Looking Into the Vessel: The More You See, the More You Want to See
Morton J. Kern, MD, FACC, Associate Editor, JACC: Cardiovascular Imaging,
Jagat Narula, MD, PhD, FACC, Editor-in-Chief, JACC: Cardiovascular Imaging*
University of California, Irvine, Irvine, California.
From the first time man pondered his universe, the quest to see better has never ceased. The telescope permitted a better view of the heavens and the earth. The microscope brought a new inner world into view. New ways of imaging created new science. The quest continues in our time and in our field of endeavor.
Imaging applied to one of the greatest advances in cardiology, intravascular stenting, has led us to better results. No one would forget that the intravascular ultrasound image demonstrating that the full apposition of the stent struts to the vessel wall reduced abrupt thrombotic occlusion and permitted us to stent patients without the impossible task of warfarin anticoagulation and its bleeding complications (1). As a consequence, interventional cardiologists now implant the more advanced stents routinely. However, the role of imaging became the key to understanding the greatest downside of drug-eluting stenting, namely abrupt thrombotic occlusion (2,3). Using electron microscopy, Finn et al. (4) recently demonstrated that the increased number of stent struts uncovered by endothelium was directly related to thrombotic subacute death. Ongoing imaging studies now describe the reconstitution of the neoendothelium (5,6), the character of endothelial dysfunction (7), and the importance of the nature of underlying atherosclerotic plaque (8–10).
Imaging at the macroscopic level refers to the modalities permitting direct visualization of the coronary artery and includes principally angiography (including standard invasive angiography and noninvasive computed tomography and magnetic resonance angiography) and angioscopy. After setting the stage and defining the necessity to see more, advances in radiographic techniques utilizing flat-panel digital systems and computed tomographic angiography now permit increased resolution to the submillimeter level and provide enhanced images of the vessel lumen and vessel wall. These images are critically important to the better diagnosis of dissection, thrombus, and plaque vulnerability. Nonetheless, the inherent limitations of radiographic resolution highlight the inability to give microscopic information about the diseased vessel. Better imaging with visible light transmitted through catheter-based optical fibers permits a direct macroscopic examination of the vessel surface. Using fiberoptic bundles incorporating 6,000 fibers with an outer diameter of 0.75 mm, 70° of field of view, and image depth ranging up to 5 mm from the tip, angioscopy shows fine detail of plaque topography, cholesterol quantitation and distribution (through color intensity), and the likelihood of superficial thrombosis. Although confirming many suppositions about the mechanisms of acute coronary syndrome, angioscopy cannot be expected to yield more than the luminal surface data. The requirement of a blood-free field for optimal imaging has restricted widespread use of this technique. While a side-viewing imaging catheter is under development, this technique will likely remain confined to the macroscopic world. Whether angioscopy can provide new information will depend on the ingenuity of investigation and the ability to manipulate the transmitted signal light to the vessel coupled with particular novel biologic markers (11).
On the other hand, the microscopic characteristics of the vessel have been uncovered by high-frequency imaging using reflected ultrasound and coherent light. Such technologies have already proven the intimate relationship between the atherosclerotic substrate and the healing response particularly relevant to the early and late clinical outcomes of the stented patient. Enhanced acoustic tomographic images using either pulse-echo sequence or vectors have resulted in improvements in the resolution, depth of penetration, and attenuation of the acoustic tissue signature. Conventional intravascular ultrasound (IVUS) catheters utilize frequencies from 20 to 40 MHz with resolution of approximately 20 to 40 µm, respectively. Depending on factors such as emitted pulse length and position of the imaging structure, radial resolution may range from 40 to 150 µm. By color-coding ultrasound radiofrequency backscatter, IVUS data can be correlated to the vascular histology of the normal and diseased arteries. This method—virtual histology—uses algorithms to generate a color map of the vessel structure content coding for fibrous, necrotic, calcific, and fibrofatty tissue (12,13). Significant correlations between virtual histology ultrasound frequency maps with corresponding histopathology from in vivo specimens have been validated by direct atherectomy (13). Likewise, the study of plaque composition and associated coronary artery remodeling in both culprit and nonculprit lesions have demonstrated the quantity and distribution of thin-cap fibroatheroma thought to be the most vulnerable, rupture prone morphology. The virtual histology findings of a focal necrotic core >10% cross-sectional area of the plaque without overlying fibrous tissue defining the thin-cap fibroatheroma was significantly more prevalent in patients with acute rather than stable coronary syndromes (14). The current limitations of virtual histology include low resolution (about 250 µm), no classification for thrombus, blood, or intimal hyperplasia, inability to image through calcific deposits, and the lack of outcome data relating virtual histology findings to various clinical presentations. It is likely that the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, a natural history trial using 3-vessel imaging, IVUS, palpography, and virtual histology in 700 acute coronary syndrome patients with a 5-year clinical follow-up will address the clinical relevance of virtual histology.
