The interplay of collagen, macrophages, and microcalcification in atherosclerotic plaque cap rupture mechanics.

The rupture of an atherosclerotic plaque cap overlying a lipid pool and/or necrotic core can lead to thrombotic cardiovascular events. In essence, the rupture of the plaque cap is a mechanical event, which occurs when the local stress exceeds the local tissue strength. However, due to inter- and intra-cap heterogeneity, the resulting ultimate cap strength varies, causing proper assessment of the plaque at risk of rupture to be lacking. Important players involved in tissue strength include the load-bearing collagenous matrix, macrophages, as major promoters of extracellular matrix degradation, and microcalcifications, deposits that can exacerbate local stress, increasing tissue propensity for rupture. This review summarizes the role of these components individually in tissue mechanics, along with the interplay between them. We argue that to be able to improve risk assessment, a better understanding of the effect of these individual components, as well as their reciprocal relationships on cap mechanics, is required. Finally, we discuss potential future steps, including a holistic multidisciplinary approach, multifactorial 3D in vitro model systems, and advancements in imaging techniques. The obtained knowledge will ultimately serve as input to help diagnose, prevent, and treat atherosclerotic cap rupture.

Cross-Sectional Validation of a Novel Computed Tomography-Based Carotid Mean Calcium Density Measurement.

Background The purpose of this study was to validate a technique for measuring mean calcium density and to determine associations of cardiovascular risk factors with carotid calcium density. Methods and Results We performed a cross-sectional study in a random sample of 100 stroke-free participants from the population-based Rotterdam Study. The mean calcium density of the combined left and right carotid bifurcations was quantified with a threshold of 130 Hounsfield Units (HU) using a novel density technique. To validate the methodology, carotid calcium volumes acquired using the technique in the current study were compared with measurements computed using dedicated clinical software (semiautomatic technique based on a threshold of ≥130 HU). Next, we investigated the associations of participant demographics, total calcium volume, and known cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking status) with the newly derived mean carotid calcium density measurement using linear regression analyses. Calcium volumes obtained with the 2 methods showed a high agreement (intraclass correlation coefficient=0.99, P<0.001), underlining the validity of the density technique. The total calcium volume was statistically significantly associated with the mean calcium density (cardiovascular risk factors adjusted model (B: 0.48 [95% CI, 0.30-0.66], P<0.001). We also found an association between hypercholesterolemia and mean calcium density (0.46 [0.09-0.83], P=0.017). No other significant associations were found between participant demographics or cardiovascular risk factors and mean carotid calcium density. Conclusions We demonstrated the feasibility of a carotid calcium density measurement technique. The data warrant a subsequent longitudinal study to determine the association between carotid calcium density and the risk of cerebrovascular events.

Morphometric and Mechanical Analyses of Calcifications and Fibrous Plaque Tissue in Carotid Arteries for Plaque Rupture Risk Assessment.

OBJECTIVE: Atherosclerotic plaque rupture in carotid arteries is a major source of cerebrovascular events. Calcifications are highly prevalent in carotid plaques, but their role in plaque rupture remains poorly understood. This work studied the morphometric features of calcifications in carotid plaques and their effect on the stress distribution in the fibrous plaque tissue at the calcification interface, as a potential source of plaque rupture and clinical events. METHODS: A comprehensive morphometric analysis of 65 histology cross-sections from 16 carotid plaques was performed to identify the morphology (size and shape) and location of plaque calcifications, and the fibrous tissue fiber organization around them. Calcification-specific finite element models were constructed to examine the fibrous plaque tissue stresses at the calcification interface. Statistical correlation analysis was performed to elucidate the impact of calcification morphology and fibrous tissue organization on interface stresses. RESULTS: Hundred-seventy-one calcifications were identified on the histology cross-sections, which showed great variation in morphology. Four distinct patterns of fiber organization in the plaque tissue were observed around the calcification. They were termed as attached, pushed-aside, encircling and random patterns. The stress analyses showed that calcifications are correlated with high interface stresses, which might be comparable to or even above the plaque strength. The stress levels depended on the calcification morphology and fiber organization. Thicker calcification with a circumferential slender shape, located close to the lumen were correlated most prominently to high interface stresses. CONCLUSION: Depending on its morphology and the fiber organization around it, a calcification in an atherosclerotic plaque can act as a stress riser and cause high interface stresses. SIGNIFICANCE: This study demonstrated the potential of calcifications in atherosclerotic plaques to cause elevated stresses in plaque tissue and provided a biomechanical explanation for the histopathological findings of calcification-associated plaque rupture.

