Hemodynamics of Stent Implantation Procedures in Coronary Bifurcations: an in vitro study

Stent implantation in coronary bifurcations presents unique challenges and currently there is no universally accepted stent deployment approach. Despite clinical and computational studies, to date, the effect of each stent implantation method on the coronary artery hemodynamics is not well understood. In this study the hemodynamics of stented coronary bifurcations under pulsatile flow conditions were investigated experimentally. Three implantation methods, provisional side branch (PSB), culotte (CUL), and crush (CRU), were investigated using time-resolved particle image velocimetry (PIV) to measure the velocity fields. Subsequently, hemodynamic parameters including wall shear stress (WSS), oscillatory shear index (OSI), and relative residence time (RRT) were calculated and the pressure field through the vessel was non-invasively quantified. The effects of each stented case were evaluated and compared against an un-stented case. CRU provided the lowest compliance mismatch, but demonstrated detrimental stent interactions. PSB, the clinically preferred method, and CUL maintained many normal flow conditions. However, PSB provided about a 300% increase in both OSI and RRT. CUL yielded a 10% and 85% increase in OSI and RRT, respectively. The results of this study support the concept that different bifurcation stenting techniques result in hemodynamic environments that deviate from that of un-stented bifurcations, to varying degrees.Comment: 33 pages, 8 figures, 3 table

Investigating the effect of drug release on in-stent restenosis: A hybrid continuum – agent-based modelling approach

Background and objective: In-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation. Methods: The framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries. Results: The studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM – fast RP led to similar ISR degrees as high DM – moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response. Conclusion: The application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES

In silico biomechanical design of the metal frame of transcatheter aortic valves: multi-objective shape and cross-sectional size optimization

Transcatheter aortic valve (TAV) implantation has become an established alternative to open-hearth surgical valve replacement. Current research aims to improve the treatment safety and extend the range of eligible patients. In this regard, computational modeling is a valuable tool to address these challenges, supporting the design phase by evaluating and optimizing the mechanical performance of the implanted device. In this study, a computational framework is presented for the shape and cross-sectional size optimization of TAV frames. Finite element analyses of TAV implantation were performed in idealized aortic root models with and without calcifications, implementing a mesh-morphing procedure to parametrize the TAV frame. The pullout force magnitude, peak maximum principal stress within the aortic wall, and contact pressure in the left ventricular outflow tract were defined as objectives of the optimization problem to evaluate the device mechanical performance. Design of experiment coupled with surrogate modeling was used to define an approximate relationship between the objectives and the TAV frame parameters. Surrogate models were interrogated within a fixed design space and multi-objective design optimization was conducted. The investigation of the parameter combinations within the design space allowed the successful identification of optimized TAV frame geometries, suited to either a single or groups of aortic root anatomies. The optimization framework was efficient, resulting in TAV frame designs with improvedmechanical performance, ultimately leading to enhanced procedural outcomes and reduced costs associated with the device iterative development cycle

A fully coupled computational fluid dynamics – agent-based model of atherosclerotic plaque development: Multiscale modeling framework and parameter sensitivity analysis

Background: Peripheral Artery Disease (PAD) is an atherosclerotic disorder that leads to impaired lumen patency through intimal hyperplasia and the build-up of plaques, mainly localized in areas of disturbed flow. Computational models can provide valuable insights in the pathogenesis of atherosclerosis and act as a predictive tool to optimize current interventional techniques. Our hypothesis is that a reliable predictive model must include the atherosclerosis development history. Accordingly, we developed a multiscale modeling framework of atherosclerosis that replicates the hemodynamic-driven arterial wall remodeling and plaque formation. Methods: The framework was based on the coupling of Computational Fluid Dynamics (CFD) simulations with an Agent-Based Model (ABM). The CFD simulation computed the hemodynamics in a 3D artery model, while 2D ABMs simulated cell, Extracellular Matrix (ECM) and lipid dynamics in multiple vessel cross-sections. A sensitivity analysis was also performed to evaluate the oscillation of the ABM output to variations in the inputs and to identify the most influencing ABM parameters. Results: Our multiscale model qualitatively replicated both the physiologic and pathologic arterial configuration, capturing histological-like features. The ABM outputs were mostly driven by cell and ECM dynamics, largely affecting the lumen area. A subset of parameters was found to affect the final lipid core size, without influencing cell/ECM or lumen area trends. Conclusion: The fully coupled CFD-ABM framework described atherosclerotic morphological and compositional changes triggered by a disturbed hemodynamics

An agent-based model of cardiac allograft vasculopathy: toward a better understanding of chronic rejection dynamics

