To study the vulnerable plaque, we must look beyond contrast-filled arteries (i.e., lumenology). An angiogram cannot evaluate the vessel wall, plaque dimensions, composition, distribution, or other morphology. In fact, many vulnerable plaques are angiographically invisible due to their small size and compensatory enlargement (positive remodeling) of the vessel wall. As a result, the search for the vulnerable plaque remains ongoing. Modality 1: Tissue Characterization Using Ultrasound What Does Standard IVUS Offer? It is well accepted that intravascular ultrasound (IVUS) imaging is superior to angiography in providing two-dimensional cross-sectional tomographic views. Plaque constituents such as calcification, fibrous tissue, thrombus, and plaque fractures or dissections are readily identified and, in most cases, can be differentiated with standard imaging technique8 [Fig 1]. Limitations of IVUS Imaging. IVUS has limited resolution (>100 microns even for 40 MHz systems), and signal quality is influenced by reflections from surrounding tissues. Standard IVUS cannot determine subendothelial plaque components. Even with high frequency systems, imaging quality is hampered by increased signal backscatter. Fibrous cap thickness and protruding plaque fractures can only be marginally visualized.8-9 In contrast, arterial calcifications, associated more with stable than unstable syndromes, are easily observed.10 The true arterial vessel size, measured by IVUS rather than plaque area, has a dynamic role in arterial lumen remodeling and subsequent plaque stability.11 IVUS Radiofrequency Signal Analysis. Tissue characterization by intravascular ultrasound radiofrequency signal analysis provides much more detail than standard IVUS. Positive Data. Komiyama et al.12 examined radiofrequency signals from 24 regions of interest in noncalcified in vitro plaques. Regions of interest were histologically categorized into plaques with and without lipid cores. Statistical parameters of the radiofrequency envelope differentiated lipid core, unlike visual analysis of IVUS images. Conclusion. Data indicated that when compared to IVUS imaging, the parameters of radiofrequency signal analysis were more accurate in detecting and quantitating lipid cores, one of the principle features associated with plaque vulnerability. Plaque Elasticity IVUS Elastography. The elastic properties of atherosclerotic plaque can be used to differentiate histologic components. Radiofrequency data obtained from arterial tissue during diastole and systole can be used to construct elastograms or strain plaque images differentiating hard and soft tissue component regions. Positive Data. de Korte et al.13-14, using IVUS elastography, characterized different plaque components in diseased human femoral and coronary arteries in vitro. IVUS images were obtained at varying intraluminal pressures and radiofrequency signals were used to compute regional strain maps of arterial tissue. The strain map was color-coded and plotted as an additional image over the IVUS echogram [Fig 2]. Histologic examination of the tissue demonstrated correlation between high strain regions and the presence of collagen, smooth muscle cells and macrophages in 125 tissue cross-sections. Three histologic types of plaques: fibrous; fibro-fatty; and fatty could be differentiated from the stress strain echo maps. The degree of strain was significantly different in fibrous and fatty tissue plaque types (P<0.002). The investigators noted the different strain values among fibrous, fibro-fatty, and fatty plaques, and that intravascular elastography can distinguish between different plaque morphologies related to activation. Conclusions. IVUS elastography and radiofrequency tissue analysis provide unique characterizations of a plaque and arterial morphology, all with the use of a single device. Modality 2: Tissue Characterization Using Reflected Laser Light What is OCT? Optical coherence tomography uses laser light to create IVUS-like images with extraordinarily high resolution.15 Through an 0.006 inch glass fiber coupled to a miniaturized optic system, coherent infrared light can be directed to and reflected within the tissue to create a detailed tissue image with an spatial resolution of <30 microns. An imaging guidewire of 0.014 can be used to differentiate lipid from water-based tissues and precisely quantitate the fibrous cap thickness, despite a signal penetration depth of only 1 to 2mm. OCT versus IVUS. Compared to IVUS, OCT offers higher resolution, sufficient to easily differentiate intima, plaque, and lipid pools16 [Fig 3]. OCT can also differentiate tissue characteristics based on polarization properties. High birefringence (splitting a ray into two parallel rays polarized perpendicularly [syn: double refraction]) by polarization shift will identify fibrous tissue, collagen and lipid. Low birefringence reflects calcium. By overlying low and high