Over one million people are diagnosed with coronary heart disease (CHD) annually. Recent post-mortem analyses have suggested that sudden cardiac deaths are caused by the rupture of vulnerable plaque, as opposed to stable plaque occlusion. Optical coherence tomography (OCT) is a high-resolution imaging technique that offers microscopic visualisation of biological tissues. When used as an intravenous realtime imaging technique, OCT provides researchers and physicians with the ability to visualise the composition of stenoses (fibrous, lipid-rich or calcified), as well as thin-capped lesions that may be more prone to rupture. OCT can therefore aid in determining the appropriate treatment and later follow-up examinations. Furthermore, the high resolution gives physicians more information regarding new therapies, such as atherectomy devices and drug-eluting stents (DES).
Beginning in the early years of life, atherosclerosis damages the lining of the coronary arteries and makes the arteries susceptible to the formation of blood clots or stenoses that restrict blood flow to the heart. Atherosclerotic plaque can build up for years before vessel narrowing becomes apparent - a debilitating or fatal heart attack is often the first indication of underlying disease. In spite of the availability of effective drug therapies and other remarkable therapeutic advances in interventional cardiology, more than 650,000 Americans die every year of heart attacks related to CAD. Diagnostic methods have not kept pace with the demand to select and apply therapies more effectively. Better imaging methods may help bridge this diagnostic gap.
Coronary Artery Imaging
X-ray angiography is the oldest and most widely used technology for imaging the coronary arteries. During the angiography procedure, fluoroscopic X-ray images are collected as a radiopaque contrast agent is injected locally into the target arteries through a catheter inserted in the arm or leg. By carefully scrutinising these images, cardiologists can detect the narrowing of coronary blood vessels. Although invaluable for guiding interventional therapies, X-ray angiography has two main limitations - it is too invasive for use as a widespread screening tool and it provides little information about atherosclerotic lesions growing inside the vessel wall.
Results of post-mortem analyses point to rupture, fissuring or ulceration of lesions hidden in the walls of the coronary arteries as the main mechanism that triggers sudden coronary death.1,2 Lesions prone to sudden rupture, so-called 'vulnerable plaques' (see Figure 1), often do not restrict blood flow sufficiently to be visible in X-ray angiograms.
The ideal coronary imaging technology would be capable of identifying not only vessel narrowing, but also the characteristics of plaque hidden in the vessel walls. To permit widespread screening, the ideal technology would be completely non-invasive and inexpensive. Although a technology that meets all of these ideals is not yet available, a number of coronary imaging modalities have emerged over the past two decades to confront the limitations of X-ray angiography.
Introduced in the late 1980s, intravascular ultrasound (IVUS) was the first imaging technique to show the benefits of imaging inside the walls of coronary arteries. IVUS imaging systems employ a rotating ultrasonic transducer (or array of fixed transducers) mounted at the tip of a catheter to obtain a cross-sectional view of an artery. Intravascular ultrasound is used most often in clinical practice to size stents (mesh devices used to prop open vessels), determine plaque volume and locate calcium deposits. The resolution of current IVUS imaging systems (100-300µm) is not sufficient to visualise the thin fibrous caps that characterise plaque susceptible to rupture (see Figure 1). Coronary angioscopy was introduced in the 1980s as a means of obtaining a clearer view of the interior of the artery. The angioscope is a miniature fibre optic endoscope that threads into the heart through a catheter. After occluding the artery briefly with a balloon and flushing the residual blood from the field of view, the cardiologist can view thrombus, plaque, arterial dissections and other vascular abnormalities. Although angioscopy gives a rough indication of the composition of a coronary lesion according to its morphology and colour, it is unable to assess lesions below the surface. Like IVUS, angioscopy is too invasive and expensive for general diagnostic screening and is therefore applied mainly in studies focused on the research and development (R&D) of new interventional therapies. A relative newcomer to the field of coronary imaging, electron-beam computed tomography (EBCT) has gained popularity recently as a screening tool.
EBCT employs X-rays generated by steered electron beams to capture snapshots of the coronary arteries without subjecting the patient to catheterisation or other invasive procedures. To assess the risk of CAD, EBCT quantifies the degree of calcification ('hardening') of the arteries. Although the calcium scores that EBCT provides have no direct relationship to factors that underlie sudden cardiac death, high scores can encourage at-risk patients to undergo additional assessments.
