Sep. 1, 1998 DURHAM, N.C.--Hawaiian crooner Don Ho's "tiny bubbles" is meant to tug at the heart strings. Now, researchers at Duke University Medical Center have created tiny bubbles of their own to help them understand how the heart is hurting. They hope the red-blood-cell-sized microbubbles filled with a special type of helium gas will eventually allow doctors to make more detailed measurements of blood flow in human organs, such as the heart.
The study, published in the Sept. 1 issue of the Proceedings of the National Academy of Sciences, shows it is feasible to suspend helium gas in the microbubbles, inject it into the blood vessels of a mouse, and take detailed magnetic resonance images (MRI) of the vessels. The research was supported by the National Institutes of Health, the National Center for Research Resources, the National Science Foundation, and the Whitaker Foundation.
The researchers are using "hyperpolarized" helium gas as a contrast agent to create high-resolution MRI images. They use lasers to "excite" or hyperpolarize the helium's nucleus. The hyperpolarized gas is inert to humans and animals, yet it yields a strong MRI signal.
"We see this as an opportunity to get structure and function information about blood flow and vessel health in a single MRI scan," said G. Allan Johnson, director of Duke's Center for In Vivo Microscopy and principal investigator of the study. "The microbubbles provide a unique sensitive signal source, with no background signal, which allows us to see blood vessels in great detail."
Johnson said the technique combines the strengths of several imaging technologies in one method. Like angiography or conventional MRI, it could be valuable in vascular imaging, and like positron emission tomography (PET) imaging, it could be used in perfusion studies, which measure how much blood is reaching tissue within an organ. Such studies are important in assessing, for example, whether arteries partially blocked by cholesterol plaques are dangerously reducing blood flow to the heart or other organs.
Right now, doctors measure blood flow to the heart, brain or other organs using PET, which uses radioactive tracers to measure flow. Such studies are useful, but offer fairly low resolution, as well as some exposure to radioactivity. In addition, the tracer stays in the bloodstream for minutes to hours and recirculates throughout the body every minute, reducing the accuracy of measurements. By contrast, the microbubble signal is "tapped" when the MRI magnet measures it, and is destroyed. It does not recirculate, Johnson said.
Also, typical MRI scanners measure protons in water, which is found almost everywhere in the body, meaning measurements have significant background signals. Helium is not normally found in the body, so the MRI picks up only signal, with no background.
"This research could open up a new clinical resource -- one in which vascular, perfusion and anatomical imaging can be done all in one place, in a single non-invasive study," Johnson said
In 1995, a group of researchers in Duke's Center for In Vivo Microscopy generated the first clear image of a human lung using inhaled hyperpolarized helium gas. That technique is now being tested in human clinical trials.
To extend that work, biomedical engineering graduate student Mark Chawla, Johnson, and a team of physicists and physiologists wanted to explore the use of hyperpolarized helium gas imaging in other areas of the body. Unfortunately, the gas doesn't dissolve well in blood, making it difficult to introduce into the blood stream.
To solve the problem, Chawla adapted a technique sometimes used by ultrasound radiologists. He created tiny microbubbles of helium in a solution of commercially available ultrasound contrast fluid. When he injected these microbubbles into anesthetized mice and took MRI images of the animals, he was able to create detailed images of the animals' arteries and veins.
"We believe these microbubbles, since they are about the size of a red blood cell, will be an accurate indicator of actual blood flow, whereas current liquid contrast agents can leak out of tiny blood vessels," Chawla said.
The microbubbles are different from larger air bubbles, which can cause embolisms, or blockages, of arteries. The microbubbles are very small -- from 2 to 30 microns. The red blood cell is about 5 to 8 microns. The microbubbles circulate along with blood cells throughout the bloodstream, ending up in the lung, where the helium is exhaled and the microbubbles dissipate.
While the scientists say their research is promising, they caution that more research is needed to make the technique applicable to human studies. They must show, for example, that the microbubbles won't coalesce into larger bubbles that could cause embolisms. This is unlikely, said Chawla, because ultrasound microbubbles have not done so, but safety studies will be done to rule out that possibility.
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