Capturing Multi-Scale Dynamics of Aortic Valve Calcification With a Coupled Fluid-Structure and Systems Biology Model.

Calcific aortic valve disease (CAVD) arises from coupled interactions between blood flow, tissue mechanics, and cellular signaling. Hemodynamic forces influence endothelial and interstitial cell behavior, while the resulting tissue remodeling alters valve motion and flow patterns. Capturing this two-way feedback requires models that integrate fluid-structure mechanics with biochemical regulation, yet such multiscale coupling remains technically challenging. Previous computational models have focused on isolated aspects of the disease: fluid-structure interaction (FSI) simulations reproduce valve deformation and flow, and systems biology (SB) models describe molecular signaling that drives fibrosis and calcification. However, without coupling, these approaches cannot predict how mechanical dysfunction initiates biochemical remodeling or how biochemical changes feed back on mechanics. Here, we present a multi-physics computational framework that couples three-dimensional FSI simulations of aortic valve dynamics with a mechanistic SB model of calcification signaling. The FSI module resolves pulsatile blood flow and leaflet deformation, yielding local wall shear stresses and tissue strains throughout the cardiac cycle. These mechanical quantities are used as inputs to the SB module, which represents key biochemical pathways governing inflammation, TGF- β /SMAD signaling, and nitric-oxide (NO)-mediated inhibition within valvular cells. Simulations predict long-term calcification trajectories for valves of varying thickness, showing that fibrosis-induced stiffening lowers shear stress, reduces NO synthesis, and enhances TGF- β activation, thereby accelerating calcification. The framework is modular and extensible, allowing future incorporation of additional pathways, as well as implementation of full two-way coupling between the FSI and SB models. By integrating physics-based hemodynamics with systems-level biochemistry, this study provides a proof-of-principle demonstration of a next-generation, multi-scale modeling platform for studying cardiovascular disease that unites blood flow dynamics and biochemical signaling.