Intima heterogeneity in stress assessment of atherosclerotic plaques.

Atherosclerotic plaque rupture is recognized as the primary cause of cardiac and cerebral ischaemic events. High structural plaque stresses have been shown to strongly correlate with plaque rupture. Plaque stresses can be computed with finite-element (FE) models. Current FE models employ homogeneous material properties for the heterogeneous atherosclerotic intima. This study aimed to evaluate the influence of intima heterogeneity on plaque stress computations. Two-dimensional FE models with homogeneous and heterogeneous intima were constructed from histological images of atherosclerotic human coronaries (n = 12). For homogeneous models, a single stiffness value was employed for the entire intima. For heterogeneous models, the intima was subdivided into four clusters based on the histological information and different stiffness values were assigned to the clusters. To cover the reported local intima stiffness range, 100 cluster stiffness combinations were simulated. Peak cap stresses (PCSs) from the homogeneous and heterogeneous models were analysed and compared. By using a global variance-based sensitivity analysis, the influence of the cluster stiffnesses on the PCS variation in the heterogeneous intima models was determined. Per plaque, the median PCS values of the heterogeneous models ranged from 27 to 160 kPa, and the PCS range varied between 43 and 218 kPa. On average, the homogeneous model PCS values differed from the median PCS values of heterogeneous models by 14%. A positive correlation (R2 = 0.72) was found between the homogeneous model PCS and the PCS range of the heterogeneous models. Sensitivity analysis showed that the highest main sensitivity index per plaque ranged from 0.26 to 0.83, and the average was 0.47. Intima heterogeneity resulted in substantial changes in PCS, warranting stress analyses with heterogeneous intima properties for plaque-specific, high accuracy stress assessment. Yet, computations with homogeneous intima assumption are still valuable to perform sensitivity analyses or parametric studies for testing the effect of plaque geometry on PCS. Moreover, homogeneous intima models can help identify low PCS, stable type plaques with thick caps. Yet, for thin cap plaques, accurate stiffness measurements of the clusters in the cap and stress analysis with heterogeneous cap properties are required to characterize the plaque stability.

Peak cap stress calculations in coronary atherosclerotic plaques with an incomplete necrotic core geometry.

BACKGROUND: Stress calculations in atherosclerotic coronary vulnerable plaques can aid in predicting coronary cap rupture. In vivo plaque geometry and composition of coronary arteries can merely be obtained via intravascular imaging. Only optical driven imaging techniques have sufficient resolution to visualize the fibrous cap, but due to limited penetration depth deeper components such as the backside of the necrotic core (NC) are generally not visible. The goal of this study was to investigate whether peak cap stresses can be approximated by reconstructing the backside of the NC. METHODS: Manual segmentations of coronary histological cross-sections served as a geometrical ground truth and were obtained from seven patients resulting in 73 NCs. Next, the backside was removed and reconstructed according to an estimation of the relative necrotic core thickness (rNCt). The rNCt was estimated at three locations along the NC angle and based on either group averaged parameters or plaque specific parameters. Stress calculations were performed in both the ground truth geometry and the reconstructed geometries and compared. RESULTS: Good geometrical agreement was found between the ground truth NC and the reconstructed NCs, based on group averaged rNCt estimation and plaque specific rNCt estimation, measuring the NC area difference (25.1 % IQR 14.0-41.3 % and 17.9 % IQR 9.81-32.7 %) and similarity index (0.85 IQR 0.77-0.90 and 0.88 IQR 0.79-0.91). The peak cap stresses obtained with both reconstruction methods showed a high correlation with respect to the ground truth, r(2) = 0.91 and r(2) = 0.95, respectively. For high stress plaques, the peak cap stress difference with respect to the ground truth significantly improved for the NC reconstruction based plaque specific features (6 %) compared to the reconstruction group averaged based (16 %). CONCLUSIONS: In conclusion, good geometry and stress agreement was observed between the ground truth NC geometry and the reconstructed geometries. Although group averaged rNCt estimation seemed to be sufficient for the NC reconstruction and stress calculations, including plaque specific data further improved stress predictions, especially for higher stresses.

