H.E. Barrett

On the effect of calcification volume and configuration on the mechanical behaviour of carotid plaque tissue.

Vascular calcification is a complex molecular process that exhibits a number of relatively characteristic morphology patterns in atherosclerotic plaques. Treatment of arterial stenosis by endovascular intervention, involving forceful circumferential expansion of the plaque, can be unpredictable in calcified lesions. The aim of this study was to determine the mechanical stretching mechanisms and define the mechanical limits for circumferentially expanding carotid plaque lesions under the influence of distinct calcification patterns. Mechanical and structural characterisation was performed on 17 human carotid plaques acquired from patients undergoing endarterectomy procedures. The mechanical properties were determined using uniaxial extension tests that stretch the lesions to complete failure along their circumferential axis. Calcification morphology of mechanically ruptured plaque lesions was characterised using high resolution micro computed tomography imaging. Scanning electron microscopy was used to examine the mechanically induced failure sites and to identify the interface boundary conditions between calcified and non-calcified tissue. The mechanical tests produced four distinct trends in mechanical behaviour which corresponded to the calcification patterns that structurally defined each mechanical group. Each calcification pattern produced unique mechanical restraining effects on the plaque tissue stretching properties evidenced by the variation in degree of stretch to failure. Resistance to failure appears to rely on interactions between calcification and non-calcified tissue. Scanning electron microscopy examination revealed structural gradations at interface boundary conditions to facilitate the transfer of stress. This study emphasises the mechanical influence of distinct calcification configurations on plaque expansion properties and highlights the importance of pre-operative lesion characterisation to optimise treatment outcomes.

Simulation of human atherosclerotic femoral plaque tissue: the influence of plaque material model on numerical results.

BackgroundDue to the limited number of experimental studies that mechanically characterise human atherosclerotic plaque tissue from the femoral arteries, a recent trend has emerged in current literature whereby one set of material data based on aortic plaque tissue is employed to numerically represent diseased femoral artery tissue. This study aims to generate novel vessel-appropriate material models for femoral plaque tissue and assess the influence of using material models based on experimental data generated from aortic plaque testing to represent diseased femoral arterial tissue.MethodsNovel material models based on experimental data generated from testing of atherosclerotic femoral artery tissue are developed and a computational analysis of the revascularisation of a quarter model idealised diseased femoral artery from a 90% diameter stenosis to a 10% diameter stenosis is performed using these novel material models. The simulation is also performed using material models based on experimental data obtained from aortic plaque testing in order to examine the effect of employing vessel appropriate material models versus those currently employed in literature to represent femoral plaque tissue.ResultsSimulations that employ material models based on atherosclerotic aortic tissue exhibit much higher maximum principal stresses within the plaque than simulations that employ material models based on atherosclerotic femoral tissue. Specifically, employing a material model based on calcified aortic tissue, instead of one based on heavily calcified femoral tissue, to represent diseased femoral arterial vessels results in a 487 fold increase in maximum principal stress within the plaque at a depth of 0.8 mm from the lumen.ConclusionsLarge differences are induced on numerical results as a consequence of employing material models based on aortic plaque, in place of material models based on femoral plaque, to represent a diseased femoral vessel. Due to these large discrepancies, future studies should seek to employ vessel-appropriate material models to simulate the response of diseased femoral tissue in order to obtain the most accurate numerical results.

Mechanical properties and composition of carotid and femoral atherosclerotic plaques: A comparative study

This study compares the mechanical properties of excised carotid and femoral human plaques and also develops a predictor of these properties based on plaque composition. Circumferential planar tension tests were performed on 24 carotid and 16 femoral plaque samples. Composition was characterised using Fourier Transform Infrared spectroscopy. Stretch at failure, strength, and stiffness are significantly higher in the carotid group (P=.012, P<.001 and P=.002, respectively). The ratio of calcified to lipid plaque content demonstrates the strongest correlation with the stretch at failure and strength (R2=.285, P<.001 and R2=.347, P<.001). No composition based parameter correlates significantly with stiffness. The significantly different mechanical properties of the two groups aids in explaining the varying endovascular treatment outcomes clinically observed in these vessels. Furthermore, determining the ratio of calcified to lipid plaque content may be useful in predicting individual plaque mechanical response to endovascular treatment.

The influence of composition and location on the toughness of human atherosclerotic femoral plaque tissue.

