during imaging protocols that vary the ultrasound PI.     

Contrast echocardiography

The intravenous application of an ultrasound contrast agent induces enhanced display of blood in all its pathways. Within cardiology, this principle is mainly utilized for signal enhancement of color Doppler and spectral Doppler in order to improve quantification of congenital and acquired valvular lesions and also for improved endocardial delineation during stress tests and in the evaluation of LV function. The new domaine of myocardial perfusion imaging by contrast echocardiography, however, needed profound technical developments before realization of the clinical potential could even be conceived. These are based on the complex reactions of microbubbbles in the acoustic field in order to allow the sensitive and bubble specific display of intramyocardial contrast effects. The presently available acquisition techniques, second harmonic imaging and harmonic power Doppler, demonstrate significant improvements if compared to traditional fundamental 2-d echocardiography; however, they are still subjected to important limitations. There are many anatomical, physiological, and technical reasons for insufficient display of intramyocardial microbubbles, the most important one being attenuation. It is hoped that the most recently developed imaging modality, pulse inversion technique, allows the necessary diagnostic accuracy and reproducibility in myocardial perfusion imaging.     

Assessment of inflammation with contrast ultrasound

Future clinical applications of contrast-enhanced ultrasound will likely expand beyond the assessment of microvascular perfusion. One promising direction is the development of site-targeted microbubbles that are retained within regions of a specific disease process and thereby allow phenotypic characterization of tissue. Inflammation is an ideal disease state for targeting with microbubbles because the pathophysiologic processes that initiate and support the inflammatory response occur within the microcirculation, where microbubbles reside. This review describes methods that have been used to direct microbubbles to regions of inflammation. These methods rely on either (1) intrinsic properties of albumin or lipid microbubbles that promote their attachment to leukocyte adhesion molecules, or (2) conjugation of monoclonal antibodies or other ligands to the microbubble surface that recognize specific endothelial cell adhesion molecules. This review also considers ultrasound imaging methods that may be used to detect microbubbles retained within inflamed tissue.     

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.     

Myocardial perfusion imaging using contrast echocardiography

BACKGROUND: Intense work during the last two decades has brought forth the use of myocardial contrast echocardiography to the clinical threshold for the diagnosis and evaluation of coronary artery disease. CLINICAL USE: A number of ultrasound contrast agents have been developed that act as red blood cell tracers and display myocardial perfusion when imaged by dedicated ultrasound imaging modalities. A considerable amount of experimental and clinical research has shown that myocardial contrast echocardiography can aid in the recognition of acute and chronic myocardial infarction, viable myocardium, and functionally significant coronary stenoses. Comparison of this technique to nuclear imaging and coronary arteriography has demonstrated excellent diagnostic accuracy in the evaluation of various coronary syndromes. Optimal practice of perfusion imaging requires a thorough knowledge of microbubble characteristics and imaging modalities, as well as good experience in the method. PERSPECTIVES: The technique continues to evolve from intermittent gated examination to real-time perfusion imaging that allows evaluation of both perfusion and functional parameters. The opportunity to target sites of pathology with specially engineered microbubbles could also aid in many therapeutic applications besides diagnostic imaging.     

Contrast echocardiography in Canada: Canadian Cardiovascular Society/Canadian Society of Echocardiography position paper

As an adjunct to transthoracic, transesophageal and stress echocardiography, contrast echocardiography (CE) improves the diagnostic accuracy of technically suboptimal studies when used in conjunction with harmonic imaging. Intravenous ultrasound contrast agents are indicated for left ventricular (LV) opacification and improvement of LV endocardial border delineation in patients with suboptimal acoustic windows. Demonstrated benefits of CE include improvement in the accuracy of LV measurements, regional wall motion assessment, evaluation of noncompaction cardiomyopathy, thrombus detection, Doppler signal enhancement and conjunctive use with stress echocardiography. Studies have shown the value of CE in the assessment and quantification of myocardial perfusion, and recent clinical trials have suggested a role for contrast perfusion imaging in the stratification of patients with suspected coronary artery disease. While it adds some time and cost to the echocardiographic study, CE frequently obviates the need for additional specialized, expensive and less accessible cardiac investigations, and allows for prompt and optimal subsequent patient management. Despite its proven advantages, CE is presently underused in Canada, and this situation will, unfortunately, not improve until several barriers to its use are overcome. Resolving these important hurdles is vital to the future of CE and to its eventual implementation into clinical practice of promising contrast-based diagnostic and therapeutic applications, including the assessment of perfusion by myocardial CE.     