birefringent images on the OCT image map, tissue structure can be highlighted by tissue composition. OCT Limitations. Successful clinical application must overcome two hurdles: a low penetration depth and blood absorbency interference by signal. Studies of methods to overcome both issues are in progress. Raman Spectroscopy: Using Reflected Laser Light to Distinguish Plaque. Reflected laser light from tissues can also be analyzed using spectral modeling by a spectrometer. Spectral characteristics, called Raman spectra, identify chemical alterations in atherosclerotic tissue.17 Raman spectra can differentiate non-atherosclerotic, non-calcified plaque from calcified plaque. Like OCT, the penetration depth of the Raman spectroscopy is only 1.0 to 1.5mm, but is sufficient to examine tissue beneath fibrous caps and within an atheromatous core. Positive Data. Near-infrared Raman spectroscopy was applied to 165 coronary artery samples using 830 nanometer infrared light. Quantification of the relative weights of cholesterol, cholesterol esters, triglycerides, phospholipids, and calcium salts were examined in the target location by Romer T.J., et al 17 [Fig 4]. Spectroscopy data was validated by histological examination. Nonatherosclerotic tissue contained an average of 4 + 3% cholesterol. Noncalcified plaques and calcified plaques had 26 + 10% and 19 + 10% cholesterol in noncalcified regions. Quantitative chemical signal information was converted using a diagnostic algorithm based on the first 97 samples. It demonstrated a strong correlation between the relative weights of cholesterol and calcium salts with histologic diagnoses at the same location. Prospective testing of this algorithm correctly classified 64 of 68 samples. Limitations. Raman spectroscopy is limited by strong image artifact from background fluorescence and the absorbance of laser light by blood. Since Raman spectroscopy doesn™t provide information on morphology, it must be paired with IVUS or OCT systems. Conclusion. Combined with OCT, Raman spectroscopy may be useful in monitoring progression or regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic interventions. Optically Coherent Light as a Guidance Tool for Total Occlusions. Using optical fibers, the interference pattern of two reflected coherent light beams (wavelengths 1300 nanometers) can distinguish different tissue types of human atherosclerotic plaques. This method is termed optical coherence reflectometry (OCR). Positive Data (Study 1). To distinguish calcified white from yellow atherosclerotic plaque, Yamashita T. et al18 examined the slope of the initial portion of the OCR curve. They compared the guidewire position of the OCR signal to positioning with simultaneous intravascular ultrasound imaging [Fig 5]. In 16 arterial surface segments, calcified plaques had steeper OCR slopes than white or yellow plaques (P<0.01). IVUS and OCR positioning corresponded correctly in 82%. The sensitivity and specificity of OCR for detection of plaque versus median adventitial boundary was 79% and 89%, respectively (P < 0.001). Positive Data (Study 2). Clinical application of this technique to negotiate occluded coronary arteries was reported by Cordero et al.19 in six patients with chronic total occlusions >6 months. A crossing rate of 100% was achieved in the six cases. The OCR system helped determine intraluminal wire position. In some cases, recanalization was finally achieved with standard guidewires after creating initial channels with the OCR system. Conclusion. The initial clinical experience was favorable, indicating achievement of a TIMI grade three flow in three of the six patients and TIMI grade two flow in two of the six patients for these difficult and chronic total occlusions. OCR may have similar potential for further application in other difficult lesion patient subsets. Modality 3: Tissue Characterization Through Thermal Activity Activation of macrophages in plaques promotes rupture, thrombosis, and vasoconstriction, activities associated with increased temperature within an atheroma. Positive Data (Study 1). Confirming a significant correlation between macrophage density and local temperature, Casscells et al20 showed a temperature rise of up to 2.2?C (36?F) within macrophage-rich areas of freshly obtained carotid endarterectomy specimens. In human atherosclerotic coronary arteries, a 3F thermography catheter demonstrated thermal heterogeneity with a spatial resolution of 0.5mm in coronary arteries.21,22 Increased thermal activity was more common in patients with ACS. Increased thermal activity was noted in: 20% of cases in patients with stable angina, 40% with unstable angina; and 67% with acute myocardial infarction.22 No thermal heterogeneity was seen in arterial specimens from control subjects. Positive Data (Study 2). Increased local temperature in human coronary atherosclerotic plagues was also identified as an independent prediction