Contrast Echocardiography

Clinical Agents for Contrast Echocardiography

Currently, several microbubble ultrasound contrast agents are being commercially produced, marketed, and used in patients in many countries ( Table 3.1 ). These agents are stable, acoustically active, and size-controlled so that they are able to pass freely through pulmonary and systemic capillaries based on two major design features: (1) high-molecular-weight gas in the microbubble core, and (2) microbubble encapsulation. ^, Ambient air (nitrogen and oxygen) and the high-molecular-weight gases that have been used in UEA preparations are several orders of magnitude more compressible than water or tissue. The stability of a gas bubble in any given medium depends on its size, its surface tension, and the solubility and diffusion characteristics of the gas. Microbubbles composed entirely of air are no longer manufactured because of their instability caused by rapid loss of gas through diffusion. Instead, UEAs have been composed with gases such as octafluoropropane (C ₃ F ₈ ), decafluorobutane (C ₄ F ₁₀ ), and sulfur hexafluoride (SF ₆ ), which have low diffusion coefficients and low solubility in water or blood (Ostwald coefficient), resulting in enhanced stability. These gases are inert and safe for human use and are eventually cleared through respiration.

The encapsulation of the microbubbles using biocompatible shell materials such as albumin or lipid surfactants is a second common feature of contemporary UEAs that enhances in vivo stability by reducing outward diffusion of the gas core. Encapsulation also reduces surface tension of the microbubbles, thereby improving their shelf life and in vivo stability, and allows control of microbubble size distribution. Much of the albumin used in microbubble shells is predicted to exist in a denatured form resulting from the manufacturing process. When used in microbubbles, lipids generally are arranged as a monolayer with inner orientation of the hydrocarbon residues because of the hydrophobic nature of perfluorocarbons. The chemical nature and self-assembly of the components of the encapsulated microbubbles result in differences in not only contrast agent composition but also size distribution (polydisperse rather than monodisperse diameters), storage, and preparation protocols ( Fig. 3.1 ). The shell composition is the dominant feature for determining the physical properties of microbubble volumetric resonation (cavitation) in an acoustic field.

Investigational Agents

Many different investigational contrast agents have been developed that are not currently in routine clinical use. These agents have been specially formulated for specific diagnostic or therapeutic purposes ( Table 3.2 ). Nanoscale contrast agents (emulsions, nanodroplets, and acoustically active liposomes) that are less than 1 μm in diameter have been developed based on the potential of these agents to have longer intravascular circulation times, to potentially exit the vascular space in certain circumstances, and to be better matched with high-frequency ultrasound imaging based on the inverse relationship between bubble size and ideal resonant frequency. To improve the ordinarily low degree of ultrasound signal enhancement from submicron agents, phase-shifting nanodroplets have been developed that possess a condensed liquid-phase perfluorocarbon core that undergoes expansion and vaporization to gas phase during the negative-pressure phase of an acoustic field.

There has been extensive investigation into the use of targeted microbubble contrast agents that bear binding ligands for performing ultrasound-based molecular imaging. Clinical areas of interest for this technology include imaging of tissue ischemia, vascular inflammation and atherosclerosis, thrombus formation, and angiogenesis. ^, Novel microbubble agents have also been formulated for therapeutic purposes, including payload-containing microbubbles for gene or drug delivery and agents designed specifically for sonothrombolysis (i.e., dissolution of thrombus through cavitation energy). Full elaboration of these cutting-edge experimental agents is beyond the scope of this chapter, yet knowledge of their applications in contrast echocardiography is important for realizing their possible future role in improving patient care.

Safety and Microvascular Behavior of Microbubbles

The UEAs that have been approved by regulatory authorities have been shown to be among the safest contrast agents used in all forms of cardiovascular noninvasive imaging. ^, The safety issues that are unique to microbubbles relate to three primary factors: (1) their microvascular behavior; (2) the physical and biochemical bioeffects from acoustic cavitation; and (3) interaction of microbubbles with components of the mammalian innate and adaptive immune processes.