Intravascular OCT Imaging
The potential utility of OCT as an intravascular imaging technology was recognised soon after publication of the first OCT images of biological tissue. The results of early studies demonstrated the unique ability of OCT to resolve atherosclerotic lesions in microscopic detail, particularly those lesions believed to be prone to sudden rupture.3,4 OCT imaging within the beating heart has become practical only recently owing, in large part, to technological advances made during the past few years. Key features of OCT that make it attractive for intra-coronary imaging are high resolution and the small size of fibre-based imaging probes. Healthy coronary arteries have walls that are only a fraction of a millimetre thick; highly stenosed arteries may have residual lumens with diameters less than 1mm. OCT is suited well to imaging structures with these dimensions.
Intracoronary imaging with OCT in the clinical setting presents a number of challenges beyond those that researchers face when developing laboratory-based systems. To be both safe and effective, an OCT system must acquire images without disrupting other procedures in the cardiac catheterisation laboratory. For delivery using standard guidewires and guide catheters, OCT probes must be small relative to the diameter of the target coronary artery. Since they are disposed after a single use, they must also be inexpensive to manufacture. Moreover, to obtain a smooth sequence of images inside the lumen of large-diameter arteries in the beating heart, acquisition at high frame rates (more than 15 frames per second) is essential.
LightLab Imaging Intravascular OCT Imaging System
The system consists of four main components - high-speed imaging engine, computer with keyboard and two displays, probe interface unit (PIU) and coronary imaging probe. Inside the imaging engine, an efficient polarisation-diversity interferometer splits broadband (polychromatic) light emitted by a polarised superluminescent diode (SLD) into reference and sample beams. The SLD emits optical power in excess of 15mW at a peak wavelength in the 1,280-1,350nm band over a 35-50nm full width at half maximum (FWHM) bandwidth.
The coherence length of the SLD yields resolution in the radial dimension equal to about 15µm. The sample beam couples into the imaging probe through a motorised rotary fibre coupler inside the PIU. To permit longitudinal scanning of a blood vessel for the collection of three-dimensional (3-D) image sequences, the PIU contains a motorised mechanism that pulls the optical fibre back within the transparent sheath of the OCT probe as the fibre rotates. Buttons on the PIU enable the operator to control image acquisition, pullback and storage without accessing the computer keyboard.
A fraction of the light back-scattered from the artery passes back through the imaging probe into the interferometer where it mixes with a reference beam. The polarisation of the reference beam is oriented along an axis that splits signal power equally between the two outputs of the polarisation splitter. The orthogonally polarised signals are detected separately and, after high-speed digitisation, the signals are filtered and demodulated by programmable digital circuits. To obtain a signal whose magnitude does not depend on the polarisation state of the light returning from the sample arm, the sum of their squared signal magnitudes is formed. This type of polarisation diversity processing ensures that polarisation changes caused by bending and rotation of the optical fibre in the sample arm do not create image artefacts.
Since interference occurs only when the optical distances travelled by the sample and reference beams match within the coherence length of the source, the position of the reference mirror determines the sampling depth in the tissue. To achieve the high frame rates required for coronary imaging, a multifaceted, cam-shaped reflector mounted on an air-bearing motor scans the reference-arm path length.5 This scanning apparatus achieves linear translation of the reference path over a range of 4.5mm in air at a repetition rate up to 4,000 scan lines per second.
The basic building block of the OCT imaging probe is the fibre optic imaging core, composed of a single-mode fibre with a microlens/beam deflector assembly at its tip (see Figure 3).
At less than 400µm in diameter, the imaging core employs an advanced micro-lens assembly at its tip to focus and direct the sample beam.6 The assembly consists of segments of fibre with refractive-index profiles tailored to achieve the desired beam focus. Due to the fact that fibre segments are fusion-spliced via arc welds, the mechanical strength of the lens assembly is similar to that of untreated fibre. To deflect the focused beam perpendicular to the long axis of the fibre, one end of the distal coreless segment is polished at an angle close to 45˚. As shown in Figure 4, the lens focuses to a near diffraction-limited focal spot equal to 20-30µm diameter at a working distance of 2mm.
