Abstract
Contrast echocardiography describes a variety of imaging approaches that rely on the detection of acoustically active contrast agents, usually in the form of encapsulated microbubbles that remain within the vascular space. In the clinical setting, contrast echocardiography has most commonly been used to improve image quality to enhance diagnostic performance and confidence. Frequent situations when contrast is used as an adjunct to routine echocardiography are for the better detection of ventricular endocardial borders or for the detection of intracavitary masses or thrombus. Contrast echocardiography can also be used to detect physiologic or pathophysiologic features that cannot be evaluated with noncontrast echocardiography, such as for the assessment of myocardial perfusion. This chapter focuses on the methods used for performing contrast echocardiography, composition and safety of ultrasound contrast agents, and circumstances where the use of contrast during echocardiography has been shown to improve patient care or healthcare costs.
Keywords
contrast echocardiography, left ventricular opacification, microbubbles, microcirculation, myocardial perfusion imaging
Introduction
Contrast echocardiography describes a set of specialized cardiovascular ultrasound techniques that rely on the administration of acoustically active contrast agents to complement standard imaging and Doppler echocardiography. Although there are many different types of acoustically active ultrasound contrast agents, those that are approved for clinical use are composed of gas-filled microbubbles encapsulated within a stabilizing exterior shell composed of surfactant materials, albumin, or biocompatible polymers ( Fig. 12.1 ). The vast majority of microbubbles administered in humans are smaller than red blood cells, which allows their passage through the pulmonary circulation and distribution throughout the intravascular compartment after intravenous injection. For most forms of contrast ultrasound imaging, the signal from these agents is attributable largely to the linear and nonlinear oscillations of the microbubbles as they pass within the range of the acoustic imaging field. The type and magnitude of the ultrasound emission from microbubbles relates to acoustic variables (pressure, frequency, and pulse duration), microbubble size and concentration, and shell viscoelastic properties. The unique signature of microbubble oscillation is best detected by contrast-specific regimes, which have been described in Chapter 3 , and is displayed as increased echogenicity or opacification.
In broad terms, contrast has been used in clinical practice either to better detect or characterize cardiovascular structures not well seen with noncontrast echocardiography, for example, endocardial-blood pool interfaces, or to detect physiologic or pathophysiologic features that cannot be evaluated with noncontrast echocardiography, for example, myocardial perfusion. Accordingly, the use of contrast during routine echocardiography has been advocated to improve diagnostic accuracy and confidence in specific patients or circumstances and to expand the role of echocardiography in applications where standard B-mode or Doppler echocardiography do not suffice.
In this chapter, we will discuss the clinical application of contrast ultrasound in a wide variety of circumstances where microbubble contrast agents have been proven to or theoretically can impact patient care. These applications will include the use of microbubbles for assessing (1) ventricular cavity size and function, (2) abnormal cardiovascular structures, (3) cardiovascular hemodynamics, and (4) tissue perfusion which relies on the detection of microbubbles as they transit the microcirculation (microvascular contrast echocardiography [MCE]).
Introduction
Contrast echocardiography describes a set of specialized cardiovascular ultrasound techniques that rely on the administration of acoustically active contrast agents to complement standard imaging and Doppler echocardiography. Although there are many different types of acoustically active ultrasound contrast agents, those that are approved for clinical use are composed of gas-filled microbubbles encapsulated within a stabilizing exterior shell composed of surfactant materials, albumin, or biocompatible polymers ( Fig. 12.1 ). The vast majority of microbubbles administered in humans are smaller than red blood cells, which allows their passage through the pulmonary circulation and distribution throughout the intravascular compartment after intravenous injection. For most forms of contrast ultrasound imaging, the signal from these agents is attributable largely to the linear and nonlinear oscillations of the microbubbles as they pass within the range of the acoustic imaging field. The type and magnitude of the ultrasound emission from microbubbles relates to acoustic variables (pressure, frequency, and pulse duration), microbubble size and concentration, and shell viscoelastic properties. The unique signature of microbubble oscillation is best detected by contrast-specific regimes, which have been described in Chapter 3 , and is displayed as increased echogenicity or opacification.
