Lighting Up the Artery: Intracoronary Imaging with Optical Coherence Tomography

Introduction Atherosclerotic plaques can develop in the early years of life and build up for years before they become clinically apparent. Often, an acute coronary syndrome (ACS) is the first indication of underlying atherosclerotic disease. These cardiac events are frequently triggered by vulnerable plaques, currently defined as nonobstructive, lipid-rich, thin-cap fibroatheroma (TCFA). Percutaneous coronary intervention (PCI) has always focused on management only after plaque rupture has produced an acute event, because current imaging technology does not possess sufficient resolution to reliably identify these vulnerable plaques before rupture occurs. Noninvasive modalities, such as multidetector-row computed tomography (MDCT), coronary angiography and magnetic resonance imaging (MRI), are limited in resolution when compared to more invasive modalities. Angiography, though invasive, has a resolution of > 500 µm, and is thus very limited when it comes to visualizing the components of atherosclerotic plaque.1 Intravascular ultrasound (IVUS), an intracoronary modality currently in use, has provided in vivo (in a living organism) visualization of coronary vessel pathology. With IVUS, even the image resolution of approximately 150 µm remains a daunting hurdle regarding the visualization of vulnerable plaque. Other intracoronary modalities under investigation are optical coherence tomography (OCT), intracoronary thermography, near-infrared spectroscopy and intracoronary MRI. Of these, OCT has the highest imaging resolution (in the range of 10 to 20 µm) and therefore has the greatest potential to detect vulnerable plaque and help guide PCI. Theory OCT is a recently-developed, catheter-based intravascular imaging technology that provides micron-scale resolution. It is the laser light equivalent of ultrasound imaging, measuring the intensity of backscattered infrared light rather than sound waves, and translates these optical echoes into a high-resolution, two-dimensional tomographic image. Unlike ultrasound, the echo delay time cannot be directly measured due to the high-speed propagation of light. Therefore, high-resolution cross-sectional images are obtained according to the principle of low-coherence interferometry (Figure 1).2 In this principle, a beam of light is divided by the beamsplitter into a reference arm and a sample arm. In the reference arm, light is directed at a moving mirror, while light in the sample arm is directed at the tissue of interest. The beams are reflected back by the reference mirror and the tissue, and recombined at the beamsplitter. When light in both arms travels the same optical distance and is recombined, it causes the greatest interference to occur. When light from both arms doesn’t travel the same distance, the interference is less. The detector measures the intensity of the interference and uses this information to create an image of the arterial wall. The motion of the mirror enables measurement at different depths within the arterial wall. Historical Development OCT was originally developed in the early 1990s at the Massachusetts Institute of Technology in Cambridge, Massachusetts, as an imaging tool in ophthalmology to assess the retina. Extension of this technology into other fields soon followed once it was found to be capable of imaging nontransparent tissue. Brezinski and colleagues first recognized OCT as a feasible tool for intravascular imaging in the mid-1990s, when they demonstrated a successful OCT image of a cadaveric left anterior descending (LAD) artery with good histopathology correlation.3 Subsequent advances in OCT technology enabled faster image acquisition rates, sufficient for in vivo intracoronary imaging.4 Eventually, this led to the first publication of OCT intracoronary imaging in human patients in 2002.5 One major challenge of intracoronary OCT imaging is providing an efficient delivery system to ensure safe insertion of the OCT probe into the target artery and provide optimal imaging with clearance of blood from the field of view (the presence of blood significantly weakens the ability of OCT to provide a quality image). The OCT probe was originally developed by modifying a commercial IVUS catheter. The core of the IVUS catheter was replaced by a single optical fiber with a microlens and microprism attached at the distal end. Unlike a rotary IVUS catheter, the OCT catheter does not use a torque cable. Instead, the optical fiber rotates and translates inside a plastic sheath. Investigation into a more efficient OCT catheter has led to a microelectromechanical (MEMS), motor-based OCT catheter design. By rotating only the optical tip of the catheter, the MEMS design can eliminate unstable vibration and uneven rotational speed while increasing scan speed. Although the diameter of the motor is currently 1.5 mm, the MEMS design is still considerably too large for intracoronary application at this stage.2 First-generation or what is referred to as “time-domain” OCT systems, which are currently on the market, employ a catheter delivery system integrated within an occlusion or angioplasty balloon catheter (Figure 2). The imaging probe is inserted through the guidewire lumen. Clearance of blood is achieved by briefly inflating the balloon and flushing the residual blood from the target vessel before imaging. While traditional OCT can only