Contrast Ultrasound and Targeted Microbubbles: Diagnostic and Therapeutic Applications for Angiogenesis

Angiogenesis represents the formation of new capillaries from existing vasculature, and as such plays a critical role in the response to ischemia in the setting of chronic coronary artery and peripheral vascular disease. Recent technological advances in non-invasive imaging modalities now allow the molecular imaging of angiogenesis. One such technique is contrast-enhanced ultrasound using microbubbles targeted against molecular markers of the angiogenic process. The ability to non-invasively image the angiogenic process would be useful in risk stratifying patients with arterial occlusive disease and would aid in the evaluation of new therapies to promote angiogenesis in ischemic cardiac and skeletal muscle. Furthermore, ultrasound technologies have also been developed that allow targeted angiogenic gene therapy using high-power ultrasound and DNA-bearing microbubbles. This review will focus specifically on recent advances in (1) contrast-enhanced ultrasound molecular imaging techniques for the evaluation of angiogenesis and (2) ultrasound-mediated gene delivery for therapeutic angiogenesis, techniques that have potential for translation to clinical practice.     

Microbubbles and ultrasound: from diagnosis to therapy.

The development of ultrasound contrast agents, containing encapsulated microbubbles, has increased the possibilities for diagnostic imaging. Ultrasound contrast agents are currently used to enhance left ventricular opacification, increase Doppler signal intensity, and in myocardial perfusion imaging. Diagnostic imaging with contrast agents is performed with low acoustic pressure using non-linear reflection of ultrasound waves by microbubbles. Ultrasound causes bubble destruction, which lowers the threshold for cavitation, resulting in microstreaming and increased permeability of cell membranes. Interestingly, this mechanism can be used for delivery of drugs or genes into tissue. Microbubbles have been shown to be capable of carrying drugs and genes, and destruction of the bubbles will result in local release of their contents. Recent studies demonstrated the potential of microbubbles and ultrasound in thrombolysis. In this article, we will review the recent advances of microbubbles as a vehicle for delivery of drugs and genes, and discuss possible therapeutic applications in thrombolysis.     

Current applications of contrast echocardiography

Transthoracic echocardiography is a practical, widely available non-invasive imaging technique examining cardiac structure and function at rest and during stress. However, diagnostically useful images are not provided in a non-negligible proportion of patients, mainly because of obesity and lung disease. The use of echo-contrast agents (microbubbles consisting of high molecular weight gas encapsulated in a outer shell which have ultrasound characteristics distinctly different from those of the surrounding blood cells and heart tissue) solves these issues, providing cardiac chamber opacification and improving endocardial border definition, consequently allowing a more accurate quantification of left ventricular function. Besides improving the assessment of left ventricular function, echo-contrast agents may be used also to assess the myocardial perfusion at the capillary level, providing useful information about myocardial blood flow. Aim of the present paper is to provide an overview of the main clinical applications of contrast echocardiography, i.e. left ventricular opacification and myocardial contrast echocardiography.     

The clinical applications of myocardial contrast echocardiography.

Recent updates in the field of echocardiography have resulted in improvements in both image quality and techniques allowing echocardiography to maintain it's position as the primary non-invasive imaging modality. In particular, the development of new ultrasound contrast agents and imaging techniques have now made possible the assessment of myocardial perfusion. Myocardial contrast echocardiography utilises acoustically active gas filled microspheres (microbubbles), which have rheology similar to that of red blood cells. The detection of myocardial perfusion during echocardiographic examinations permits simultaneous assessment of global and regional myocardial structure, function, and perfusion, enabling the optimal non-invasive assessment of coronary artery disease. Myocardial contrast echocardiography is equally adept in assessing chronic coronary artery disease, acute coronary syndromes and hibernating myocardium.     

Contrast‐enhanced ultrasound for quantification of tissue perfusion in humans

Contrast‐enhanced ultrasound is an imaging technique that can be used to quantify microvascular blood volume and blood flow of vital organs in humans. It relies on the use of microbubble contrast agents and ultrasound‐based imaging of microbubbles. Over the past decades, both ultrasound contrast agents and experimental techniques to image them have rapidly improved, as did experience among investigators and clinicians. However, these improvements have not yet resulted in uniform guidelines for CEUS when it comes to quantification of tissue perfusion in humans, preventing its uniform and widespread use in research settings. The objective of this review is to provide a methodological overview of CEUS and its development, the influences of hardware and software settings, type and dosage of ultrasound contrast agent, and method of analysis on CEUS‐derived perfusion data. Furthermore, we will discuss organ‐specific imaging challenges, advantages, and limitations of CEUS.     