Calcifications in atherosclerotic plaques and impact on plaque biomechanics.

The catastrophic mechanical rupture of an atherosclerotic plaque is the underlying cause of the majority of cardiovascular events. The infestation of vascular calcification in the plaques creates a mechanically complex tissue composite. Local stress concentrations and plaque tissue strength properties are the governing parameters required to predict plaque ruptures. Advanced imaging techniques have permitted insight into fundamental mechanisms driving the initiating inflammatory-driven vascular calcification of the diseased intima at the (sub-) micron scale and up to the macroscale. Clinical studies have potentiated the biomechanical relevance of calcification through the derivation of links between local plaque rupture and specific macrocalcification geometrical features. The clinical implications of the data presented in this review indicate that the combination of imaging, experimental testing, and computational modelling efforts are crucial to predict the rupture risk for atherosclerotic plaques. Specialised experimental tests and modelling efforts have further enhanced the knowledge base for calcified plaque tissue mechanical properties. However, capturing the temporal instability and rupture causality in the plaque fibrous caps remains elusive. Is it necessary to move our experimental efforts down in scale towards the fundamental (sub-) micron scales in order to interpret the true mechanical behaviour of calcified plaque tissue interactions that is presented on a macroscale in the clinic and to further optimally assess calcified plaques in the context of biomechanical modelling.

Contour segmentation of the intima, media, and adventitia layers in intracoronary OCT images: application to fully automatic detection of healthy wall regions.

PURPOSE: Quantitative and automatic analysis of intracoronary optical coherence tomography images is useful and time-saving to assess cardiovascular risk in the clinical arena. METHODS: First, the interfaces of the intima, media, and adventitia layers are segmented, by means of an original front propagation scheme, running in a 4D multi-parametric space, to simultaneously extract three non-crossing contours in the initial cross-sectional image. Second, information resulting from the tentative contours is exploited by a machine learning approach to identify healthy and diseased regions of the arterial wall. The framework is fully automatic. RESULTS: The method was applied to 40 patients from two different medical centers. The framework was trained on 140 images and validated on 260 other images. For the contour segmentation method, the average segmentation errors were [Formula: see text] for the intima-media interface, [Formula: see text] for the media-adventitia interface, and [Formula: see text] for the adventitia-periadventitia interface. The classification method demonstrated a good accuracy, with a median Dice coefficient equal to 0.93 and an interquartile range of (0.78-0.98). CONCLUSION: The proposed framework demonstrated promising offline performances and could potentially be translated into a reliable tool for various clinical applications, such as quantification of tissue layer thickness and global summarization of healthy regions in entire pullbacks.

Carotid plaque fissure: An underestimated source of intraplaque hemorrhage.

BACKGROUND AND AIMS: Plaque fissuring, a phenomenon morphologically distinct from the classical rupture of a thinned fibrous cap, has not been well characterized in carotid atherosclerosis. The aim of this study was to establish the prevalence of plaque fissures in advanced carotid plaques with an otherwise intact luminal surface, and to determine whether they might be a source of intraplaque hemorrhage (IPH). METHODS: We evaluated 244 surgically intact, 'en bloc' embedded, serially sectioned carotid endarterectomy specimens and included only those plaques with a grossly intact luminal surface. RESULTS: Among the 67 plaques with grossly intact luminal surface, cap fissure was present in 39 (58%) plaques. A total of 60 individual fissures were present, and longitudinally mean fissure length was 1.3 mm. Most fissures were found distal to the bifurcation (63%), proximal to the stenosis (88%), and in the posterior (opposite the flow divider) or lateral quadrants (80%). 36% of the fissures remained in the superficial third of the plaque. 52% extended from the lumen surface to the middle third of the plaque and 12% reached the outer third of the plaque on cross section. Fissures often occurred between two tissue planes and were connected to IPH (fresh: 63%; any type: 92%) and calcifications (43%). No correlation was found with patient characteristics such as symptom status, carotid stenosis, hypertension, diabetes, smoking and medications (statins or antiplatelet agents). CONCLUSIONS: Plaque fissures are common in advanced carotid plaques with an otherwise grossly intact luminal surface and are associated with fresh intraplaque hemorrhage. As they occur on the interface between plaque components with different mechanical properties, further biomechanical studies are needed to unravel the underlying failure mechanisms.

