Abstract 268: Atherosclerosis in Silico: A Computational Model for Early Inflammatory Events, Including the Effects of High-Density Lipoproteins

Abstract

Objective: To develop a computational model to visualize in continuous time how the early plaque develops under different physiological conditions and to use it to explore the effects of changing concentrations of HDL. Methods: Atherosclerosis is the result of a sequence of specific responses to a failure of the endothelium. We devised a model for the interactions between modified LDL, monocytes and macrophages, HDL, chemoattractants and other cytokines immediately after endothelial injury. We included the dynamics of these interactions both at the endothelium and inside the intima. We computed the results for the model on a cross-section of an artery for different levels of blood cholesterol and immune system activity and produced a series of simulations to display the model results. Results: Using the model, we can visualize the changing movement and distribution of modified LDL, cytokines, macrophages and foam cells in the early plaque as a function of time, rather than as static post-mortem images. The model shows qualitatively how a fatty streak is initiated and develops after the initial inflammation, including distortion of the blood vessel wall by the developing plaque. The simulations show an initial phase with high macrophage densities in the plaque which settles to a low level of chronic inflammation and sustained foam cell accumulation. When we increase the level of HDL early in plaque development, the simulated plaque ceases to grow and may regress; when we increase HDL by the same amount but at a later time in plaque development, then the plaque continues to grow. Conclusion: This model provides a new tool for visualizing and for thinking about early atherosclerosis. It allows us to explore the effects of blood cholesterol levels and the level of the inflammatory response on the size and lipid density of the plaque. The results of model simulations suggest that the timing of increases in HDL may be important in determining whether or not a plaque regresses and, hence, that the inherent dynamics of the process of plaque formation may have an influence on the efficacy of HDL action.