New York, NY - A new type of iodine-based contrast agent that interacts with activated macrophages may one day be used in humans during multislice computed tomography to identify plaques at risk of disruption and thrombus formation [1]. In a study published online April 8, 2007 in Nature Medicine, Dr Fabien Hyafil (Mount Sinai School of Medicine, New York, NY) and colleagues tested the contrast agent in rabbits and say the in vivo detection of macrophages could lead to improved diagnosis and prognosis, not only in atherosclerosis but also in other diseases.

If this technique or some related technique pans out, it could really change the way that we practice cardiology.

"The thought was to inject a contrast agent during CT, like we do when we do lumen imaging, but let's have that contrast agent be more specific, with properties that would let it interact with the vessel wall and target important cells or important plaque components," senior author on the study, Dr Zahi A Fayad (Mount Sinai School of Medicine), explained. "And one of the more important components of plaque is inflammation: we know that plaques that have a lot of macrophages in them are basically unstable plaques; that's widely accepted."

Commenting on the study for heartwire, Dr Deepak Bhatt (Cleveland Clinic, OH) called the concept "intriguing."

"If this technique or some related technique pans out, it could really change the way that we practice cardiology," Bhatt said. "We could really be preventive cardiologists."

The ability to noninvasively screen for high-risk, or "vulnerable," plaques is one of cardiology's holy grails. Fayad reminded heartwire that existing noninvasive imaging technologies are doing a better and better job of imaging the coronary lumen and identifying stenoses, but they cannot characterize the vessel wall. While MRI has shown promise for plaque characterization, the technology is still limited by respiratory and cardiac motion. In CT, the iodine contrast solution that is used can help identify stenoses, but it does not interact with the vessel wall, he said.

For their study, Fayad, Hyafil, and colleagues used an iodinated nanoparticulate contrast agent called N1177 (Nanoscan Imaging, Lansdale, PA). First, they tested the uptake of N1177 by mice macrophages in vitro, reporting that dark granules could be seen in the cytoplasm of macrophages incubated with N1177, but not in macrophages incubated with conventional CT contrast agent.

Next, investigators injected the N1177 contrast agent into nonatherosclerotic rabbits and evaluated its kinetics and distribution in the blood and macrophage-rich tissues, using serial CT imaging. This time, organs known to contain macrophages such as the liver and spleen were found to contain higher amounts of N1177, as evidenced by greater CT enhancement, than those same organs prior to contrast injection or following standard contrast dye injection.

Finally, using a model of atherosclerotic disease involving balloon injury to the aortas of hypercholesterolemic rabbits, investigators report that enhancement of atherosclerotic plaque in rabbit aortas, as seen on CT, was greater after injection of N1177 than after standard CT contrast dye. No such enhancement was seen in nonatherosclerotic rabbits after injection of either contrast agent. Subsequent pathological studies showed that N1177 uptake was indeed highest in aortic sections with the highest distribution of macrophages.

"The main purpose of this study was to do a very thorough characterization to figure out where these particles are landing—are they really landing in the macrophages or not," Fayad said. "In this study, we demonstrated that we can look directly at macrophages with CT, which is the ultimate, noninvasive coronary imaging system today."

That's Star-Trek-type thinking.

According to Bhatt, the future of such an agent and technique is based on several premises, starting with the assumption that macrophage-rich plaques are indeed high-risk plaques. "We don't really know for sure if these plaques are definitely the ones that are killing people," Bhatt said. "The only way to know that for sure would be to use this technology in humans, and assuming that it's not toxic and that there are no safety issues, identify those with vulnerable plaques based on this test and see if those folks do go on to have more heart attacks, strokes, and deaths. The next step would be to prove that that information is clinically useful. That is, you've identified a patient with vulnerable plaques—now, can you do an intervention to modify that risk? And once that is done, assuming it could be done, then the picture is complete."

He continued: "There are a lot of steps there between the basic science and the therapeutics, but I think the logic is sound."

Bhatt also pointed out that the use of a noninvasive screening test using CT is extremely attractive compared with other, invasive methods for characterizing plaques, such as IVUS or optical coherence tomography.

"If you take the 50 million people who are at moderate risk for atherosclerotic disease in the US and do an invasive procedure on them, that would break the bank, and beyond that, there is always going to be some degree of risk with an invasive procedure. That's not practical. . . . Of the different technologies I've seen—with the caveat that this study is really early and in an animal model—it just seems extremely promising."

The study authors note that, should the agent work in humans, it might eventually be possible to couple the diagnostic agent with some kind of therapeutic agent that could specifically target macrophages in various disease states, not just atherosclerosis, but also infectious and autoimmune diseases where macrophages play a role.

"That's Star-Trek-type thinking," Bhatt acknowledged, "but I think a lot of doctors are Star Trek fans. In the back of our minds, we're all thinking it should be possible to get there. This study really did excite me because it's really a first step toward Star-Trek-type therapy.