Effects of varied lipid core volume and fibrous cap thickness on stress distribution in carotid arterial plaques

The rupture of atherosclerotic plaques is known to be associated with the stresses that act on or within the arterial wall. The extreme wall tensile stress is usually recognized as a primary trigger for the rupture of the plaque. The present study used one-way fluid-structure interaction simulation to investigate the impacts of fibrous cap thickness and lipid core volume to the wall tensile stress value and distributions on the fibrous cap. Von Mises stress was employed to represent the wall tensile stress (VWTS). A total of 13 carotid bifurcation cases were manipulated based on a base geometry in the study with varied combinations of fibrous cap thickness and lipid core volume in the plaque. Values of maximum VWTS and a stress value of VWTS_90, which represents the cut-off VWTS value of 90% in cumulative histogram of VWTS possessed at the computational nodes on the luminal surface of fibrous cap, were used to assess the risk of plaque rupture for each case. Both parameters are capable of separating the simulation cases into vulnerable and more stable plaque groups, while VWTS_90 is more robust for plaque rupture risk assessment. The results show that the stress level on the fibrous cap is much more sensitive to the changes in the fibrous cap thickness than the lipid core volume. A slight decrease of cap thickness can cause a significant increase of stress. For all simulation cases, high VWTS appears at the fibrous cap near the lipid core (plaque shoulder) regions.     

Micro-CT based analysis of a new paradigm for vulnerable plaque rupture: cellular microcalcifications in fibrous caps

In this paper, we further investigate the new paradigm for the rupture of thin cap fibroatheroma (TCFA) proposed in Vengrenyuk et al. (2006 PNAS 103:14678) using a multilevel micro-CT based 3D numerical modeling. The new paradigm proposes that the rupture of TCFA is due to stress-induced interfacial debonding of cellular--level, 10-20 microm microcalcifications in the fibrous cap proper. Such microcalcifications, which lie below the visibility of current in vivo imaging techniques, were detected for the first time using confocal microscopy and high resolution microcomputed tomography (micro-CT) imaging in Vengrenyuk et al. (2006) In the present study, we use high resolution (7 microm) micro-CT imaging to construct accurate geometries of both these microcalcifications and larger mm size macrocalcifications at the cap shoulders to evaluate their biomechanical stability. The analysis shows that cellular-level calcifications by themselves are not dangerous unless they lie in a region of high background stress. This high level of background stress only occurs in caps whose thickness is < approximately 80 microm. Whereas a spherical microcalcification will increase peak circumferential stress (PCS) by a factor of two, in agreement with previous local analytical solutions, this can be increased several fold by elongated microcalcifications. The most dangerous situation is when a microinclusion appears in close proximity to a region where the PCS is already high. This stress will be substantially increased if the inclusion is elongated. In contrast, macrocalcifications at the cap shoulders are shown to actually increase plaque stability.     

3D computational parametric analysis of eccentric atheroma plaque: influence of axial and circumferential residual stresses

Plaque rupture plays a role in the majority of acute coronary syndromes. Rupture has usually been associated with stress concentrations, which are mainly affected by the plaque geometry and the tissue properties. The aim of this study is to evaluate the influence of morphology on the risk of plaque rupture, including the main geometrical factors, and to assess the role of circumferential and axial residual stresses by means of a parametric 3D finite element model. For this purpose, a 3D parametric finite element model of the coronary artery with eccentric atheroma plaque was developed. Healthy (adventitia and media in areas without atheroma plaque) and diseased (fibrotic and lipidic) tissues were considered in the model. The geometrical parameters used to define and design the idealized coronary plaque anatomy were the lipid core length, the stenosis ratio, the fibrous cap thickness, and the lipid core ratio. Finally, residual stresses in longitudinal and circumferential directions were incorporated into the model to analyse the influence of the important mechanical factors in the vulnerability of the plaque. Viewing the results, we conclude that residual stresses should be considered in the modelling of this kind of problems since they cause a significant alteration of the vulnerable plaque region limits. The obtained results show that the fibrous cap thickness and the lipid core length, in combination with the lipid core width, appear to be the key morphological parameters that play a determinant role in the maximal principal stress (MPS). However, the stenosis ratio is found to not play a significant role in vulnerability related to the MPS. Plaque rupture should therefore be observed as a consequence, not only of the cap thickness, but as a combination of the stenosis ratio, the fibrous cap thickness and the lipid core dimensions.     