Unlike rotary IVUS probes, the OCT imaging probe does not employ a torque cable. Instead, the optical fibre rotates and translates inside a plastic sheath that contains a specially formulated mixture of fluids. Eliminating the torque cable simplifies fabrication of the catheter and reduces cost.
A major challenge of applying OCT in coronary applications is to provide an efficient delivery system that enables the cardiologist to insert the OCT probe into the target artery and clear the strongly scattering red blood cells from the field of view of the probe. Since blood flow to the heart of most patients cannot be interrupted for more than 20-30 seconds, imaging must be accomplished within a short interval. To occlude the blood flow in the target lesion, an occlusion balloon catheter inflated with contrast media is employed. The imaging probe with a spring mounted on its tip is inserted proximal to the balloon through the guidewire lumen. Blood flow is interrupted briefly by inflating the balloon and flushing the residual blood from the target vessel before imaging.
Clinical Experience in Cardiology
Over the past few years, intra-coronary imaging using OCT has been explored in several cardiology centres in Europe, Japan, Taiwan and the US. The first coronary imaging studies in humans, performed at the Massachusetts General Hospital, demonstrated the ability of intravascular OCT to visualise the components of coronary plaques.7 This pioneering study showed a good correlation between OCT image features and histopathological findings obtained in earlier in vitro studies. In particular, OCT features of three distinct plaque types (fibrous, lipid-rich and calcified) were identified. A more extensive study by the same group found that excised plaques of these three types could be differentiated with sensitivity greater than 84% and specificity greater than 94%.8Figure 5 compares histology of a variety of lesions with OCT images of plaques obtained with the LightLab OCT imaging system.
With its ability to view atherosclerotic lesions in vivo with such high resolution, OCT will provide researchers with the tool they need to better understand the natural progression of CAD and to answer long-standing questions about cause-and-effect relationship between vulnerable plaque and the risk of heart attack.
In addition to the potential applications of intravascular OCT in clinical research, OCT is poised to play an important role in the guidance of the therapeutic interventions. Cardiologists perform nearly one million coronary catheterisations each year in the US alone. Most of these interventions involve the implantation of one or more stents. To minimise the likelihood that tissue will grow into a stent and cause restenosis of the vessel, the stent must be sized and positioned accurately. Although IVUS is already used effectively for guidance of stent implantation in many cardiac centres, the higher resolution of OCT offers a number of advantages in this application, as suggested by the examples in Figure 6.
Compared with IVUS, OCT provides a clearer view of the stent struts and their positions relative to the vessel wall, making poor apposition, tissue prolapse and wall dissections easier to identify. The prevention of in-stent restenosis is the major impetus behind the development of DES, certain classes of which have been shown in recent studies to reduce restenosis rates markedly compared with bare metal stents. Intravascular OCT imaging enables earlier detection of excessive regrowth of the inner layer of the vessel, as illustrated in Figure 6b. A variety of atherectomy devices are under development that would benefit from more precise image guidance.
Although OCT cannot visualise structures as deep within the arterial wall as IVUS, its depth of penetration is sufficient to image lesions embedded within thick plaque. Figure 7 shows OCT images of lesions located below the surface of the arterial wall.
The ability to detect such lesions, which are not visible in X-ray angiograms, suggests the intriguing possibility of treating coronary lesions before they become symptomatic. Many challenging tasks lie ahead before this new treatment strategy can become a reality. Foremost among these is the task of predicting the progression of a lesion on the basis of OCT image characteristics. To spot suspect lesions, the ability to survey a long segment of the vessel is also essential. The longitudinal-mode (L-mode) scan, in which the catheter is pulled back through the artery at a constant rate as images are acquired, may play an important role in this regard. Of course, even if lesions with a high probability of causing future trouble can be identified, effective therapies must be devised to halt their progression.
Researchers are working to further extend the capabilities of intravascular OCT. The design of delivery catheters with improved blood-clearing efficiency continues to evolve. Polarisation, spectroscopy, Doppler and other imaging modes promise to improve the ability of OCT to assess plaque composition.9 Recent studies by Tearney et al. demonstrate that OCT can detect and quantify macrophages, a key inflammatory cell involved in the destruction of the fibrous cap of vulnerable plaques.10 As its capabilities grow, intravascular OCT moves closer to becoming a powerful diagnostic tool that will provide new insights into the aetiology and treatment of CAD.
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