A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: Potential implications for plaque rupture
Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, New York AJP Heart and Circulatory Physiology
(Impact Factor: 3.84).
07/2012; 303(5):H619-28. DOI: 10.1152/ajpheart.00036.2012
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.
Available from: Frank Gijsen
- "In some of these studies (Loree et al. 1992; Cheng et al. 1993; Williamson et al. 2003; Maldonado et al. 2012), the variations in plaque properties were limited, leading to only minor changes in cap stresses. However, in a recent review we showed that available experimental data indicate that the intima properties might show much more variation (Akyildiz et al. 2014). "
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ABSTRACT: 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.
Available from: Aad van der Lugt
- "The MRI-derived geometry can be used as input for finite element analysis (FEA) to numerically compute the intraplaque stress distribution in vivo [2,13–15]. One of the largest limitations of current MRI-based carotid plaque FEA is the lack of knowledge of the patient-specific mechanical properties of the various tissues, prompting an oversimplified 'one-size-fits-all' approach by assigning literature-based material elasticity (i.e., stiffness) values to plaque components    . In vitro material testing studies on carotid plaque tissues consistently report differences of multiple orders-of-magnitude in the elasticity between patients      . "
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ABSTRACT: The material properties of atherosclerotic plaques govern the biomechanical environment, which is associated with rupture-risk. We investigated the feasibility of noninvasively estimating carotid plaque component material properties through simulating ultrasound (US) elastography and in vivo magnetic resonance imaging (MRI), and solving the inverse problem with finite element analysis. 2D plaque models were derived from endarterectomy specimens of nine patients. Nonlinear neo-Hookean models (tissue elasticity C1) were assigned to fibrous intima, wall (i.e., media/adventitia), and lipid-rich necrotic core. Finite element analysis was used to simulate clinical cross-sectional US strain imaging. Computer-simulated, single-slice in vivo MR images were segmented by two MR readers. We investigated multiple scenarios for plaque model elasticity, and consistently found clear separations between estimated tissue elasticity values. The intima C1 (160 kPa scenario) was estimated as 125.8 ± 19.4 kPa (reader 1) and 128.9 ± 24.8 kPa (reader 2). The lipid-rich necrotic core C1 (5 kPa) was estimated as 5.6 ± 2.0 kPa (reader 1) and 8.5 ± 4.5 kPa (reader 2). A scenario with a stiffer wall yielded similar results, while realistic US strain noise and rotating the models had little influence, thus demonstrating robustness of the procedure. The promising findings of this computer-simulation study stimulate applying the proposed methodology in a clinical setting.
Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.
Available from: Elena Aikawa
- "Specifically, the hazard ratio associated with cardiovascular morbidity and mortality is inversely related to the density of the calcification within the vessels . Small microcalcifications that form within the fibrous cap of an atherosclerotic plaque lead to substantial stress accumulation within the cap that can cause subsequent plaque rupture   , the leading cause of myocardial infarction . Biomechanical analyses indicate that as destabilizing microcalcifications transition to large macrocalcifications that form beneath a thick fibrous cap, the vascular atherosclerotic plaque becomes more stable    (Fig. 1). "
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ABSTRACT: Cardiovascular calcification is a commonly observed but incompletely understood mechanism of increased atherosclerotic plaque instability and accelerated aortic valve stenosis. Traditional histological staining and imaging techniques are nonspecific for the type of mineral present in calcified tissues, information that is critical for proper validation of in vitro and in vivo models. This review highlights current gaps in our understanding of the biophysical implications and the cellular mechanisms of valvular and vascular calcification and how they may differ between the two tissue types. We also address the hindrances of current cell culture systems, discussing novel platforms and important considerations for future studies of cardiovascular calcification.
Copyright © 2015. Published by Elsevier Inc.
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