Coupling 3D fluid-structure interaction (FSI) with systems biology to predict calcification of aortic valve for progressively thicker valves

Heart valve calcification is a progressive condition in which calcium deposition leads to leaflet stiffening, reduced orifice area, impaired hemodynamics, and ultimately, valvular failure. This pathological remodeling arises from fibroblastic and osteogenic differentiation of valvular interstitial cells (VICs), governed by complex biochemical signaling cascades that are tightly regulated by local mechanical cues such as strain and wall shear stress. Consequently, accurately modeling the interplay between mechanical forces and calcification biochemistry requires a coupled, multiscale approach. In this work, we present a novel multiphysics framework that integrates full 3D fluid–structure interaction (FSI) simulations of the aortic valve with a systems biology model of fibroblast-driven calcification. Three valve thickness cases (0.3, 0.5, and 0.75 mm) are examined to represent progressive fibrotic remodeling. Mechanical inputs—including strain and shear stress fields that are converted into representative variables—are extracted from immersed boundary-based FSI simulations and used to drive a PySB-implemented chemical kinetics model. The signaling network incorporates key mechanosensitive pathways, including endothelial nitric oxide (NO) production, inflammation, and TGF-β/SMAD signaling, which collectively regulate calcium accumulation in the tissue. The model outputs a temporal trajectory of calcification in Agatston score units, which demonstrates good agreement with available clinical data for the healthy cases, while predicting accelerated calcification in fibrotic valve conditions. This integrated framework provides a foundation for future patient-specific modeling of valve degeneration and may serve as a virtual platform for testing therapeutic strategies targeting mechano-biochemical signaling.