Stress analysis of carotid plaque rupture based on in vivo high resolution MRI

Atheromatous carotid plaque rupture is responsible for the majority of ischaemic strokes in the developed world. Plaque rupture has been associated with plaque morphology, plaque components' properties, inflammation and local stress concentration. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in vivo. This study combined the recent advances in finite element analysis (FEA) and MRI, and performed stress analysis of five vulnerable carotid plaques based on the geometry derived from in vivo MRI. Image segmentation was based on multi-spectral MRI and co-registered with histology for plaque characterization. Plaque fibrous cap, lipid pool and vessel wall were modelled as isotropic, incompressible hyperelastic materials undergoing large deformation under pulse pressure loading. High stress concentrations were predicted at the shoulders and the thinnest fibrous cap regions of the plaque, and the mean maximal stresses were found to be higher in the ruptured plaques (683.3 kPa) than those in the unruptured plaques (226.9 kPa). The effect of the relative stiffness of fibrous cap to lipid pool on the stress within the cap itself was studied. It was shown that larger relative stiffness of fibrous cap to lipid pool resulted in higher stress within the cap. Thus, it is likely that high stress concentrations in vulnerable plaque may cause plaque rupture and lead to acute ischaemic sequelae. A combination of in vivo high resolution MRI and FEA could potentially act as a useful tool to assess plaque vulnerability and risk stratify patients with carotid atheroma.     

A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture

The role of microcalcifications (μCalcs) in the biomechanics of vulnerable plaque rupture is examined. Our laboratory previously proposed (Ref. 44), using a very limited tissue sample, that μCalcs embedded in the fibrous cap proper could significantly increase cap instability. This study has been greatly expanded. Ninety-two human coronary arteries containing 62 fibroatheroma were examined using high-resolution microcomputed tomography at 6.7-μm resolution and undecalcified histology with special emphasis on calcified particles <50 μm in diameter. Our results reveal the presence of thousands of μCalcs, the vast majority in lipid pools where they are not dangerous. However, 81 μCalcs were also observed in the fibrous caps of nine of the fibroatheroma. All 81 of these μCalcs were analyzed using three-dimensional finite-element analysis, and the results were used to develop important new clinical criteria for cap stability. These criteria include variation of the Young's modulus of the μCalc and surrounding tissue, μCalc size, and clustering. We found that local tissue stress could be increased fivefold when μCalcs were closely spaced, and the peak circumferential stress in the thinnest nonruptured cap (66 μm) if no μCalcs were present was only 107 kPa, far less than the proposed minimum rupture threshold of 300 kPa. These results and histology suggest that there are numerous μCalcs < 15 μm in the caps, not visible at 6.7-μm resolution, and that our failure to find any nonruptured caps between 30 and 66 μm is a strong indication that many of these caps contained μCalcs.     

Quantifying effects of plaque structure and material properties on stress distributions in human atherosclerotic plaques using 3D FSI models

BACKGROUND: Atherosclerotic plaques may rupture without warning and cause acute cardiovascular syndromes such as heart attack and stroke. Methods to assess plaque vulnerability noninvasively and predict possible plaque rupture are urgently needed. METHOD: MRI-based three-dimensional unsteady models for human atherosclerotic plaques with multi-component plaque structure and fluid-structure interactions are introduced to perform mechanical analysis for human atherosclerotic plaques. RESULTS: Stress variations on critical sites such as a thin cap in the plaque can be 300% higher than that at other normal sites. Large calcification block considerably changes stress/strain distributions. Stiffness variations of plaque components (50% reduction or 100% increase) may affect maximal stress values by 20-50%. Plaque cap erosion causes almost no change on maximal stress level at the cap, but leads to 50% increase in maximal strain value. CONCLUSIONS: Effects caused by atherosclerotic plaque structure, cap thickness and erosion, material properties, and pulsating pressure conditions on stress/strain distributions in the plaque are quantified by extensive computational case studies and parameter evaluations. Computational mechanical analysis has good potential to improve accuracy of plaque vulnerability assessment.     