In broad terms, contrast has been used in clinical practice either to better detect or characterize cardiovascular structures not well seen with noncontrast echocardiography, for example, endocardial-blood pool interfaces, or to detect physiologic or pathophysiologic features that cannot be evaluated with noncontrast echocardiography, for example, myocardial perfusion. Accordingly, the use of contrast during routine echocardiography has been advocated to improve diagnostic accuracy and confidence in specific patients or circumstances and to expand the role of echocardiography in applications where standard B-mode or Doppler echocardiography do not suffice.
In this chapter, we will discuss the clinical application of contrast ultrasound in a wide variety of circumstances where microbubble contrast agents have been proven to or theoretically can impact patient care. These applications will include the use of microbubbles for assessing (1) ventricular cavity size and function, (2) abnormal cardiovascular structures, (3) cardiovascular hemodynamics, and (4) tissue perfusion which relies on the detection of microbubbles as they transit the microcirculation (microvascular contrast echocardiography [MCE]).
Left Ventricular Opacification
Endocardial Enhancement
Currently, the most common application of contrast echocardiography in clinical practice is to assess left ventricular (LV) function and regional wall motion when endocardial delineation is otherwise difficult. Despite advances in ultrasound imaging technology that have continuously improved image resolution and quality, the inability to adequately visualize the endocardial borders is still common. The intravenous administration of microbubbles in most subjects allows excellent discrimination between the LV blood pool and myocardium, thereby improving the ability to assess ventricular chamber dimensions and both global and regional systolic function ( 
).
Enhanced definition of the endocardial border is achieved by opacification of the LV cavity blood pool that provides contour recognition against the darker myocardium. Because only approximately 5%–10% of the mass of the myocardium is attributable to its microvascular blood volume (MBV) the contrast signal in the myocardium is a small fraction of that within the LV cavity. An exception to this occurs when microbubble concentration is very high, well beyond saturation of the dynamic range for the blood pool, and the myocardial signal can approach that of the blood pool, making endocardial definition difficult ( Fig. 12.2A ). Very high concentration of microbubbles in the blood pool also causes attenuation of the imaging beam, thereby producing shadowing of far field structures. Accordingly, left ventricular opacification (LVO) is generally performed with either small repetitive intravenous boluses of contrast or a continuous infusion of contrast at modest rates that result in full opacification of the blood pool without attenuation when imaged using low-power ultrasound to avoid microbubble destruction. Contemporary ultrasound imaging systems incorporate contrast-specific presets based on amplitude modulation or phase-inversion because of their ability to reliably produce high contrast signal and clear definition of the endocardial borders. However, the application of these algorithms can sometimes be disadvantageous when assessing regional wall motion during exercise or dobutamine stress due to the inherent reduction in frame rate with multipulse protocols, the production of “flash” artifact from tissue motion, and visualization of hyperemic myocardial perfusion at peak stress that can make differentiation of the border between myocardium and blood pool less clear. Although LVO is very effective at defining endocardial borders, it is important to recognize that, like all forms of imaging, the quality is affected by rib attenuation and beam-altering artifacts (see Fig. 12.2B , 
).
Assessing Left Ventricular Wall Motion and Systolic Function
Defining the LV endocardial borders is necessary for detecting the presence of wall motion abnormalities, assessing LV dimensions, and calculating left ventricular ejection fraction (LVEF). Endocardial definition is insufficient in up to 20%–30% of patients referred for stress echocardiography. Poor echocardiographic windows are particularly a problem in subjects who are obese, suffer from chronic obstructive pulmonary disease, are on ventilators, or cannot be optimally positioned for imaging. LVO with contrast echocardiography provides an opportunity to improve endocardial border resolution. Studies using intravenously injected lipid or albumin encapsulated contrast agents have included both unselected patients and those with technically difficult conventional two-dimensional (2D) imaging. These studies have unequivocally demonstrated that the use of contrast in both populations increases the number of interpretable studies, increases the number of interpretable LV segments with regard to evaluating wall motion, decreases interobserver variability, and increases reader confidence. The ability of contrast to transform an uninterpretable echocardiographic study into a diagnostic one appears to be particularly impactful in intensive care unit patients who have technically limited acoustic windows. Interobserver variability for detecting regional wall motion abnormalities with contrast echocardiography has been shown in a multicenter study to be superior to that of cardiac magnetic resonance imaging (MRI), cine ventriculography, and noncontrast echocardiography.