MRI-based biomechanical parameters for carotid artery plaque vulnerability assessment.

Carotid atherosclerotic plaques are a major cause of ischaemic stroke. The biomechanical environment to which the arterial wall and plaque is subjected to plays an important role in the initiation, progression and rupture of carotid plaques. MRI is frequently used to characterize the morphology of a carotid plaque, but new developments in MRI enable more functional assessment of carotid plaques. In this review, MRI based biomechanical parameters are evaluated on their current status, clinical applicability, and future developments. Blood flow related biomechanical parameters, including endothelial wall shear stress and oscillatory shear index, have been shown to be related to plaque formation. Deriving these parameters directly from MRI flow measurements is feasible and has great potential for future carotid plaque development prediction. Blood pressure induced stresses in a plaque may exceed the tissue strength, potentially leading to plaque rupture. Multi-contrast MRI based stress calculations in combination with tissue strength assessment based on MRI inflammation imaging may provide a plaque stress-strength balance that can be used to assess the plaque rupture risk potential. Direct plaque strain analysis based on dynamic MRI is already able to identify local plaque displacement during the cardiac cycle. However, clinical evidence linking MRI strain to plaque vulnerability is still lacking. MRI based biomechanical parameters may lead to improved assessment of carotid plaque development and rupture risk. However, better MRI systems and faster sequences are required to improve the spatial and temporal resolution, as well as increase the image contrast and signal-to-noise ratio.

A Framework for Local Mechanical Characterization of Atherosclerotic Plaques: Combination of Ultrasound Displacement Imaging and Inverse Finite Element Analysis.

Biomechanical models have the potential to predict plaque rupture. For reliable models, correct material properties of plaque components are a prerequisite. This study presents a new technique, where high resolution ultrasound displacement imaging and inverse finite element (FE) modeling is combined, to estimate material properties of plaque components. Iliac arteries with plaques were excised from 6 atherosclerotic pigs and subjected to an inflation test with pressures ranging from 10 to 120 mmHg. The arteries were imaged with high frequency 40 MHz ultrasound. Deformation maps of the plaques were reconstructed by cross correlation of the ultrasound radiofrequency data. Subsequently, the arteries were perfusion fixed for histology and structural components were identified. The histological data were registered to the ultrasound data to construct FE model of the plaques. Material properties of the arterial wall and the intima of the atherosclerotic plaques were estimated using a grid search method. The computed displacement fields showed good agreement with the measured displacement fields, implying that the FE models were able to capture local inhomogeneities within the plaque. On average, nonlinear stiffening of both the wall and the intima was observed, and the wall of the atheroslcerotic porcine iliac arteries was markedly stiffer than the intima (877 ± 459 vs. 100 ± 68 kPa at 100 mmHg). The large spread in the data further illustrates the wide variation of the material properties. We demonstrated the feasibility of a mixed experimental-numerical framework to determine the material properties of arterial wall and intima of atherosclerotic plaques from intact arteries, and concluded that, due to the observed variation, plaque specific properties are required for accurate stress simulations.

The effects of plaque morphology and material properties on peak cap stress in human coronary arteries.

Heart attacks are often caused by rupture of caps of atherosclerotic plaques in coronary arteries. Cap rupture occurs when cap stress exceeds cap strength. We investigated the effects of plaque morphology and material properties on cap stress. Histological data from 77 coronary lesions were obtained and segmented. In these patient-specific cross sections, peak cap stresses were computed by using finite element analyses. The finite element analyses were 2D, assumed isotropic material behavior, and ignored residual stresses. To represent the wide spread in material properties, we applied soft and stiff material models for the intima. Measures of geometric plaque features for all lesions were determined and their relations to peak cap stress were examined using regression analyses. Patient-specific geometrical plaque features greatly influence peak cap stresses. Especially, local irregularities in lumen and necrotic core shape as well as a thin intima layer near the shoulder of the plaque induce local stress maxima. For stiff models, cap stress increased with decreasing cap thickness and increasing lumen radius (R = 0.79). For soft models, this relationship changed: increasing lumen radius and increasing lumen curvature were associated with increased cap stress (R = 0.66). The results of this study imply that not only accurate assessment of plaque geometry, but also of intima properties is essential for cap stress analyses in atherosclerotic plaques in human coronary arteries.

