Identification of Vulnerable Plaques with Optical Coherence Tomography

Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo. Optical coherence tomography (OCT) is a new intravascular imaging method using a fiber-optic technology. The greatest advantage of OCT is its extraordinary high-resolution about 10-20 μm, which is approximately 10 times higher than that of intravascular ultrasound (IVUS). The high resolution afforded by this imaging modality is giving new insights into atherosclerotic plaque and the vascular responses after percutaneous coronary intervention (PCI). This report reviews the possibility of OCT for identification of vulnerable plaques in vivo.


Introduction
Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo. Optical coherence tomography (OCT) is a new intravascular imaging method using a fiber-optic technology. The greatest advantage of OCT is its extraordinary high-resolution about 10-20 μm, which is approximately 10 times higher than that of intravascular ultrasound (IVUS). The high resolution afforded by this imaging modality is giving new insights into atherosclerotic plaque and the vascular responses after percutaneous coronary intervention (PCI). This report reviews the possibility of OCT for identification of vulnerable plaques in vivo.

Vulnerable plaque and pathology
The term "vulnerable plaque" is used to describe thrombosis prone plaques. Plaque rupture is the most frequent cause of coronary thrombosis, accounting for 60-65% for all coronary thrombi. The precursor lesion for plaque rupture is characterized by a thin fibrous cap heavily infiltrated macrophages and an underlying necrotic core. Virmani et al defined plaque vulnerability based on the actual thickness of the histological section from measurements made of plaque ruptures. The thin-cap fibroatheroma (TCFA) was defined as a lesion with a fibrous cap < 65 μm thick. A thickness of 65 μm was chosen as a criterion of instability because in rupture the mean cap thickness was 23 ± 19 μm; 95% of caps measured less than 65 μm within a limit of only two standard deviations. In addition to plaque rupture, plaque erosion can also result in coronary thrombosis. Erosion is usually found in the lesion with intimal thickening or thick-cap fibroatheroma. The thick fibrous cap in contrast to thin fibrous cap contains abundance of smooth muscle cells, proteoglycans and type III collagen but very few inflammatory cells.

Current OCT technology
OCT is an optical analogue of IVUS using near-infrared light. The wavelength used is 1,310 nm, which minimizes absorption of the light w a v e s b y w a t e r , p r o t e i n , l i p i d s , a n d hemoglobin without tissue damage. Based on the principles of low-coherence interferometry, the OCT system produces images with an axial resolution of 10-20 μm and a lateral resolution of 25-30 μm (Table 1). An optic probe, with dimensions similar to those of a coronary guide wire, delivers light to the tissue and collects the light reflected from the tissue. The image wire of current time-domain OCT system (M2/M3 TD-OCT imaging system, LightLab Imaging, Inc., Westford, Massachusetts) consists of a 0.006 inch (0.15 mm) fiber-optic core that rotates inside a sheath with a diameter of 0.016 inch (0.41 mm) ( Figure  1). Because the near-infrared light signals are attenuated by red blood cells, OCT needs a blood-free imaging zone. To remove blood from the coronary artery and deliver the image wire, an over-the-wire occlusion balloon catheter is used. The diameter of the catheter shaft is 4.4 Fr and the balloon, designed for low-pressure inflation, was thin-walled polyurethane with a diameter of 3.8 mm at 0.3 atmospheres (< 8.5 mm at 1.0 atmospheres) and a length of 6.5 mm. Lactated Ringer's flushing solution is injected through the central inner lumen, which is shared with the image wire, and exits from the distal tip. The OCT imaging procedure starts with advancing the tip of a 0.014 inch (0.36 mm) coronary guide wire into the distal coronary artery. The occlusion catheter is then advanced over the wire until the balloon is positioned proximal to the target lesion. After the guide wire and OCT image wire are exchanged, lactated Ringer's solution is continuously flushed through the central lumen of the occlusion catheter by a power injector, and the balloon is inflated gradually by a custom inflation device until blood flow is fully occluded. Motorized pullback OCT imaging is performed at a rate of 1.0 mm/sec for a length of 30 mm. Images are acquired at 15 frames/sec and are digitally archived. The images are saved in the OCT imaging system console. During the procedure, electrocardiographic and hemodynamic features should be carefully monitored. Yamaguchi et al evaluated the safety and feasibility of OCT in 76 patients with coronary artery disease. Procedural success rates were 97%, and significant adverse cardiac events, including vessel dissection, acute myocardial infarction or fatal arrhythmia, were not observed. An inherent limitation of OCT is need for a blood-free imaging zone. The coronary occlusion for OCT image acquisition limits evaluation of left main or ostial coronary lesions. In addition, the time constraint imposed by blood flow interruption as well as slow frame rate of current OCT system prevents scanning of a significant length of a coronary artery during a single flush. Recently, a second-generation OCT technology, termed Fourier-domain OCT (C7 FD-OCT imaging system, LightLab Imaging, Inc., Westford, Massachusetts), has been developed that solves the current time-domain OCT problems by imaging at much higher frame rates (100 frame/sec), a faster pullback speed (20 mm/sec), and a wider scan diameter (8.3mm) without loss of image quality (Table 2). These advantages result from the elimination of mechanical scanning of the reference mirror and signal-to-noise advantages of Fourier-domain signal processing ( Figure 2). Imaging catheter of Fourier-domain OCT (Dragonfly Imaging Catheter, LightLab Imaging, Inc., Westford, Massachusetts), which is designed for rapid-exchange delivery, has 2.5-2.8 Fr crossing profile and can be delivered over a 0.014-inch guidewire through a 6 Fr or larger guide catheter. Injecting angiographic contrast media, or a mixture of commercially available dextran 40 and lactated Ringer's solution (low-molecular-weight Dextran L Injection, Otsuka Pharmaceutical Factory, Tokushima, Japan) through the guide catheter (4-6 ml/sec, 2-3 second) can achieve effective clearing of blood for Fourier-domain OCT imaging. The high frame rate and fast pullback speed of Fourier-domain OCT allows to image long coronary segments with minimal ischemia, eliminating the need for proximal vessel balloon occlusion during image acquisition.