UNLABELLED The toughness of femoral atherosclerotic tissue is of pivotal importance to understanding the mechanism of luminal expansion during cutting balloon angioplasty (CBA) in the peripheral vessels. Furthermore, the ability to relate this parameter to plaque composition, pathological inclusions and location within the femoral vessels would allow for the improvement of existing CBA technology and for the stratification of patient treatment based on the predicted fracture response of the plaque tissue to CBA. Such information may lead to a reduction in clinically observed complications, an improvement in trial results and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. This study characterises the toughness of atherosclerotic plaque extracted from the femoral arteries of ten patients using a lubricated guillotine cutting test to determine the critical energy release rate. This information is related to the location that the plaque section was removed from within the femoral vessels and the composition of the plaque tissue, determined using Fourier Transform InfraRed spectroscopy, to establish the influence of location and composition on the toughness of the plaque tissue. Scanning electron microscopy (SEM) is employed to examine the fracture surfaces of the sections to determine the contribution of tissue morphology to toughness. Toughness results exhibit large inter and intra patient and location variance with values ranging far above and below the toughness of healthy porcine arterial tissue (Range: 1330-3035 for location and 140-4560J/m(2) for patients). No significant difference in mean toughness is observed between patients or location. However, the composition parameter representing the calcified tissue content of the plaque correlates significantly with sample toughness (r=0.949, p<0.001). SEM reveals the presence of large calcified regions in the toughest sections that are absent from the least tough sections. Regression analysis highlights the potential of employing the calcified tissue content of the plaque as a preoperative tool for predicting the fracture response of a target lesion to CBA (R(2)=0.885, p<0.001). STATEMENT OF SIGNIFICANCE This study addresses a gap in current knowledge regarding the influence of plaque location, composition and morphology on the toughness of human femoral plaque tissue. Such information is of great importance to the continued improvement of endovascular treatments, particularly cutting balloon angioplasty (CBA), which require experimentally derived data as a framework for assessing clinical cases and advancing medical devices. This study identifies that femoral plaque tissue exhibits large inter and intra patient and location variance regarding tissue toughness. Increasing calcified plaque content is demonstrated to correlate significantly with increasing toughness. This highlights the potential for predicting target lesion toughness which may lead to an increased adoption of the CBA technique and also further the uptake of endovascular treatment.

On the influence of wall calcification and intraluminal thrombus on prediction of abdominal aortic aneurysm rupture

Objective: Parameters other than maximum diameter that predict rupture of abdominal aortic aneurysms (AAAs) may be helpful for risk‐benefit analysis in individual patients. The aim of this study was to characterize the biomechanical‐structural characteristics associated with AAA walls to better identify the related mechanistic variables required for an accurate prediction of rupture risk. Methods: Anterior AAA wall (n = 40) and intraluminal thrombus (ILT; n = 114) samples were acquired from 18 patients undergoing open surgical repair. Biomechanical characterization was performed using controlled circumferential stretching tests combined with a speckle‐strain tracking technique to quantify the spatial heterogeneity in deformation and localized strains in the AAA walls containing calcification. After mechanical testing, the accompanying microstructural characteristics of the AAA wall and ILT types were examined using electron microscopy. Results: No significant correlation was found between the AAA diameter and the wall mechanical properties in terms of Cauchy stress (rs = −0.139; P = .596) or stiffness (rs = −0.451; P = .069). Quantification of significant localized peak strains, which were concentrated in the tissue regions surrounding calcification, reveals that peak strains increased by a mean of 174% as a result of calcification and corresponding peak stresses by 18.2%. Four ILT types characteristic of diverse stages in the evolving tissue microstructure were directly associated with distinct mechanical stiffness properties of the ILT and underlying AAA wall. ILT types were independent of geometric factors, including ILT volume and AAA diameter measures (ILT stiffness and AAA diameter [rs = −0.511; P = .074]; ILT stiffness and ILT volume [rs = −0.245; P = .467]). Conclusions: AAA wall stiffness properties are controlled by the load‐bearing capacity of the noncalcified tissue portion, and low stiffness properties represent a highly degraded vulnerable wall. The presence of calcification that is contiguous with the inner wall causes severe tissue overstretching in surrounding tissue areas. The results highlight the use of additional biomechanical measures, detailing the biomechanical‐structural characteristics of AAA tissue, that may be a helpful adjunct to improve the accuracy of rupture prediction. Clinical Relevance: The mechanical‐structural calcification information presented in this study marks a crucial starting point for a risk‐benefit analysis to better predict abdominal aortic aneurysm rupture risk. Calcification plays an integral role in the structural degradation of abdominal aortic aneurysm walls, which is mechanically represented by diminished stiffness properties. This degradative influence coupled with significant straining influences of calcification predisposes surrounding noncalcified tissue to significantly increased stresses, which may help disclose the walls localized site of highest rupture risk. Thus, this information may help assess whether a survival benefit can be achieved from clinical intervention.

