Early investigations revealed that ECG localized in areas of heart muscle tissue (myocardium) with reduced blood supply (ischemia), while exhibiting extremely low uptake in normal myocardium. "The agent has been shown to be target-specific for ischemia," explained Cell>Point's president David Rollo. "This means that an area of ischemia imaged with Tc-99m ECG will present as a region of increased uptake."

This so-called hot-spot imaging is in contrast to the cold-spot imaging exhibited by myocardial perfusion imaging (MPI), the traditional means of evaluating heart conditions. Cold-spot imaging agents exhibit lower uptake in regions of ischemia, requiring doctors to look for black holes that represent areas of reduced blood flow. This is a difficult process and can contribute to diagnostic uncertainties. Studies to date have indicated that ECG appears to have improved sensitivity and specificity to ischemia, as compared with MPI.

Hot-spot imaging can utilize specific reconstruction software that includes, for example, OSEM reconstruction, attenuation correction, scatter correction and resolution recovery. This leads to improved spatial resolution over traditional back projection methods (7 mm versus 10 mm). The use of such reconstruction methods also enhances the contrast resolution, easing detection of abnormal regions.

"Further, hot-spot imaging has the advantage of further enhancing the target-to- background ratio by performing delayed imaging, which increase the uptake in the lesion as the background diminishes," Rollo added. "This is not possible with cold-spot agents."


Another major advantage of ECG imaging is that it has the potential to only require an at-rest image, while MPI needs one image with the patient at rest and one during exercise (stress). Acquiring these two images can take up to seven hours, often requiring the patient to return the next day. In contrast, Cell>Point estimates from Phase 1 studies that an ECG study may only take about one hour.

"We believe there may be cases where a stress study may be useful to enhance the region of ischemic uptake," Rollo noted. "For example, where the perfusion deficit creates marginal ischemia – a relative decrease in flow of less than 50%. This would use a physiologic stress agent as opposed to exercise stress. However, this will need to be validated in clinical studies."

ECG has also been shown to have ischemic memory, such that once the ischemic pathway is activated, it remains active until normal perfusion is restored in the affected myocardial region. This means that focal uptake of ECG will continue, potential enabling applications such as, for example, detection of ischemia in individuals that had previous cardiac symptoms that weren't evaluated at the time.

Early findings

The Phase 1 studies are now completed. The study focused on cardiac safety but also included proof-of-concept studies, with the aim of evaluating ECG's potential as an alternative to MPI. The ultimate goal was to determine whether ECG could provide more accurate diagnostic information than MPI without the need for stress imaging. Importantly, no cardiac adverse events related to the agent were reported.

The phase 1b study, which included 13 patients, also served to determine the agent's uptake characteristics. In normal subjects, no ECG uptake was seen in the myocardium. In abnormal patients, regions of ischemia (determined via MPI studies) exhibited well defined regions of ECG uptake. It was also shown that abnormal uptake could be detected within minutes of injection and that the rate of uptake over time appeared to be related to the severity of ischemia.

The Phase 2 objective will be to evaluate whether ECG, administered only as a rest imaging procedure, can provide at least comparable results to a full stress/rest MPI study using 99mTc-Cardiolite, a traditional MPI agent. "The phase 2 study is now in the development stage and is expected to begin in Q1 of 2012," Rollo told medicalphysicsweb.