While documented risk factors (e.g., hypertension, diabetes, etc.) for atherosclerosis are systemic in nature, atherosclerotic plaques appear in a heterogeneous distribution in the vasculature. This heterogeneity is thought to be related in part to the fact that the plaques tend to develop in areas of disturbed blood flow such as bifurcations and curvatures. Moreover, the coronary arteries, which also experience the added mechanical deformations of cyclic flexing, stretching, and twisting due to their tethering to a beating heart, are particularly susceptible to atherogenesis. This suggests that both fluid-induced (shear) and deformation-induced (mural) stress contribute to location specific susceptibility or protection from disease. We hypothesized that local variations in shear and mural stress associated with dynamic motion of arterial segments influence the distribution of early markers of atherogenesis.
To test this hypothesis, we utilized our unique, well-established, and validated ex vivo vascular perfusion system in a combined experimental / computational study. Pairs of freshly-harvested porcine arterial segments were perfused ex vivo under normal hemodynamic conditions. One of the paired segments was exposed to coronary levels of either cyclic axial stretching, flexure, or twist. Post-perfusion tissue processing provided the extent and spatial distribution of early markers of atherogenesis, including endothelial permeability, apoptosis, and proliferation. Finite element analysis and computational fluid dynamics techniques were used to estimate the mural and shear stress distributions, respectively, for reconstructed models of each experimentally perfused segment. Quantitative correlations between biological marker and mechanical stress distributions were determined using multiple linear regression analysis.
Vessel segments exposed to cyclic axial stretch and flexure showed significant increases in both permeability and apoptosis. In addition, we demonstrated that all three deformations generated complex, non-uniform distributions of both biologic endpoints and mechanical stresses. These distributions displayed a high degree of specimen-to-specimen variability which was attributed to the highly variable vessel geometries. Several specific mechanical stress measures, both mural and shear, were shown to be associated with cellular atherogenic marker distribution. Future work should be aimed at more fully elucidating the molecular mechanism linking mechanical stress in the tissue to these cellular based responses.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08212007-151939 |
| Date | 30 January 2008 |
| Creators | VanEpps, J. Scott |
| Contributors | David A. Vorp, Sanjeev G. Shroff, William R. Wagner, Suresh Mulukutla |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08212007-151939/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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