Established and emerging roles for ultrasound enhancing agents (contrast echocardiography)

Abstract The ability to opacify the left ventricle and delineate the endocardium after intravenous injection of microbubble ultrasound enhancing agents is of established value to quantify volumes and function in suboptimal unenhanced images, particularly in stress echocardiograms. However, applications other than quantitation of left ventricle structure and function exist for contrast enhanced left ventricular opacification. Contrast agents enable recording of Doppler velocity signals in patients with poor ultrasound transmission, providing estimates of aortic stenosis gradient and pulmonary artery pressures. Contrast echo is of value in detecting apical hypertrophic cardiomyopathy and accompanying apical aneurysms. Most importantly, ultrasound enhancing agents can identify apical and left atrial masses when they cannot be visualized in unenhanced images, and can distinguish thrombi from tumors by visualizing the vascularity inherent in tumors. Contrast agents distinguish trabecular from compacted myocardium in noncompaction syndrome, and hypertrabeculation with other abnormal conditions. A major potential application of ultrasound enhancing agents is myocardial opacification, which can assist in identifying nonviable myocardium. Also, the delayed reappearance of myocardial perfusion after microbubble destruction identifies impaired contrary flow and can diagnose coronary stenosis. Innovative applications of ultrasound contrast agents currently under investigation, include visualizing the vaso vasorum to identify plaques and assess their vulnerability, and theranostic agents to deliver drugs and biologists and to assist in sonothrombolysis. It is anticipated that the role of ultrasound contrast agents will continue to increase in the future.

1 | INTRODUCTION C. Richard (Dick) Conti was an "impact player." He made an impact on everything that he engaged in, changing it for the better and leaving his imprint. He was a superb clinician, productive clinical investigator, gifted teacher, and effective administrator. His influence upon the University of Florida, the American College of Cardiology, and of course on Clinical Cardiology is easily visible. He succeeded one of us (AND) as President of the American College of Cardiology. We worked closely together, traveled extensively, and shared many experiences, some serious and some humorous. His advice was always sage and of great value. Dick was a giant intellect, an indefatigable worker, and a "tell it like it is" person; it was impossible not to like him. It is truly our honor to have the opportunity to contribute a manuscript to this issue in his memory.

| HISTORY
The first significant clinical description of contrast echocardiography is usually credited to Drs. Gramiak  There are currently a number of ultrasound enhancing agents approved for this application (Table 1) and the safety of the procedure has been well established. Left ventricular opacification with ultrasonic contrast agents has achieved an established role in clinical echocardiography and is currently applied routinely on a daily basis to define the endocardial border and assess left ventricular size and contraction. However, additional applications of ultrasonic contrast agents have been identified, and several potential applications are currently under development for standard application in clinical cardiology ( Ultrasound enhancing agents may also be of value in defining endocardial landmarks on three-dimensional echocardiography which is less sensitive in imaging low intensity targets than conventional two-dimensional imaging. Despite documentation that ventricular opacification by con-  (Figure 7). However, the use of contrast agents provides the optimal distinction of tumors from thrombi. Specifically, administration of an ultrasound contrast agent will enhance the vascular bed of a tumor but not a thrombus. It has been demonstrated that tumors will manifest an ultrasound intensity comparable to myocardium after the injection of contrast, whereas thrombi will not. 12 Thus, ultrasound enhancing agents often yield additional information even when a mass is clearly visualized in the left ventricle.

| MYOCARDIAL CONTRAST ECHOCARDIOGRAPHY
Preclinical studies initially demonstrated that the direct intracoronary injection of CO 2 was capable of intensely opacifying the myocardium, thereby providing the potential to assess myocardial perfusion and coronary blood flow 16 (Figure 10). In fact, intracoronary contrast injection of microbubbles from agitated radiographic contrast agents were of great importance to defining the no-flow phenomenon following coronary recanalization. 17 However, significant technical advances were required to achieve opacification of the myocardium following intravenous injection. It was recognized that the transmission of a low energy ultrasound beam could resonate contrast bubbles to enable visualization, and that progressively higher energy pulses could result in second harmonic signals and then ultimately destroy the contrast agent. Myocardial opacification by intravenous contrast agent injection was ultimately achieved using relatively low energy ultrasound transmission and imaging schemes to distinguish the agent from myocardium ( Figure 11). Even with these advances the yield of high-quality contrast myocardial perfusion images has continued to be lower than those of left ventricular opacification. Importantly, it was observed that following the destruction of contrast microbubbles by a high energy ultrasonic pulse, the time course of reappearance of myocardial opacification F I G U R E 6 Left Panel: the apical 4 chamber recording before contrast injection while the right panel clearly demonstrates an apical thrombus following administration of an ultrasound enhancing agent F I G U R E 7 Left panel delineates an apical thrombus that is free of any ultrasound reflectances. Middle panel show the echo of a patient with a large apical tumor that contains reflectances generated by tissue in homogeneity. Right panel demonstrates the same tumor after contrast agent administration which clearly delineates the persistent vasculature.
F I G U R E 8 Left Panel demonstrates a marked hypertrabecular pattern in a patient with noncompaction while the right panel illustrates that contrast fills the intrabecular clefts delineating the compacted myocardium served as the basis for estimating coronary blood flow and volume. 18 Moreover, a decrease in the refilling time of a myocardial segment after contrast destruction in destroy/refill sequences was found to be a marker of coronary artery disease. In this regard, contrast echocardiography provided analogous information regarding myocardial perfusion to radionuclide and magnetic resonance techniques.
Contrast myocardial perfusion studies have been demonstrated to be accurate and applied frequently to identify viable myocardium by virtue of opacification produced by persistent microcirculation in a manner similar to radionuclide and magnetic resonance techniques ( Figure 12). 19 Demonstration of myocardial opacification following intravenous injection of ultrasound enhancing agents led to an immediate enthusiasm and anticipation that this methodology could be applied  is feasible and has the potential to become a first line modality to assess myocardial perfusion. Technical advances will be important to achieving widespread application for this indication. The potential applications of ultrasound contrast agents continue to grow and be explored both for diagnosis and therapy. It is anticipated that the use of contrast agents will continue to play an increasingly important role in the echocardiography laboratory of the future.
F I G U R E 11 The myocardial contrast echocardiogram obtained in a normal subject. Left panel is taken at the arrival of left ventricular contrast while the right panel shows myocardial opacification delineating myocardial perfusion.
F I G U R E 12 Left panel demonstrates myocardial contrast echocardiogram in a patient with an anterior myocardial infarction in whom virtually no apical opacification is seen indicative of nonviable myocardium. The panel on the right shows another patient with an anterior apical myocardial infarction in whom at least partial apical opacification exists suggesting myocardial viability.