Patient-Specific, Multi-Scale Modeling of Neointimal Hyperplasia in Vein Grafts

Abstract

Neointimal hyperplasia is amongst the major causes of failure of bypass grafts. The disease progression varies from patient to patient due to a range of different factors. In this paper, a mathematical model will be used to understand neointimal hyperplasia in individual patients, combining information from biological experiments and patient-specific data to analyze some aspects of the disease, particularly with regard to mechanical stimuli due to shear stresses on the vessel wall. By combining a biochemical model of cell growth and a patient-specific computational fluid dynamics analysis of blood flow in the lumen, remodeling of the blood vessel is studied by means of a novel computational framework. The framework was used to analyze two vein graft bypasses from one patient: a femoro-popliteal and a femoro-distal bypass. The remodeling of the vessel wall and analysis of the flow for each case was then compared to clinical data and discussed as a potential tool for a better understanding of the disease. Simulation results from this first computational approach showed an overall agreement on the locations of hyperplasia in these patients and demonstrated the potential of using new integrative modeling tools to understand disease progression.

Multi-Scale, Patient-Specific Computational Flow Dynamics Models Predict Formation of Neointimal Hyperplasia in Saphenous Vein Grafts

“…24 This preliminary study of 3 patients couples CFD analyses with a model of smooth muscle cells and collagen turnover, including growth factor and NO production. 7 The results show a change from an initial, predominantly homogeneous distribution of smooth muscle cells and collagen at day 146 to a localized area of growth corresponding to areas in which the graft experienced low shear and oscillations ( Supplementary Figure 4 and 5). In addition, our analysis shows that morphometric indicators alone might not be enough to identify successful grafts.…”

“…CFD analyses were performed as described in a previous publication. 7 A non-Newtonian Carreau-Yasuda model was used for blood viscosity, with parameters reported in previous studies. 16 For comparison, simulations were also run with a Newtonian model (viscosity of 0.035 dynes•s /cm 2 ).…”

“…Hemodynamic stress indices linked to vascular remodeling, specifically TAWSS and a term encompassing low shear together with oscillations -the highly oscillatory, low magnitude shear (HOLMES) -( Supplementary Table I) were extracted at each node and imported into a mathematical model of NIH progression, described in Supplementary Figure 2. The output of the simulation model for each patient is the predicted (calculated) values of NIH growth along the graft, following the same blueprint described in our previous work, 7 and summarized in Supplementary Table III. In a nutshell, based on the 'base' configuration for each patient (a vein-graft free of NIH, representing conditions just after implantation), CFD analyses are coupled to a mathematical (time-dependent) model of NIH growth that takes into account smooth muscle cells and collagen turnover, growth factors and NO production.…”

“…1 Both experimental studies and clinical observations suggest that one of the factors destabilizing the remodeling process is a lower level of wall shear stress on the arterial wall, 2 and numerous computational fluid dynamics (CFD) studies of blood flow have used shear stress indices -including Time-Averaged Wall Shear Stress (TAWSS), and Oscillatory Shear Index (OSI), for example -as markers to identify potentially problematic areas of vascular remodeling ( Supplementary Table I). 3,4 We hypothesized that both low and oscillatory levels of shear stress should be considered simultaneously when assessing the proclivity of a certain region in bypass grafts to develop NIH, 5,6 and we simulated NIH progression using a multi-scale computational framework that we previously developed, 7 comparing our results to a patient-specific clinical dataset (obtained with the patients' informed consent for research and publication).…”

A twofold usage of an agent-based model of vascular adaptation to design clinical experiments

“…Our group of investigators, also along with others [12, 13], studied vascular adaptation both on an experimental [11] and on a computational perspective, from deterministic differential equation systems [14] to Multi-Scale Models (MSMs) [15] to Agent-Based Models (ABMs) [16] regulated by cellular automata principles based on Monte Carlo simulations.…”