The accurate assessment of left ventricular (LV) dimensions (diameters and volumes) and both regional and segmental wall motion requires detection of endocardial borders. Despite rapid developments in ultrasound technology, echocardiographic imaging is still limited up to 20% of patients due to physical factors such as obesity and chronic lung disease. Increasingly, echo is being used to guide therapy in critically ill patients who may have barriers to high quality echocardiographic images due to mechanical ventilation, surgical dressings, and inability to position the patient appropriately. The ability to produced left ventricular cavity opacification (LVO) with contrast echocardiography provides a valuable option for improving endocardial border resolution in these patients (Fig. 1).1)

The purpose of LVO is to produce an image that has homogeneous opacification of the entire LV cavity against the darker myocardium. Therefore, LVO is generally performed using just enough microbubbles to produce full opacification of the LV cavity without attenuation (shadowing of far field structures from high microbubble concentration in the near field), and using low to medium acoustic powers which minimize microbubble destruction. By more clearly defining the endocardial surfaces, LVO has been shown to improve the both the accuracy and reproducibility in assessment of LV volumes and left ventricular ejection fraction.2)3) The importance of this role is underscored by the increasing clinical use of volumes and LV ejection fraction to help guide important treatment decisions such as the implantation of a defibrillator or bi-ventricular pacemaker, or the timing of valve surgery. The use of LVO for better defining LV dimensions or function has predictably been shown to be higher in those who have lower quality non-contrast images.4) However, the use of contrast echocardiography for LVO has been shown in certain populations to provide incremental value irrespective of the baseline study. These populations include patients hospitalized in an intensive care unit who generally have poorer quality images as a modifying factor, and patients receiving cardiotoxic chemotherapies in whom serial assessment of LV function is used to guide therapy.4)5)6)7) In these populations in particular, the use of contrast has also been shown to reduce overall costs by avoiding the need for other more expensive methods for assessing LV function.5)8)

LVO is also playing an increasing role in the practice of stress echocardiography. The use of microbubble contrast has been shown to increase the number of interpretable myocardial segments at rest and during stress.9)10) Because it is often difficult to predict which patients will have a deterioration in image quality during stress from hyperventilation and increase in cardiac translation, lower threshold for use of contrast in stress echocardiography has been advocated by some.

Contrast echocardiography has also been used in several niche applications of where LVO is critically important. It is quite useful for evaluating for the presence of intracavitary masses or thrombi and for detecting ventricular pseudoaneurysm.11)12) In particular, LVO can play a role in better defining pathology at the LV apex where image quality is often reduced because near field artifact caused by rib reverberation or because of lack of distance for harmonic signal generation. For this reason, LVO has been shown to provide useful information for detecting or excluding apical hypertrophic cardiomyopathy, non-compaction cardiomyopathy, and eosinophilic cardiomyopathy.13)14)15)

Myocardial contrast echocardiography (MCE) refers to the detection of contrast material present within the myocardial microcirculation. In the absence of any kinetic information, the degree of contrast enhancement is proportional to the relative microvascular blood volume which is the fraction of the LV mass that is attributable to actively perfused intramuscular vasculature. In order to quantify this signal, one needs to either subtract myocardial signal (pre-contrast) from the contrast-enhanced signal or to employ contrast-specific imaging techniques that eliminate tissue signal through frequency filtering and/or multipulse correlation/decorrelation techniques. In general, MCE is performed with slightly higher contrast doses than LVO due to the need to opacify myocardial tissue which is only approximately 5-10% blood volume. The volume of blood in the coronary vascular bed is distributed almost equally between the arterial system, the microcirculation, and the venous system (Fig. 2).16) However, most of the arterial and venous blood volume are located at the epicardium. Hence, the microcirculation represents the majority of the intramyocardial myocardial blood volume, of which approximately 80% at rest is contained within the capillary compartment. Thus, myocardial contrast enhancement represents the primarily the capillary blood volume.17)