Feasibility of wall stress analysis of abdominal aortic aneurysms using three-dimensional ultrasound.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) are local dilations that can lead to a fatal hemorrhage when ruptured. Wall stress analysis of AAAs is a novel tool that has proven high potential to improve risk stratification. Currently, wall stress analysis of AAAs is based on computed tomography (CT) and magnetic resonance imaging; however, three-dimensional (3D) ultrasound (US) has great advantages over CT and magnetic resonance imaging in terms of costs, speed, and lack of radiation. In this study, the feasibility of 3D US as input for wall stress analysis is investigated. Second, 3D US-based wall stress analysis was compared with CT-based results. METHODS: The 3D US and CT data were acquired in 12 patients (diameter, 35-90 mm). US data were segmented manually and compared with automatically acquired CT geometries by calculating the similarity index and Hausdorff distance. Wall stresses were simulated at P = 140 mm Hg and compared between both modalities. RESULTS: The similarity index of US vs CT was 0.75 to 0.91 (n = 12), with a median Hausdorff distance ranging from 4.8 to 13.9 mm, with the higher values found at the proximal and distal sides of the AAA. Wall stresses were in accordance with literature, and a good agreement was found between US- and CT-based median stresses and interquartile stresses, which was confirmed by Bland-Altman and regression analysis (n = 8). Wall stresses based on US were typically higher (+23%), caused by geometric irregularities due to the registration of several 3D volumes and manual segmentation. In future work, an automated US registration and segmentation approach is the essential point of improvement before pursuing large-scale patient studies. CONCLUSIONS: This study is a first step toward US-based wall stress analysis, which would be the modality of choice to monitor wall stress development over time because no ionizing radiation and contrast material are involved.

Local anisotropic mechanical properties of human carotid atherosclerotic plaques - characterisation by micro-indentation and inverse finite element analysis.

Biomechanical models have the potential to predict failure of atherosclerotic plaques and to improve the risk assessment of plaque rupture. The applicability of these models depends strongly on the used material models. Current biomechanical models employ isotropic material models, although it is generally accepted that plaque tissue behaves highly anisotropic. The aim of the present study is to determine the local anisotropic mechanical properties of human atherosclerotic plaque tissue by means of micro-indentation tests. The indentation was performed on top of an inverted confocal microscope allowing the visualisation and quantification of the collagen fibre deformations perpendicular to the indentation direction of the plaque. Based on this, the anisotropic properties of plaque tissue perpendicular to the indentation direction (middle of the fibrous cap, shoulder of the cap, remaining intima tissue) were derived. There were no significant differences between the different indentation locations for the fibre stiffness (total median 80.6kPa, 25th-75th percentile 17.7-157.0kPa), and fibre dispersion.

Effect of shear stress alteration on atherosclerotic plaque vulnerability in cholesterol-fed rabbits.

Previously, we created an experimental murine model for the induction of vulnerable plaque (VP). Although this murine model offers the opportunity to study the different molecular biological pathways that regulate plaque destabilization, the size of the animals severely limits the use of the model for in vivo diagnostics and percutaneous interventions. This study aimed to create a VP model in the rabbit, based on the murine model, to aid the assessment and development of novel diagnostic and interventional tools. New Zealand white rabbits were fed on a 2% cholesterol diet. After 1 week, a shear stress-altering device was implanted around the right carotid artery. Twelve weeks after cast placement, the carotid artery was isolated and processed for (immuno-)histological analysis to evaluate the presence of a VP phenotype. Atherosclerotic plaques with high lipid and macrophage content, low vascular smooth muscle cell content and intimal neovascularization were located upstream and downstream of the cast. The plaques lacked a significant necrotic core. In conclusion, we were able to create atherosclerotic plaques with a phenotype beyond that of a fatty streak, with a high percentage of lipids and macrophages, a thick cap with some vascular smooth muscle cells and neovascularization. However, as there was only a small necrotic core, the overall phenotype seems less vulnerable as compared to the thin fibrous cap atheroma in patients.