Fusion of fibrous cap thickness and wall shear stress to assess plaque vulnerability in coronary arteries: a pilot study.

PURPOSE: Identification of rupture-prone plaques in coronary arteries is a major clinical challenge. Fibrous cap thickness and wall shear stress are two relevant image-based risk factors, but these two parameters are generally computed and analyzed separately. Accordingly, combining these two parameters can potentially improve the identification of at-risk regions. Therefore, the purpose of this study is to investigate the feasibility of the fusion of wall shear stress and fibrous cap thickness of coronary arteries in patient data. METHODS: Fourteen patients were included in this pilot study. Imaging of the coronary arteries was performed with optical coherence tomography and with angiography. Fibrous cap thickness was automatically quantified from optical coherence tomography pullbacks using a contour segmentation approach based on fast marching. Wall shear stress was computed by applying computational fluid dynamics on the 3D volume reconstructed from two angiograms. The two parameters then were co-registered using anatomical landmarks such as side branches. RESULTS: The two image modalities were successfully co-registered, with a mean (±SD) error corresponding to [Formula: see text] of the length of the analyzed region. For all the analyzed participants, the average thinnest portion of each fibrous cap was [Formula: see text], and the average WSS value at the location of the fibrous cap was [Formula: see text]. A unique index was finally generated for each patient via the fusion of fibrous cap thickness and wall shear stress measurements, to translate all the measured parameters into a single risk map. CONCLUSION: The introduced risk map integrates two complementary parameters and has potential to provide valuable information about plaque vulnerability.

Quantification of fibrous cap thickness in intracoronary optical coherence tomography with a contour segmentation method based on dynamic programming.

OBJECTIVES: Fibrous cap thickness is the most critical component of plaque stability. Therefore, in vivo quantification of cap thickness could yield valuable information for estimating the risk of plaque rupture. In the context of preoperative planning and perioperative decision making, intracoronary optical coherence tomography imaging can provide a very detailed characterization of the arterial wall structure. However, visual interpretation of the images is laborious, subject to variability, and therefore not always sufficiently reliable for immediate decision of treatment. METHODS: A novel semiautomatic segmentation method to quantify coronary fibrous cap thickness in optical coherence tomography is introduced. To cope with the most challenging issue when estimating cap thickness (namely the diffuse appearance of the anatomical abluminal interface to be detected), the proposed method is based on a robust dynamic programming framework using a geometrical a priori. To determine the optimal parameter settings, a training phase was conducted on 10 patients. RESULTS: Validated on a dataset of 179 images from 21 patients, the present framework could successfully extract the fibrous cap contours. When assessing minimal cap thickness, segmentation results from the proposed method were in good agreement with the reference tracings performed by a medical expert (mean absolute error and standard deviation of 22 ± 18 µm) and were similar to inter-observer reproducibility (21 ± 19 µm, R = .74), while being significantly faster and fully reproducible. CONCLUSION: The proposed framework demonstrated promising performances and could potentially be used for online identification of high-risk plaques.

Atherosclerotic plaque fibrous cap assessment under an oblique scan plane orientation in carotid MRI.

Carotid magnetic resonance imaging (MRI) is used to noninvasively assess atherosclerotic plaque fibrous cap (FC) status, which is closely related to ischemic stroke. Acquiring anisotropic voxels improves in-plane visualization, however, an oblique scan plane orientation could then obscure a FC (i.e., contrast below the noise level) and thus impair a reliable status assessment. To quantify this, we performed single-slice numerical simulations of a clinical 3.0T, 2D T1-weighted, black-blood, contrast-enhanced pulse sequence with various voxel dimensions: in-plane voxel size of 0.62 mm × 0.62 mm and 0.31 mm × 0.31 mm, slice thickness of 1, 2, and 3 mm. Idealized plaque models (FC thickness of 0.5, 1, and 1.5 mm) were imaged at various scan plane angles (0°-40° in steps of 10°), and the FC contrast was quantified. We found that when imaging thin FCs with anisotropic voxels, the FC contrast decreased when the scan plane orientation angle increased. However, a reduced in-plane voxel size at the cost of an increased slice thickness often led to enhanced FC contrast even in the presence of scan plane orientation angles of up to 40°. It can be concluded that while isotropic-voxel imaging eliminates the issue of scan plane obliqueness, it comes at the cost of reduced FC contrast, thus likely decreasing the reliability of FC status assessment in carotid MRI. If scan plane orientation obliquity at the slice of interest is moderate (<40°) or otherwise diminished through careful scan planning, voxel anisotropy could increase FC contrast and, in effect, increase the reliability of FC status assessment.

