The year has brought some interesting changes to contrast-enhanced echocardiography, but, as real-time imaging for myocardial perfusion continues its crossover from research settings to clinical reality, the long road holds both promise and challenge for improved assessment of coronary artery disease and tissue viability.
Manufacturers have altered their echo equipment to better deliver perfusion needs; education among researchers and end-users is increasing; and observers believe the strides made this year have been important ones in reaching the Holy Grail of myocardial perfusion.
Frost & Sullivan (Mountain View, Calif.) estimates the world ultrasound contrast media market at $49 million in 1999, growing at a rate of 37 percent. In a recent report on the world contrast media market, the company characterizes the market as still in its early stages of development.
The report lists the major market drivers as:
- Ease of use of ultrasound equipment compared with other modalities stimulates demand for contrast development;
- Establishment of specific codes for use of contrast materials during contrast echocardiography to market growth;
- Widening scope of applications provides new impetus to ultrasound contrast media sales;
- Heightened interest in ultrasound contrast media spurring R&D investment;
- Cost effectiveness of ultrasound equipment makes it more attractive to end-users; and
- Improved diagnostic capabilities with harmonic imaging using contrast promote procedural growth.
On the other side of the coin, potential factors which may limit growth include:
- Higher cost per dose of ultrasound contrast media;
- Availability of only a few types of ultrasound, curtailing market potential;
- Very low percentage of ultrasound procedures employ contrast media; and
- Lack of reimbursement retards revenue growth.
Echocardiography also is competing with contrast media developed for other modalities such as CT and MRI; and failure of alliances disrupts the research and development process.
What’s up, docs?
Currently, Molecular Biosystems Inc.’s (MBI of San Diego) Optison is the only FDA-approved intravenous contrast agent to opacify the left side of the heart. Echo historically has looked at wall motion to tell which areas are properly perfused. Now with new technology, the user can see the contrast itself and see it go into the muscle. Harmonic imaging is a fundamental requirement to conduct contrast-enhanced echo, allowing a clear separation of the contrast from the heart tissue.
Using Acuson’s Coherent Contrast technology, the contrast agent is absent within the myocardium (left), but present 2 seconds later (right).
“If you’re trying to look at the borders inside the heart and see where the muscle is and the blood flow is and how the contractions are going, you need to know exactly where the endocardial border is,” says Naji E. Karam, M.D., director of the Chest Pain Center at St. Anthony Hospital (Oklahoma City, Okla.) and assistant professor of medicine at the University of Oklahoma Health Science Center (Oklahoma City). “That’s what contrast does very well.”
ATL Ultrasound, a Philips Medical Systems Co. (Bothell, Wash.), is among the companies in the industry continuing research in the assessment of myocardial contrast in real-time.
“Real-time perfusion imaging allows us to investigate the use of contrast in pharmacological stress echo for the assessment of ischemia, and this research effort has made some major efforts this year,” says Curtis LeBleu, ATL’s manager of cardiology market development. “We have learned that myocardial contrast can be assessed in both terms of the volume we can see in real-time, and then with flash imaging we can assess the myocardial refill rates or velocity in real-time as well.”
Flash imaging has the ability to destroy the contrast agent on demand and then assess the time in which it takes to refill with contrast, to assess the blood velocity as well as the volume. Work in this area remains a research effort.
Several protocols are being investigated for clinical use, but the real advance, adds LeBleu, is that “now all these protocols are possible in real-time, where last year, in order to assess contrast within the myocardium, you needed to trigger the image acquisition. You got one frame for every heartbeat or every several heartbeats. It was by acquiring a sequence of images over time that you were able to assess the speed of refill. Now, we can assess the refill rate in real-time with a combination of real-time perfusion imaging and flash destruction imaging.”
Work also continues on the approved indication of left ventricular opacification (LVO), providing clearer endocardial border delineation (where the blood ends and the heart muscle wall begins). ATL has progressed from using high mechanical indices or high acoustic pressures to low mechanical index imaging to see apical filling and endocardial border definition better.
“This is making the exam easier and more complete for wall motion assessment or wall thickening assessments,” LeBleu says.
In the last year, Acuson Corp. (Mountain View, Calif.) introduced its Coherent Contrast imaging product, which images contrast at a very low mechanical index, enabling the contrast agent’s harmonic signal to be detected. Acuson also incorporated into its ultrasound machines the ability to deliver high-energy signals that burst bubbles deliberately, then immediately return to a low mechanical index to view a nondestructive reappearance of contrast after deliberate bursting of those bubbles.
“We have gone to the stage collectively in the industry now of proving the principle of being able to demonstrate regions of the myocardium that are perfused by observing myocardium contrast,” says John Davidson, marketing manager of product line for Acuson.
For Agilent Technologies Inc. (Andover, Mass.), Power Modulation, which looks at function and perfusion, is used in conjunction with its S3 transducer to detect and better destroy contrast. The technology, released in July, images bubbles in real time.
“What we’ve done both with our transducer and our technology is improve the uniformity of the transmit field, as well as come up with a technique to eliminate tissue and visualize bubbles better,” explains Pat Rafter, Agilent’s contrast R&D engineer. Using its Impulse capability, Power Modulation helps quantify different regions of tissue. How fast the bubble comes back shows the rate of blood flow in those areas.
As evidence on the diagnostic front continues to mount, the therapeutic area is garnering its share of attention. The promise of the ability to use diagnostic ultrasound to transfer genetic material in an animal’s myocardial cells, pick up infections and deliver drugs locally expands the potential for contrast-enhanced technology.
Education is key
Count preceptorship programs among the advances over the last year, too. Investigators have created training programs providing professional education opportunities for physicians who are interested in starting to use the new technology. The lack of continuity has created problems in the past.
