Turbulence drives arteriovenous remodeling: an experimentally validated multi-scale model of neointimal hyperplasia

<i>Objectives.</i>Arteriovenous fistula (AVF) failure is a frequent clinical problem among end stage renal patients seeking durable long term dialysis access. The most common histological<i>in vivo</i>observation of AVF failure is endothelial injury at the juxta-anastomosis area (JAA) followed by thrombus deposition and subsequent neointimal hyperplasia (NH). While hemodynamic factors have been postulated to affect AVF remodeling and failure, the spatial correlations between changes in hemodynamics post AVF creation and<i>in vivo</i>physiologic observations remain poorly understood. In this work, we developed a novel computational fluid dynamics (CFDs) model of an AVF using a pre-established aortocaval mouse model and integrated it with agent-based modeling (ABM) for NH.<i>Approach.</i>The CFD simulation was performed using an animal-specific aortocaval fistula geometry derived from<i>in vivo</i>CTA images with prescribed boundary conditions (BCs) obtained from<i>in vivo</i>ultrasound measurements. CFD results were validated against<i>in vivo</i>ultrasound velocity measurements at the level of the fistula. CFD allowed quantification of turbulence intensities throughout the fluid domain of the AVF.<i>Results.</i>Turbulence was significantly elevated at the JAA and in regions of venous outflow stenosis. Turbulence intensity served as an input parameter for a simple two-rule ABM to test the hypothesis that non-homeostatic hemodynamic changes resulting from AVF creation drive spatial gradients in endothelial damage and proliferation of vascular smooth muscle cells leading to an increase in venous thickness or NH<i>. Significance.</i>Our findings show that increased velocity and turbulence in the JAA parallels<i>in vivo</i>NH formation, and that further from the JAA (both cranial and caudal) velocity and turbulence decrease incrementally. The results corroborate that perturbed hemodynamics in the JAA are potential triggers for NH and the source of thickness gradients observed in AVFs.