EARLY Cardiovascular OCT


2.  First 15 Years of OCT

2.A Early OCT

OCT’s introduction to cardiology, and for that matter imaging in nontransparent tissue in general, began with a fortuitous fellows lecture by Arthur Weyman MD Massachusetts General Hospital in 1994.22  It was described that the major problem in coronary artery disease was that imaging techniques at that time lacked the resolution to identify vulnerable plaque. One of the authors, attending that lecture, realized that electromagnetic radiation based techniques had the greatest potential to solve the problem (over 50 technologies were assessed). Most noteworthy was a technique used in transparent samples called Optical Coherence Tomography (OCT), a pioneering extension of low coherence interferometry particularly by James Fujimoto PhD, Eric Swanson MS, and David Huang from Massachusetts Institute of Technology (MIT).1-4 So OCT started as a technology which was sought out to address a clinical problem and a technology looking for applications to be applied to.  The technology had been used to image cracks in fiber optics and the transparent tissue of the eye.5, 6 OCT had unprecedented resolution, however, it had not successfully been applied to imaging nontransparent tissue.

There were several significant limitations in developing OCT technology for intravascular imaging. First, the penetration depth of OCT imaging at this time was only 500 μm in nontransparent tissue, while a penetration depth of at least a few millimeters was necessary.1, 2 Second, the technology was too slow to be used for intravascular imaging, taking nearly 40 seconds to produce an image.1, 2, 5, 6 Third, imaging through a catheter or endoscope had not been performed. Fourth, registration of images with nontransparent tissue pathology, which is needed to verify the effectiveness of the technology, would be difficult at these resolutions. Finally, the system electronics would need considerable modifications.5 In spite of these early obstacles, the technology was ultimately proficient for in vivo intravascular imaging within 5 years.9

Pilot work was started in a collaboration between our group then at MGH and the Fujimoto lab at MIT. Initially our results had only limited success, but in 1996 in an article published in Circulation, we achieved significant positive results with the technology.3 There were several significant observations in the study. First, OCT images demonstrated a high correlation with histopathology. Second, the center wavelength was changed from 830 nm to 1300 nm that showed superior penetration (2-3 mm versus 500 µm) in nontransparent tissue due to substantially reduced scattering and absorption relative to the visible light region and the infrared water absorption peak.24  Consequently, mean wavelengths around 1300 nm resulted in maximum penetration. The third significant observation was the ability to image through calcified plaques. Ultimately, the study demonstrated the capability to identify thin walled lipid filled plaques, which typically lead to most ACS.3 In figure 3, an OCT image of atherosclerotic plaque is seen with the corresponding histopathology.  The intimal cap, at points less than 40 µm in diameter, is seen both by OCT and histopathology.  This is also illustrated in figure 4 where a lipid filled (black area) region is covered by a thin intimal wall (arrow).

After these preliminary observations, the project took two distinct directions: comparison with high frequency intravascular ultrasound (IVUS) and the advancement of the technology for in vivo intravascular imaging.7, 8 In early studies done in collaboration with Neil Weissman MD of Washington Hospital, we found that when we compared OCT with IVUS, OCT demonstrated superior resolution both quantitatively and qualitatively.  Comparative images of IVUS (40 MHz) and OCT are shown in figure 5.  The superior image quality is evident from the image and quantitatively, the axial resolution of OCT was 16±1 µm compared with 110±7 µm for IVUS.  As it is difficult to due standardized quantitative measurements in vivo, a phantom was built to compare the two technologies for assessing stents.  The stent was expanded within a clear, soft plastic tubing with an internal diameter of 4 mm. A single mode optical fiber with a 125-µm outer diameter was anchored (using epoxy glue) within the stent and used for calibration. The model was submerged in saline during OCT and IVUS imaging.  Beginning from the distal end, the stent model was imaged alternately with OCT and IVUS 5 times in multiple locations and pullback was performed. OCT and IVUS images were coregistrated by pulling the OCT and IVUS catheters over the same distance using a precision translation stage. From the OCT and IVUS images, the maximum separations between the stent struts and the inner surface of the tube were determined to be 503 ± 20 µm vs. 731 ± 60 µm with a paired T-test value of P < 0.0004. Minimum separations were 168 ± 20 µm vs. 146 ± 60 µm with P ≤ 0.1650, respectively.  To confirm the OCT accuracy in determining distance, we measured the size of a small fiber diameter on the OCT image of the single mode optical fiber. The resultant value is 130 ± 14 µm and is very close to the actual fiber diameter of 125 µm which was confirmed with a micron scale caliper.  In comparison, the fiber diameter measured from the IVUS images was 154 ± 30 µm.

