Based on a new study conducted by researchers from the Perelman School of Medicine at the University of Pennsylvania, a new MRI technique to map and track creatine at higher resolutions in the heart may enable clinicians and scientists to discover abnormalities and disorders earlier than standard diagnostic methods.
The preclinical findings reveal 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 distribute energy to all cells through creatine kinase reaction, including those involved in contraction of the heart. When heart tissue becomes damaged from a loss of blood supply, even in the very early stages, creatine levels drop. Researchers utilized this process in a large animal model with a method known as CEST, or chemical exchange saturation transfer, which measures exact molecules in the body, to track the creatine on an area basis.
The team, led professor of Radiology and director of the Center for Magnetic Resonance and Optical Imaging at Penn Medicine, by Ravinder Reddy, PhD, discovered that imaging creatine through CEST MRI offers higher resolution as opposed to basic magnetic resonance spectroscopy (MRS), a commonly used method for measuring creatine. However, its poor resolution makes it difficult to conclude precisely which regions 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. 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,” said Reddy.
Currently, magnetic resonance imaging (MRI)-based stress tests are also used to spot dead heart tissue, which is the warning sign of future problems (coronary artery disease, for example), yet its reach is limited. MRI is often combined with contrast agents to help light up problem areas, however it is often not sensitive enough to find ischemic (but not yet infarcted) regions with deranged metabolism.
"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," said professor of Surgery, and director of Cardiac Surgical Research at Penn Medicine, and study co-author, Robert C. Gorman, MD.
To showcase CEST's ability to detect heart disease, the researchers implemented the creatine CEST approach in an MRI scanner, in healthy and infarcted myocardium (muscle tissue in heart) in large animals. During the process, the nuclear magnetization of amine (NH2) creatine protons is saturated by a radiofrequency pulse from the MRI. After the exchange with water, the degree of saturation is observed as the water signal drops, and therefore the concentration of creatine becomes apparent (In the body, creatine is converted to creatinine, which can be measured through blood and urine tests and is an important tool for assessing renal function).
The team demonstrated that the creatine CEST method can record changes in creatine levels, and point out infarcted areas in heart muscle tissue, just as MRS methods can. However, they found, CEST has two orders of magnitude higher sensitivity than MRS.
“That advantage could help spot smaller damaged areas in the heart missed by traditional methods,” the authors noted.
Furthermore, 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 effectively track the molecule.
“The method can also be used to investigate alterations in normal heart function that are also seen in many other types of non-ischemic heart disease, such as abnormal cardiac hypertrophy, as well as disorders in the brain,” said Reddy.
"Though at much lower levels than in the heart, creatine levels change in the brain when abnormalities arise. 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,” he added.
CEST has been employed to image tissue pH, map proteins and specific gene expression, but this is the first time to the authors' knowledge 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," said Christina Liu, PhD, who oversees funding for molecular imaging research by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health.
Findings of the study have since been published online in Nature Medicine.