examine surfaces one point at a time, the second generation of OCT products, often referred to as optical frequency domain imaging (OFDI), can look at over 1,000 points simultaneously, allowing for rapid data acquisition. With these faster, next-generation OCT systems, the need for balloon occlusion of the proximal vessel has been eliminated. Instead, operators rely only on routine injection of contrast/saline solution during angiography to provide the necessary optical window for imaging. Advantages of OCT OCT has the highest imaging resolution of any currently-available technology. Table 1 summarizes the specification of various intracoronary imaging technologies. Cross-sectional resolutions of catheter-based OCT systems are in the range of 10–20 µm. In a study comparing IVUS and OCT intracoronary imaging in human patients, the mean axial resolution for OCT imaging was 13 µm compared with the IVUS axial resolution of 98 µm.6 Unlike IVUS, OCT allows for better visualization of calcified areas without the problem of acoustic shadowing inherent in IVUS. Because of its superior resolution, OCT has the capability to identify the key features of a vulnerable plaque, such as the thin fibrous cap and lipid-rich plaques (Figure 3), and potentially detect and quantify the number of macrophages in atherosclerotic plaques.7 The higher resolution afforded by OCT also offers a number of advantages in guidance and surveillance of stent implantation when compared with IVUS, which is hampered by echogenic shadow from metal struts. OCT provides a more detailed view of the stent struts and their positions relative to the vessel wall. This allows for easier identification of poor apposition, wall dissection, stent fracture and tissue prolapse (Figure 4). In 42 imaged stents in 39 patients, OCT consistently outperformed IVUS in the detection of dissection, tissue prolapse and incomplete stent deployment.8 OCT imaging also enables detection of restenosis of the inner layer of the vessel (Figure 5). It can also play an important role in image guidance of other coronary interventions, such as atherectomy. Current Challenges Major limitations of endovascular OCT are its signal attenuation by blood and its limited penetration depth in tissue. Hemoglobin and red blood cells (RBC) weaken, or attenuate light from the OCT catheter through absorption and scattering of light, respectively. Several techniques have been developed to overcome this limitation and have focused on displacing the blood medium with saline flushes or balloon occlusion. Saline flushes limit scan times to approximately two seconds per flush, thereby restricting the length of vessel segments that can be imaged. A previously published technique employed brief proximal vessel occlusion and saline flush to remove blood from the imaging window. Although feasibility and safety data have been documented using this technique,9 there are always potential ischemic complications with balloon occlusion and possible fluid overload with saline flushes. A possible alternative approach is isovolumic replacement of blood with an optically transparent, hemoglobin-based blood substitute, which has been tested in mouse myocardium.10 Because of its oxygen-carrying capacity, immiscibility (i.e., not capable of being mixed) resulting in the effective clearance of blood, and optical transparency at near infrared wavelengths, the use of a blood substitute has the potential to improve intravascular optical imaging applications. With the next-generation OFDI systems, attenuation by blood will be of minor concern. The current time-domain OCT systems have a sampling rate of just 4–16 frames/second, while the next-generation OFDI system can increase its sampling rate to 80 frames/second.2 This permits high-speed acquisition and real-time imaging, reduces motion artifacts, and offers larger tissue-volume screening. Importantly, the next-generation OFDI system is fast enough to image long vessel segments while performing a 50–60 mm pullback, removing the need for balloon occlusion. Because faster pullback substantially decreases the amount of time needed to clear blood from an artery, image acquisition can occur over the brief seconds that arteries are filled with contrast during routine angiography. Infrared light utilized by OCT does not reach the back wall of thick atherosclerotic lesions. Penetration in nontransparent tissues is restricted to a depth of 2–3 mm, which is adequate for evaluation of the intima and plaque composition and to make thin-cap measurements. Unlike IVUS, which has greater penetration depth, OCT is unable to assess positive remodeling and is unable to fully image the total lipid pool in plaques with large necrotic cores, an important feature of vulnerable plaque. Sawada and colleagues evaluated the feasibility of the combined use of virtual histology IVUS (VH-IVUS) and OCT for detecting in vivo TCFAs (thin-cap fibroatheromas), and concluded that a combination of complementary tools such as VH-IVUS and OCT might be a feasible approach for more accurate detection of TCFAs. In this study, OCT was unable to identify several TCFAa with large necrotic cores due to its low signal penetration. Several approaches to overcome this limitation are under development. In particular, the second-generation OFDI system can increase the penetration depth to 7 mm.12 Clinical Applications In recent years, intracoronary OCT imaging has been investigated