Effect of calcification on the mechanical stability of plaque based on a three-dimensional carotid bifurcation model

Background

This study characterizes the distribution and components of plaque structure by presenting a three-dimensional blood-vessel modelling with the aim of determining mechanical properties due to the effect of lipid core and calcification within a plaque. Numerical simulation has been used to answer how cap thickness and calcium distribution in lipids influence the biomechanical stress on the plaque.

Method

Modelling atherosclerotic plaque based on structural analysis confirms the rationale for plaque mechanical examination and the feasibility of our simulation model. Meaningful validation of predictions from modelled atherosclerotic plaque model typically requires examination of bona fide atherosclerotic lesions. To analyze a more accurate plaque rupture, fluid-structure interaction is applied to three-dimensional blood-vessel carotid bifurcation modelling. A patient-specific pressure variation is applied onto the plaque to influence its vulnerability.

Results

Modelling of the human atherosclerotic artery with varying degrees of lipid core elasticity, fibrous cap thickness and calcification gap, which is defined as the distance between the fibrous cap and calcification agglomerate, form the basis of our rupture analysis. Finite element analysis shows that the calcification gap should be conservatively smaller than its threshold to maintain plaque stability. The results add new mechanistic insights and methodologically sound data to investigate plaque rupture mechanics.

Conclusion

Structural analysis using a three-dimensional calcified model represents a more realistic simulation of late-stage atherosclerotic plaque. We also demonstrate that increases of calcium content that is coupled with a decrease in lipid core volume can stabilize plaque structurally.     

Morphological and Stress Vulnerability Indices for Human Coronary Plaques and Their Correlations with Cap Thickness and Lipid Percent: An IVUS-Based Fluid-Structure Interaction Multi-patient Study

Plaque vulnerability, defined as the likelihood that a plaque would rupture, is difficult to quantify due to lack of in vivo plaque rupture data. Morphological and stress-based plaque vulnerability indices were introduced as alternatives to obtain quantitative vulnerability assessment. Correlations between these indices and key plaque features were investigated. In vivo intravascular ultrasound (IVUS) data were acquired from 14 patients and IVUS-based 3D fluid-structure interaction (FSI) coronary plaque models with cyclic bending were constructed to obtain plaque wall stress/strain and flow shear stress for analysis. For the 617 slices from the 14 patients, lipid percentage, min cap thickness, critical plaque wall stress (CPWS), strain (CPWSn) and flow shear stress (CFSS) were recorded, and cap index, lipid index and morphological index were assigned to each slice using methods consistent with American Heart Association (AHA) plaque classification schemes. A stress index was introduced based on CPWS. Linear Mixed-Effects (LME) models were used to analyze the correlations between the mechanical and morphological indices and key morphological factors associated with plaque rupture. Our results indicated that for all 617 slices, CPWS correlated with min cap thickness, cap index, morphological index with r = -0.6414, 0.7852, and 0.7411 respectively (p<0.0001). The correlation between CPWS and lipid percentage, lipid index were weaker (r = 0.2445, r = 0.2338, p<0.0001). Stress index correlated with cap index, lipid index, morphological index positively with r = 0.8185, 0.3067, and 0.7715, respectively, all with p<0.0001. For all 617 slices, the stress index has 66.77% agreement with morphological index. Morphological and stress indices may serve as quantitative plaque vulnerability assessment supported by their strong correlations with morphological features associated with plaque rupture. Differences between the two indices may lead to better plaque assessment schemes when both indices were jointly used with further validations from clinical studies.     

Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.     

Mechanical stresses in carotid plaques using MRI-based fluid-structure interaction models

Risk assessment in patients with carotid atherosclerosis relies on the degree of luminal stenosis. Incorporating morphological information on plaque composition obtained noninvasively through the use of magnetic resonance imaging (MRI) could include other variables besides the degree of stenosis into carotid plaque risk assessment. Knowledge of the morphologic composition of the plaque allows determination of mechanic stresses exerted on the protective fibrous cap, which may be of importance in the assessment of plaque vulnerability. Based on image processing of transverse MRI scans, longitudinal 2D fluid-structure interaction (FSI) simulations of carotid atherosclerotic plaques were performed facilitating in-vivo estimation of longitudinal internal fibrous cap stresses. The FSI simulation combined finite element analysis (FEA) with computational fluid dynamics (CFD) simulations of blood-flow variables. Preliminary results from two symptomatic patients revealed longitudinal stress levels (max. 254.1 and 143.2 kPa) approaching established criteria for plaque rupture at known predilection sites of plaque rupture. Determination of longitudinal fibrous cap stresses may prove useful in assessing plaque vulnerability and improve risk stratification in patients with carotid atherosclerosis.     

