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: 4.01). 07/2012; 303(5):H619-28. DOI: 10.1152/ajpheart.00036.2012
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.
    Diabetologia 08/2014; · 6.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Biomechanical models are used extensively to study risk factors, such as peak stresses, for vulnerable atherosclerotic plaque rupture. Typically, 3D patient-specific arterial models are reconstructed by interpolating between cross sectional contour data which have a certain axial sampling, or image, resolution. The influence of the axial sampling resolution on computed stresses, as well as the comparison of 3D with 2D simulations, is quantified in this study. A set of histological data of four atherosclerotic human coronary arteries was used which were reconstructed in 3D with a high sampling (HS) and low sampling (LS) axial resolution, and 4 slices were treated separately for 2D simulations. Stresses were calculated using finite element analysis (FEA). High stresses were found in thin cap regions and regions of thin vessel walls, low stresses were found inside the necrotic cores and media and adventitia layers. Axial sampling resolution was found to have a minor effect on general stress distributions, peak plaque/cap stress locations and the relationship between peak cap stress and minimum cap thickness. Axial sampling resolution did have a profound influence on the error in computed magnitude of peak plaque/cap stresses (±15.5% for HS vs. LS geometries and ±24.0% for HS vs. 2D geometries for cap stresses). The findings of this study show that axial under sampling does not influence the qualitative stress distribution significantly but that high axially sampled 3D models are needed when accurate computation of peak stress magnitudes is required.
    Journal of biomechanics 12/2012; · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Post-mortem pathological studies have shown that a "vulnerable" plaque is the dominant patho-physiological mechanism responsible for acute coronary syndromes (ACS). One way to improve our understanding of these plaques in vivo is by using histological "surrogates" created by intravascular ultrasound derived virtual histology (IVUS-VH). Our aim in this analysis was to determine the relationship between site-specific differences in individual plaque areas between ACS plaques and stable plaques (SP), with a focus on remodelling index and the pattern of calcifying necrosis.
    Cardiovascular diagnosis and therapy. 08/2014; 4(4):287-298.