The majority of the estimated 1 million myocardial infarctions (MIs) that occur each year in the United States arise from structurally mild coronary artery plaques that suddenly rupture and close the artery in previously asymptomatic patients, causing MI or stroke.
In 2011, a large Phase III trial, called Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT), looked at whether angiography and intracoronary imaging could detect these vulnerable plaques before they rupture, enabling early intervention. The trial demonstrated that standalone structural imaging is useful, but not clinically ready to predict which plaques are vulnerable to rupture and MIs. To improve the ability to predict and prevent plaque rupture, investigators at Massachusetts General Hospital are developing a novel imaging technique intended to complement structural imaging with a new dimension of information about the plaque’s biological processes, using molecular imaging.
Combining Structural and Molecular Imaging
The intravascular angiography imaging technologies that are currently used in the clinical setting focus on the external physical structure of the plaques and vessels. But the characteristics that influence how plaques grow and whether they rupture are fundamentally rooted in molecular and, in particular, inflammatory processes. Structural imaging alone cannot detect these processes, so they cannot make the distinction between biologically vulnerable and stable plaques.
The technique under development at Mass General combines optical frequency domain imaging (OFDI) with fluorescent imaging using optical near-infrared fluorescence (NIRF) molecular imaging. In NIRF imaging, injectable NIR fluorescent probes label molecules that indicate plaque instability, including enzymes, fibrin, lipids, macrophages and inflammatory cytokines. Probes for both beams of light (OFDI and NIRF) are placed in the same catheter and focused on the same location in the coronary arteries at the same time. The combination provides simultaneous information about the structure and the molecular biology of a plaque.
Pre-Clinical Testing of OFDI-NIRF
Farouc Jaffer, MD, PhD, an interventional cardiologist with the Mass General Institute for Heart, Vascular and Stroke Care, is currently testing OFDI-NIRF in animal models, with plans to take this work into patients within the next two years. By working first in rabbits and now in swine, he is finding that OFDI-NIRF can capture information, including macrophage protease activity that may be more predictive of plaque rupture. He is collaborating with Guillermo Tearney, MD, PhD, a pathologist and researcher in the Wellman Center for Photomedicine at Mass General, in an effort to bring intravascular optical imaging systems into human arteries.
Implications for Patient Management
The researchers expect that OFDI-NIRF, once translated to human subjects, will improve patient management by detecting vulnerable plaques in high-risk patients early enough to intervene. As the OFDI-NIRF method is invasive, requiring the injection of fluorescent contrast agents and intravascular imaging, it would not be used as a first-line screening or on patients who have already been diagnosed with a closed artery. However, the procedure may become justified for evaluating coronary plaques within high-risk patients, including those with prior heart attacks or angina. About one-third of MIs each year occur in patients who had a previous MI. In addition, for the many patients who will receive intravascular OFDI structural imaging during cardiac catheterization, adding the NIRF molecular component will be a relatively safe and efficient procedure that could ultimately save lives.
Another application for OFDI-NIRF may be for diagnosing stent injury, in particular unhealed stents. The technique could identify both a newly implanted stent device and the type of tissue around it, and also identify the inflammatory activity at the same location.
OFDI-NIRF may also facilitate new drug development and testing for coronary artery disease, Dr. Tearney predicts. The technology could help in pre-clinical testing of a drug candidate by elucidating the molecular mechanism of action. OFDI-NIRF could simplify the clinical trial process as well by serving as an intermediate biomarker that predicts outcome with good reliability. Because of the lack of an existing intermediate biomarker, trial investigators currently must follow large patient cohorts over many years to determine the appropriate outcome metric, making such trials expensive and difficult to conduct.
The combined structural and molecular imaging technique is broadly applicable to different organ systems and other diseases, including cancers of the colon, esophagus and lung. Uses will also likely expand as new imaging agents providing different types of contrast for specific cells and molecular activities are developed.
|Farouc A. Jaffer, MD, PhD
|Guillermo J. Tearney, MD, PhD