Synthetic molecule helps detect heart attack in the making

A new bright spot in heart disease research may soon allow physicians to peer directly into patients' blood vessels and find dangerous cholesterol-filled plaques before they rupture and cause a heart attack.

Scientists at New York's Mount Sinai Medical Center and the New York University School of Medicine, under the direction of Dr. Edward A. Fisher, M.D., Ph.D., and Dr. Zahi A. Fayad, M.D., Ph.D., have developed a synthetic molecule that delivers an imaging enhancer to cholesterol-filled cells embedded in the arterial walls. In animal tests, the enhancer improved cholesterol detection by 79 percent.

The new technique would allow physicians to diagnose unstable plaques before they rupture, and save lives by identifying the highest risk patients, says Fayad, director of the Mount Sinai cardiovascular imaging research laboratory.

When used with magnetic resonance imaging (MRI), the plaques appear bright, allowing physicians to measure inflammation in artery walls and assess overall cholesterol buildup. The technique also could be used to follow a patient's response to therapy.

Details of the new technique were described today at the 233rd national meeting of the American Chemical Society, the world's largest scientific society, by David Cormode, Ph.D., a postdoctoral researcher at the Mount Sinai School of Medicine, who worked with the group.

Efforts to view cholesterol buildup in arteries have long been hindered by the inability to deliver imaging agents directly into plaques. Even in diseased arteries, the lining is often intact, preventing particles from entering the plaque.

But high-density lipoprotein, also known as HDL or 'good' cholesterol, moves freely through this barrier to carry cholesterol out of plaques to the liver, where it is eliminated from the body.

Using an artificially synthesized peptide, the scientists devised a way to construct HDL-like molecules that could travel through the barrier and attach to the cells in which cholesterol accumulates. The peptide, called 37pA, mimics a major protein found in HDL and contains two structures required for lipid binding.

Cormode found a way to reconstitute the peptides with phospholipids similar to those found on the outer shell of HDL. The result: a disc-like structure with the peptides on the outside of a phospholipids bilayer.

He then spiked the outer phospholipid layer with chelated gadolinium, a metal chemically bonded to organic molecules to render it nontoxic. The gadolinium, long used in blood contrast agents, allows the cholesterol to stand out in an MRI image.

Twenty-four hours after injecting the HDL-like molecules into mice, MRI tests showed that measuring and assessing cholesterol-filled cells in the arterial walls yielded a 79 percent increase in detection compared with the initial baseline images taken the day before. Mice without the plaques showed no enhancement of imaging.

The effects of the contrast agent provided a viewing window of up to 48 hours. In addition, the strength of the signal correlated with the presence of the macrophage cells in which cholesterol accumulated. The more cholesterol-filled cells in an area, the brighter the signal.

Development of the technique may help physicians better assess the risk of heart attack or stroke for individual patients, and follow patients to see how they're responding to therapy.

"For patients with a heavy plaque burden, we can start aggressive treatment to lower low-density lipoproteins and then do a repeat scan to see if the plaque is regressing," says Fisher, who is Leon H. Charney Professor of Cardiovascular Medicine at New York University School of Medicine.

Though the procedure requires more testing, Fayad says the technique could become part of standard clinical practice in the next few years.