Mechanical properties of human atherosclerotic intima tissue.

Progression and rupture of atherosclerotic plaques in coronary and carotid arteries are the key processes underlying myocardial infarctions and strokes. Biomechanical stress analyses to compute mechanical stresses in a plaque can potentially be used to assess plaque vulnerability. The stress analyses strongly rely on accurate representation of the mechanical properties of the plaque components. In this review, the composition of intima tissue and how this changes during plaque development is discussed from a mechanical perspective. The plaque classification scheme of the American Heart Association is reviewed and plaques originating from different vascular territories are compared. Thereafter, an overview of the experimental studies on tensile and compressive plaque intima properties are presented and the results are linked to the pathology of atherosclerotic plaques. This overview revealed a considerable variation within studies, and an enormous dispersion between studies. Finally, the implications of the dispersion in experimental data on the clinical applications of biomechanical plaque modeling are presented. Suggestions are made on mechanical testing protocol for plaque tissue and on using a standardized plaque classification scheme. This review identifies the current status of knowledge on plaque mechanical properties and the future steps required for a better understanding of the plaque type specific material properties. With this understanding, biomechanical plaque modeling may eventually provide essential support for clinical plaque risk stratification.

Compressive mechanical properties of atherosclerotic plaques--indentation test to characterise the local anisotropic behaviour.

Accurate material models and associated parameters of atherosclerotic plaques are crucial for reliable biomechanical plaque prediction models. These biomechanical models have the potential to increase our understanding of plaque progression and failure, possibly improving risk assessment of plaque rupture, which is the main cause of ischaemic strokes and myocardial infarction. However, experimental biomechanical data on atherosclerotic plaque tissue is scarce and shows a high variability. In addition, most of the biomechanical models assume isotropic behaviour of plaque tissue, which is a general over-simplification. This review discusses the past and the current literature that focus on mechanical properties of plaque derived from compression experiments, using unconfined compression, micro-indentation or nano-indentation. Results will be discussed and the techniques will be mutually compared. Thereafter, an in-house developed indentation method combined with an inverse finite element method is introduced, allowing analysis of the local anisotropic mechanical properties of atherosclerotic plaques. The advantages and limitations of this method will be evaluated and compared to other methods reported in literature.

MRI strain imaging of the carotid artery: present limitations and future challenges.

Rupture of atherosclerotic plaques in the carotid artery is a main cause of stroke. Current diagnostics are not sufficient to identify all rupture-prone plaques, and studies have shown that biomechanical factors improve current plaque risk assessment. Strain imaging may be a valuable contribution to this risk assessment. MRI is a versatile imaging technique that offers various methods that are capable of measuring tissue strain. In this review, MR imaging techniques with displacement (DENSE), velocity (PC MRI), or strain (SENC) encoding protocols are discussed, together with post-processing techniques based on time-resolved MRI data. Although several MRI techniques are being developed to improve time-resolved MR imaging, current technical limitations related to spatial and temporal resolutions render MRI strain imaging currently unfit for carotid plaque strain evaluation. A novel approach using non-rigid image registration of MR images to determine strain in carotid arteries based on black blood cine MRI is proposed in this review. This and other post-processing techniques based on time-resolved MRI data may provide a good estimate of plaque strain, but are also dependent on the spatial and temporal resolution of the MR images. However, they seem to be the most promising approach for MRI based plaque strain analysis in the near future.

The influence of inaccuracies in carotid MRI segmentation on atherosclerotic plaque stress computations.