Ultrasound molecular imaging of cardiovascular disease

Myocardial contrast echocardiography utilizes intravenously injected gas-filled microspheres as acoustically active red blood cell tracers. During ultrasound imaging, unimpeded microsphere transit through the intramyocardial microcirculation causes transient myocardial opacification, which can be mapped and quantified as myocardial perfusion. Ultrasound molecular imaging utilizes similar acoustically active microspheres, which are modified to bear a receptor-specific ligand on the surface, conferring microsphere binding to a disease-specific endothelial epitope. Because the microspheres adhere to the endothelium, ultrasound imaging reveals a persistent, rather than transient, contrast effect, indicating the presence and location of the molecule of interest in real time. Molecular contrast echocardiography has been developed to detect upregulated leukocyte adhesion molecules during microvascular inflammation, such as occurs in cardiac transplant rejection and ischemia-reperfusion. Principles of microsphere targeting and ultrasound imaging of microvascular epitopes have been extended to larger vessels to image molecular markers of atherosclerosis. This Article summarizes the current status of cardiovascular ultrasound molecular imaging. Experimental proofs of concept will be outlined and the clinical extension of these concepts to the molecular imaging of cardiovascular disease using clinical ultrasound technology will be discussed.     

Transmural penetration of intravenously applied microbubbles during contrast-enhanced ultrasound as a new diagnostic feature in patients with GVHD of the bowel

GVHD is a common complication in patients after allo-SCT. Early detection is important because early therapy may improve the outcome. We evaluated contrast-enhanced ultrasound (CEUS) in patients with GVHD to assess typical imaging features. CEUS was performed in nine patients with histologically proven GVHD. As a control four healthy volunteers and six patients with Crohn's disease (CD) were examined. We employed a high-resolution multi-frequency transducer (6-9?MHz) with contrast harmonic imaging. After the injection of 2.4?mL SonoVue (Bracco, Milan, Italy) intravenously data were acquired and stored digitally. Regions of interest were manually placed over the surrounding mesenteric fat, bowel wall and bowel lumen. Maximum signal increase of each compartment was calculated. Patients with CD and GVHD showed significant contrast uptake in the bowel wall. In contrast to CD patients and healthy volunteers, patients with GVHD showed transmural penetration of microbubbles into the bowel lumen. We assume that the damaged gut mucosal barrier in GVHD enables the microbubbles to penetrate through the bowel wall into the bowel lumen. The penetration of microbubbles into the bowel lumen may serve as a novel diagnostic feature for GVHD if confirmed in controlled clinical trials.     

Real-time contrast imaging: a new method to monitor capillary recruitment in human forearm skeletal muscle

OBJECTIVE: Muscle capillary perfusion can be measured by contrast-enhanced ultrasound. We examined whether a less time-consuming ultrasound technique, called "real-time imaging," could be used to measure capillary recruitment in human forearm skeletal muscle. METHODS: We measured microvascular blood volume and microvascular flow velocity using bolus injections of contrast microbubbles after forearm muscle exercise and a two-hour infusion of insulin into the brachial artery (both associated with capillary recruitment) and after sodium nitroprusside infusion (no changes in flow distribution). RESULTS: After an intravenous bolus injection of the contrast agent, the steady-state concentration of contrast agent in forearm muscle lasted long enough (approximately 190 seconds) for the duration of the measurements (which take 70-80 seconds), rendering the continuous infusion of microbubbles unnecessary. Microvascular blood-volume measurements showed a good short-time reproducibility and a good reproducibility after repositioning of the forearm. Reproducibility of microvascular flow velocity was too low. Exercise and insulin infusion both increased microvascular blood volume, consistent with capillary recruitment. Sodium nitroprusside had no effect. CONCLUSION: Real-time contrast imaging, after bolus injections of an ultrasound contrast agent, provides reliable information about capillary recruitment in human forearm skeletal muscle, and may offer a valuable tool in studying human (patho)physiology.