The most common application of MCE is to quantify myocardial tissue perfusion in ischemic heart disease. There are situations where a simple binary "yes or no" answer to the question of perfusion is sufficient. An example is when MCE is used to assess whether reperfusion therapy for myocardial infarction has been successful at restoring blood flow to the myocardium. For evaluating myocardial viability, one needs to only spatially assess the presence or absence of an intact microvasculature which can be done by examining microvascular blood volume which is described in a later section. In patients with known coronary artery disease (CAD), MCE can also provide information on myocardial viability either early after infarction or in those with chronic ischemic LV dysfunction.18)19)20) Improvements in MCE imaging technology now allow for the assessment of transmurality of infarction which correlates well with delayed gadolinium enhancement on magnetic resonance imaging.21)

For most other situations such as the detection of ischemia at rest or during stress, assessment of myocardial microvascular blood flow is required. This measurement involves the assessment of both microvascular blood volume and the transit rate of contrast through the myocardium. Because MCE can be performed rapidly at the bedside and provides information immediately to the healthcare team, it has been used to diagnose or exclude acute myocardial infarction in patients with suspected acute coronary syndrome.22)23) In these patients, the addition of perfusion to wall motion improves diagnostic accuracy (particularly in those with left bundle branch block or other reasons for LV dysfunction) and also provides incremental information to wall motion on prognosis by discriminating patients with ongoing ischemia (reduced flow and function) from those with stunning who have had spontaneous return of perfusion (Fig. 3).23) Although MCE is highly sensitive in detecting resting hypoperfusion, specificity can be detrimentally altered by attenuation artifacts particularly in basal segments and the lateral LV wall. In this situations, the addition of wall motion data can improve specificity (i.e., reduce false positives) since resting hypoperfusion should always be associated with abnormal LV function.

In those with known myocardial infarction, MCE can also provide important information on the size of the ischemic territory, the presence and amount of collateral blood flow, whether therapy for epicardial revascularization has been successful, and whether microvascular no-reflow is present.24)25)26)27)

There have been many clinical trials that have demonstrated that stress-rest MCE can be used with high diagnostic accuracy to detect CAD in those without active acute coronary syndrome or those presenting to the emergency department with unstable symptoms but no evidence for ongoing myocardial necrosis. These studies have generally compared vasodilator, exercise, or inotropic stress MCE with either other methods for detecting ischemia (e.g., SPECT radionuclide perfusion imaging, stress echo for wall motion) or with angiography.28)29)30)31)32) Unlike the flow-function relationship at rest, during stress wall motion may apparently normal in region with abnormal flow reserve due to moderate coronary stenosis.28)33) Accordingly, MCE during dobutamine and vasodilator stress has been shown to be more sensitive than wall motion alone at detecting ischemia, especially if workload achieved during stress is below target.28) MCE has also been shown to provide a better estimate of the territory of ischemia and to improve diagnosis of multivessel CAD.28)30)34)

The ability of MCE to quantify microvascular perfusion has led to numerous other applications in cardiovascular disease. MCE with intra-arterial injection of contrast agent is considered vital for intraprocedural optimization of alcohol septal ablation by mapping the perfusion territory of the septal perforating vessel engaged.35) Echocardiographic perfusion imaging may also aid in the differentiation of cardiac masses by differentiation of thrombus from tumor, and for identification of high vascularized malignant masses such as angiosarcoma.36) Certain perfusion patterns can also be used to suggest the presence of stress cardiomyopathy (e.g., takotsubo cardiomyopathy), particularly if performed early in the process.37) In a related matter, quantitative MCE at rest and during vasodilator stress has been used as one of the few confirmative tests for microvascular dysfunction as the cause of angina symptoms in patients without epicardial arterial stenosis. The ability to assess skeletal muscle blood flow and flow reserve with contrast ultrasound is also currently being investigated as a method for assessing the presence and impact of peripheral artery disease (Fig. 4).38) The clinical need for such a technique is emphasized by increasing the prevalence of diabetes which results in more diffuse disease and co-existence of obstructive disease and microvascular dysfunction. Finally there are exciting potential future applications of contrast echocardiography that are reviewed elsewhere and which include molecular imaging and therapeutic applications such as sonothrombolysis.

