New Techniques for the Evaluation of the Vulnerable Plaque

Evidence accumulated along converging lines of investigation indicates that acute coronary syndromes are due to the activation of a vulnerable plaque. The tools available for interventionalists to identify such vulnerable plaques are currently limited to angiography and intravascular ultrasound (IVUS) imaging. However, within the next decade, catheter-based research techniques will emerge into the clinical setting to address and treat the vulnerable plaque. This review will discuss various current and future anatomic and physiologic methods to characterize the vulnerable plaque. Anatomy of a vulnerable plaque. An atheromatous plaque becomes vulnerable to sudden activation and/or rupture when a constellation of processes is activated by various trigger mechanisms. To varying degrees, an atheromatous lesion is comprised of a lipid core covered by a cap of fibrous tissue. Subintimal vascular smooth muscle cells express collagen and elastin, imparting tensile strength to an extracellular matrix. Inflammatory cells, such as macrophages, produce various enzymes and procoagulant factors. Disruption of the vulnerable plaque expresses thrombogenic material, leading to intraluminal thrombus. This process is the most frequent cause of acute coronary syndrome.1,2 The vulnerability of a culprit plaque is thus determined by a critical mass of a highly thrombogenic lipid core, the thickness of the atheromatous fibrous cap and the presence of an increased population of inflammatory cells.3 The fibrous cap is usually less than 40 microns thick and consists of a collagen-rich matrix and smooth muscle cells. It may be thinned and partially eroded by both inflammatory T-lymphocytes and invading smooth muscle cells. Abundant activated macrophages moving into the plaque from the vaso vasorum produce proteolytic enzymes, such as matrix metalloproteinases, that promote collagen degradation, leading to cap thinning.3 When the cap is thin and exposed to high circumferential stress at the luminal border of the plaque, plaque rupture is more likely to occur.4 Likewise, the lipid pool size contributes to the rupture potential. Davies et al. estimated that when at least 40% of the plaque consists of lipid, an atheroma is at risk for rupture.5 The population of smooth muscle cells in atherosclerotic plaque also influences the integrity of extracellular matrix. Thrombosis occurs when plaques rupture in those regions with few smooth muscle cells.3 In atherosclerotic lesions, apoptosis (death) of smooth muscle cells becomes a source of extracellular matrix depletion, weakening the arterial wall. Cytokines and “Fas” ligands play a role in plaque activation by stimulating inflammatory responses, triggering cell death.6 Lack of smooth muscles cells interferes with the fibrous cap strength and ability to maintain a collagenous matrix. Plaques that rupture are associated with the thin friable caps, principally due to lack of collagen and collagenous matrix proteins.3 Other plaques (or other areas within the same plaque) have a thick fibrous cap with a predominance of quiescent smooth muscle cells securely separating the lumen from the distant lipid core. In this plaque type, activated macrophages account for Tissue characterization using ultrasound: Morphology, composition and function. Catheter-based techniques using ultrasound can uniquely characterize the atherosclerotic plaque in vivo. It is well accepted that IVUS imaging is superior to angiography providing two-dimensional cross-sectional tomographic views. When digitally reconstructed, IVUS can display 3-dimensional images of the artery and plaque with accurate measurements of lumen, plaque and vessel area (and volume). 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 technique (Figure 1).10 However, IVUS has limited resolution (> 100 microns, even for 40 MHz systems) and signal quality is influenced by reflections from surrounding tissues. Standard IVUS currently cannot determine subendothelial plaque components.11 Even with high-frequency systems, imaging quality is hampered by increased signal backscatter of blood. The fibrous cap thickness and protruding plaque fractures can be only marginally visualized.10 In contrast, arterial calcifications (associated more with stable than unstable syndromes) are easily observed.12 Using IVUS, De Servi et al. found more focal calcification in patients with unstable clinical presentations (Braunwald class IB) than in those in class II and IIIB.13 Echocardiographically