A. J. Narracott

Computational fluid dynamics modelling in cardiovascular medicine

This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length- and time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, population-averaged data. Model integration is progressively moving towards ‘digital patient’ or ‘virtual physiological human’ representations. When combined with population-scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education- and service-related challenges.

The effects of stenting on shear stress: relevance to endothelial injury and repair

Stent deployment following balloon angioplasty is used routinely to treat coronary artery disease. These interventions cause damage and loss of endothelial cells (EC), and thus promote in-stent thrombosis and restenosis. Injured arteries are repaired (intrinsically) by locally derived EC and by circulating endothelial progenitor cells which migrate and proliferate to re-populate denuded regions. However, re-endothelialization is not always complete and often dysfunctional. Moreover, the molecular and biomechanical mechanisms that control EC repair and function in stented segments are poorly understood. Here, we propose that stents modify endothelial repair processes, in part, by altering fluid shear stress, a mechanical force that influences EC migration and proliferation. A more detailed understanding of the biomechanical processes that control endothelial healing would provide a platform for the development of novel therapeutic approaches to minimize damage and promote vascular repair in stented arteries.

Neonatal lungs--can absolute lung resistivity be determined non-invasively?

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 ± 1.7Ωm was found over the frequency range 4kHz to 813kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

A Thermal Analogy for Modelling Drug Elution from Cardiovascular Stents

Restriction of blood flow by the narrowing or occlusion of arteries is one of the most common presentations of cardiovascular disease. One treatment involves the introduction of a metal scaffold, or stent, designed to prevent recoil and to provide structural stability to the vessel. On the occasions that this treatment is ineffective, failure is usually associated with re-invasion of tissue. This can be prevented by local delivery of drugs which inhibit tissue growth. The drug might be delivered locally in a polymer coating on the stent. This paper develops and explores the use of a thermal analogue of the drug delivery process and the associated three-dimensional convection–diffusion equation to model the spatial and temporal distribution of drug concentration within the vessel wall. This allows the routine use of commercial finite element analysis software to investigate the dynamics of drug distribution, assist in the understanding of the treatment process and develop improved delivery systems. Two applications illustrate how the model might be used to investigate the effects of controllable or measurable parameters on the progression of the process. It is demonstrated that the geometric characteristics of the stent can have significant impact on the homogeneity of the dosing in the vessel wall.

Development and validation of models for the investigation of blood clotting in idealized stenoses and cerebral aneurysms

An in vitro model of blood clotting is presented using hypercoaguable milk as an analog for blood. Milk clot formation was studied for periods of 2, 5, 10, 20, and 30 min within an idealized stenosis geometry. Clot formation was recorded using photography, clot casting, and clot mass calculation. The distribution of clot within the fluid was seen to be in good agreement with a previous study that used a residence time model to predict areas of clot formation in thrombin solution. A numerical model was formulated within computational fluid dynamics package CFX that allowed local activation of blood clotting to be simulated. This model was applied to the analysis of an idealized cerebral aneurysm geometry. An idealized coil geometry was included within the aneurysm and clotting fluid concentration and fluid residence time were modeled using transport equations within CFX. The viscosity of the fluid was defined as a function of both residence time and clotting fluid concentration. The model was seen to produce features consistent with observations of thrombosis within cerebral aneurysms, while avoiding the unrealistic build up of clot in near-wall regions that is associated with a pure residence time model.

Neonatal lungs: Maturational changes in lung resistivity spectra

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Electrical impedance tomographic measurements have been used on 155 normal children over the first three years of life and 25 pre-term infants, to determine the absolute resistivity of lung tissue as a function of frequency. The results show consistent changes with increasing age in both lung tissue resistivity (5.8Ωm at birth to 20.9Ωm at 3 years of age) and in the changes of resistivity with frequency (Cole parameter ratio R/S=0.41 at birth and 0.84 at 3 years of age). Comparison with a lung model showed that the measurements are consistent with maturational changes in the number and size of alveoli, the extracapillary blood volume and the size of the extracapillary vessels. However, the results show that the process of maturation is not complete at the age of three years.

