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Updated: Jul 8, 2025
Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
Published on: May 10, 2021
Multiscale computational modeling of aortic valve calcification
Javid Azimi-Boulali1, Gretchen J Mahler2, Bruce T Murray1
1Department of Mechanical Engineering, Binghamton University, Binghamton, NY, 13902, USA.
Insights
Calcific aortic valve disease (CAVD) involves calcium buildup on heart valves. A new computational model shows cell death from fibrosis and calcification contributes to nodule formation and disease progression.
Area of Science:
- Cardiovascular biology
- Computational modeling
- Biomedical engineering
Background:
- Calcific aortic valve disease (CAVD) is a prevalent cardiovascular condition impacting millions globally.
- The exact mechanisms driving CAVD pathogenesis remain incompletely understood, though transforming growth factor beta (TGF-β) signaling is implicated.
- CAVD leads to aortic valve stenosis and potential heart failure if untreated.
Purpose of the Study:
- To develop a multiscale computational model simulating TGF-β-stimulated CAVD.
- To integrate cellular dynamics, subcellular signaling, and tissue-level chemical diffusion.
- To investigate the roles of endothelial-to-mesenchymal transition (EndMT), fibrosis, and calcification in CAVD.
Main Methods:
- Developed a multiscale computational model incorporating cellular behavior, subcellular signaling (TGF-β pathway), and tissue diffusion.
- Modeled key CAVD processes: EndMT, fibrosis, and calcification.
- Simulated cell nutrient deprivation and subsequent calcium nodule formation.
Main Results:
- Identified cell death due to nutrient deprivation in fibrotic/calcified regions as a source of calcium nodules.
- Observed that cell death contributes to a varied distribution of nodule sizes.
- Found increased fibrosis and calcification near the endothelial layer due to higher cell activity.
Conclusions:
- The study provides insights into CAVD mechanisms and TGF-β signaling.
- Cellular processes and nutrient dynamics are critical in CAVD progression.
- The multiscale modeling framework offers a tool for studying complex diseases and developing therapeutic strategies for CAVD and related conditions like cancer.
Abstract:
Calcific aortic valve disease (CAVD) is a common cardiovascular disease that affects millions of people worldwide. The disease is characterized by the formation of calcium nodules on the aortic valve leaflets, which can lead to stenosis and heart failure if left untreated. The pathogenesis of CAVD is still not well understood, but involves several signaling pathways, including the transforming growth factor beta (TGF ) pathway. In this study, we developed a multiscale computational model for TGF -stimulated CAVD. The model framework comprises cellular behavior dynamics, subcellular signaling pathways, and tissue-level diffusion fields of pertinent chemical species, where information is shared among different scales. Processes such as endothelial to mesenchymal transition (EndMT), fibrosis, and calcification are incorporated. The results indicate that the majority of myofibroblasts and osteoblast-like cells ultimately die due to lack of nutrients as they become trapped in areas with higher levels of fibrosis or calcification, and they subsequently act as sources for calcium nodules, which contribute to a polydispersed nodule size distribution. Additionally, fibrosis and calcification processes occur more frequently in regions closer to the endothelial layer where the cell activity is higher. Our results provide insights into the mechanisms of CAVD and TGF signaling and could aid in the development of novel therapeutic approaches for CAVD and other related diseases such as cancer. More broadly, this type of modeling framework can pave the way for unraveling the complexity of biological systems by incorporating several signaling pathways in subcellular models to simulate tissue remodeling in diseases involving cellular mechanobiology.