identified vulnerable plaques also appear to be associated with more negative remodeling after plaque rupture. Ward et al.14 reviewed data indicating that true arterial vessel size by IVUS rather than plaque area has a more dynamic role in arterial lumen remodeling and subsequent plaque stability. Tissue characterization by IVUS radiofrequency (RF) signal analysis provides more detailed information on atherosclerotic plaques type. Komiyama et al.15 examined RF signals from 24 regions of interest in noncalcified in vitro plaques. Sampling 30 MHz IVUS signals digitized at 500 MHz in 8 bit resolution, regions of interest were histologically categorized into plaques with and without lipid cores. Statistical parameters of the RF envelope differentiated lipid core as compared to the visual analysis of IVUS images. In the plaque group with lipid cores, the percent area of the lipid core in each region of interest could be quantitated by computerized planimetry. Using this technique, sensitivity and specificity of the mean-to-standard deviation ratio (MSR) for lipid core detection was greater than visual video imaging (83% versus 92%, respectively). Parameters of integrated backscattered MSR, skewness and kurtosis were significantly correlated with percent of core area. These data indicated that compared to IVUS imaging, the parameters of RF signal analysis were more accurate in detecting and quantitating lipid cores as one of the principle features associated with plaque vulnerability. Plaque elasticity. The functional activity of an atherosclerotic plaque reflects its composition. The elastic properties of atherosclerotic plaque can be used to differentiate histologic components. RF 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.16 Using IVUS elastography, de Korte et al.17 characterized different plaque components in diseased human femoral and coronary arteries in vitro. IVUS images were obtained at varying intraluminal pressures and RF signals were used to compute regional strain maps of arterial tissue. The strain map was color-coded and plotted as another image over the IVUS echogram (Figure 2). Histologic examination of the tissue demonstrated a correlation between high strain regions and collagen, smooth muscle cells and macrophages in 125 tissue cross-sections. Three histologic types of plaques (fibrous, fibro-fatty or 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 Tissue characterization using light: Angioscopy and optical coherence tomography. Coronary angioscopy uses projected white light through thin, flexible glass fibers incorporated into catheters in order to see the color of the arterial surface through the clear saline irrigation, permitting identification of red/white thrombus, yellow lipid-rich or white lipid-poor plaques in patients with acute coronary syndromes (ACS). Due to technical limitations and lack of clinical enthusiasm related to temporary blood flow occlusion, angioscopy never achieved widespread clinical application despite data indicating that angioscopically visualized thrombosis at the culprit lesions after PCI was related to increased adverse clinical outcomes.18 De Feyter et al. showed that angioscopic plaque rupture and thrombus occurred more in unstable compared to stable anginal syndromes (68% versus 17%, respectively).19 In a study of combined IVUS and angioscopy, Takano et al.20 found that yellow plaques with increased distensibility determined by an IVUS distensibility index in an artery with compensatory enlargement (positive remodeling) are highly susceptible to activation and rupture. Asakura et al.21 examined arteries in patients 1 month after MI to determine the prevalence of angioscopic surface characteristics. The diameter stenosis of the culprit lesion and maximum diameter of non-culprit arterial segments were measured angiographically. In 21 culprit lesions in 20 arteries, the diameter stenoses of culprit lesions and maximum non-culprit lesion diameters were 27 ± 17% and 19 ± 13%, respectively. Yellow plaques were equally prevalent in infarct-related and non-infarct-related coronary arteries (3.7 ± 1.6 versus 3.4 ± 1.8 plaques per artery). However, thrombi were detected in non-culprit segments in only 1 coronary artery (2%). The investigators concluded that in patients with MI, even when all 3 major arteries are widely diseased and have multiple yellow and non-disrupted plaques, acute MI represents a pancoronary process associated with vulnerable plaque activation and thrombus generation on target plaque