Carotid arterial plaque stress analysis using fluid–structure interactive simulation based on in-vivo magnetic resonance images of four patients

The rupture of atherosclerotic plaques is known to be associated with the stresses that act on or within the arterial wall. The extreme wall tensile stress (WTS) is usually recognized as a primary trigger for the rupture of vulnerable plaque. The present study used the in-vivo high-resolution multi-spectral magnetic resonance imaging (MRI) for carotid arterial plaque morphology reconstruction. Image segmentation of different plaque components was based on the multi-spectral MRI and co-registered with different sequences for the patient. Stress analysis was performed on totally four subjects with different plaque burden by fluid–structure interaction (FSI) simulations. Wall shear stress distributions are highly related to the degree of stenosis, while the level of its magnitude is much lower than the WTS in the fibrous cap. WTS is higher in the luminal wall and lower at the outer wall, with the lowest stress at the lipid region. Local stress concentrations are well confined in the thinner fibrous cap region, and usually locating in the plaque shoulder; the introduction of relative stress variation during a cycle in the fibrous cap can be a potential indicator for plaque fatigue process in the thin fibrous cap. According to stress analysis of the four subjects, a risk assessment in terms of mechanical factors could be made, which may be helpful in clinical practice. However, more subjects with patient specific analysis are desirable for plaque-stability study.     

Numerical modeling of stress in stenotic arteries with microcalcifications: a parameter sensitivity study

As a follow-up to the work presented in Wenk et al. (2010, "Numerical Modeling of Stress in Stenotic Arteries With Microcalcifications: A Micromechanical Approximation," ASME J. Biomech. Eng., 132, p. 091011), a formal sensitivity study was conducted in which several model parameters were varied. The previous work only simulated a few combinations of the parameters. In the present study, the fibrous cap thickness, longitudinal position of the region of microcalcifications, and volume fraction of microcalcifications were varied over a broader range of values. The goal of the present work is to investigate the effects of localized regions of microcalcifications on the stress field of atherosclerotic plaque caps in a section of carotid artery. More specifically, the variations in the magnitude and location of the maximum circumferential stress were assessed for a range of parameters using a global sensitivity analysis method known as Sobol' indices. The stress was calculated by performing finite element simulations of three-dimensional fluid-structure interaction models, while the sensitivity indices were computed using a Monte Carlo scheme. The results indicate that cap thickness plays a significant role in the variation in the magnitude of the maximum circumferential stress, with the sensitivity to volume fraction increasing when the region of microcalcification is located at the shoulder. However, the volume fraction played a larger role in the variation in the location of the maximum circumferential stress. This matches the finding of the previous study (Wenk et al., 2010, "Numerical Modeling of Stress in Stenotic Arteries With Microcalcifications: A Micromechanical Approximation," ASME J. Biomech. Eng., 132, p. 091011), which indicates that the maximum circumferential stress always shifts to the region of microcalcification.     

Lumen irregularity dominates the relationship between mechanical stress condition, fibrous-cap thickness, and lumen curvature in carotid atherosclerotic plaque

