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Congres Report
 

Special Lectures 3

 
Assessment of Coronary Disease by Myocardial Contrast Echocardiography

Anthony DeMaria

University of California, San Diego, USA

 

Advances in the technology of myocardial contrast echocardiography (MCE) have produced more effective contrast agents and refined recording techniques, which allow visualization of left ventricular (LV) cavity opacification and enhancement of Doppler signals. The degree of opacification reflects myocardial perfusion and coronary blood flow. During continuous intravenous infusion, the contrast microbubbles can be destroyed with a high-intensity ultrasonic pulse, eliminating myocardial opacification. In a healthy heart, the contrast bubbles and opacification reappear within a single cardiac cycle. When stenosis is present, the reappearance of contrast occurs within four or more cardiac cycles.

Dr. Anthony DeMaria, University of California, San Diego, USA, stated there are a number of potential clinical applications for MCE in patients with coronary artery disease (CAD). These include:

  • Evaluation of coronary artery stenosis (current primary focus)
  • Areas of risk or infarct
  • Reperfusion efficacy
  • No-reflow phenomenon
  • Myocardial viability
  • Coronary collateral flow
  • Coronary flow reserve
  • Targeted marker or drug delivery.

Many of the obstacles to using contrast echocardiography in the clinical setting have been overcome. The first obstacle was the production of ultrasound contrast microbubbles that do not dissolve when injected into the blood. This obstacle has been overcome using microbubble shells and high molecular weight, high density gases with a low potential to dissolve. Currently, one of three agents approved in the United States is being marketed. Additionally, two new investigational contrast agents have polymer shells that can be customized for different properties. They have been developed specifically for  myocardial perfusion and have been shown to be noninferior to radionuclide techniques for detecting coronary stenosis.

Another obstacle to developing contrast agents is the lack of real contrast, with the technique producing a white blood volume signal superimposed on white tissue. Techniques used to differentiate the microbubbles from tissue include ECG gating, harmonics, non-linear signals, and destruction of the bubbles with ultrasound energy. For example, ECG gating yields a very intense signal from the contrast within the myocardium; a second high-intensity pulse clears the myocardium, with the difference representing contrast opacification. When the bubbles are destroyed with high-intensity ultrasound, they gradually refill again. Using this technique, time intensity curves (destroy-refill curves) can be produced, in which the rate of reappearance is a function of blood flow velocity and the maximal intensity is a function of blood flow volume.

As opposed to radionuclides and MRI, contrast perfusion defects are time dependent. Thus, a defect may appear early in the refilling sequence but disappear later. In the presence of severe stenosis, the contrast reappears very slowly. DeMaria and his colleagues have developed myocardial signal intensity curves in a group of animals with different gradations of stenosis. As the severity of the stenosis increases, both the rate of coronary blood flow velocity and the ultimate blood volume diminish significantly, likely because of the closing of capillaries in severe stenosis.

The development of MCE also has been hindered by lack of a standardized protocol. Some of the different modalities include the use of bolus versus infusion to inject the contrast agent, gray-scale versus Doppler imaging, low energy real-time versus triggered imaging, and vasodilator versus inotropic stressors.

 

Studies of MCE

Until recently, multicenter randomized trials of MCE have been lacking. Virtually all of the reported trials have been single center studies. However, two large randomized multicenter trials have been completed. A pilot study of Cardiosphere demonstrated excellent sensitivity and good specificity compared to radionuclide and coronary angiography, leading to a multicenter study. Cardiosphere has a polymer shell covered with albumin for blood compatibility. Because this agent is very robust, it requires imaging with high energy ECG gating. Using Cardiosphere in a normal heart, during stress the entire myocardium is opacified by the first refilling beat, while at rest the entire myocardium is filled by the fourth refilling beat. In an abnormal heart, during stress there is a defect during the first refilling beat. If the defect fails to refill by the fourth beat, then it is a fixed defect, most likely an infarction. A defect that fills by the fourth beat is reversible. The results of this study have not yet been presented.

A second agent, AI-700 (Imagify) was studied in the Real-Time Assessment of Myocardial Perfusion (RAMP) studies. AI-700 is composed of perflubutane polymer microspheres with a phospholipid covering. These phase 3 international multicenter trials were designed as dual injection myocardial imaging studies in patients with known or suspected ischemic heart disease. Efficacy was analyzed by intra-subject comparison of AI-700 echocardiogram to angiography (RAMP 2) and to angiography and nuclear imaging (RAMP 1).

A total of 652 patients participated in the RAMP studies. The objective was to show the non-inferiority of AI-700 compared to radionuclides. Both real-time and ultra harmonic gated imaging were used. Stenosis was defined as 70% narrowing. The global jeopardy score was obtained from the angiograms. In normal patients, under dipyridamole stress, the opacification of the myocardium was clearly identifiable and uniform using AI-700. In patients with CAD, imaging with AI-700 clearly showed stenoses when using dipyridamole stress.

The preliminary data from RAMP 1 showed that with AI-700 MCE there were fewer patients with CAD compared with radionuclide results. In RAMP 2, the incidence of CAD was considerably higher. In RAMP 1, the sensitivity of AI-700 was lower than was achieved with the radionuclides. However, in RAMP 2 where coronary angiography was used as an independent standard, the sensitivity of the global jeopardy scores using AI-700 ultrasound was superior to the sensitivity obtained with radionuclides. Preliminary data on accuracy, sensitivity, and specificity for anterior and posterior defects show equivalence between MCE and SPECT. According to DeMaria, the results of these studies show that MCE will be a clinically valuable tool in the identification of coronary stenosis. MCE also will be quicker and less expensive and will reduce exposure to radiation compared to radionuclide techniques.

Additionally, MCE has the potential to provide information about myocardial viability. In a patient with no myocardial perfusion to an area of infarct there is no contrast, whereas in a patient with at least patchy perfusion, some contrast is visible, indicating that revascularization will improve contraction and enhance prognosis. In a literature review of MCE for myocardial viability in post myocardial infarction (MI) patients, DeMaria found that the sensitivity (83%) and specificity (75%) of MCE were as good as other techniques such as positron emission tomography (PET) and delayed enhancement MRI. A recent study reported that in patients with evidence of no myocardial viability, indicated by a very high contrast defect score, survival is reduced and the percentage of cardiac events is increased.  

MCE is not available clinically for several reasons:

  • Inadequate images in difficult patients
  • Complex pulsing sequences
  • No agreed upon protocol
  • Limited reproducibility of quantitation
  • Unpublished multicenter studies
  • No insurance reimbursement for MCE.

However, the studies will be published soon and then there will be reimbursement. Additionally, a technique has been developed to quantify myocardial blood flow by MCE and will eventually be used in the clinical setting.

DeMaria concluded that MCE has enormous potential. In the future, designer bubbles will be produced that will be easily imaged and provide options for different applications. Additionally, animal studies have shown that the microbubbles have the potential to be used for delivery of targeted markers, drugs, and genes.

 
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