surface. Optical coherence tomography (OCT) uses light to create IVUS-like images with extraordinary high resolution. Through a similar glass fiber-optic system, coherent infrared light can be directed and reflected within the tissue to create a detailed tissue image with a spatial resolution of 2–30 microns. This detail permits differentiation of lipid from water-based tissues and precisely quantitates fibrous cap thickness despite a penetration depth of only 1–2 mm.22 Compared to IVUS, OCT provides image resolution sufficient to differentiate intima, plaque and lipid pools (Figure 3).23 OCT can also differentiate tissue characteristics based on polarization properties. High birefringence by polarization shift identifies fibrous tissue, collagen and lipid composition. Low birefringence reflects calcium. By overlying low and high birefringent images on the OCT image map, tissue structure can be highlighted by tissue composition. Like angioscopy, successful clinical application must overcome a low penetration depth and blood absorbence interference by signal. 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.24 Raman spectra can differentiate non-atherosclerotic, noncalcified plaque from calcified plaque. Near-infrared Raman spectroscopy was applied to 165 coronary artery samples using 830 nm infrared light. Quantification of the relative weights of cholesterol, cholesterol esters, triglycerides, phospholipids, and calcium salts were examined in the target location by Romer, et al. (Figure 4).24 Spectroscopy data were validated by histological examination. Non-atherosclerotic tissue contained an average of 4 ± 3% cholesterol, whereas noncalcified plaques and calcified plaques had 26 ± 10% and 19 ± 10% cholesterol in noncalcified regions, respectively. Quantitative chemical signal information was converted using a diagnostic algorithm based on the first 97 samples and demonstrated a strong correlation between the relative weights of cholesterol and calcium salts with histologic diagnosis at the same location. Prospective testing of this algorithm correctly classified 64 of 68 samples. Like OCT, the penetration depth of the Raman spectroscopy is only 1.0–1.5 mm, but is sufficient to examine tissue beneath fibrous caps and within an atheromatous core. Raman spectroscopy is limited by strong image artifacts from background fluorescence and the absorbance of laser light by blood. Since Raman spectroscopy provides no information on morphology, it must be paired with IVUS, angioscopy or OCT systems. Raman spectroscopy may be useful for monitoring progression or regression of atherosclerosis, predicting plaque rupture, and selecting proper therapeutic interventions. Optically coherent light can also be used as a guidance tool for total occlusions. Using optical fibers, the interference pattern of two reflected coherent light beams (1,300 nm wavelength) can distinguish different tissue types of human atherosclerotic plaques. This method is termed optical coherence reflectometry (OCR). Yamashita et al.25 examined the slope of the initial portion of the OCR curve to distinguish calcified white from yellow atherosclerotic plaque. The guidewire position of the OCR signal was compared to positioning with simultaneous IVUS imaging. In 16 arterial surface segments, calcified plaques had steeper OCR slopes than white or yellow plaques (-227.2 ± 82.2, -81.5 ± 12.9, -103.6 ± 19.6, DB/MM; p 6 months. A crossing rate of 100% was achieved in the 6 cases. The determination of intraluminal wire position was facilitated by the OCR system. In some cases, recanalization was finally achieved with standard guidewires after creating initial channels with the OCR system. The initial clinical experience was favorable, indicating achievement of a TIMI grade three flow in 3 of the 6 patients and TIMI grade two flow in 2 of the 6 patients for these difficult and chronic total occlusions. OCR may have similar potential for further application in other difficult lesion patient subsets. Tissue characterization: Calcium scores and thermal activity. The amount of calcification within the coronary arteries reflects the degree of coronary artery disease (CAD) and can be detected and scored by fast complete tomography or electron beam complete tomography (EBCT). The EBCT calcium score generally correlates with risk of clinical events, although one cannot identify a target region or specific plaque. However, the relationship between plaque calcification and the predisposition to plaque rupture is controversial. Some investigators