Principles of Contrast Echocardiography

Introduction

Contrast echocardiography is a broad term used to describe an array of approaches that can be used to improve and expand diagnostic capabilities by acoustic enhancement of the blood pool during cardiac ultrasound imaging. Ultrasound contrast agents are generally composed of gas-filled encapsulated microparticles, usually microbubbles that are 1–5 μm in diameter, or nanoparticles. The most common clinical application of contrast echocardiography has been to better delineate the endocardial contours of the left ventricular (LV) cavity, termed left ventricular opacification (LVO; Fig. 3.1 ). Although there are many reasons clinicians opt for performing LVO in a given patient, the most frequent indication is to better evaluate global or regional LV systolic function ( Video 3.1, Video 3.2 ). Justification for this application of LVO is based on (1) the inability to fully examine LV myocardial thickening in 10%–20% of unselected patients; (2) the frequent use of echo to guide management in critically ill patients who have difficult acoustic windows due to positive pressure ventilation or inability to cooperate with the ultrasound examination; and (3) frequent use of echo to make critical decisions based on the presence of segmental wall motion, where every myocardial segment needs to be well seen with a high degree of reader confidence (e.g., stress echocardiography, point-of-care echo for detection of myocardial ischemia or evaluation of heart failure). There are many other clinical situations where LVO has had a positive impact in clinical echocardiography ( Box 3.1 ).

Refinements in contrast ultrasound technology that improve the detection of microbubble signal in the coronary circulation relative to myocardial tissue signal have permitted the imaging of the myocardial microcirculation. These techniques are broadly referred to as myocardial contrast echocardiography (MCE). The most basic approach to MCE is to spatially evaluate the presence of an intact microcirculation. The presence of a functional microvascular bed can be used to assess myocardial viability, to characterize a cardiac mass as a tumor rather than thrombus based on the presence of functional microvessels, and to detect therapeutic or spontaneous reperfusion in acute myocardial infarction ( Fig. 3.2 ; Video 3.3, Video 3.4, Video 3.5 ). Quantitative or semiquantitative assessment of perfusion requires not only quantification of the intact microvasculature but also temporal information of microbubble transit through the microcirculation. This measurement generally requires destruction of microbubbles within the acoustic sector and evaluation of signal reappearance. This approach can be used to detect resting ischemia, flow heterogeneity during stress echocardiography, or microvascular dysfunction, or to assess the presence/adequacy of collateral blood flow.

In this chapter, the basic principles of contrast echocardiography will be described, including an overview of contrast agents and the specific imaging modalities that have been developed to improve microbubble signal-to-noise ratio during clinical imaging. Clinical applications of contrast echocardiography are detailed in Chapter 12 .

Microbubble Contrast Agents

Signal enhancement during contrast echocardiography relies on the dynamic interaction of ultrasound pressure waves, with a highly compressible and expandable particle that is smaller in scale than the wavelength of ultrasound applied. As will be described later, particle expansion and compression during ultrasound pressure peaks and nadirs, respectively, produces volumetric oscillations of these particles, which is the primary source of ultrasound signal generation. The rationale for using microbubbles, as ultrasound contrast agents is based on their compressibility/expandability, and on their in vivo stability. Air and high-molecular-weight gases that have been used in microbubble contrast agent preparations are several orders of magnitude more compressible than water or tissue. During most forms of clinical contrast echocardiography, contrast oscillation and the subsequent acoustic energy response occurs for particles that are resident within the vascular compartment of interest (e.g., the LV cavity or myocardial microcirculation).

The initial description of contrast enhancement by microbubbles was made by Gramiak and Shah, when a cloud of echo signals was detected in the right heart, coming from the formation of microbubbles formed by fluid dynamic forces during rapid, high-pressure intravenous injection of a water-soluble fluorophore used at the time for measurement of cardiac output during heart catheterization. Over the ensuing years, several different forms of nonencapsulated microbubbles generated by hand agitation or low-frequency sonication were investigated, including for myocardial enhancement by MCE after intracoronary injection. These techniques were limited by the wide range of microbubble sizes produced, the inability of most of these microbubbles to pass to the left heart after intravenous injection, and the potential for large bubbles to become entrapped within the microcirculation when given as an intraarterial injection.