Plaque characterization
Several histological examinations have demonstrated that OCT is highly sensitive and specific for plaque characterization. The high resolution of OCT allows us to identify 3-layer of coronary artery wall. In the OCT image, intima is observed as a signal rich layer nearest www.intechopen.com the lumen, media is visualized as a signal poor middle layer, and adventitia is identified as a signal-rich outer layer of artery wall ( Figure 3). OCT enables more accurate estimation of the intimal thickness in comparison with IVUS which can not distinguish the boundary of the intima and media. Kume et al compared the coronary intima -media thickness and the intimal thickness of 54 coronary arterial segments evaluated by histological examination with the results of OCT and IVUS. There was a better agreement in intima -media thickness between OCT and histological examination than between IVUS and histological examination (r=0.95, p<0.001, mean difference = -0.01 ± 0.07 mm for OCT; r=0.88, p<0.001, mean difference = -0.03 ± 0.10 mm for IVUS). Moreover, there was an excellent agreement in the intimal thickness between OCT and histological examination (r=0.98, p<0.001, mean difference = 0.01 ± 0.04 mm). Yabushita el al developed objective OCT image criteria for differentiating distinct components of atherosclerotic tissue. In their histology-controlled OCT study with 357 autopsy segments from 90 cadavers, fibrous plaques were characterized by homogeneous signal-rich regions (Figure 4), fibrocalcific plaques by signal-poor regions with sharp borders ( Figure 5), and lipid-rich plaques by signal-poor regions with diffuse borders ( Figure 6). Validation test revealed good intra-and inter-observer reliability (κ = 0.83-0.84) as well as excellent sensitivity and specificity-71-79% and 97-98% for fibrous plaques, 95-96% and 97% for fibrocalcific plaques, and 90-94% and 90-92% for lipid-rich plaques, respectively. These definitions have formed the basis of plaque composition interpretation (

Vulnerable plaque detection
Since OCT has a near-histological grade resolution, many in-vitro and in vivo studies have been done to validate the capability of OCT to visualize vulnerable plaque features.

Plaque rupture and erosion
OCT can detect plaque rupture ( Figure 7) and erosion ( Figure 8)