The range of clinical decisions that are based on a precise measurement of LV dimensions or LVEF continues to expand and evolve. Quantitative measurements are a component of patient selection for implantable defibrillators, cardiac resynchronization therapy, left-sided valve replacement/repair and for guiding optimal drug therapy with medications used for heart failure or cardiotoxic chemotherapeutic regimens. The gravity of the aforementioned decisions, both from the patient’s perspective and based on the socioeconomic impact of the treatments, emphasizes the importance of reliable and reproducible measurements of LV volumes and LVEF. When using radionuclide or invasive left ventriculography or cardiac MRI as a gold standard, LVO with intravenous contrast administration has been shown to be more accurate and more precise than unenhanced images with regard to measuring LV volumes and LVEF even in a population not selected for difficult acoustic windows ( Fig. 12.3 ). Contrast administration has been shown to consistently improve interobserver variability with regard to measurement of LV volumes or LVEF, particularly in patients with two or more adjacent poorly visualized segments, and results in the lowest interobserver variability compared to cardiac MRI, noncontrast echocardiography, and ventriculography.
The cost effectiveness of using contrast echocardiography in selected patients has been examined in several studies. Although the cost of the contrast agent and additional time for preparing for and performing contrast echocardiography represent added costs, the added time may be minimized by imaging protocols that allow the decision to use contrast to be made early in the study, thereby eliminating the “struggle time” wasted when a sonographer tries unsuccessfully to improve unenhanced images. Another consideration in assessing the cost-effectiveness of contrast echocardiography is downstream costs of other diagnostic tests that must be used or inappropriate therapies that are used as a result of nondiagnostic echocardiograms. All studies performed to date examining cost-effectiveness have demonstrated that the reduction in downstream resource utilization makes the routine performance of contrast echocardiography in patients with technically limited windows an effective strategy. Beyond just cost-savings, the ability to better understand regional and global LV function in inpatients and outpatients with technically difficult echocardiograms has been demonstrated to have an impact on management regarding changes in therapy or subsequent procedures performed ( Fig. 12.4 ). It should be recognized that in this type of analysis the lack of change in management does not necessarily indicate that the information did not impact patient care. It has been proposed that the superior information provided by contrast when image quality is otherwise limited is the reason for the finding of a significant one-third reduction in mortality in those receiving contrast in retrospective studies performed in critically ill patients undergoing echocardiogiography.
Stress Echocardiography
Stress echocardiography has become a cornerstone in the noninvasive evaluation of patients with suspected coronary artery disease (CAD). When performed in appropriate pretest probability populations, the sensitivity of stress echocardiography for detecting obstructive epicardial disease is between 80% and 90%, while the specificity is just under 80%. Conventionally, stress echocardiography relies on the detection of regional abnormalities and contractile reserve. Accordingly, optimal performance of stress echocardiography relies on the ability to see every segment, the ability to see every segment well , and a high level of reader confidence. Contrast echocardiography for LVO during stress has been shown to increase the number of interpretable segments, to increase subjective study quality, and to increase reader confidence. LVO has a greater impact in those patients with technically difficult baseline images and when images are interpreted by less experienced readers. The impact of LVO is particularly high in segments that most commonly suffer from poor endocardial discrimination, such as the basal lateral and basal inferior regions. The ability to ensure that the true LV apex is imaged and not foreshortened is also a valuable contribution of LVO. It has been advocated by some that contrast should be used in the majority of patients referred for stress echocardiography because of difficulties in being able to predict which patients who have adequate baseline images will have a deterioration in poststress image quality due to hyperventilation or excessive cardiac translation. However, this recommendation is tempered by the finding that the impact of using contrast is greatest in those with poor or marginal image quality at baseline.