Detection and quantification of coronary atherosclerotic plaque by 64-slice multidetector CT: a systematic head-to-head comparison with intravascular ultrasound.

OBJECTIVE: We evaluated the ability of 64-slice multidetector computed tomography (MDCT)-derived plaque parameters to detect and quantify coronary atherosclerosis, using intravascular ultrasound (IVUS) as the reference standard. METHODS: In 32 patients, IVUS and 64-MDCT was performed. The MDCT and IVUS datasets of 44 coronary arteries were co-registered using a newly developed fusion technique and quantitative parameters were derived from both imaging modalities. The threshold of >0.5 mm of maximum wall thickness was used to establish plaque presence on MDCT and IVUS. RESULTS: We analyzed 1364 coregistered 1-mm coronary cross-sections and 255 segments of 5-mm length. Compared with IVUS, 64-MDCT enabled correct detection in 957 of 1109 cross-sections containing plaque (sensitivity 86%). In 180 of 255 cross-sections atherosclerosis was correctly excluded (specificity 71%). On the segmental level, MDCT detected 213 of 220 segments with any atherosclerotic plaque (sensitivity 96%), whereas the presence of any plaque was correctly ruled out in 28 of 32 segments (specificity 88%). Interobserver agreement for the detection of atherosclerotic cross-sections was moderate (Cohen's kappa coefficient K=0.51), but excellent for the atherosclerotic segments (K=1.0). Pearson's correlation coefficient for vessel plaque volumes measured by MDCT and IVUS was r=0.91 (p<0.001). Bland-Altman analysis showed a slight non-significant underestimation of any plaque volume by MDCT (p=0.5), with a trend to underestimate noncalcified and overestimate mixed/calcified plaque volumes (p=0.22 and p=0.87 respectively). CONCLUSION: MDCT is able to detect and quantify atherosclerotic plaque. Further improvement in CT resolution is necessary for more reliable assessment of very small and distal coronary plaques.

Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography.

Recently, small calcifications have been associated with unstable plaques. Plaque calcifications are both in intravascular ultrasound (IVUS) and multi-slice computed tomography (MSCT) easily recognized. However, smaller calcifications might be missed on MSCT due to its lower resolution. Because it is unknown to which extent calcifications can be detected with MSCT, we compared calcification detection on contrast enhanced MSCT with IVUS. The coronary arteries of patients with myocardial infarction or unstable angina were imaged by 64-slice MSCT angiography and IVUS. The IVUS and MSCT images were registered and the arteries were inspected on the presence of calcifications on both modalities independently. We measured the length and the maximum circumferential angle of each calcification on IVUS. In 31 arteries, we found 99 calcifications on IVUS, of which only 47 were also detected on MSCT. The calcifications missed on MSCT (n = 52) were significantly smaller in angle (27° ± 16° vs. 59° ± 31°) and length (1.4 ± 0.8 vs. 3.7 ± 2.2 mm) than those detected on MSCT. Calcifications could only be detected reliably on MSCT if they were larger than 2.1 mm in length or 36° in angle. Half of the calcifications seen on the IVUS images cannot be detected on contrast enhanced 64-slice MSCT angiography images because of their size. The limited resolution of MSCT is the main reason for missing small calcifications.

Three-dimensional registration of histology of human atherosclerotic carotid plaques to in-vivo imaging.