Calcification Volume Reduces Stretch Capability and Predisposes Plaque to Rupture in an in vitro Model of Carotid Artery Stenting

OBJECTIVE/BACKGROUND Carotid artery stenting (CAS) in calcified arteries carries a higher peri-operative risk. This study investigates the relationship between the stretching limits of carotid plaque samples and calcification in order to determine a stretch tolerance criterion for endovascular intervention. METHODS Seventeen carotid plaque samples were acquired from standard endarterectomy procedures. The maximum stretch capability of the global plaque was determined by circumferentially extending the tissue to complete failure. Quantitative assessment of calcification was performed using high resolution computed tomography, including measures of percent calcification volume fraction (%CVF) and calcification configuration. Maximum stretch properties were then related to calcification measures in order to evaluate the predictive power of calcification for determining plaque stretching limits. RESULTS A strong negative correlation was found between %CVF and stretch ratio with respect to specific calcification configuration types. All plaques with < 70% stenosis superseded the minimum required stretch threshold. Severe stenosis (> 70%) warrants a stretch of at least 2.33 during revascularisation and only plaques containing concentric calcifications with < 20% CVF successfully reached this minimum required stretch threshold. CONCLUSION The addition of calcification measures to the stenosis classification may help in guiding endovascular intervention techniques to achieve a balance between an acceptable residual patency level while avoiding plaque rupture in calcified carotid plaques.

On the effect of computed tomography resolution to distinguish between abdominal aortic aneurysm wall tissue and calcification: A proof of concept

PURPOSE The purpose of this study is to determine the optimal target CT spatial resolution for accurately imaging abdominal aortic aneurysm (AAA) wall characteristics, distinguishing between tissue and calcification components, for an accurate assessment of rupture risk. MATERIALS AND METHODS Ruptured and non-ruptured AAA-wall samples were acquired from eight patients undergoing open surgical aneurysm repair upon institutional review board approval and informed consent was obtained from all patients. Physical measurements of AAA-wall cross-section were made using scanning electron microscopy. Samples were scanned using high resolution micro-CT scanning. A resolution range of 15.5-155μm was used to quantify the influence of decreasing resolution on wall area measurements, in terms of tissue and calcification. A statistical comparison between the reference resolution (15.5μm) and multi-detector CT resolution (744μm) was also made. RESULTS Electron microscopy examination of ruptured AAAs revealed extremely thin outer tissue structure <200μm in radial distribution which is supporting the aneurysm wall along with large areas of adjacent medial calcifications far greater in area than the tissue layer. The spatial resolution of 155μm is a significant predictor of the reference AAA-wall tissue and calcification area measurements (r=0.850; p<0.001; r=0.999; p<0.001 respectively). The tissue and calcification area at 155μm is correct within 8.8%±1.86 and 26.13%±9.40 respectively with sensitivity of 87.17% when compared to the reference. CONCLUSION The inclusion of AAA-wall measurements, through the use of high resolution-CT will elucidate the variations in AAA-wall tissue and calcification distributions across the wall which may help to leverage an improved assessment of AAA rupture risk.

Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review

Specific patient cohorts are at increased risk of vascular calcification. Functional matrix-gla protein (MGP), a tissue-derived vitamin K dependent protein, is reported to be an important inhibitor of vascular calcification and may have clinical potential to modify the progression of vascular calcification through regulation of functional MGP fractions. This systematic review examines twenty-eight studies which assess the relationship between circulating protein expressions of MGP species and vascular calcification in different arterial beds. The included studies examined participants with atherosclerosis, chronic kidney disease (CKD), diabetes, healthy participants, vitamin K supplementation, measured plasma vitamin K levels and vitamin K antagonist usage. The current review reports conflicting results regarding MGP fractions with respect to local calcification development indicating that a multifaceted relationship exists between the MGP and calcification. A primary concern regarding the studies in this review is the large degree of variability in the calcification location assessed and the fraction of MGP measured. This review suggests that different underlying molecular mechanisms can accelerate local disease progression within the vasculature, and specific circulating fractions of MGP may be influenced differently depending on the local disease states related to vascular calcification development. Further studies examining the influence of non-functional MGP levels, with respect to specific calcified arterial beds, are warranted.