Thin-cap fibroatheroma
OCT might be the best tool available to detect TCFAs in vivo (Figure 9). Kume et al examined the reliability of OCT for measuring the fibrous cap thickness. In the examination of 35 lipid-rich plaques from 38 human cadavers, there was a good correlation of the fibrous cap thickness between OCT and histological examination (r = 0.90; p<0.001). In the clinical setting, Sawada et al compared the feasibility for detecting TCFA between OCT and virtual histology IVUS. Although the positive ratio of virtual histology IVUS for detecting TCFA was 45.9%, that of OCT was 77.8%. Jang et al analyzed OCT images among 57 patients who presented with stable angina pectoris (SAP), ACS, or AMI. The AMI group was more likely than the ACS group, who was more likely than the SAP group, to have a thinner cap, more lipid, and a higher percentage of TCFA (72% vs. 50% vs. 20%, respectively, p = 0.012). On top of its reliability as a tool to measure the fibrous-cap thickness in vivo, a recent OCT study conducted by Takarada et al demonstrated that the lipid-lowering therapy with statin for 9 months follow-up significantly increased the fibrous-cap thickness in patients with hypercholesterolemia (151 ± 110 to 280 ± 120 µm, p<0.01). As therapies to prevent or make regression of atherosclerosis are developed, OCT can help to assess the treatment efficacy. Fig. 9. Thin-cap fibroatheroma. A fibrous cap is identified as a signal-rich homogenous region overlying a lipid core, which is characterized by a signal-poor region in the OCT image. Thin-cap fibroatheroma is defined as a plaque with a fibrous cap measuring <65 μm.

Thrombus
The OCT characteristics of coronary thrombi were studied by Kume et al in 108 coronary arterial segments at postmortem examination. Red thrombus ( Figure 10-A), which mainly consists of red-blood cell, is identified as high-backscattering protrusions inside the lumen of the artery with signal-free shadow, while white thrombus (Figure 10-B), which mainly consists of platelet and fibrin, is identified as signal-rich, low-backscattering protrusions in the OCT image. Using a measurement of the OCT signal attenuation within the thrombus, the authors demonstrated that a cut-off value of 250 µm in the 1/2 width of signal attenuation can differentiate white from red thrombi with a high sensitivity (90%) and specificity (88%).

Plaque neovascularization
Plaque neovascularization is a common feature of vulnerable plaque. Proliferation of microvessels is considered to be related with intraplaque haemorrhage and plaque destabilization. The high resolution of OCT provides an opportunity to detect plaque neovascularization in vivo ( Figure 11). Kitabata et al demonstrated increase of micro-vessels density in TCFAs by www.intechopen.com using OCT. The presence of micro-vessels in the plaques was also associated with positive vessel remodeling and elevated hs-CRP levels. The OCT evaluation of micro-vessels density might be helpful to assess plaque vulnerability.   11. Micro-vessels in the coronary plaque. Vessels within the intima (arrows) appear as signal poor voids that are sharply delineated.

Macrophages
A unique aspect of OCT is its ability to visualize the macrophages (Figure 12). Tearney et al proposed the potential of OCT to assess macrophage distribution within fibrous caps. There was a high degree of positive correlation between OCT and histological measurements of fibrous cap macrophage density (r<0.84, P<0.001). A range of OCT signal standard deviation www.intechopen.com thresholds (6.15% to 6.35%) yielded 100% sensitivity and specificity for identifying caps containing >10% CD68 staining. Fig. 12. Macrophage. Macrophages (arrows) are seen as signal-rich, distinct or confluent punctuate regions that exceed the intensity of background speckle noise.

Multiple lesion instability
In the diffuse nature of coronary atherosclerosis, plaque instability might be expected to develop in a multifocal pattern. Virmani et al showed that 70% of cases of sudden cardiac death had non-ruptured TCFAs. Most non-ruptured TCFAs and ruptured plaque are localized in the proximal 1/3 of the major coronary arteries. In a 3-vessel VH-IVUS study, Hong et al demonstrated that 72% of patients with AMI or UAP had multiple VH-IVUSderived TCFAs. Asakura et al performed 3-vessel angioscopic examination in AMI and showed that yellow plaques were equally prevalent in the infarct-related and non-infarctrelated coronary arteries. In the multifocal OCT study, Tanaka et al reported that 7% of patients with acute coronary syndrome had >2 OCT-derived TCFAs in the entire culprit coronary artery. Kubo et al evaluated non-culprit vessels by using OCT and demonstrated a greater frequency of multiple OCT-derived TCFAs in AMI patients than in SAP patients. Fujii et al performed a prospective OCT analysis of all 3 major coronary arteries to evaluate the incidence and predictors of TCFAs in patients with AMI and SAP. Multiple TCFAs were observed more frequently in AMI patients than in SAP patients (69% vs. 10%, p<0.001). In the entire cohort, multivariate analysis revealed that the only independent predictor of TCFA was AMI (OR=4.12, 95% CI=2.35-9.87, p=0.020,). These OCT results support the theory that acute coronary syndrome is a multifocal process ( Figure 13).

