Multiscale Systems Biology Model of Calcific Aortic Valve Disease Progression

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Wisconsin-Madison

Details

Original languageEnglish (US)
Pages (from-to)2922-2933
Number of pages12
JournalACS Biomaterials Science and Engineering
Volume3
Issue number11
StatusPublished - Nov 13 2017
Peer-reviewedYes

Abstract

Calcific aortic valve disease is a common cause of aortic stenosis, a life threatening condition. In this study, a mathematical model is developed to simulate the cascade of mechanosensitive biochemical events that occur upon damage to the endothelial layer, leading to calcification. The model contains two phases. In the initiation phase, the model accounts for low-density lipoprotein (LDL) penetration into the subendothelial space, oxidation of LDL, and monocyte penetration and differentiation to activated macrophages. In the calcification phase, transforming growth factor beta is secreted from macrophages, inducing differentiation of valvular interstitial cells into activated myofibroblasts that can enable calcium deposition. Wall shear stress and mechanical strain are taken into account with simplified models updated based on calcification progression. The model parameters are estimated based on experimental data. Next, a statin therapy simulation is performed to evaluate the effect of lipid lowering therapy on calcification progression, demonstrating an age-dependent effectiveness in statin therapy. A new potential therapy targeting transforming growth factor-β activation is proposed and simulated. The long-term evolution of calcification is compared to two sets of published longitudinal clinical data, showing promising agreement. The proposed model can provide clinically valuable data, potentially guiding surgeons in valve replacement decision makings.

    Research areas

  • atherosclerosis, calcification progression, hemodynamics, inflammation, predictive modeling, statin therapy

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