Significant technological advances required for in vivo vascular imaging were made at this time and this included the development of an OCT catheter, a high speed data acquisition system to get imaging near video rate, noise reduction in the system electronics, and synchronization of the catheter and engine components.9, 14

The next major objective for OCT was to move to in vivo imaging.9, 14, 25 This was achieved by two methods. First, imaging was performed in vivo of normal rabbit aorta and structural detail was delineated at unprecedented resolution.9, 25 These studies confirmed in vivo the concerns that blood would substantially deteriorate OCT imaging.  In figure 6 A, essentially no attenuation occurred except by a small clot while the vessel was flushed with saline.  In contrast in B, in the presence of blood, the arterial wall is not noted except where the catheter is in close proximity to the wall.  Figures 6 C and D show a stent placed in the rabbit aorta imaging by both OCT and high frequency ultrasound (40 MHz).  A subsequent animal study was performed in pigs by another group that confirmed these results.26  Second, LightLab Imaging Inc. (formerly Coherent Diagnostic Technologies llc) of Westford, Massachusetts was formed by E. Swanson, M. Brezinski, J. Fujimoto, and Carl Zeiss in 1998 (four years after the first feasibility data was demonstrated), an important advance toward in vivo human imaging since it provided a format to produce catheters that met with regulatory and patient safety requirements.16 Approximately one to two years later, in vivo human imaging was pursed by a separate group at MGH, headed by the respected team of Gary Tearney MD, PhD and Brett Bouma PhD.27  By the early millennium, the first in vivo human studies were successfully performed by Lightlab and this group at MGH, a prerequisite for a technology to risk stratify plaque and stent placement. 

2.B OCT in the New Millennium

OCT studies in the early part of this decade focused primarily on three areas, in vivo single time point studies, technology development, and in vitro studies.  During this period, access to the technology was limited to a small number of investigators, particularly few clinical scientists with experience in longitudinal clinical trails.  This in part may explain why, as the end of the decade approaches, a clear clinical application for OCT has yet to be established.

The most significant in vivo single time point studies over this period were those that confirmed previous in vitro/animal studies that the technology was able to identify thin intimal caps, lipid cores, intimal thickening, resolve stent struts, superior performance to IVUS (within 2-3 mm), and the difficulty that blood represents to imaging.  This is not to trivialize the importance of performing these confirmatory studies as they were required for overcoming significant regulatory and safety obstacles needed for success.  But there were no well controlled clinical trials (and minimal studies of markers of plaque vulnerability) that demonstrated a true clinical need for intracoronary OCT imaging at a time when it was clear its greatest potential applications were guiding stent placement and identifying high risk plaque.  This will be more clear in the discussion below. 