Drug-eluting stent in vulnerable lesion
Drug-eluting stent has been reported to impair local vascular healing with delayed endothelization. The patients with ACS present a higher risk for thrombotic complication after stent implantation in comparison with SAP. Therefore, vascular response after drugeluting stent implantation in the vulnerable lesion is a great concern. Recently, Kubo et al used OCT to evaluate lesion morphologies after drug-eluting stent implantation in the www.intechopen.com unstable lesions. Inadequate stent apposition (67% vs. 32%, p=0.038) and tissue protrusion (79% vs. 42%, p=0.005) after PCI were observed more frequently in UAP patients compared with SAP patients. Plaque rupture was significantly increased after PCI in UAP patients (42% to 75%, p=0.018). The persistence of core cavity after plaque rupture at 9 months' follow-up ( Figure 14) was observed more frequently in UAP patients compared with SAP patients (28% vs. 4%, p=0.031). At 9 months' follow-up, the incidence of inadequately apposed stent (33% vs. 4%, p=0.012) and partially uncovered stent by neointima (72% vs. 37%, p=0.019) was significantly greater in UAP patients than that in SAP patients. Residual plaque rupture behind the stent and uncovered stent struts might be important risks for late stent thrombosis because the lipid content of exposed necrotic core and metal stent is highly thrombogenic (Figure 14). Although arterial healing with excessive neointimal growth leads to restenosis, neointima (or endothelium) that seals the underlying thrombogenic components may protect against late stent thrombosis.

Atherosclerotic changes in neointimal tissue inside stent
Atherosclerotic changes and consequent plaque vulnerability occur in the neointimal tissue inside the stent. Takano et al observed the neointimal characteristics of bare-metal stents in early phase (<6 months) and late phase (> 5 years) by using OCT. Lipid-rich neointima was often seen in the late phase compared with the early phase (67% vs. 0%, p<0.001). The appearance of intraintima neovascularization was more prevalent in the late phase than the early phase (62% vs. 0%, p<0.001). Kashiwagi et al used OCT to examine the stented segments in cases with very late stent thrombosis, and reported neointimal plaque rupture. Atherosclerotic progression in neointimal tissue inside the stents might contribute to late clinical events after stent treatment ( Figure 15).
Fig. 14. Residual plaque rupture behind coronary stent. The OCT image at 9-month followup after drug-eluting stent implantation shows persistence of core cavity and inadequatelyapposed stent struts without neointimal coverage. Fig. 15. A case with neointimal plaque rupture inside bare-metal stent. A 60-year-old man was given a diagnosis of stable angina and treated with a bare-metal stent (3.5 x 18 mm) deployed to the mid-portion of the left anterior descending artery 8 years ago. A follow-up coronary angiography at 6 months after the procedure presented no restenosis. Eight years after stent deployment, he suddenly suffered recurrence of angina and was admitted to the hospital. A coronary angiography showed severe in-stent restenosis of the previously stented segment of the LAD (arrow). Before any interventions, OCT was performed. OCT clearly revealed plaque rupture (arrowhead) and cavity formation (*) within well expanded stent struts (arrows).

Limitations
OCT has a relatively shallow axial penetration depth of 2mm. The OCT signal does not reach the back wall of thick atherosclerotic lesions. The penetration depth of OCT depends on tissue characteristics. Lipid-rich plaque or coronary thrombus causes OCT signal attenuation, which interrupts to observe deep layers of coronary artery wall. OCT is not appropriate for the visualization of whole vessel and the evaluation of arterial remodeling.

Current technology challenges
Recently, Tearney et al reported that Fourier-domain OCT, called optical frequency-domain imaging by author's group, enables imaging of the 3-dimensional microstructure of long segments of coronary arteries. In addition, Fourier-domain OCT facilitates the acquisition of spectroscopic and polarization, Doppler and other imaging modes for plaque characterization. When Fourier-domain OCT is fully exploited, it has the potential to dramatically change the way that physicians and researchers understand the coronary artery disease in order to better diagnose and treat disease.

Conclusion
The high resolution of OCT provides histology-grade definition of the microstructure of coronary plaque in vivo. OCT allows a greater understanding of the pathophysiology of vulnerable plaque. Whether OCT will have an established clinical role in vulnerable plaque detection must depend on the outcomes of future prospective natural history studies. Precise identification of thrombosis-prone vulnerable plaque could change our approach to the treatment of coronary atherosclerotic disease and contribute to prevention of ACS.