The organ-specific vascular kinetic profile (rheology) of UEAs in the microcirculation is vital for understanding tracer kinetics and safety. Investigational studies using first-pass tracer kinetics or intravital microscopy have firmly established that albumin and lipid microbubbles transit the myocardial and muscle microcirculation unimpeded, do not coalesce or aggregate, and have a velocity profile similar to that of red blood cells (RBCs) in arterioles, venules, and capillaries ( Fig. 3.2 ). ^, The similar rheology of UEAs and RBCs is a critical consideration when using MCE to assess microvascular perfusion. This rheologic profile and the ability to control microbubble size through encapsulation are important for minimizing capillary or pre-capillary lodging and ensuring that microbubbles will transit to the systemic circulation after intravenous injection. Because lodging in the pulmonary circulation is minimized, administration of UEAs (including full-dose administration of a polydisperse-sized microbubble agent) in patients with at least moderate preexisting pulmonary hypertension has been shown not to increase either pulmonary pressure or pulmonary vascular resistance. Concern for possible systemic microvascular lodging in patients with a permanent or transient right-to-left shunt has been raised. However, only a small proportion of microbubbles are large enough to lodge in peripheral microvessels (see Table 3.1 ), and microscopy has indicated that any size-based retention is a transient event because of gradual deflation. Accordingly, use of commercially produced UEAs in the presence of a right-to-left shunt has been demonstrated to be safe, and the presence of known or suspected shunts is no longer a contraindication to their use.

Clearance of UEAs from the blood pool generally is performed by reticuloendothelial organs. The dominant removal mechanism for lipid-based agents is opsonization, whereby serum complement facilitates receptor-mediated uptake by monocytic/phagocytic cells such as Kupffer cells of the liver. Complement-mediated interaction with phagocytic cells and microbubble removal are increased by specific lipids (e.g., phosphatidylserine) in the microbubble shell and by the use of other lipids that produce a larger net charge (zeta potential) on the shell surface. The rate of removal is decreased by the presence of polymeric moieties such as polyethylene glycol, which reduce opsonization and microbubble–cell interactions. Although albumin-shelled microbubbles can be opsonized, other pathways may be involved, such as the ability of specific integrins on phagocytic cells to bind denatured albumin.

Because complement can be activated by microbubble shell components, pseudoanaphylactic reactions (i.e., not mediated by immunoglobulin E) are possible. For any lipid-based particles, these reactions are predicted to be influenced by the peak blood pool concentration of the lipid. Fortunately, serious pseudoanaphylactic reactions for lipid-based agents are rare, with serious cardiopulmonary reactions occurring in only 0.01% of doses administered. ^, Lipid-shelled microbubbles can also produce back or flank pain; this may be attributable to a mild form of complement-mediated renal cortex retention whereby the generation of discomfort is more likely caused by mediators that activate pain receptors than by any tissue injury.

Microbubble resonance in an ultrasound field is categorized as either stable cavitation (volumetric oscillation without destruction) or inertial cavitation (exaggerated nonlinear oscillation that results in abrupt agent destruction). In vitro and preclinical animal studies have indicated that inertial cavitation can cause transient endothelial microporation, vascular permeability, calcium-dependent cell activation, purinergic pathway activation, and even petechial hemorrhage. However, the major deleterious effects of inertial cavitation occur at acoustic pressures and microbubble doses beyond the limits approved by regulatory agencies. Within the approved pressure ranges, bioeffects produced by microbubble inertial cavitation have been leveraged to enhance gene/drug delivery or to promote shear-mediated flow augmentation or lysis of blood clots. ^, Extensive safety studies performed in the course of regulatory approval and post-marketing studies in humans have not detected any evidence of tissue injury or vascular disruption. A large retrospective study of hospital inpatients demonstrated that the mortality rate was lower in those receiving UEAs during echocardiography, suggesting that the net beneficial impact of contrast echocardiography on diagnosis and management outweighed any safety concerns. Because premature ventricular contractions have been reported during very-high-power imaging, regulatory guidelines for some agents caution that safety has not been established when imaging at the very high end of the mechanical index for clinical scanners.

With regard to special patient categories, most UEAs have been assigned a Category C classification in pregnancy, indicating lack of definitive data in humans. Several studies have established the safety of UEAs in pediatric populations, ^, although no agent is yet approved for left ventricular opacification (LVO) in these patients. Although there are warnings against intraarterial administration of commercially produced UEAs, some agents have been administered off-label into branches of the left anterior descending (LAD) coronary artery to define the perfusion territories in the course of planning for alcohol septal ablation in patients with hypertrophic cardiomyopathy (HCM).