believe that calcium stabilizes the plaque, while others believe that it increases the shear stress and hence the risk of rupture. Almost all patients with a recent ACSs have measurable coronary calcium because of pre-existing moderate-to-advanced coronary artery disease. In these same individuals, flow-obstructing coronary lesions are not necessarily linked to calcium. Prospective studies indicate that extensive coronary calcium by EBCT is related to increased incidences of MI, obstructive coronary disease and death.27 In contrast to calcium, inflammation and activation of macrophages in plaques promote rupture, thrombosis and vasoconstriction, activities associated with increased temperature within an atheroma. Casscells et al.28 showed a temperature rise up to 2.2 °C in macrophage-rich areas in freshly obtained carotid endarterectomy specimens, confirming a significant correlation between macrophage density and local temperature. In human atherosclerotic coronary arteries, a 3 French thermography catheter demonstrated thermal heterogeneity with a spatial resolution of 0.5 mm in coronary arteries.29 Increased thermal activity was more common in patients with ACS. Increased thermal activity was noted in 20% of cases in patients with stable angina, in 40% with unstable angina (UA), and in 67% with acute MI.29 No thermal heterogeneity was seen in arterial specimens from control subjects. Increased local temperature in human coronary atherosclerotic plaques was also identified as an independent predictor of clinical outcomes in patients undergoing PCI.30 Stefanadis et al.30 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%), UA (35%) and 3 patients with acute MI (30%). The temperature difference increased progressively among the three groups (0.132 ± 0.18 °C, 0.637 ± 0.26 °C and 0.94 ± 0.58 °C for EA, UA and AMI patients, respectively). Over the follow-up period of 18 months, patients with greater temperature differences in the plaque compared to normal vessel wall had more adverse events (odds ratio, 2.14; p 0.5 °C was associated with increased risk of adverse events (41% compared to only 7% of patients with ?T Plaque characterization by magnetic resonance imaging. Current whole-body MRI at 1.5 T is limited by a resolution of > 400 µm. A catheter-based magnet coil positioned within the target vessel can resolve atherosclerotic tissue images to 120–300 µm, with an 80% concordance of plaque size and intimal thickness when compared to pathologic examination.31 The high-resolution 9 T MRI (spatial resolution, ~ 100 µm) permits examination of serial responses of atherosclerotic pathology to pharmacologic and mechanical therapies (Figure 5).32 MRI atherosclerotic plaque imaging will continue to advance significantly in the coming decade with the development of open magnets and enhanced imagery software. Physiologic significance of vulnerable plaques. The emergence of sensor-tipped angioplasty guidewires for coronary physiologic measurements has enabled interventionalists to examine blood flow responses before and after PCI. Coronary physiology provides the rationale to proceed with either PCI, coronary artery bypass surgery or medical therapy to stabilize potentially vulnerable lesions. Vulnerable plaques may or may not limit blood flow and thus the use of pressure/flow measurements for plaque assessment has important clinical implications. An epicardial coronary artery stenosis produces increasing resistance to blood flow with a proportionately increasing pressure along the P-V resistance curve (Figure 6). Coronary flow resistance is determined at the epicardial level by the lesion length and morphology (entrance/exit angles, length, eccentricity, and luminal topography). Coronary reserve is dependent on both epicardial lesion resistance and the status of the microvasculature. In addition, because net coronary flow is the result of both the conduit and microvascular bed resistance, quantitative anatomic variables (angiographic, IVUS or OCT) cannot accurately predict the functional response of flow through a given stenosis. Sensor-tipped angioplasty-style guidewires can measure post-stenotic absolute coronary vasodilatory reserve (CVR), relative CVR (rCVR), and pressure-derived fractional flow reserve (FFR) (Figure 7). These measurements are now commonly used for both clinical and research purposes; they can characterize the function of the epicardial, microvascular and collateral coronary circulation.33–35 For example, the impact of diffuse CAD compared to a focal stenosis on coronary flow can be separated using an FFR pull-back method. Relative CVR, the ratio of CVR target to CVR in an angiographically normal reference artery, examines the status of the microvascular bed. 