Abstract
Introduction: Although the atherosclerosis-prone mouse model is widely studied and has contributed much to the current understanding of atherogenesis, rupture of plaques in mice has not been conclusively observed. Consequently, uncertainty of the utility of the mouse model for studying endpoints like plaque rupture pervades in the field. In this study, we investigated the biomechanical likelihood of plaque rupture in mice. Hypothesis: The highest stresses are located away from the fibrous cap of lesions in mice. Methods: We studied acute models of atherosclerosis (15 ApoE-/- and 15 LDLr-/- mice, high-fat diet 8 weeks with simultaneous Angiotensin II osmotic pumps) and a chronic model (15 ApoE-/- mice aged 1 year, regular chow diet). The ascending and descending aortas and brachiocephalic artery were harvested for histological staining of morphology. To preserve in vivo anatomy as accurately as possible, vessels were perfused with a vascular casting compound at each mouse's measured diastolic blood pressure and then embedded in methyl methacrylate resin blocks, which minimize sectioning artifacts. Histology sections were the input geometry for a lesion-specific finite element analysis (FEA) computer model of solid mechanics within the vessel wall. For comparison, we performed similar FEA simulation on 15 human coronary plaques of the thin-cap fibroatheroma (TCFA) phenotype. Results: In human lesions, highest stresses tended to be located on the fibrous cap or shoulders of the plaque, consistent with current understanding of plaque rupture. However, in mouse plaque simulations, the highest stresses and strains were located away from the lesions on the thin plaque-free wall. Conclusion: The characteristic difference in peak stress location explains the lack of plaque rupture in mice. This study demonstrates that local mechanical strains in the fibrous cap of murine atherosclerotic lesions are insufficient to cause plaque rupture, in contrast to human lesions.
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