Non-invasive Stenotic Renal Artery Haemodynamics by in silico Medicine

Background: Measuring the extent to which renal artery stenosis (RAS) alters renal haemodynamics may permit precision medicine by physiologically guided revascularization. This currently requires invasive intra-arterial pressure measurement with associated risks and is rarely performed. The present proof-of-concept study investigates an in silico approach that uses computational fluid dynamic (CFD) modeling to non-invasively estimate renal artery haemodynamics from routine anatomical computed tomography (CT) imaging of RAS. Methods: We evaluated 10 patients with RAS by CT angiography. Intra-arterial renal haemodynamics were invasively measured by a transducing catheter under resting and hyperaemic conditions, calculating the translesional ratio of distal to proximal pressure (Pd/Pa). The diagnostic and quantitative accuracy of the CFD-derived virtual Pd/Pa ratio (vPd/Pa) was evaluated against the invasively measured Pd/Pa ratio (mPd/Pa). Results: Hyperaemic haemodynamics was infeasible and CT angiography in 4 patients had insufficient image resolution. Resting flow data is thus reported for 7 stenosed arteries from 6 patients (one patient had bilateral RAS). The comparison showed a mean difference of 0.015 (95% confidence intervals of ± 0.08), mean absolute error of 0.064, and a Pearson correlation coefficient of 0.6, with diagnostic accuracy for a physiologically significant Pd/Pa of ≤ 0.9 at 86%. Conclusion: We describe the first in silico estimation of renal artery haemodynamics from CT angiography in patients with RAS, showing it is feasible and diagnostically accurate. This provides a methodological framework for larger prospective studies to ultimately develop non-invasive precision medicine approaches for studies and interventions of RAS and resistant hypertension

The unexplained success of stentplasty vasospasm treatment

Background Cerebral vasospasm (CVS) following subarachnoid hemorrhage occurs in up to 70% of patients. Recently, stents have been used to successfully treat CVS. This implies that the force required to expand spastic vessels and resolve vasospasm is lower than previously thought. Objective We develop a mechanistic model of the spastic arterial wall to provide insight into CVS and predict the forces required to treat it. Material and Methods The arterial wall is modelled as a cylindrical membrane using a constrained mixture theory that accounts for the mechanical roles of elastin, collagen and vascular smooth muscle cells (VSMC). We model the pressure diameter curve prior to CVS and predict how it changes following CVS. We propose a stretch-based damage criterion for VSMC and evaluate if several commercially available stents are able to resolve vasospasm. Results The model predicts that dilatation of VSMCs beyond a threshold of mechanical failure is sufficient to resolve CVS without damage to the underlying extracellular matrix. Consistent with recent clinical observations, our model predicts that existing stents have the potential to provide sufficient outward force to successfully treat CVS and that success will be dependent on an appropriate match between stent and vessel. Conclusion Mathematical models of CVS can provide insights into biological mechanisms and explore treatment approaches. Improved understanding of the underlying mechanistic processes governing CVS and its mechanical treatment may assist in the development of dedicated stents

Modeling intracranial aneurysm stability and growth: An integrative mechanobiological framework for clinical cases

We present a novel patient-specific fluid-solid-growth framework to model the mechanobiological state of clinically detected intracranial aneurysms (IAs) and their evolution. The artery and IA sac are modeled as thick-walled, non-linear elastic fiber-reinforced composites. We represent the undulation distribution of collagen fibers: the adventitia of the healthy artery is modeled as a protective sheath whereas the aneurysm sac is modeled to bear load within physiological range of pressures. Initially, we assume the detected IA is stable and then consider two flow-related mechanisms to drive enlargement: (1) low wall shear stress; (2) dysfunctional endothelium which is associated with regions of high oscillatory flow. Localized collagen degradation and remodelling gives rise to formation of secondary blebs on the aneurysm dome. Restabilization of blebs is achieved by remodelling of the homeostatic collagen fiber stretch distribution. This integrative mechanobiological modelling workflow provides a step towards a personalized risk-assessment and treatment of clinically detected IAs

The Biomolecular Interaction Network Database and related tools 2005 update

The Biomolecular Interaction Network Database (BIND) (http://bind.ca) archives biomolecular interaction, reaction, complex and pathway information. Our aim is to curate the details about molecular interactions that arise from published experimental research and to provide this information, as well as tools to enable data analysis, freely to researchers worldwide. BIND data are curated into a comprehensive machine-readable archive of computable information and provides users with methods to discover interactions and molecular mechanisms. BIND has worked to develop new methods for visualization that amplify the underlying annotation of genes and proteins to facilitate the study of molecular interaction networks. BIND has maintained an open database policy since its inception in 1999. Data growth has proceeded at a tremendous rate, approaching over 100 000 records. New services provided include a new BIND Query and Submission interface, a Standard Object Access Protocol service and the Small Molecule Interaction Database (http://smid.blueprint.org) that allows users to determine probable small molecule binding sites of new sequences and examine conserved binding residues

A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms

Influence of differing material properties in media and adventitia on arterial adaptation application to aneurysm formation and rupture

Experimental and computational studies suggest a substantial variation in the mechanical responses and collagen fibre orientations of the two structurally important layers of the arterial wall. Some observe the adventitia to be an order of magnitude stiffer than the media whilst others claim the opposite. Furthermore, studies show that molecular metabolisms may differ substantially in each layer. Following a literature review that juxtaposes the differing layer-specific results we create a range of different hypothetical arteries: (1) with different elastic responses, (2) different fibre orientations, and (3) different metabolic activities during adaptation. We use a finite element model to investigate the effects of those on: (1) the stress response in homeostasis; (2) the time course of arterial adaptation; and (3) an acute increase in luminal pressure due to a stressful event and its influence on the likelihood of aneurysm rupture. Interestingly, for all hypothetical cases considered, we observe that the adventitia acts to protect the wall against rupture by keeping stresses in the media and adventitia below experimentally observed ultimate strength values. Significantly, this conclusion holds true in pathological conditions