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 interventions36,37 and leading to appropriate therapy for the best outcomes. Absolute and relative coronary flow reserve (CVR, rCVR). Absolute CVR (the ratio of hyperemic to basal flow) measures the capacity of the dual system of coronary artery and supplied vascular bed to achieve maximal oxygen supply in response to a given hyperemic stimulation. CVR is useful for lesion assessment only when the value is normal. To determine whether an abnormal CVR reflects abnormal stenosis physiology on abnormal microcirculation, the ratio of the target vessel to an angiographically normal reference vessel CVR (called relative CVR, rCVR) can be used. rCVR (CVR target/CVR ref) assumes that global myocardial reserve (i.e., the microcirculation) is uniformly responsive and distributed, nullifying the confounding effects of hemodynamics and the microcirculation. In young patients with angiographically and IVUS demonstrated normal arteries, CVR commonly exceeds 3.0. The values for CVR associated with non-obstructed coronary arteries in patients with chest pain syndromes, transplanted hearts, and in normal arteries in patients with obstructive coronary artery disease (CAD) elsewhere are 2.8 ± 0.6, 3.1 ± 0.9, and 2.5 ± 0.95, respectively.38 In patients with CAD, target artery CVR values associated with negative ischemic testing are generally > 2.0.39 rCVR values associated with unobstructed post-angioplasty and stent results and negative stress testing are > 0.80.40,41 CVR is highly variable due to the multiple factors that can alter either basal or hyperemic flow. Wienke et al.42 measured CVR in 141 patients with 242 unobstructed coronary arteries and found that individual CVR values could be corrected for patient age by relating them to a mean basal average peak velocity (BAPV) of 15 cm/second and age of 55 years (CVR corrected = 2.85 times CVR measured times 10x, where X = 0.48 log (BAPV) + 0.0025 x age – 1.16). The use of the correction formula showed that only patients with diabetes had a significant decrease in traditional CVR and corrected CVR, whereas hypertension and current smoking had no influence on corrected CVR. Standardizing CVR for variations in basal average peak velocity and patient age may discriminate between intrinsic and extra-cardiac factors impairing CVR. Pressure-derived FFR.Using coronary pressure measured at constant and minimal myocardial resistances (i.e., maximal hyperemia), Pijls et al.43 derived an estimate of the percentage of normal (i.e., in the theoretical absence of stenosis) coronary blood flow expected to go through a stenotic artery, called the FFR. The FFR, calculated as the ratio of post-stenotic or distal coronary pressure to aorta pressure (as the pressure in an unobstructed artery, i.e., the theoretical normal artery pressure) obtained at sustained minimal resistance (i.e., maximal hyperemia), reflects both antegrade and collateral myocardial perfusion rather than merely trans-stenotic pressure loss (i.e., a stenosis pressure gradient). Because it is calculated only at peak hyperemia, FFR is further differentiated from CVR by being largely independent of basal flow, driving pressure, heart rate, systemic blood pressure or status of the microcirculation.44 The FFR, but not the resting pressure of hyperemic pressure gradient, is strongly related to provocable myocardial ischemia (FFR Clinical outcomes related to catheter-based anatomic and physiologic data. The new modalities of RF IVUS plaque analysis, OCT, Raman spectroscopy, and thermography and MRI have yet to be widely applied clinically. Longitudinal studies relating current two-dimensional 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.45 Complete and full stent strut apposition to the vessel wall (by IVUS) is associated with reduced subacute thrombosis, and complete stent strut apposition may not occur in 30–40% of angiographically-guided cases.46 For lesions of uncertain physiologic significance, IVUS lumen cross-sectional areas of = 2.5 with 0.90 was achieved after balloon angioplasty alone, there was 0.94 after Wiktor stent implantation was associated with complete stent strut apposition in > 80% of IVUS-documented procedures.50 For clinical decision making, several studies have demonstrated

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