Abstract 13736: Mathematical Modeling Identifies Vessel Size and Geometry as Key Factors Determining the Rate of Plaque Development in Mouse and Human
The Entelos® CV PhysioLab® (CVPL) is a mathematical model of CHD developed for use in the prediction of clinical trial outcomes. The CVPL quantitatively simulates the dynamic interactions of lipoproteins (Lp) with cellular and extracellular components of the arterial wall. The model incorporates known drivers of plaque growth including Lp retention, endothelial dysfunction, macrophage recruitment and egress, cellular cholesterol uptake and efflux to HDL and vascular cell death. One advantage of mathematical modeling is that it enables systematic exploration of of individual biological properties and pathways, which can be difficult or impossible in an experimental setting. We used the CVPL to continuously vary vessel diameter from large (e.g., carotid artery) to small (e.g., arterioles) without changing other physiological rate constants and identified that, for a given Lp profile, there are physical limitations on the diameter and composition of a vessel that constrain the rate of plaque development. This provides a mechanistic rationale for observed variation in the rate of plaque progression in differently sized human vessels. We extended the study by recalibrating the model with relevant pre-clinical data to create an Apoe-/- Mouse PhysioLab® reproducing the dynamics of murine plaques. Examining the dual models for the impact of species differences in Lp, vessel size and plaque geometry, we identified parameter changes necessary to reproduce observed plaque differences, including complete inhibition of macrophage egress in the Apoe-/- mouse, consistent with published data. These simulations, demonstrate how in silico models can result in important mechanistic understandings of disease etiology and, furthermore, that paired quantitative models calibrated to human and animal data may provide a methodology for improving translation from pre-clinical discovery to the clinic. Figure 1: Model representations of human (a) and mouse (b) plaque
- © 2012 by American Heart Association, Inc.