Nominal size in six bileaflet mechanical aortic valves: A comparison of orifice size and biologic equivalence

OBJECTIVES Nominal size remains the standard by which valves are compared, but its relationship with orifice area and the patient tissue annulus diameter may differ according to valve design. The aims of this study were to measure the orifice size and compare biologic equivalence in six bileaflet mechanical heart valve designs. METHODS The inflow aspect of each of 29 valves was photographed then digitized, and the maximum internal diameter and orifice area were calculated. Biologic equivalence was assessed with a series of machined polypropylene blocks. RESULTS The orifice area ranged between 159 and 222 mm(2) for the six size 19 valves. The internal diameter ranged from 1.6 to 4.6 mm less than the manufacturers nominal size. Biologic equivalence assessed from an estimate of tissue annulus diameter with machined blocks ranged from 1.0 and 3.5 mm larger than nominal size for the intra-annular valves. This diameter ranged from 3.5 mm smaller to 1.5 mm larger than nominal size for the supra-annular valves. CONCLUSION There are major differences between nominal size and biologic equivalence. This may lead to confusion when attempting to make comparisons between different valve designs with the same nominal size. A clearer sizing nomenclature is required and could be based on in vitro assessment of tissue annulus diameter or an alphanumeric code.

Endothelial repair process and its relevance to longitudinal neointimal tissue patterns: Comparing histology with in silico modelling

Re-establishing a functional endothelium following endovascular treatment is an important factor in arresting neointimal proliferation. In this study, both histology (in vivo) and computational simulations (in silico) are used to evaluate neointimal growth patterns within coronary arteries along the axial direction of the stent. Comparison of the growth configurations in vivo and in silico was undertaken to identify candidate mechanisms for endothelial repair. Stent, lumen and neointimal areas were measured from histological sections obtained from eight right coronary stented porcine arteries. Two re-endothelialization scenarios (endothelial cell (EC) random seeding and EC growth from proximal and distal ends) were implemented in silico to evaluate their influence on the morphology of the simulated lesions. Subject to the assumptions made in the current simulations, comparison between in vivo and in silico results suggests that endothelial growth does not occur from the proximal and distal ends alone, but is more consistent with the assumption of a random seeding process. This may occur either from the patches of endothelium which survive following stent implantation or from attachment of circulating endothelial progenitor cells.

Influence of intermittent compression cuff design on calf deformation: computational results

The intermittent compression of the calf with an external pressure cuff for the prevention of deep vein thrombosis (DVT) is a well established treatment for surgical patients. The exact mechanisms by which DVT is prevented are poorly understood. This study presents a finite element model of calf cross section, based on MR images of calf geometry, to examine the variation in calf deformation during compression with four different cuff types. Cuff pressure distribution is modelled using interface pressures obtained in a volunteer study. The model has been validated against gross calf deformation obtained from MR images of the compressed calf. This validation has illustrated the importance of out-of-plane boundary conditions, material properties and the variation in cuff loading in the axial direction. In the future this model may have merit in determining optimum pressure loading regimes for intermittent pneumatic compression (IPC) cuff design.

A framework for different levels of integration of computational models into web-based virtual patients.

Background Virtual patients are increasingly common tools used in health care education to foster learning of clinical reasoning skills. One potential way to expand their functionality is to augment virtual patients’ interactivity by enriching them with computational models of physiological and pathological processes. Objective The primary goal of this paper was to propose a conceptual framework for the integration of computational models within virtual patients, with particular focus on (1) characteristics to be addressed while preparing the integration, (2) the extent of the integration, (3) strategies to achieve integration, and (4) methods for evaluating the feasibility of integration. An additional goal was to pilot the first investigation of changing framework variables on altering perceptions of integration. Methods The framework was constructed using an iterative process informed by Soft System Methodology. The Virtual Physiological Human (VPH) initiative has been used as a source of new computational models. The technical challenges associated with development of virtual patients enhanced by computational models are discussed from the perspectives of a number of different stakeholders. Concrete design and evaluation steps are discussed in the context of an exemplar virtual patient employing the results of the VPH ARCH project, as well as improvements for future iterations. Results The proposed framework consists of four main elements. The first element is a list of feasibility features characterizing the integration process from three perspectives: the computational modelling researcher, the health care educationalist, and the virtual patient system developer. The second element included three integration levels: basic, where a single set of simulation outcomes is generated for specific nodes in the activity graph; intermediate, involving pre-generation of simulation datasets over a range of input parameters; advanced, including dynamic solution of the model. The third element is the description of four integration strategies, and the last element consisted of evaluation profiles specifying the relevant feasibility features and acceptance thresholds for specific purposes. The group of experts who evaluated the virtual patient exemplar found higher integration more interesting, but at the same time they were more concerned with the validity of the result. The observed differences were not statistically significant. Conclusions This paper outlines a framework for the integration of computational models into virtual patients. The opportunities and challenges of model exploitation are discussed from a number of user perspectives, considering different levels of model integration. The long-term aim for future research is to isolate the most crucial factors in the framework and to determine their influence on the integration outcome.