Cardiovascular disease is the leading cause of mortality in the United States (777,000 cases in 2010).1 In a large percentage of patients, the first occurrence of coronary artery disease is either sudden death or acute myocardial infarction. Approximately 20–30% of the patients with acute myocardial infarction die before they get to a hospital. It is known that certain unstable atherosclerotic plaques, called vulnerable plaques, give rise to acute coronary events. Plaque stability is dependent on various factors including macro/microscopic structure, as well as chemical/molecular composition. Therefore, the thorough characterization of coronary plaques can potentially enable the identification of the highest risk lesions in patients.
One type of vulnerable plaque, the thin-cap fibroatheroma (TCFA), has been shown to be the culprit lesion in ∼80% of sudden cardiac deaths. The TCFA is typically a minimally occlusive plaque characterized by a thin <65μm fibrous cap, a large necrotic lipid pool, and activated macrophages near the cap. An approach to study the evolution of vulnerable plaques is non-invasive (or intracoronary) imaging of individual lesions at multiple time points. Unfortunately, the microscopic features of vulnerable plaques are not reliably identified by conventional technologies such as intravascular ultrasound,2 computerized tomography,3 and magnetic resonance imaging,4 nor with experimental intracoronary modalities.5 Among various modalities to detect vulnerable plaques, optical frequency domain imaging (OFDI) appears to be one of the most promising.6
Figure 1. Microstructural and fluorescence clinical system capable of intravascular imaging. The tray has the main components for the microstructural subsystem (swept-source laser, interferometer, polarization-diverse receiver, and acquisition platform).
OFDI is a derivative of optical coherence tomography. It provides high-resolution, high-speed, and depth-resolved cardiovascular information by performing frequency-domain interferometric optical ranging. OFDI can be roughly considered an optical analog of ultrasound imaging. By using IR light, however, OFDI can provide much higher resolution and tissue contrast. While OFDI has been documented to be capable of identifying lipid in arterial tissue, it is not established for distinguishing necrotic core, one of the key features of TCFA. We have, therefore, proposed to complement OFDI information with fluorescence data to enable comprehensive evaluation of coronary pathology in vivo.7
Figure 2. Overlap of microstructural and fluorescence information to validate the catheter capacity to detect both signals simultaneously. The inset shows the ball lens employed (fiber diameter is 125μm).
We designed and built a multimodal clinical system capable of intravascular imaging. The system is composed of a combined microstructural and fluorescence console, a rotary junction to spin and retract the optical probe, and a new generation of intravascular catheters. The main components for the microstructural imaging subsystem are a swept-source laser, fiber-based interferometer, polarization-diverse receiver, and acquisition platform. For the fluorescence subsystem, we employed a visible laser and a photomultiplier tube as the detector. The system acquires cross-sectional images of the sample at 100fps, where each frame is composed of (1024) microstructural depth-profiles and fluorescence data. (see Figure 1).
To use our multimodal system, it is indispensable to design and construct a suitable catheter. We designed, built, and tested a double-clad, fiber-based multimodal catheter. At the distal end is a fused ball lens (see Figure 2 inset), which focuses microstructural and fluorescence-excitation light onto the sample. The outer diameter of the catheter, including sheath, is less than 1mm, in accordance with the size of a human coronary lumen. We tested the multimodal catheter in a phantom experiment. Fluorescent dye was fixed at the outer surface of a cylindrical vessel, and the multimodal catheter was placed inside the lumen. A rotary junction was used to perform a helical scan. Figure 2 shows the overlap of microstructural and fluorescence information, as well as the microstructure of the ball lens edge, sheath, cylindrical vessel, and fluorescent dye. Dye fluorescence was detected and rendered on the image. Fluorescence and microstructural coregistration, as seen from the location of the dye on the microstructural image, validates the capacity to detect both signals simultaneously.
One of our long-term goals is to provide a single intracoronary device that thoroughly characterizes the features of coronary lesions, as is needed for optimal interventional cardiology. Our combined microstructural and fluorescence technology is a step in this direction. In the near future, we aim to perform the first clinical study of concurrent microstructural and molecular arterial imaging. We believe that this study will help make it possible to perform near IR fluorescence molecular imaging with targeted agents.
Gary Tearney has rights to receive royalties and non-clinical sponsored research from Terumo Co., Japan. The authors gratefully acknowledge the support of J. Gardecki. This research was supported in part by the National Institutes of Health (R01HL076398 and R01HL093717).
Paulino Vacas-Jacques, Hao Wang, Ehsan Hamidi, Gary Tearney
Wellman Center for Photomedicine
Massachusetts General Hospital
Paulino Vacas-Jacques is a research fellow at the Wellman Center for Photomedicine and Harvard Medical School focusing on the implementation of mesoscopic optical tomography, as well as combined optical frequency domain imaging and molecular/chemical imaging for intravascular applications. His research interests include frequency domain optical spectroscopy and lab-on-a-chip technologies.
Hao Wang is a PhD candidate from the Department of Biomedical Engineering at Boston University. His research focuses on the improvement of coronary diagnosis by the extraction of molecular information from atherosclerotic plaques using optical spectroscopy methods and the combination of these methods with optical coherence tomography (OCT).
Ehsan Hamidi received his PhD degree in electrical engineering at Purdue University in 2010. He is a research fellow at the Wellman Center and an affiliated postdoctoral fellow at Harvard Medical School working on multimodality optical frequency domain and fluorescence imaging and spectrally encoded endoscopy.
Gary Tearney is a pathologist and an engineer who has spent more than 20 years developing and validating new imaging technologies to combat human disease. He directs a laboratory that is responsible for first in-human studies with pulmonary, coronary vessel, and esophageal OCT devices. He is currently the principal investigator of about 10 clinical trials that are examining the utility of these technologies. He also serves as organizing chair of SPIE's Diagnostic and Therapeutic Applications of Light in Cardiology and Endoscopic Microscopy annual conferences. He serves on the program committee for SPIE's Optical Coherence Tomography and Coherence Domain Optical Methods in Biomedicine conference.
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