High mechanical stress condition over the fibrous cap (FC) has been widely accepted as a contributor to plaque rupture. The relationships between the stress, lumen curvature, and FC thickness have not been explored in detail. In this study, we investigate lumen irregularity-dependent relationships between mechanical stress conditions, local FC thickness (LT(FC)), and lumen curvature (LC(lumen)). Magnetic resonance imaging slices of carotid plaque from 100 patients with delineated atherosclerotic components were used. Two-dimensional structure-only finite element simulations were performed for the mechanical analysis, and maximum principal stress (stress-P?) at all integral nodes along the lumen was obtained. LT(FC) and LC(lumen) were computed using the segmented contour. The lumen irregularity (L-δir) was defined as the difference between the largest and the smallest lumen curvature. The results indicated that the relationship between stress-P?, LT(FC), and LC(lumen) is largely dependent on L-δir. When L-δir ≥ .31 (irregular lumen), stress-P? strongly correlated with lumen curvature and had a weak/no correlation with local FC thickness, and in 73.4% of magnetic resonance (MR) slices, the critical stress (maximum of stress-P? over the diseased region) was found at the site where the lumen curvature was large. When L-δir ≤ 0.28 (relatively round lumen), stress-P? showed a strong correlation with local FC thickness but weak/no correlation with lumen curvature, and in 71.7% of MR slices, the critical stress was located at the site of minimum FC thickness. Using lumen irregularity as a method of identifying vulnerable plaque sites by referring to the lumen shape is a novel and simple method, which can be used for mechanics-based plaque vulnerability assessment.     

Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control

Patients with type 2 diabetes are at a high risk for acute cardiovascular events, which usually arise from the rupture of a vulnerable coronary lesion characterized by specific morphological plaque features. Thus, the identification of vulnerable plaques is of utmost clinical importance in patients with type 2 diabetes. However, there is currently no scoring system available to identify vulnerable lesions based on plaque characteristics. Thus, we aimed to characterize the diagnostic value of optical coherence tomography (OCT) - derived lesion characteristics to quantify plaque vulnerability both as individual parameters and when combined to a score in patients with type 2 diabetes. OCT was performed in the coronary culprit lesions of 112 patients with type 2 diabetes. The score, which quantifies plaque vulnerability, was defined as the predicted probability that a lesion is the cause for an acute coronary syndrome (ACS) (vs. stable angina (SAP)) based on its specific plaque morphology. Multivariable logistic regression analysis demonstrated that plaque vulnerability was independently predicted by the minimal fibrous cap thickness overlying a lesion’s lipid core (odds ratio (OR) per 10 μm 0.478, p = 0.002), the medium lipid arc (OR per 90° 13.997, p < 0.001), the presence of macrophages (OR 4.797, p = 0.015) and the lipid plaque length (OR 1.290, p = 0.098). Receiver-operating-characteristics (ROC) analyses demonstrated that these parameters combined to a score demonstrate an excellent diagnostic efficiency to identify culprit lesions of patients with ACS (vs. SAP, AUC 0.90, 95% CI 0.84-0.96). This is the first study to present a score to quantify lesion vulnerability in patients with type 2 diabetes. This score may be a valuable adjunct in decision-making and useful in guiding coronary interventions.     

hs-CRP、D-二聚体和Lp-PLA2与冠心病患者冠状动脉粥样硬化易损斑块的相关性

目的:研究超敏C反应蛋白(hs-CRP)、D-二聚体和脂蛋白相关磷脂酶A2(Lp-PLA2)与冠心病患者冠状动脉粥样硬化易损斑块的相关性。方法:选择2014年1月~2016年12月在我院进行冠状动脉造影和血管内超声检查的患者106例,按照检查结果分为易损斑块组、稳定斑块组和对照组。检测和比较三组患者的血清hs-CRP、D-二聚体和Lp-PLA2水平,并采用Pearson相关分析探讨其与纤维帽厚度、斑块偏心指数和血管重构指数的相关性。结果:易损斑块组和稳定斑块组的血清hs-CRP、D-二聚体和Lp-PLA2水平明显高于对照组(P0.05),且易损斑块组的血清hs-CRP、D-二聚体和Lp-PLA2水平明显高于稳定斑块组(P0.05)。hs-CRP与纤维帽厚度呈负相关(r=-0.712,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.813,0.756,P0.05);D-二聚体与纤维帽厚度呈负相关(r=-0.654,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.912,0.853,P0.05);Lp-PLA2与纤维帽厚度呈负相关(r=-0.796,P0.05),与斑块偏心指数和血管重构指数呈正相关(r=0.836,0.729,P0.05)。结论:hs-CRP、D-二聚体和Lp-PLA2与冠心病患者冠状动脉粥样硬化易损斑块具有较高的相关性,可作为评估冠状动脉粥样斑块不稳定性的参考指标。     

Study of carotid arterial plaque stress for symptomatic and asymptomatic patients