Biomechanical finite element analysis (FEA) based on in vivo carotid magnetic resonance imaging (MRI) can be used to assess carotid plaque vulnerability noninvasively by computing peak cap stress. However, the accuracy of MRI plaque segmentation and the influence this has on FEA has remained unreported due to the lack of a reliable submillimeter ground truth. In this study, we quantify this influence using novel numerical simulations of carotid MRI. Histological sections from carotid plaques from 12 patients were used to create 33 ground truth plaque models. These models were subjected to numerical computer simulations of a currently used clinically applied 3.0 T T1-weighted black-blood carotid MRI protocol (in-plane acquisition voxel size of 0.62 × 0.62 mm2) to generate simulated in vivo MR images from a known underlying ground truth. The simulated images were manually segmented by three MRI readers. FEA models based on the MRI segmentations were compared with the FEA models based on the ground truth. MRI-based FEA model peak cap stress was consistently underestimated, but still correlated (R) moderately with the ground truth stress: R = 0.71, R = 0.47, and R = 0.76 for the three MRI readers respectively (p < 0.01). Peak plaque stretch was underestimated as well. The peak cap stress in thick-cap, low stress plaques was substantially more accurately and precisely predicted (error of -12 ± 44 kPa) than the peak cap stress in plaques with caps thinner than the acquisition voxel size (error of -177 ± 168 kPa). For reliable MRI-based FEA to compute the peak cap stress of carotid plaques with thin caps, the current clinically used in-plane acquisition voxel size (∼0.6 mm) is inadequate. FEA plaque stress computations would be considerably more reliable if they would be used to identify thick-cap carotid plaques with low stresses instead.

Local axial compressive mechanical properties of human carotid atherosclerotic plaques-characterisation by indentation test and inverse finite element analysis.

The fibrous cap of an atherosclerotic plaque may be prone to rupture if the occurring stresses exceed the strength of the cap. Rupture can cause acute thrombosis and subsequent ischaemic stroke or myocardial infarction. A reliable prediction of the rupture probability is essential for the appropriate treatment of atherosclerosis. Biomechanical models, which compute stresses and strain, are promising to provide a more reliable rupture risk prediction. However, these models require knowledge of the local biomechanical properties of atherosclerotic plaque tissue. For this purpose, we examined human carotid plaques using indentation experiments. The test set-up was mounted on an inverted confocal microscope to visualise the collagen fibre structure during the tests. By using an inverse finite element (FE) approach, and assuming isotropic neo-Hookean behaviour, the corresponding Young's moduli were found in the range from 6 to 891kPa (median 30kPa). The results correspond to the values obtained by other research groups who analysed the compressive Young's modulus of atherosclerotic plaques. Collagen rich locations showed to be stiffer than collagen poor locations. No significant differences were found between the Young's moduli of structured and unstructured collagen architectures as specified from confocal collagen data. Insignificant differences between the middle of the fibrous cap, the shoulder regions, and remaining plaque tissue locations indicate that axial, compressive mechanical properties of atherosclerotic plaques are independent of location within the plaque.

Effects of intima stiffness and plaque morphology on peak cap stress.

BACKGROUND: Rupture of the cap of a vulnerable plaque present in a coronary vessel may cause myocardial infarction and death. Cap rupture occurs when the peak cap stress exceeds the cap strength. The mechanical stress within a cap depends on the plaque morphology and the material characteristics of the plaque components. A parametric study was conducted to assess the effect of intima stiffness and plaque morphology on peak cap stress. METHODS: Models with idealized geometries based on histology images of human coronary arteries were generated by varying geometric plaque features. The constructed multi-layer models contained adventitia, media, intima, and necrotic core sections. For adventitia and media layers, anisotropic hyperelastic material models were used. For necrotic core and intima sections, isotropic hyperelastic material models were employed. Three different intima stiffness values were used to cover the wide range reported in literature. According to the intima stiffness, the models were classified as stiff, intermediate and soft intima models. Finite element method was used to compute peak cap stress. RESULTS: The intima stiffness was an essential determinant of cap stresses. The computed peak cap stresses for the soft intima models were much lower than for stiff and intermediate intima models. Intima stiffness also affected the influence of morphological parameters on cap stresses. For the stiff and intermediate intima models, the cap thickness and necrotic core thickness were the most important determinants of cap stresses. The peak cap stress increased three-fold when the cap thickness was reduced from 0.25 mm to 0.05 mm for both stiff and intermediate intima models. Doubling the thickness of the necrotic core elevated the peak cap stress by 60% for the stiff intima models and by 90% for the intermediate intima models. Two-fold increase in the intima thickness behind the necrotic core reduced the peak cap stress by approximately 25% for both intima models. For the soft intima models, cap thickness was less critical and changed the peak cap stress by 55%. However, the necrotic core thickness was more influential and changed the peak cap stress by 100%. The necrotic core angle emerged as a critical determinant of cap stresses where a larger angle lowered the cap stresses. Contrary to the stiff and intermediate intima models, a thicker intima behind the necrotic core increased the peak cap stress by approximately 25% for the soft intima models. Adventitia thickness and local media regression had limited effects for all three intima models. CONCLUSIONS: For the stiff and intermediate intima models, the cap thickness was the most important morphological risk factor. However for soft intima models, the necrotic core thickness and necrotic core angle had a bigger impact on the peak cap stress. We therefore need to enhance our knowledge of intima material properties if we want to derive critical morphological plaque features for risk evaluation.

