A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: Potential implications for plaque rupture
ABSTRACT 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.
- SourceAvailable from: Aad van der Lugt
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- "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      . "
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.Medical Engineering & Physics 06/2015; 37(8). DOI:10.1016/j.medengphy.2015.06.003 · 1.84 Impact Factor
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- "These observations provide insights into the role calcification may play in the stability of the atherosclerotic plaque and suggest that it is not only the amount of vascular calcification, but the morphology, size and location that affect plaque vulnerability. A recent biomechanical explanation for the contribution of low density, spotty calcifications to plaque rupture is centered on the presence of small microcalcifications that exist within the thin fibrous cap of atherosclerotic plaques [3▪,9–11,12▪▪]. "
ABSTRACT: Purpose of review Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths. Calcification has emerged as a significant predictor of cardiovascular morbidity and mortality, challenging previously held notions that calcifications stabilize atherosclerotic plaques. In this review, we address this discrepancy through recent findings that not all calcifications are equivalent in determining plaque stability. Recent findings The risk associated with calcification is inversely associated with calcification density. As opposed to large calcifications that potentially stabilize the plaque, biomechanical modeling indicates that small microcalcifications within the plaque fibrous cap can lead to sufficient stress accumulation to cause plaque rupture. Microcalcifications appear to derive from matrix vesicles enriched in calcium-binding proteins that are released by cells within the plaque. Clinical detection of microcalcifications has been hampered by the lack of imaging resolution required for in-vivo visualization; however, recent studies have demonstrated promising new techniques to predict the presence of microcalcifications. Summary Microcalcifications play a major role in destabilizing atherosclerotic plaques. The identification of critical characteristics that lead to instability along with new imaging modalities to detect their presence in vivo may allow early identification and prevention of acute cardiovascular events.Current Opinion in Lipidology 10/2014; 25(5):327-332. DOI:10.1097/MOL.0000000000000105 · 5.80 Impact Factor
Computer Methods in Biomechanics and Biomedical Engineering 08/2014; 17 Suppl 1(sup1):16-7. DOI:10.1080/10255842.2014.931071 · 1.79 Impact Factor
- "These include intravascular ultrasound (IVUS) (Rioufol et al 2002, Carlier and Tanaka 2006), optical coherence tomography (OCT) (Jang et al 2002, Tearney et al 2008) and magnetic resonance imaging (IV-MRI) (Larose et al 2005, Briley-Saebo et al 2007). Diagnosis of high-risk atherosclerotic plaques remains problematic as the thickness of the fibrous cap alone is not a sufficient predictor of plaque stability (Virmani et al 2000, Ohayon et al 2008, Fleg et al 2012, Maldonado et al 2012). "