Cardiac allograft vasculopathy (CAV) is a coronary artery disease affecting 50% of heart transplant (HTx) recipients, and it is the major cause of graft loss. CAV is driven by the interplay of immunological and non-immunological factors, setting off a cascade of events promoting endothelial damage and vascular dysfunction. The etiology and evolution of tissue pathology are largely unknown, making disease management challenging. So far, in vivo models, mostly mouse-based, have been widely used to study CAV, but they are resource-consuming, pose many ethical issues, and allow limited investigation of time points and important biomechanical measurements. Recently, agent-based models (ABMs) proved to be valid computational tools for deciphering mechanobiological mechanisms driving vascular adaptation processes at the cell/tissue level, augmenting cost-effective in vivo lab-based experiments, at the same time guaranteeing richness in observation time points and low consumption of resources. We hypothesize that integrating ABMs with lab-based experiments can aid in vivo research by overcoming those limitations. Accordingly, this work proposes a bidimensional ABM of CAV in a mouse coronary artery cross-section, simulating the arterial wall response to two distinct stimuli: inflammation and hemodynamic disturbances, the latter considered in terms of low wall shear stress (WSS). These stimuli trigger i) inflammatory cell activation and ii) exacerbated vascular cell activities. Moreover, an extensive analysis was performed to investigate the ABM sensitivity to the driving parameters and inputs and gain insights into the ABM working mechanisms. The ABM was able to effectively replicate a 4-week CAV initiation and progression, characterized by lumen area decrease due to progressive intimal thickening in regions exposed to high inflammation and low WSS. Moreover, the parameter and input sensitivity analysis highlighted that the inflammatory-related events rather than the WSS predominantly drive CAV, corroborating the inflammatory nature of the vasculopathy. The proof-of-concept model proposed herein demonstrated its potential in deepening the pathology knowledge and supporting the in vivo analysis of CAV

Relationship between hemodynamics and in-stent restenosis in femoral arteries

Although percutaneous transluminal angioplasty with stenting is one of the preferred treatments of lower extremity peripheral artery disease, this procedure suffers from a 66% 1-year primary patency rate. The unfavorable outcome is mostly attributable to in-stent restenosis, an inflammatory-driven arterial response, characterized by excessive smooth muscle cell proliferative and synthetic activity ultimately leading to lumen re-narrowing. The etiology of in-stent restenosis is multifactorial, involving different systemic, biological and biomechanical drivers. Among the biomechanical factors, a key role has been recognized to the stent-induced hemodynamic alteration, influencing smooth muscle cell activity both directly and through endothelium-dependent mechanisms. In this scenario, computational fluid dynamics simulations of stented femoral arteries allowed quantifying the local hemodynamics and identifying wall shear stress-based hemodynamic predictors of in-stent restenosis. This contributed to enhance the current knowledge of the fluid dynamic-related mechanisms of post-stenting lumen remodeling. However, given the multiscale and multifactorial nature of in-stent restenosis, multiscale mechanobiological modeling relating the intervention-induced mechanical stimuli to the complex network of biological events has recently emerged as a fundamental approach to decipher the underlying pathological pathways. This involves the analysis of interactions, cause-effect relationships, feedback mechanisms and cascade signaling pathways across different spatial and temporal scales, thus allowing tracking the effect of the interventioninduced perturbation to the molecular, cellular and finally tissue response. The present chapter examines the state-of-the-art of computational fluid dynamics studies of in-stent restenosis in femoral arteries and provides an overview on the emerging field of multiscale mechanobiological modeling of arterial adaptation following endovascular procedures

Semi-Automatic Reconstruction of Patient-Specific Stented Coronaries based on Data Assimilation and Computer Aided Design

Purpose The interplay between geometry and hemodynamics is a significant factor in the development of cardiovascular diseases. This is particularly true for stented coronary arteries. To elucidate this factor, an accurate patient-specific analysis requires the reconstruction of the geometry following the stent deployment for a computational fluid dynamics (CFD) investigation. The image-based reconstruction is troublesome for the different possible positions of the stent struts in the lumen and the coronary wall. However, the accurate inclusion of the stent footprint in the hemodynamic analysis is critical for detecting abnormal stress conditions and flow disturbances, particularly for thick struts like in bioresorbable scaffolds. Here, we present a novel reconstruction methodology that relies on Data Assimilation and Computer Aided Design. Methods The combination of the geometrical model of the undeployed stent and image-based data assimilated by a variational approach allows the highly automated reconstruction of the skeleton of the stent. A novel approach based on computational mechanics defines the map between the intravascular frame of reference (called L-view) and the 3D geometry retrieved from angiographies. Finally, the volumetric expansion of the stent skeleton needs to be self-intersection free for the successive CFD studies; this is obtained by using implicit representations based on the definition of Nef-polyhedra. Results We assessed our approach on a vessel phantom, with less than 10% difference (properly measured) vs. a customized manual (and longer) procedure previously published, yet with a significant higher level of automation and a shorter turnaround time. Computational hemodynamics results were even closer. We tested the approach on two patient-specific cases as well. Conclusions The method presented here has a high level of automation and excellent accuracy performances, so it can be used for larger studies involving patient-specific geometries