Left Ventricular Opacification for Masses and Miscellaneous Left Ventricular Abnormalities
Thrombus formation in the LV cavity can occur from several pathophysiological processes but most commonly occurs in the setting of ischemic LV dysfunction involving the anteroapical region. The presence of an LV thrombus on echocardiography is associated with a fivefold increased risk of an embolic complication after myocardial infarction (MI). The ability to accurately detect thrombus not only impacts anticoagulation decisions but is also important for the evaluation of embolization risk in subjects being evaluated for percutaneous valve procedures that involve placement of large catheters in the LV or for placement of an apical inlet cannula for LV assist devices. The ability to detect thrombus by nonenhanced echocardiography depends largely on image quality. Moreover, the majority of LV thrombi occur at the apex that lies in the near field on apical views and is subject to artifacts from clutter, rib reverberation, power heterogeneity, and weak harmonic signal generation. Accordingly, the prevalence of apical LV thrombus on nonenhanced echocardiography has varied widely, and the sensitivity for detecting thrombus when using cine-MRI as a gold standard has been shown to be as low as 50%. The diagnostic accuracy and interobserver variability for detecting LV thrombi with echocardiography has been shown to be markedly improved by LVO ( 
), resulting in a level of accuracy similar to that achieved with cine-MRI. The clinical impact of LVO for thrombus detection has been demonstrated in post-myocardial infarction patients who are at particularly high risk for thrombus formation. In patients whose noncontrast echocardiograms were either inconclusive or suspicious but not definitive for thrombus, LVO excluded thrombus and reversed recommendations for oral anticoagulation therapy in almost one-third of patients with suspected thrombus and detected thrombus in 11% of patients in whom noncontrast echo was inadequate for thrombus evaluation ( Fig. 12.5 ). An additional application of contrast in the post-MI setting is the delineation of incomplete myocardial rupture (pseudoaneurysm).
The role of contrast in establishing the diagnosis of hypertrophic cardiomyopathy is based on its ability to define endocardial borders permitting accurate measurement of regional myocardial thickness. The artifacts that are common in the near field pose problems in imaging the LV apex and lead to a missed diagnosis of hypertrophic cardiomyopathy in around 10% of patients with apical hypertrophic cardiomyopathy. Both cardiac MRI and contrast-enhanced ultrasound have been shown to be extremely useful for diagnosing apical hypertrophic cardiomyopathy and differentiating it from apical foreshortening. Moreover, a subset of patients with apical hypertrophic cardiomyopathy also present with localized apical aneurysms for which a variety of mechanisms have been proposed ( 
). Accordingly, recent guidelines have advocated using contrast in the evaluation of suspected apical hypertrophic cardiomyopathy.
Two other disease states that often have pathologic changes manifest at the LV apex are eosinophilic cardiomyopathy and LV noncompaction cardiomyopathy. Eosinophilic cardiomyopathy is often a progressive disease manifest by eosinophilic infiltration, myonecrosis, and finally fibrosis culminating in a restrictive cardiomyopathy. Superimposed thrombus is common. Eosinophilic degranulation and myocyte necrosis both contribute to the loss of normal antithrombotic properties of the endocardium and release of prothrombotic substances. The ability of contrast to clearly visualize a filling defect involving the LV or right ventricular (RV) apex created by the inflammatory process and thrombosis facilitates the diagnosis of eosinophilic cardiomyopathy. Moreover, the ability to perform myocardial perfusion imaging (see below) is often helpful for spatially delineating myocardium from thrombus, thereby differentiating this entity from a severe form of apical hypertrophic cardiomyopathy.
Left ventricular noncompaction cardiomyopathy (LVNC) has many different phenotypic manifestations and occurs secondary to the incomplete consolidation of the myocardial trabecular network that normally occurs by a gestational age of around 18 weeks. The result is a spongiform appearance to the myocardium that is usually regional, most often involving the apex and distal lateral walls. Mutations in several genes ( G4.5, ZASP , α-dystrobrevin) have been implicated in this disease. Several echocardiographic criteria for diagnosing LVNC and differentiating it from simply prominent LV trabeculation have been proposed. Some of the major elements of these criteria are the systolic or diastolic ratio of noncompacted to compacted myocardium of 2:1, at least three major trabulecula, flow into trabecular recesses, and compacted myocardial thickness of less than 8 mm. The use of contrast has been shown to be helpful not only for delineating the presence of hypertrabeculation and intertrabecular flow but also for measuring the relative thickness of the compacted and noncompacted myocardial layers ( 
).
