Contrast Echocardiographic Imaging in Clinical Trials

The World Health Organization continues to note that cardiovascular disease remains the leading cause of death from noncommunicable diseases worldwide.

The World Health Organization continues to note that cardiovascular disease remains the leading cause of death from noncommunicable diseases worldwide. In 2012, 17.5 million deaths due to heart disease were reported with the majority of these due to ischemic heart disease. Almost half of all heart attack deaths in the United States occur outside of the hospital despite a tremendous reduction seen in mortality for those who make it to the emergency department. Due to this discrepancy, clinical trials to evaluate novel diagnostic and therapeutic tools to better detect disease and predict mortality are ongoing. Contrast echocardiography plays a significant role in the evaluation of cardiovascular disease, both as a diagnostic tool and as a method to evaluate the efficacy of various therapies.

The technology of imaging the heart using sound waves has existed for over four decades. The desire to improve the quality of the acquired images has been present just as long. Options for improving the imaging quality of the heart include using technological advances in sound transmission and reception or by enhancing the acoustical qualities of the patient being imaged.

Tremendous technical advances in echocardiography have pushed image quality to new levels but the challenge of a high signal to noise ratio is ever-present. Augmenting the reflected sound through contrast echocardiography has been shown to significantly increase the signal to noise ratio and therefore compliments the improvements seen in echocardiographic hardware.

Contrast echocardiography began simply with saline agitated with room air. These bubbles, filled with nitrogen and oxygen, were resilient enough to briefly tolerate the ultrasound waves directed at them but would get trapped and harmlessly rupture in the pulmonary capillary bed. As a result, the left heart would only receive agitated saline and opacify if these bubbles could bypass this circulation using a right-to-left shunt (i.e. patent foramen ovale, atrial septal defect, pulmonary arteriovenous malformations). Other contrast agents were developed which contained inert gasses surrounded by a more resilient membrane derived from protein, fat or polymer. The differences over agitated saline allowed these newer agents to form microbubbles of a size <5 microns (um) which allowed for passage through the pulmonary capillary bed, into the left heart and into cardiac and systemic circulation. In addition, the surface of these microbubbles are designed to have acoustic qualities which enhance reflected ultrasound waves and improve image quality.

The Food and Drug Administration has approved the use of contrast agents in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. In multiple clinical trials these contrast agents have been shown to significantly improve diagnostic accuracy in left ventricular ejection fraction evaluation both qualitatively and quantitatively when compared to the gold standard of volumetric analysis by cardiac magnetic resonance. The utility of endocardial border enhancement by these agents have also been studied in the setting of stress echocardiography. These clinical trials demonstrated a statistically significant improvement in the detection of obstructive coronary artery disease when a contrast agent is used to detect wall motion abnormalities versus those studies where contrast is not used, even in studies where the operator feels the image quality is adequate. Moreover, patients who were not considered good candidates for stress echocardiography due to their body habitus could now be included in this cohort. Despite the advantages of echo contrast in the setting of stress testing, systolic dysfunction and wall motion abnormalities are late changes for myocardium experiencing ischemia. Other imaging modalities such as SPECT imaging and stress MRI evaluate coronary perfusion which must be reduced before systolic dysfunction can even occur. This has generated another indication for echo contrast to explore.

The myocardium perfuses during diastole, starting with the endocardium followed by the epicardium. Echo contrast follows the same perfusion pattern as it mixes with blood and travels via the epicardial coronary arteries and through the capillary bed. With the addition of a stress modality (exercise, dobutamine or vasodilator) ischemia and obstructive coronary arteries can be identified using two different methods. One of these methods includes observing the endocardial borders for contrast-free areas that follow an epicardial coronary vascular territory. For example, a hemodynamically obstructed right coronary artery would demonstrate the absence of subendocardial contrast involving the base to mid inferior myocardial segments. This method has been shown in a handful of clinical trials to add incremental value in detecting coronary obstruction than using wall motion abnormalities alone and predicting future coronary events, repeat revascularization and death.

An alternative and more sensitive method to detect coronary obstruction utilizes a technique known as replenishment imaging. The microbubbles found within the echo contrast agents can rupture when a threshold of energy is delivered to them as measured by the mechanical index in ultrasound machines. Typically, a mechanical index < 0.3 is utilized in combination with other echocardiographic settings to encourage harmonic behavior of the microbubbles. During real time perfusion imaging a high mechanical index impulse is delivered to the field of view (typically in the apical four or two chamber view) destroying all visualized contrast. Intact contrast not in this field of view then flows into the imaging window and fills in the myocardial segments at equal rates (assuming no obstructive disease). As long as contrast is flowing into circulation at a constant rate and concentration, segmental myocardial perfusion can be quantified as the myocardium replenishes microbubbles. Efforts to eliminate background images including pulse inversion Doppler and power modulation have been developed to further improve the signal to noise ratio during replenishment imaging. When

compared to SPECT perfusion, this method has shown to have superior sensitivity for detecting single vessel and proximal coronary stenosis. While the Food and Drug Administration has not approved the use of echo contrast agents in myocardial perfusion imaging, the body of evidence is growing in peer reviewed journals and ongoing clinical trials which demonstrate the additive value of this new perfusion technique.

Contrast echocardiography has also found a niche in clinical trials. Patients that normally would have been excluded from cardiac studies evaluating left ventricular function now can be considered viable candidates for enrollment. Study protocols evaluating disease processes such as chemotherapy induced cardiomyopathy, indications for implantable cardiac defibrillators and three dimensional ventricular imaging have incorporated echo contrast in order to improve statistical power. Contrasted echo studies share the benefits of patient recruitment similar to trials which use cardiac magnetic resonance – that is, less subjects are required to show statistical significance in volumetric changes. This effect on enrollment benefits the time to study closure as well as reducing the budgetary burdens of managing a large scale trial. As mentioned previously, myocardial perfusion using echo contrast agents is also an area devoid of large scale clinical trials and is a high yield area for publications.

There are very few limitations in using echo contrast but are important to consider. Approximately 1 in 10,000 patients can experience an anaphylactoid reaction or rarely cardiovascular collapse. These effects primarily occur within 30 minutes of exposure to the contrast agent. Other contraindications such as suspicion or knowledge of the patient having an intravascular shunts are controversial but remain as a black box warning in package inserts. Non-diagnostic image quality and contrast induced artifacts can occur due to the user not understanding the pharmacokinetics of the contrast agent and this can be a threat to the patient as well. Common errors such as giving too much contrast (even 1 mL more) or imaging with a high mechanical index can create near field signal voids that can appear very similar to left ventricular apical thrombus – a diagnosis with significant lifestyle implications. Despite these risks, echocardiography with contrast remains the safest method available for imaging the heart and other cardiovascular structures.

Contrast echocardiography has opened the window of cardiovascular imaging. As America’s population grows in size and weight, external imaging of the cardiac structures will become more difficult. Contrast echocardiography allows those technically challenging patients to be studied noninvasively where before they would require exposure to excessive radiation and possibly other invasive procedures.

Through ingenuity and rigorous evaluation, echo contrast has moved from simply enhancing the blood pool to aiding in the detection of obstructive coronary artery disease. Ongoing clinical trials are examining the utility of quantification of myocardial perfusion using echo contrast agents with efforts made to move this idea into mainstream cardiology. With more research and efforts by the cardiac imaging community, it appears the future may not be so far away.

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Volume 5, Issue 6: Contrast Echocardiographic Imaging in Clinical Trials

Originally written by legacy Intrinsic Imaging Medical Director