The safety, reproducibility, and widespread clinical feasibility of producing LV cavity and myocardial opacification with intravenous contrast administration microbubble contrast agents relied on the advent of small but stable and acoustically active microbubbles that are able to pass freely through pulmonary and systemic capillaries. Many of these microbubble agents also have a relatively narrow size distribution (relatively monodisperse). Those that do not, termed polydisperse agents , still contain relatively few microbubbles that are greater than the average functional capillary diameter of 5–7 μm when taking into account intraluminal projection of the glycocalyx. The creation of these stable size-controlled microbubbles that produce a strong acoustic signal relied on two major modifications: (1) a change in the gases used for the microbubble core material, and (2) microbubble encapsulation.

A partial list of some of the microbubble contrast agents that are currently commercially produced, marketed, and used in patients are shown in Fig. 3.3 . One of the common features of these agents is that the gas core is not composed of ambient atmospheric air components, which are for the most part nitrogen and oxygen. The reason for this compositional modification is based on mathematical models that have been used to predict the stability of a gas bubble. The rate of disappearance for a gas bubble in any given medium is dependent on the bubble size, the surface tension, and constants that describe the solubility and diffusion capacity of the gas in the bubble. Accordingly, the stability of microbubble contrast agents used in humans is improved when they contain gases with low diffusion coefficients and low solubility in water or blood, which is described by the ratio of the amount of gas dissolved in the surrounding liquid to that in the gas phase, or the Ostwald coefficient. These gases also must be inert, safe to use in humans, and cleared readily through respiration. These requirements are met in contemporary agents by using high-molecular-weight gases such as perfluorocarbons that remain in gas form at room and body temperature—for example, octafluoropropane (C ₃ F ₈ ), decafluorobutane (C ₄ F ₁₀ ), or sulfur hexafluoride (SF ₆ ).

The encapsulation of the microbubbles represents a second common feature of contemporary contrast agents. On the most basic level, encapsulation with a “shell” composed of biocompatible materials such as protein (albumin) or lipid surfactants enhances in vivo stability by providing a barrier function that reduces outward diffusion of the gas core. Encapsulation also has an important role reducing surface tension of microbubbles, which allows tight control of microbubble size distribution, and both “on the shelf” and in vivo stability of small gas-filled particles. The use of air (mostly nitrogen) as the primary gas core component in microbubble contrast agents is still possible, provided encapsulation is performed with a relative thick and impermeable shell. However, first-generation contrast agents such as Albunex, which contained air and an albumin shell, still did not prove to be stable enough for reproducible LVO or for myocardial opacification, particularly in those with reduced cardiac output that result in long transit times from intravenous injection to systemic circulation, or in those receiving supplemental oxygen. The problem of air diffusion can be solved by the use of even more impermeable “air-tight” shells composed of thick layers of biopolymers. However, this compositional modification results in relatively inflexible microbubbles that can only be imaged well with very high acoustic powers.

The chemical nature and self-assembly of the components of the microbubble outer shell are heavily influenced by the gas composition and the process used to entrain gas into an encapsulated particle. For example, much of the albumin in the shell of microbubble agents is predicted to exist in a denatured form, owing to the temperature and pressure environment during manufacture. Because of the somewhat hydrophobic nature of perfluorocarbons, lipids in the microbubble shell arrange not as a bilayer configuration, as found in cell membranes, but rather as a monolayer configuration with inner orientation of the hydrocarbon residues. In research studies, nanoparticle ultrasound contrast agents with lipid bilayer configuration or multilamellar membranes based on a core that is mostly aqueous have also been produced. However, signal on conventional imaging has been low for these agents, due to the small amount of entrained gas.