Contrast Echocardiography For Doppler Spectral Enhancement
While an off-label use, enhancement of Doppler signals with echo contrast has been shown to be helpful in a number of scenarios, notably in providing better delineation of aortic stenotic and tricuspid regurgitant spectra, which, in turn, provide more definitive assessments of aortic stenosis and pulmonary artery pressure. The doses used for Doppler enhancement are typically low. See also Chapter 29 .
Safety of Microbubble Contrast Agents
A more complete review of the safety of microbubble contrast agents is presented in Chapter 2 of this text. Important safety-related issues that influence clinical use will be summarized here. A series of steps to evaluate microbubble safety have been taken as part of the process of regulatory approval for each of the contrast agents that are currently being marketed for use in contrast echocardiography. These studies include the evaluation of vital signs, hemodynamics, blood chemistries, blood counts, complement activation, and the rheologic behavior of contrast. The approval process has also required a demonstration that cavitation of these agents within approved ultrasound power guidelines does not produce any adverse bioeffects. Despite the demonstrated safety of these agents, in 2007, the United Sates Food and Drug Administration placed a “black box” warning on ultrasound contrast agents based on adverse cardiovascular events that occurred in four critically ill patients (out of several million doses administered) and that were deemed to be possibly but not definitely related to contrast administration. This warning triggered several large registry studies demonstrating that severe cardiopulmonary reactions with lipid microbubbles are extremely rare, occurring at a rate of 0.01% of subjects receiving contrast agents. Moreover, a propensity-matched study of hospitalized patients demonstrated that those receiving ultrasound contrast agents during echocardiography have a lower, not higher, mortality rate, possibly indicating improved care based on the information provided by the contrast-enhanced echocardiogram. Studies examining the safety of ultrasound contrast agents in pulmonary hypertension and atrial shunts have also established the safety of microbubble contrast agents in these special populations in whom there was special concern with contrast administration as reflected in the US Food and Drug Administration (FDA)-mandated labeling.
The serious reactions that are seen rarely with lipid-shelled microbubble agents are, similar to liposomal drugs, related to non-Ig E-related pseudoanaphylaxis from local complement activation (complement activation related pseudo-allergy [CARPA]). Because of this possibility, laboratories that administer contrast agents must be staffed by personnel with appropriate training in contrast use and treatment of hypersensitivity reactions. A somewhat more frequent, mostly nonserious reaction that has been reported with lipid-shelled microbubble agents is back or flank pain. Studies evaluating the mechanism of this reaction have pointed to nonobstructive retention of microbubbles within the renal glomeruli and subsequent production of mediators such as bradykinin that activate pain receptors. These reactions generally resolve shortly after terminating the administration of the contrast agent.
Despite the demonstrated safety of ultrasound contrast agents, it should be noted that product inserts identify major contraindications to their use including previous hypersensitivity or reaction to the contrast agent or intracardiac right-to-left shunts. Other contraindications that vary between agents include pregnancy, lactation, pulmonary hypertension, and severe hepatic diseases.
General Recommendations for the Use of Contrast
The positive impact that contrast has been shown to have on both diagnostic accuracy and reader confidence in a wide variety of situations has led to societal recommendations regarding its use and the roles of the different healthcare providers in establishing policy regarding contrast use. Although these documents provide strong evidence for the use of contrast in different clinical scenarios, specific recommendations for when to use contrast in an individual subject have been somewhat vague other than to recommend its use when there is inability to visualize a certain number of myocardial segments. The difficulty in providing firm recommendations stems from the wide variety of clinical questions that justify referral for echocardiography. Accordingly, it is reasonable to recommend the use of contrast based on two separate considerations that are depicted in Fig. 12.6 : (1) will contrast have a major impact on answering the clinical question; and (2) what is the quality of noncontrast echocardiographic images? With this paradigm, the more liberal use of contrast is recommended for situations such as the exclusion of any wall motion abnormalities or the precise measurement of LV systolic function or size; whereas contrast is unlikely to aid in evaluating conditions such as mitral stenosis or the presence of a pericardial effusion.