of clinical outcomes in patients undergoing PCI.22 Stefanadis C et al22 prospectively examined temperature differences between atherosclerotic plaques and the adjacent healthy vessel wall, and the event-free survival in 86 patients undergoing PCI. The study group was comprised of patients with effort angina, (35%) unstable angina (35%), and three patients with acute MI (30%). Among the three groups, the temperature difference progressively increased. Over the follow-up period of 18 months, those patients with greater temperature differences in the plaque as compared to normal vessel wall had more adverse events (odds ratio of 2.14, P<0.043). A temperature difference threshold of >0.5 centigrade was associated with increased risk of adverse events (41% compared with only 7% of patients with ?T < 0.5). Conclusion. These data indicated that an increased local temperature in atherosclerotic plaques was a strong predictor of unfavorable clinical outcome in patients with acute coronary syndromes undergoing PCI. Potential Applications. Thermography identifies regions likely to activate in the near-term, which can lead to early intervention. It may also be used to verify stabilization after mechanical or pharmacologic therapy. The Physiologic Significance of Vulnerable Plaques Vulnerable plaques may or may not limit blood flow, and thus the use of pressure/flow measurements for plaque assessment has important clinical implications. Coronary physiology provides a rationale to proceed with PCI or CABG, or to use medical therapy to stabilize potentially vulnerable lesions. Sensor-tipped angioplasty guidewires for coronary physiologic measurements have enabled interventionalists to examine blood flow responses before and after PCI. These guidewires can measure: Post stenotic absolute coronary vasodilatory reserve (CVR); Relative CVR (rCVR); Pressure-derived fractional flow reserve (FFR).7 These measurements, now in common use for both clinical and research purposes, can characterize the function of the epicardial, microvascular, and collateral coronary circulation.23-25 During PCI, combined CVR/FFR relationships may identify coronary dissection, emboli, or diffuse microvascular constriction, offering clinicians a complete functional description of the results of coronary interventions27,28, and leading to the appropriate therapy for best outcomes. Clinical Outcomes Related to Catheter-Based Anatomic and Physiologic Data The new modalities described in this article: radiofrequency IVUS plaque analysis, OCT, Raman spectroscopy and thermography, have yet to obtain wide clinical application. Long-term studies relating current 2D IVUS characterization of a vulnerable plaque to clinical outcomes are pending. Available clinical studies show that large cross-sectional IVUS lumen areas following stenting are associated with reduced restenosis.29 Complete and full stent strut apposition to the vessel wall (by IVUS) is associated with reduced subacute thrombosis, yet complete stent strut apposition may not occur in 30-40% of angiographically-guided cases.30 For lesions of uncertain physiologic significance, IVUS lumen cross-sectional areas of <3-4mm2 are associated with abnormal CVR and FFR in most patients.31 For outcomes related to physiologic measurements, threshold values (CVR <2.0, FFR <0.75) are associated with inducible myocardial ischemia in patients with stable angina, findings reproduced by many centers with several different techniques.23 In support of a provisional stent strategy (using stents after balloon angioplasty fails to achieve physiologic or anatomic endpoints), the coupled criteria of CVR >=2.5 with <35% percent QCA diameter stenosis was associated with <20% 6-month major adverse cardiac event rate.32 When FFR >0.90 was achieved after balloon angioplasty alone, there was <15% restenosis seen at 2 years follow-up.33 For clinical decision making, several studies have demonstrated <10% lesion progression requiring intervention over 1-2 year follow-up24,33, supporting the safe deferment of intervention for intermediate lesions. Conclusion Compared to angiography, catheter-based diagnostic modalities (light, sound, MRI, thermal, pressure, flow, etc.) better quantify the anatomic and physiologic features of a vulnerable plaque. Currently, IVUS and CVR/FFR can direct appropriate mechanical or medical therapies, and potentially reduce unnecessary or ineffective attempts to restore normal coronary blood flow based on non-invasive methods. There is no doubt that early assessment of the vulnerable plaque will identify new therapies and improve long-term outcomes in patients with coronary artery disease. In the near future, the most promising imaging modality appears to be OCT, with its high resolution (<20 mc) for plaque cap and lipid pool analysis. Acknowledgements: The author thanks Rhonda Arl for manuscript preparation.
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