Relating the mechanical properties of atherosclerotic calcification to radiographic density: A nanoindentation approach

Calcification morphology can determine atherosclerotic plaque stability and is associated with increased failures rates for endovascular interventions. Computational efforts have sought to elucidate the relationship between calcification and plaque rupture in addition to predicting tissue response during aggressive revascularisation techniques. However, calcified material properties are currently estimated and may not reflect real tissue conditions. The objective of this study is to correlate calcification mechanical properties with three radiographic density groups obtained from corresponding Computed Tomography (CT) images. Seventeen human plaques extracted from carotid (n = 10) and peripheral lower limb (n = 7) arteries were examined using micro-computed tomography (µCT), simultaneously locating the calcified deposits within their internal structure and quantifying their densities. Three radiographic density groups were defined based on the sample density distribution: (A) 130-299.99 Hounsfield Units (HU), (B) 300-449.99 HU and (C) >450 HU. Nanoindentation was employed to determine the Elastic Modulus (E) and Hardness (H) values within the three density groups. Results reveal a clear distinction between mechanical properties with respect to radiographic density groups (p < 0.0005). No significant differences exist in the density-specific behaviours observed between carotid and peripheral samples. Previously defined calcification classifications indicate an association with specific radiographic density patterns. Scanning Electron Microscopy (SEM) examination revealed that density group A regions consist of both calcified and non-calcified tissues. Further research is required to define the radiographic thresholds which identify varying degrees of tissue calcification. This study demonstrates that the mechanical properties of fully mineralised atherosclerotic calcification emulate that of bone tissues (17-25 GPa), affording computational models with accurate material parameters. STATEMENT OF SIGNIFICANCE: Global mechanical characterisation techniques disregard the heterogeneous nature of atherosclerotic lesions. Previous nanoindentation results for carotid calcifications have displayed a wide range. This study evaluates calcification properties with respect to radiographic density obtained from Micro-CT images. This is the first work to characterise calcifications from peripheral lower limb arteries using nanoindentation. Results demonstrate a strong positive correlation between radiographic density and calcification mechanical properties. Characterising calcifications using their density values provides clarity on the variation in published properties for calcified tissues. Furthermore, this study confirms the hypothesis that fully calcified plaque tissue behaviour similar to that of bone. Appropriate material parameters for calcified tissues can now be employed in computational simulations.

Towards the characterisation of carotid plaque tissue toughness: Linking mechanical properties to plaque composition

UNLABELLED The morphological manifestation of calcification within an atherosclerotic plaque is diverse and the response to cutting balloon angioplasty remains an elusive target to predict in the presence of extensive calcification. This study examines the resistance of plaque tissue to blade penetration by characterising the underlying toughness properties and stratifying the upper and lower scale toughness limits based on the strong mechanical influence of calcification. Mechanical toughness properties of the common, bifurcation and internal carotid artery (n=62) were determined using guillotine-cutting tests measuring the energy required to pass a surgical blade through a unit length of plaque tissue. The corresponding structural composition of the dissected plaque segments was characterised using Fourier transform infrared analysis, electron microscopy and energy dispersive x-ray spectroscopy. Mechanical results reveal a clear distinction in toughness properties within each region of the carotid vessel with significantly tougher properties localised in the bifurcation (p=0.004) and internal region (p=0.0003) compared to the common. The severity of the intra-plaque variance is highest in plaques with high toughness localised in the bifurcation region (p<0.05). Structural examination reveals that the diverse mechanical influence of the level of calcification present is characteristic of specific regions within the carotid plaque. The energy required to overcome the calcific resistance and propagate a controlled cut in the calcified tissue at each region varies further with the degree of plaque progression. The identification of the localised calcification characteristics is a key determinant in achieving successful dissection of the severely toughened plaque segments during cutting balloon angioplasty. STATEMENT OF SIGNIFICANCE Calcification plays a fundamental role in plaque tissue mechanics and demonstrates a diverse range of material moduli properties. This work addresses the characterisation of the toughness properties in human carotid plaque tissue using a fracture mechanics approach. Toughness determines the energy required to propagate a controlled cut in the plaque material. This parameter is crucial for predicting the cutting forces required during endovascular cutting balloon angioplasty intervention. Results demonstrate that a strong relationship exists between the structural calcification configurations, fracture mechanisms and associated toughness properties that are characteristic of specific regions within the carotid artery plaque. The identification of the morphological characteristics of localised calcification may serve as a valuable quantitative measure for cutting balloon angioplasty treatment.