The positive impact that contrast has on patient care has also resulted in specific recommendations for contrast policies as part of the process of accreditation of echocardiographic laboratories in countries such as the United States. Similarly, statements stating the need for training in the use of ultrasound contrast agents have been incorporated into the policies and guidelines for competency of trainees in adult cardiovascular medicine.
Myocardial Contrast Echocardiography
General Considerations
MCE refers to techniques where ultrasound contrast agents are used to assess microvascular perfusion or related parameters of physiologic importance. The ultrasound contrast agents that are conventionally used for LVO are pure intravascular tracers. Accordingly, the degree of signal enhancement in any tissue is proportional to the relative amount of functional (actively perfused) blood volume, providing that the contrast agent remains stable and is not destroyed through inertial cavitation. The actual relationship between the intensity of contrast enhancement within any tissue and microbubble intensity is also determined by the dynamic range and postprocessing algorithms of the imaging systems. When imaging the MBV within a tissue such as the myocardium, it is necessary that the concentration of microbubbles within the blood pool be well above the noise floor but still within the relatively linear or measurable portion of the microbubble concentration-contrast enhancement intensity relationship (below the dynamic range saturation point). When performing MCE, certain myocardial regions are particularly prone to attenuation artifact due to the intervening position of the RV or LV cavity, which generally possess a microbubble concentration that is 10–20-fold higher than that of myocardial tissue. The use of nontraditional echocacardiographic imaging planes can be helpful for overcoming this limitation.
Assessment of Myocardial Blood Volume
The blood volume of the coronary circulation in large mammals is approximately 12 mL of blood per 100 g of LV myocardium. This blood volume is roughly evenly distributed in arteries, veins, and the microcirculation that is composed of capillaries and medium to small arterioles and venules. Anatomically, the bulk of the large-caliber arteries and veins reside on the epicardial surface. Approximately 80%–90% of the intramyocardial MBV is represented by the microcirculation, most of which is in the capillary compartment. Accordingly, myocardial signal enhancement during MCE represents primarily microbubbles within the microcirculation and is skewed toward the capillary compartment.
Quantification of Myocardial Blood Flow
Myocardial blood flow can be defined as the volume of blood transiting through tissue at a certain rate. The two parameters needed for this calculation can be determined with MCE. If one performs MCE without destroying or otherwise altering microbubble integrity, then signal enhancement at any given point in time represents relative MBV. The calculation of absolute MBV (mL/g) requires normalizing this intensity to that in the blood pool, most commonly the LV cavity, provided that the concentration of microbubbles in tissue and the LV cavity remains within the dynamic range of the concentration-intensity relationship.
For the measurement of myocardial microvascular blood flow, kinetic information is needed. This information is provided by first destroying microbubbles through inertial cavitation that is achieved by high-power, low-frequency ultrasound. The rate at which the signal reappears into the volume of myocardium in the imaging plane reflects microvascular flux rate of blood since microbubbles have microvascular behavior similar to that of erythrocytes. Generally, this kinetic information can be achieved by one of two approaches. The first approach is to use a rapid series of high-power frames to destroy all microbubbles within the volume of the ultrasound sector. Low-power real-time imaging can then be used over the next 5 to 15 cardiac cycles to image microbubble reentry into the microcirculation ( Fig. 12.7 ). End-systolic frames gated to the T-wave of the electrocardiogram (ECG) are ordinarily used for this analysis since the signal from large intramyocardial vessels is minimized by systolic contraction. A second method for measuring flux rate is to perform image acquisition using only high-power ultrasound where microbubble signal from each frame is produced during inertial cavitation. Kinetic information is provided by progressively prolonging the interval between ultrasound frames to as long as 15 seconds between frames. This technique provides a high degree of contrast signal enhancement but requires more time than real-time low-power imaging and is technically more difficult to perform due to the need to maintain a constant imaging plane. The time (or pulsing interval) versus intensity relation can then be fit to a first-exponential function:
y = A ( 1 − e − β t )
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