Using phased reflection analysis of the high frequencies of coherent light, a fiberoptic catheter-based system can also produce tomographic vessel images. Optical coherent tomography (OCT) images have a resolution of 15 µm axially and 25 µm laterally, approximately 10-fold better than that of the ultrasound image (15,16). While improved resolution is traded for less depth of penetration, the OCT image offers new insight into the vessel and its surface and near surface substructures. Initial OCT image acquisition was limited by requiring prolonged vessel occlusion and blood replacement with an optically clear flush solution to produce a blood-free field. To increase scan image acquisition time, an optical frequency domain imaging system can now measure the optical echo time, the delay from a light source whose output is rapidly changed over a wide spectrum of wavelengths. The fast Fourier transform algorithm permits the generation of a frequency domain or wavelength dependent dataset and increases the image acquisition rate from 20 to 80–110 frames/s permitting comprehensive scanning of long-vessel segments during very brief flush clearance without the need for vessel occlusion (17). Clinical studies involving the thin-cap fibroatheroma and neoendothelization after stenting are likely to provide new information beyond stent healing. The manuscript by Kubo et al. (18), in this issue of iJACC (JACC: Cardiovascular Imaging) highlights that OCT not only allows better definition of vessel wall characteristics, it may shed light on pathogenesis and prognostic outcomes of various interventional processes. The authors of this study propose that the stents may not find optimal apposition in vulnerable and ruptured plaques. Thus, drug-eluting stents may not allow optimal neointimal formation and become a nidus for delayed stent thrombosis. Although this seems to be a very logical proposal, all patients were on dual antiplatelet therapy and the follow-up in their study was not long enough to establish this presumption (18).
Incrementally to the OCT, intravascular reflectance spectroscopy examines the interaction of emitted light and chemical composition. Several spectroscopic modalities such as near-infrared imaging and Raman and fluoroscopic spectroscopy employ diffuse reflectance to derive content of phosphates, calcium, and cholesterol (19). Near-infrared spectroscopy analyzes the light absorbance as a function of wavelength (70 to 250 nm) specifically characterizing the type of material in this spectra. A near-infrared spectroscopy catheter system utilizing catheter-based fiberoptic bundles to collect reflected light generates an image of the cholesterol spectra across the vascular surface during catheter pullback (20), and has demonstrated a more specific chemical link to the vulnerable artery and patient.
Similarly, an intravascular catheter MRI has been developed to provide a stronger contrast between the soft tissue components previously obscured by a high signal to noise ratio. An intravascular MRI coil has defined atherosclerotic plaque characteristics in animal models, and a miniaturized coil detector from a guidewire has been validated in ex vivo and in vitro arteries (21). Although there is a theoretic concern regarding local heat generation by MR imaging, animal studies have not demonstrated safety issues with regard to coagulation or intimal thermal injury (22). New approaches using catheter-based magnets and coils could also permit stand alone imaging with no external scanner (23). Based on physiologic data, other imaging technologies, such as intravascular thermography and palpography with stress-strain relationships, may provide new insights beyond microscopic morphology (24).
The successes of intravascular imaging techniques in defining morphological characteristics have stimulated a possibility of exploiting these technologies for identification of molecular characteristics and the extent of plaque inflammation. Molecular imaging has employed targeting with site-specific enhancement with antibodies, peptides, polysaccharides, and aptamers (25). A number of targets have included adhesion molecules, chemotactic peptides, matrix metalloproteinases, and cell death markers. Intravascular optical and nuclear imaging is being proposed using targeting tracers developing on the success of noninvasive imaging (26,27).
A desire to identify the potential lethal aspects of atherosclerotic plaques is driving investigators into more innovative imaging technology. Seeing more through novel imaging will verify and validate pathology and mechanisms. Seeing more will permit atherosclerotic researchers to identify best therapies for better outcomes. The clinical value to medicine will reside in the linkage between image and outcome, the study of which will remain at the forefront of our attack on acute and chronic coronary heart disease. Multimodality imaging with catheter-based structural, microscopic signal processing and molecular imaging will certainly fulfill at least part of our dream to see the future.
* Address correspondence to: Jagat Narula, MD, PhD, FACC Editor-in-Chief, JACC: Cardiovascular Imaging 3655 Nobel Drive, Suite 630 San Diego, California 92122 (Email: narula{at}uci.edu).
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