An accurate spatial relationship between 3D in-vivo carotid plaque and lumen imaging and histological cross sections is required to study the relationship between biomechanical parameters and atherosclerotic plaque components. We present and evaluate a fully three-dimensional approach for this registration problem, which accounts for deformations that occur during the processing of the specimens. By using additional imaging steps during tissue processing and semi-automated non-linear registration techniques, a 3D-reconstruction of the histology is obtained. The methodology was evaluated on five specimens obtained from patients, operated for severe atherosclerosis in the carotid bifurcation. In more than 80% of the histology slices, the quality of the semi-automated registration with computed tomography angiography (CTA) was equal to or better than the manual registration. The inter-observer variability was between one and two in-vivo CT voxels and was equal to the manual inter-observer variability. Our technique showed that the angles between the normals of the registered histology slices and the in-vivo CTA scan direction ranged 6-56 degrees , indicating that proper 3D-registration is crucial for establishing a correct spatial relation with in-vivo imaging modalities. This new 3D-reconstruction technique of atherosclerotic plaque tissue opens new avenues in the field of biomechanics as well as in the field of image processing, where it can be used for validation purposes of segmentation algorithms.

Plaque and shear stress distribution in human coronary bifurcations: a multislice computed tomography study.

AIMS: Early atherosclerosis is located in low wall shear-stress (WSS) regions, however plaques are also found in the high WSS sensing flow divider walls of coronary bifurcations. We assessed the plaque distribution and morphology near bifurcations non-invasively with 64-slice computed tomography in relation to the WSS distribution. METHODS AND RESULTS: We inspected 65 cross-sections near coronary bifurcations for the presence of plaque. Cross-sections were divided into four equal parts, which we numbered according to expected levels of WSS, with part I the lowest WSS (outer wall) and increasing WSS's in part II (inner bend), III (outer bend) and IV (flow divider). Of the cross-sections 88% had plaque. Of all parts I, 72% contained plaque. This was 62%, 38% and 31% in parts II, III and IV. In cross-sections with only 1 or 2 parts inflicted, plaque was found in part I and/or II in 94%. In 93% of the cross-sections with the flow divider inflicted, parts I and/or II were also inflicted. Plaque was never found exclusively in the flow divider part IV. CONCLUSIONS: We demonstrated that plaque is mostly present in low WSS regions, whereas plaque in high WSS regions is accompanied by plaque in adjacent low WSS regions. It is therefore plausible that plaque grows from the outer wall (low WSS) of the bifurcation towards the flow divider (high WSS).

Current diagnostic modalities for vulnerable plaque detection.

Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize such plaques. Several diagnostic methods are currently tested to detect vulnerable plaques. Angiography has a low discriminatory power to identify the vulnerable plaque, but does provide information about the entire coronary tree and serves as guide for invasive imaging techniques and therapy. Angioscopy offers a direct visualization of the plaque surface and intra-luminal structures like thrombi and tears. However, angioscopy is difficult to perform, invasive and only the proximal part of the vessels can be investigated. IVUS (intravascular ultrasound) provides some insight into the composition of plaques. The detection of vulnerable plaques is mainly based on series of case reports with a lack of prospectivity and follow-up. Palpography, an IVUS derived technique, reveals information, which is not recognizable in IVUS. It can differentiate between deformable and non-deformable tissue, which enables the technique to detect vulnerable plaques with a positive predictive value. The clinical value of palpography is currently under investigation. Thermography assesses the temperature heterogeneity as an indicator of the metabolic state of the plaque. A coincidence of temperature rise and localization of vulnerable plaque was suggested. OCT (optical coherence tomography) can provide images with ultrahigh resolution utilizing the back-reflection of near-infrared light from optical interfaces in tissue. Drawbacks are the low penetration depth into tissue and the absorbance of light by blood. Raman spectroscopy can provide quantification about the molecular composition of the plaque. Long acquisition time, the low penetration depth and light absorbance by blood limit the performance of the technique. Another light emitting technique is NIR (near infrared spectroscopy), which identifies lipid loaded plaques and is tested currently in clinical trials. Non-invasive MRI (magnetic resonance imaging) and multislice spiral computed tomography (MSCT), with their excellent ability to identify lipid-rich tissue, have been utilized to characterize potentially vulnerable plaques foremost in non-moving structures like the carotid arteries. Due to the resolution of the techniques small plaque structure cannot be assessed. The role of non-invasive imaging in vulnerable plaque detection is currently under investigation. Several invasive and non-invasive techniques are currently under development to assess the vulnerable plaque. Most of the techniques show exiting features, but none have proven their value in an extensive in vivo validation and all have a lack of prospective data.