Stroke is one of the leading causes of death in the world, resulting mostly from the sudden ruptures of atherosclerosis carotid plaques. Until now, the exact plaque rupture mechanism has not been fully understood, and also the plaque rupture risk stratification. The advanced multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in-vivo and reconstructed by computational modeling. In the study, plaque stress analysis using fully coupled fluid structure interaction was applied to 20 patients (12 symptomatic and 8 asymptomatic) reconstructed from in-vivo MRI, followed by a detailed biomechanics analysis, and morphological feature study. The locally extreme stress conditions can be found in the fibrous cap region, 85% at the plaque shoulder based on the present study cases. Local maximum stress values predicted in the plaque region were found to be significantly higher in symptomatic patients than that in asymptomatic patients (200 ± 43 kPa vs. 127 ± 37 kPa, p=0.001). Plaque stress level, defined by excluding 5% highest stress nodes in the fibrous cap region based on the accumulative histogram of stress experienced on the computational nodes in the fibrous cap, was also significantly higher in symptomatic patients than that in asymptomatic patients (154 ± 32 kPa vs. 111 ± 23 kPa, p<0.05). Although there was no significant difference in lipid core size between the two patient groups, symptomatic group normally had a larger lipid core and a significantly thinner fibrous cap based on the reconstructed plaques using 3D interpolation from stacks of 2D contours. Plaques with a higher stenosis were more likely to have extreme stress conditions upstream of plaque throat. The combined analyses of plaque MR image and plaque stress will advance our understanding of plaque rupture, and provide a useful tool on assessing plaque rupture risk.     

Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture

In a vulnerable plaque (VP), rupture often occurs at a site of high stress within the cap. It is also known that vessels do not become free of stress when all external loads are removed. Previous studies have shown that such residual stress/strain (RS/S) tends to make the stress distribution more uniform throughout the media of a normal artery. However, the influence of RS/S on the wall stress distribution in pathological coronaries remains unclear. The aim of this study was to investigate the effects of RS/S on the biomechanical stability of VPs. RS/S patterns were studied ex vivo in six human vulnerable coronary plaque samples. Because the existence of RS/S can only be assessed by releasing it, the opening angle technique was the experimental approach used to study the geometrical opening configurations of the diseased arteries, producing an arterial wall in a near-zero stress state. Reciprocally, these opening geometries were used in finite element simulations to reconstruct the RS/S distributions in closed arteries. It was found that the RS/S 1) is not negligible, 2) dramatically affects the physiological peak stress amplitude in the thin fibrous cap, 3) spotlights some new high stress areas, and 4) could be a landmark of the lipid core's developmental process within a VP. This study demonstrates that plaque rupture is not to be viewed as a consequence of intravascular pressure alone, but rather of a subtle combination of external loading and intraplaque RS/S.     

Doxycycline stabilizes vulnerable plaque via inhibiting matrix metalloproteinases and attenuating inflammation in rabbits

Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels.     

Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy

Several studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance. In this work, force mapping experiments using atomic force microscopy (AFM) were conducted in apolipoprotein E-deficient (ApoE(-/-)) mouse, which represents the most widely used experimental model for studying mechanisms underlying the development of atherosclerotic lesions. To obtain the elastic material properties of fibrous caps and lipidic cores of atherosclerotic plaques, serial cross-sections of aortic arch lesions were probed at different sites. Atherosclerotic plaque sub-structures were subdivided into cellular fibrotic, hypocellular fibrotic and lipidic rich areas according to histological staining. Hertz's contact mechanics were used to determine elasticity (Young's) moduli that were related to the underlying histological plaque structure. Cellular fibrotic regions exhibit a mean Young modulus of 10.4±5.7kPa. Hypocellular fibrous caps were almost six-times stiffer, with average modulus value of 59.4±47.4kPa, locally rising up to ～250kPa. Lipid rich areas exhibit a rather large range of Young's moduli, with average value of 5.5±3.5kPa. Such precise quantification of plaque stiffness heterogeneity will allow investigators to have prospectively a better monitoring of atherosclerotic disease evolution, including arterial wall remodeling and plaque rupture, in response to mechanical constraints imposed by vascular shear stress and blood pressure.     

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.