Biochemist Alexei A. Bogdanov, Jr., Ph.D., and colleagues at Massachusetts General Hospital and Harvard Medical School are using a cell-culture model and magnetic resonance imaging (MRI) to develop their non-invasive method. They aim to detect and trace elevated levels of an enzyme that other research groups have linked to plaque instability and cardiac risk.
Bogdanov emphasizes much work remains before the technique could reach the clinic. However, results to date are so encouraging that he presented them today at the 228th national meeting of the American Chemical Society, the world’s largest scientific society.
If doctors have early warning that a particular plaque is unstable, they may be able to prioritize or target their patient’s treatment to that artery, perhaps averting an attack or at least minimizing its damage.
“When a plaque ruptures, it exposes a surface that is thrombogenic,” or clot-inducing, Bogdanov explains. “So instead of a partial blockage of the artery, a complete blockage can develop. That leads to oxygen deprivation in surrounding tissue and then, depending on location, either heart attack or stroke.”
The chemical sequence of events is still unclear, but at the root appears to be myeloperoxidase (MPO), an enzyme secreted by white blood cells infectious bacteria.
But studies have found MPO seems to exert another, unwanted effect in arterial plaques.
“A breakdown product of MPO triggers the release of an enzyme that degrades the fibrous cap surrounding a plaque,” says Bogdanov. Rupture occurs when the cap gets too thin.
Research published in the New England Journal of Medicine last year found that patients with chest pain and elevated levels of MPO in their bloodstreams were more likely to experience a serious cardiac event in the subsequent six months. But blood tests can’t pinpoint which plaques may be about to rupture.
The Massachusetts group’s approach potentially can. Bogdanov, an expert in molecular probe development, teamed up with John Chen, M.D., Ph.D., a research fellow in the hospital’s Center for Molecular Imaging Research. Together with two other colleagues at the research center, they began investigating ways to make rupture-prone plaques appear bright white in MRI images.
The researchers designed a probe molecule that myeloperoxidase prefers to oxidize over its usual targets in the body. To that molecule they attached a magnetic tag, the rare-earth metal gadolinium. When oxidized by MPO, the probe becomes highly reactive and polymerizes, concentrating the magnetic signal wherever MPO levels are elevated. The signal, then, pinpoints plaque that is most likely to rupture.
Another imaging group is lighting up white blood cells in plaques using iron particles, notes Chen. However, “our proposed method is more specific because we target an enzyme that is secreted only in abundance in unstable plaques,” he says.
For these initial tests the Massachusetts team engineered a plaque mimic from a gel of soluble connective tissue. When the gel was bathed with MPO, the magnetic probe generated up to a two-fold increase in MRI signal. That jump was enough to generate easy-to-spot white areas on the MRI image.
The group, which includes the center’s director, radiology expert Ralph Weissleder, M.D., Ph.D., hopes to move up to animal studies within weeks. Funding for the research comes from the Radiological Society of North America and the National Institute of Biomedical Imaging and Bioengineering, the newest branch of the National Institutes of Health.
The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary membership of more than 159,000 chemists and chemical engineers. It publishes numerous scientific journals and databases, convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.
The paper on this research, INOR 302, will be presented at 11:00 a.m., Monday, Aug. 23, at the Pennsylvania Convention Center, Room 108B, during the symposium, “The Chemistry of Biological Molecular Imaging.”
Alexei A. Bogdanov, Jr., Ph.D., is an associate professor of radiology at Harvard Medical School and a fellow with the Center for Molecular Imaging Research, Department of Radiology at Massachusetts General Hospital in Charlestown, Mass.
John W. Chen, Ph.D., M.D., Ph.D., is a fellow with the Center for Molecular Imaging Research, Department of Radiology at Massachusetts General Hospital in Charlestown, Mass.