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MRI-Measured Creatine Levels May Detect
Heart Problems Earlier

A new MRI method to map creatine at higher resolutions in the heart may help clinicians and scientists find abnormalities and disorders earlier than traditional diagnostic methods, researchers at the Perelman School of Medicine at the University of Pennsylvania suggest in a new study recently published online in Nature Medicine. The preclinical findings show an advantage over less sensitive tests and point to a safer and more cost-effective approach than those with radioactive or contrasting agents.

Creatine is a naturally occurring metabolite that helps supply energy to all cells through creatine kinase reaction, including those involved in heart contractions. When heart tissue becomes damaged from a loss of blood supply, even in the very early stages, creatine levels drop. Researchers exploited this process in a large animal model with a method known as chemical exchange saturation transfer (CEST), which measures specific molecules in the body, to track the creatine on a regional basis.

The team, led by Ravinder Reddy, PhD, a radiology professor and the director of the Center for Magnetic Resonance and Optical Imaging at Penn Medicine, found that imaging creatine through CEST MRI provides higher resolution compared with standard MR spectroscopy (MRS), a commonly used technique for measuring creatine. However, its poor resolution makes it difficult to determine exactly which areas of the heart have been compromised.

“Measuring creatine with CEST is a promising technique that has the potential to improve clinical decision making while treating patients with heart disorders and even other diseases as well as spotting problems sooner,” Reddy says. “Beyond the sensitivity benefits and its advantage over MRS, CEST doesn’t require radioactive or contrast agents used in MRI, which can have adverse effects on patients, particularly those with kidney disease, and add to costs.”

MRI-based stress tests also are used to identify dead heart tissue, the warning sign of future problems such as coronary artery disease, but their reach is limited. MRI often is coupled with contrast agents to help light up problem areas, but it is often not sensitive enough to find ischemic (but not yet infarcted) regions with deranged metabolism, Reddy says.

“After a heart attack, different regions of the heart are damaged at different rates. This new technique will allow us to very precisely study regional changes that occur in the heart after heart attacks, enabling us to identify and treat patients at risk for developing heart failure before symptoms develop,” says study coauthor Robert C. Gorman, MD, a professor of surgery and the director of cardiac surgical research at Penn Medicine.

To demonstrate CEST’s ability to detect heart disease, the researchers applied the creatine CEST method in an MRI scanner for both healthy and infarcted myocardium in large animals. In the process, a radio-frequency pulse from the MRI saturated the nuclear magnetization of amine (NH2) creatine protons. After the exchange with water, the degree of saturation was observed as the water signal dropped and thus the concentration of creatine became apparent.

The team showed that the creatine CEST method can map changes in creatine levels and pinpoint infarcted areas in heart muscle tissue just as MRS methods can. However, they found that CEST has two orders of magnitude higher sensitivity than MRS. That advantage could help spot smaller damaged areas in the heart that are missed by traditional methods, the authors say.

In addition, the team used CEST to map increases in creatine over time by imaging human subjects as they flexed their calves while inside an MRI scanner to demonstrate the technology’s ability to correctly track the molecule.

The method also can be used to investigate alterations in normal heart function that are seen in many other types of nonischemic heart disease, such as abnormal cardiac hypertrophy, as well as disorders in the brain, according to Reddy. “Though at much lower levels than in the heart, creatine levels change in the brain when abnormalities arise,” he says. “Given the heightened resolution of this technique, this presents an opportunity for studying brain disorders with deranged creatine metabolism without the use of contrast agents as well.”

CEST has been used to image tissue pH and map proteins and specific gene expression, but this is the first time, to the authors’ knowledge, that it has been used to study heart tissue.

“The ability to visualize heart muscle viability at high resolution without radiation exposure or the injection of a contrast agent is a significant advancement. It could allow doctors to detect small areas of damaged heart tissue early in the course of a disease when treatments are most likely to be effective,” says Christina Liu, PhD, who oversees funding for molecular imaging research by the National Institute of Biomedical Imaging and Bioengineering.

— Source: Perelman School of Medicine at the University of Pennsylvania