at several cardiology centers worldwide, including Europe, Japan, Taiwan and the United States. As with any intravascular imaging modalities, OCT shares the same inherent risks associated with an invasive procedure. In 2002, Yang and colleagues published the first OCT imaging in humans, involving 10 patients who underwent PCI.5 Seventeen non-culprit lesion plaques were analyzed by both OCT and IVUS, the current gold standard modality for intracoronary imaging. Consistency between OCT and IVUS observations validate OCT as a feasible and safe intracoronary modality. In general, the time required for OCT imaging was 10 minutes longer than for IVUS. A larger, multicenter study published this year evaluated the safety and feasibility of intracoronary OCT imaging in the clinical setting.9 Seventy-six patients from eight different clinical centers who underwent a diagnostic angiogram and/or PCI were enrolled. In this study, a 6 French (Fr) or 8 Fr guiding catheter was used to cannulate the coronary artery under fluoroscopic guidance via the femoral approach. After baseline angiography and intracoronary administration of 200 µg nitroglycerin, IVUS followed by OCT imaging were performed. OCT images were obtained with the M2 OCT system by LightLab Imaging, Inc. (Westford, Massachusetts) (Figure 6). The OCT probe delivery system consisted of an over-the-wire occlusion balloon catheter used to deliver the OCT probe and remove blood from the target segment of the vessel. Lactated Ringer’s solution was injected through the central inner lumen, which also contained the OCT probe, and exited from the distal tip. OCT imaging began with the advancement of the occlusion catheter over a coronary guidewire until the balloon was positioned proximal to the lesion. After the guidewire and OCT probe were exchanged, lactated Ringer’s solution was continuously flushed through the central lumen of the occlusion catheter by a power injector, and the balloon was inflated gradually until blood flow was fully occluded. Motorized pullback OCT imaging was performed at a rate of 1.0 mm/sec for a length of 30 mm. Procedural success rates, defined as successful acquisition of a pullback image, were similar, and over 94% for both OCT and IVUS. Major complications such as hemodynamic instability, ventricular tachyarrhythmia, dissection, embolism, thrombus formation, myocardial infarction, emergency revascularization or death, were not observed during intracoronary imaging. Intracoronary OCT imaging has been demonstrated in a variety of clinical coronary presentations. In patients with acute myocardial infarction, OCT was able to identify plaque rupture, fibrous-cap erosion, intracoronary thrombus and TCFAs more frequently when compared to IVUS and coronary angioscopy (a full-color, three-dimensional perspective of intracoronary surface morphology) (Figure 7).13 The feasibility of OCT as a guiding tool for PCI has also been evaluated and compared with IVUS. Arterial wall damage and the number of cuts made by a cutting balloon, as well as underdeployed stent struts, were better defined with OCT than with IVUS.14 OCT imaging has been used to compare diabetic and non-diabetic subjects with coronary artery disease and found no significant differences in culprit plaque characteristics.15 Similar to IVUS, intracoronary OCT has the potential to monitor efficacy of therapy. Chia and colleagues found that patients on prior statin therapy have a reduced incidence of ruptured plaques and a trend toward thicker fibrous caps as demonstrated by in vivo OCT imaging.16 The Future of OCT OCT’s recent growth and momentum have been fueled by the rapid development of faster and more sensitive OCT systems capable of overcoming major limitations of the past, specifically, the need for temporary vessel occlusion and limited tissue penetration. While conventional time-domain OCT was utilized in most commercial systems deployed through 2005, the next generation of OCT systems is right around the corner. LightLab Imaging, Inc., a subsidiary of Goodman Co. Ltd., has been a leader in the field of intravascular OCT. Its live demonstration of real-time, next-generation spectral-domain OCT images of a recently implanted stent at the 2007 Transcatheter Cardiovascular Therapeutics conference in Washington, D.C., generated much excitement and anticipation. Around the same time, Volcano Therapeutics (Rancho Cordova, California), a major manufacturer of IVUS systems, announced its acquisition of CardioSpectra, a startup OCT company. Volcano Therapeutics envisions a central console that can run a number of different imaging technologies such as IVUS, fractional flow reserve (FFR) and OCT. OCT is fast becoming the most promising imaging tool in the field of intravascular imaging. Because of its powerful resolution, OCT has advanced our knowledge of the morphology of plaques associated with acute coronary syndrome in living human patients that was only previously understood postmortem. In addition, newer OCT markers show potential for risk-stratifying plaque beyond anatomical analysis. OCT Doppler is an exciting development, with the possibility of physiologic evaluation. Polarization-sensitive OCT for assessing collagen, OCT spectroscopy, OCT elastography and other imaging modes will further enhance the ability of OCT to assess plaque composition. The authors can be contacted at mkern@uci.edu

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