“You have had several investigators, all of whom providing education, but all of them having their own protocols or approaches they work with,” LeBleu says. “It was causing confusion in the mainstream echocardiography community because…of contradictory statements being made.”
Now, however, LeBleu says some consensus is starting. “I think that the education programs have real potential for the future to focus on protocols that people can use in their practice,” he says.
Others also opine that education has been lacking. Martin E. Goldman, M.D., director of echocardiography, and Arthur Master, M.D., professor of medicine (cardiology) at Mt. Sinai Medical Center (New York City), point to the contrast manufacturers.
“I think, unfortunately, the initial agents that came out weren’t accompanied by adequate education,” Goldman says. “People had great expectations that were turned to great disappointment in realizing their goal of seeing amazing pictures. They did not know they needed harmonic imaging. They did not know how to handle the agent, how much to use of the agent, and they thought they were going to give an injection and see perfusion, which obviously didn’t happen.”
Goldman characterizes echocardiography as “distinct and unique” and cites five components to be effective. “One, you need a very good technician. Two, you need to have a patient’s body habitus compatible to give a fairly good quality echocardiogram,” he adds. “Three, it is important to have harmonic imaging and potential real-time perfusion capability. Four, the agent itself, different qualities or properties of each agent may influence its ability to enhance myocardial perfusion. Five, the interpretation should be quantifiable rather than qualitative.”
The fifth factor is crucial. “Otherwise it’s similar to ‘The emperor has no clothes,’ Goldman explains. “You have some investigators showing examples and saying, ‘Don’t you see the defect?’ and everyone just nods their heads, afraid to disagree. What we need is something that can be available to the masses. It has to be relatively easy to perform and interpret.”
Echocardiography isn’t as far along with its quantification, because it is so dependent on technical acquisition, Goldman says.
“Contrast myocardial perfusion imaging may never be a modality that’s available to the masses,” he asserts. “It may be available at major centers that are going to take the time, patience and energy to commit to do this technology well. And that’s really the future, the same way that PET scanning is not available everywhere, perfusion imaging has to be performed very carefully to be effective.”
Jonathan Lindner, M.D., assistant professor of medicine at the University of Virginia Medical Center (Charlottesville, Va.), works on clinical applications with contrast, determining its use for diagnosis of coronary artery disease and for issues of myocardial viability. He also is targeting microbubble agents that can be retained within diseased tissue.
“The main thing that has pushed the technology forward is a much better understanding of the technology by the people who use contrast echo of the interactions between ultrasound and bubbles and a better understanding of the physiology,” Lindner says.
Because ultrasound images can destroy bubbles with high-power imaging, protocols were derived that use intermittent or triggered ultrasound imaging.
“With that you can actually look at different parameters of microvascular perfusion by looking at the amount of signal we get from bubbles at different pulsing intervals,” Lindner explains. By measuring the different amounts of signal coming from the bubbles, researchers can analyze that information to derive different measures of tissue or organ perfusion by looking at the rate at which the bubbles wash into the organ and how many bubbles are in the organ at steady state at very long pulsing intervals.
“People are starting to understand the different pieces of information contrast echo can give them and starting to use that in a much more efficient fashion to determine both perfusion and if the muscle is alive,” Lindner says.
The advantages of the technique are:
• It is not radioactive;
• It can be performed at the bedside portably;
• The information is available almost immediately to the interpreting physician;
• It is something that can be done over and over again without any problem; and
• Echo systems are fairly ubiquitous, while PET and SPECT are not.
Contrast-enhanced echo is ideal in certain technically challenging settings, such as patients in intensive care units or on mechanical ventilators, for the morbidly obese or for patients following surgery.
Neil Weissman, M.D., director of echocardiography at the Cardiovascular Research Institute at the Washington (D.C.) Hospital Center is involved with protocols using contrast to enhance the detection of wall motion abnormalities during stress echo.
“Right now, Optison is approved for endocardial border detection during resting echoes, and the natural step is to take it to other situations where it’s difficult to detect the endocardial border, and therefore assess whether there’s wall motion abnormalities and that’s stress echo,” Weissman says. “We’re using contrast during exercise stress echo to look for wall motion abnormalities, and it works very well.”
Elusive myocardial perfusion
Contrast has come of age for endocardial border definition and left ventricular opacification.
“Where I think the disappointment has come is that it’s not yet ready for prime time for the detection of myocardial perfusion,” Weissman says. “That’s why everybody is interested in contrast, because it has enormous potential to be a noninvasive marker and means of assessing myocardial perfusion.”
While Weissman characterizes himself as one of the more cautious or skeptical people when it came to predicting the time for clinical assessment of myocardial perfusion with contrast-enhanced echo, the skepticism is waning, in part due to second-generation contrast agents and the equipment manufacturers’ progress.
“Equipment companies have really optimized their machines for contrast, particularly for the detection of myocardial perfusion with contrast,” Weissman adds. “The real-time imaging for myocardial perfusion uses a very low mechanical index, and by [doing so], it doesn’t destroy the bubbles. So, I don’t think we’re ready for prime time yet, but we definitely are much closer than we were a year ago.”
The object is to see where the contrast is going. Modifications were necessary to ensure that the ultrasound waves weren’t reflecting off the tissue instead of the contrast.
As ease of use and information acquired from the technology increases, so does the likelihood of its eventual clinical viability.
“Right now, with the simple, basic technology, we can add a tremendous amount of information to our basic echocardiographic studies and avoid unnecessary testing and a lot of costs that don’t need to be paid,” St. Anthony Hospital’s Karam says. “We have gotten to the point that we have made it easier to use for everybody. Once we get the perfusion imaging available, it will complement the other information, and we will get as complete a study as you can possibly get with a very noninvasive tool.”