The mechanical role of thrombus on the growth rate of an abdominal aortic aneurysm.

OBJECTIVES: In the decision for surgical repair of abdominal aortic aneurysms (AAAs), the maximum diameter is the main factor. Several studies have concluded that the diameter may not be reliable as rupture risk criterion for the individual patient and wall stress was found to have a higher sensitivity and specificity. The AAA wall stress may also be an influential factor in growth of the AAA. This study investigates the effect of intraluminal thrombus on the wall stress and growth rate of aneurysms, using both idealized and patient-specific AAA models in wall stress computations. METHODS: Idealized AAA models were created for wall stress analysis. Thrombus was modeled as an incompressible linear elastic material and was fixed to the wall. The reduction in wall stress for a range of thrombus volumes and shear moduli was computed. For 30 patient-specific AAA models with varying thrombus volumes, the wall stress was computed with and without thrombus. The diameter growth rate was compared for AAAs with a small and large thrombus volume. The results were compared between the idealized and patient-specific models. RESULTS: The thrombus caused a reduction in wall stress, which was stronger for larger thrombi and higher elastic moduli. Any AAAs with a large thrombus were found to have significant stronger growth in diameter than aneurysms with a small thrombus (P < .01). The stress reduction due to the thrombus showed the same trend for the idealized and patient-specific models, although the effect was overestimated by the idealized models and a considerable variation between patients was observed. CONCLUSION: A larger thrombus in AAA was associated with a higher AAA growth rate, but also with a lower wall stress. Therefore, weakening of the AAA wall, under the influence of thrombus, may play a more imminent role in the process of AAA growth than the stress acting on the wall.

Effects of wall calcifications in patient-specific wall stress analyses of abdominal aortic aneurysms.

It is generally acknowledged that rupture of an abdominal aortic aneurysm (AAA) occurs when the stress acting on the wall over the cardiac cycle exceeds the strength of the wall. Peak wall stress computations appear to give a more accurate rupture risk assessment than AAA diameter, which is currently used for a diagnosis. Despite the numerous studies utilizing patient-specific wall stress modeling of AAAs, none investigated the effect of wall calcifications on wall stress. The objective of this study was to evaluate the influence of calcifications on patient-specific finite element stress computations. In addition, we assessed whether the effect of calcifications could be predicted directly from the CT-scans by relating the effect to the amount of calcification present in the AAA wall. For 6 AAAs, the location and extent of calcification was identified from CT-scans. A finite element model was created for each AAA and the areas of calcification were defined node-wise in the mesh of the model. Comparisons are made between maximum principal stress distributions, computed without calcifications and with calcifications with varying material properties. Peak stresses are determined from the stress results and related to a calcification index (CI), a quantification of the amount of calcification in the AAA wall. At calcification sites, local stresses increased, leading to a peak stress increase of 22% in the most severe case. Our results displayed a weak correlation between the CI and the increase in peak stress. Additionally, the results showed a marked influence of the calcification elastic modulus on computed stresses. Inclusion of calcifications in finite element analysis of AAAs resulted in a marked alteration of the stress distributions and should therefore be included in rupture risk assessment. The results also suggest that the location and shape of the calcified regions--not only the relative amount--are considerations that influence the effect on AAA wall stress. The dependency of the effect of the wall stress on the calcification elastic modulus points out the importance of determination of the material properties of calcified AAA wall.