Contrast specific techniques have been developed for most echocardiography imaging systems currently on the market. Most of these algorithms rely on the signals that are produced by non-linear oscillation when microbubbles are exposed to ultrasound of a sufficient power and, in particular, near the ideal resonant frequency which is in turn determined by microbubble size and composition.36) A very basic but important advance has been to detect harmonic overtones produced by microbubbles which are multiples of the fundamental (transmit) frequency.42) This simple approach to improving contrast signal-to-noise is still often used for LVO studies. Various high-power contrast-specific ultrasound imaging techniques for tissue perfusion have been developed and are reviewed elsewhere.42)43)44)45) However, most laboratories rely on multipulse techniques that through pulse correlation methods serve to eliminate linear and some non-linear tissue responses and provide high microbubble signal-to-noise ratio at low mechanical index (MI; 0.1 to 0.2) without microbubble destruction. Pulse-inversion (or phase inversion) and power modulation imaging are examples of these low-power techniques and again are described elsewhere.46)47) Although these techniques have greatly facilitated routine use of MCE for perfusion imaging, they do have some drawbacks such as reduced frame rate owing to the need for multiple pulses, and motion (flash) artifacts that are seen especially during exercise or inotropic stress.

Irrespective of the technique used to detect microbubble signal, certain principles must be kept in mind when performing contrast echocardiography. If real-time imaging is performed, then the MI must not be so high as to produce microbubble destruction. Generally for myocardial perfusion imaging an MI of 0.1 to 0.2 is used. For LVO, the MI can be a bit higher since microbubble concentration is quite high. Destruction on MCE will be manifest as low contrast signal which resolves when pauses are introduced between frames (e.g., activating an ECG triggered mode). Destruction on LVO studies will be manifest as swirling in the LV cavity, particularly at the apex when imaging in the apical views. Attention should also be paid to the location of the acoustic focus since excessive destruction at the LV apex can occur when the acoustic focus is in the far field. For MCE imaging, gain settings should optimally be set just before administration of contrast material in order to have the maximal gain without much tissue speckle. However, it is important to note that for LVO studies some tissue signal is beneficial since ventricular function is best assessed by myocardial thickening which requires not only discrimination of the endocardial surface which is highlighted by contrast but also the epicardium.

The degree of blood flow in the myocardium can be defined as the blood volume within the microcirculation which is moving at a certain flux rate through the tissue. Hence, blood flow at the myocardial capillary level can be increased or decreased through changes in functional capillary density and/or the velocity by which blood passes through the capillary bed. MCE protocols have been developed to measure perfusion through the parametric assessment of these two parameters.

When the steady state concentration of microbubbles in the blood pool is constant and microbubbles are not being destroyed by ultrasound imaging, then the signal intensity from microbubbles in the tissue reflects the relative concentration of blood within the myocardium. If this signal is normalized to blood pool, the absolute microvascular blood volume (mL per gram of tissue) can be calculated provided that intensity in the blood pool has not reached dynamic range saturation. If one then destroys microbubbles through inertial cavitation, then the rate at which the signal reappears reflects microvascular flux rate of blood since microbubbles have a similar microvascular behaviour as erythrocytes.48) Generally, this kinetic information can be achieved by two different methods. The first approach is to use a high-power set of frames to destroy all microbubbles within the volume of the ultrasound sector. Low-power real-time imaging can then be used over the next five to fifteen cardiac cycles to image microbubble re-entry into the microcirculation (Fig. 6). In general, only end-systolic frames should be used for quantitative analysis since they contain the least signal from large intramyocardial vessels. If one does not need to evaluate wall motion in the same digital clip, then only end-systolic frames need to be acquired which can be achieved through ECG gating. A second method for measuring flux rate is to perform high MI imaging which simultaneously destroys and images microbubble signal, and to progressively prolong the interval between ultrasound frames. This high MI technique has the advantage of providing more robust signal enhancement and generates several frames for each interval which reduces noise; however, it requires more time and is much more difficult to perform due to the need to keep the transducer in a fixed position between static frames. The time (or pulsing interval) versus intensity relation can then be fit to a 1-exponential function in order to determine the rate constant of the curve, which represents microvascular flux rate, and the plateau intensity once the entire elevation is refilled which when normalized to blood pool represents blood volume.