Technology developments of significance during this period included smaller OCT catheters, spectral domain OCT techniques, and methods for dealing with the difficulties of imaging through blood.28-32 The advantages and disadvantages of the spectral domain OCT techniques are discussed in the supplemental, but as a prelude, while they offer advantages with respect to acquisition rates (an issue important with rapid pull backs), potential limitations in signal detection are an issue.  With regard to the extensive amount of work done on both catheter designs and dealing with the blood issues, it can be argued that too much focus occurred in this area relative to effort into a clinical application.  A significant amount of effort even went into MEMs (micro-electro-mechanical,) technology to reduce the size of OCT catheters using microengineering101.  This seems somewhat misdirected as currently, there is no accepted application for OCT in clinical cardiology.  Therefore, one philosophy is that the simplest catheter and blood clearing schemes needed to identify a clinical usage is the optimal economical strategy, which was the approach in the 90’s.  In other words plaque and stent characterization could likely have been done without the push single pullback times.  Furthermore these high speed systems reduced dynamic range, effecting penetration and accurate evaluations of the capability of the technology.  Far too often engineering takes on a life of it’s own and large investments in technology advancements occur where a clinical need never develops.  However, the demonstration of some viable applications may require that blood be kept out of the field longer (i.e. long pull-backs) or an OCT imaging guidewire to exchange interventional devices over.  Understanding which technological advances are needed to identify clinical applications is critical in bringing the technology forward.  Currently, there is no steerable robust OCT imaging guidewire although a soft 0.017” imaging ‘wire’ has existed for sometime.16  But while it is an impressive engineering achievement to produce this wire, as it is not a guidewire, its clinical utility at this time is limited. To paraphrase two prominent articles in the business literature, to paraphrase ‘said the reason most new companies (and technologies) fail is that they are product rather than market driven119’ and ‘business (and research) plans involve outstanding execution of poor strategy120’.

But looking at what has been examined to date, OCT if ultimately effective requires a blood-free or transparent zone for imaging, accomplished by high index matched medium (transparency), saline, or some similar flush material. Some would argue with TD-OCT systems with frame rates of 15 frames/second, this imposes practical limitations on the system. A single bolus flush permits an acquisition time of about 2-3 seconds, and imaging is only possible at discrete locations.  This likely is sufficient for initial studies needed to at least suggest a role for OCT in patient management.  However, for completeness, among the strategies for preventing blood from interfering with imaging include balloon occlusions, increased data acquisition rate (in combination a flush agent), iodixanol-lactate flushes (increased viscosity), and index matching (transparency).30-32 With proximal balloon occlusion and continuous flushing, longer segments can be imaged. The disadvantage is that the configuration is relatively cumbersome compared with current IVUS systems; there is transient ischemia in the territory of the artery under study and some concern about the local consequences of balloon inflation. In addition, inadequate displacement of blood can be a problem in vessels >3.5 mm in diameter, where large bifurcations are present and in the presence of competitive flow from collaterals or bypass grafts.93 With regard to rapid pull-back using guide catheter flush without balloon occlusion, imaging at  100 frames per second (with 500+ A-lines/frame) with a pull-back rate of up to 20 mm/second has been achieved, contrasting with 15.6 frames/second (at 200 A-lines/frame) and pull-back rate of 1 mm/second for earlier techniques.15, 16 This translates into an ability to image an entire coronary artery in a matter of a few seconds and then the image generated afterwards but at a loss of dynamic range.  Index matching, making the blood optically invisible with the addition of a high refractive index compounds, demonstrates substantial potential but considerable developmental challenges exist.32  Never the less, long term this may be the ideal approach.  However, until a clinical utility has been identified, the merits of putting extensive amounts of research resources into some of these areas must be weighed carefully.

It can be argued that more in vitro and ex vivo work was needed for both interpreting OCT images of plaque in vivo, in addition to developing adjuvant techniques for plaque characterization, which has been focus of our group.  Among the adjuvant OCT work done over this period were quantitive correlation measurements of intima cap thickness by OCT and histology, polarization sensitive OCT (PS-OCT) for the assessment of collagen, elastography for assessing the tensile strength of intimal caps, image processing for improved contrast, absorption/dispersion analysis for cholesterol composition, phase sensitive OCT for tissue composition, and attempts at correlating characteristics of changes in OCT images with macrophage concentration11, 17-21, 33-35, 82-84, 90.  However, while this work is discussed below, it is very limited and almost none of it has been utilized for in vivo studies.  Furthermore, whether OCT is actually measuring macrophage concentration and even if it is, whether it is of clinical value will be discussed below (and in the supplemental).  Finding OCT markers that identify those subtypes of TFCAs that progress to ACS is probably the most important area where research is needed in the cardiovascular OCT.  It is unfortunate that these approaches, as well as others such as OCT Doppler for assessing plaque angiogenesis, have not been a greater point of emphasis.  Furthermore a large data base of histology correlated  with OCT images in vitro would have greatly aided the progression of in vivo patient management.