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For more than 60 years, humans have travelled into space. Until now, the majority of astronauts have been professional, government agency astronauts selected, in part, for their superlative physical fitness and the absence of disease. Commercial spaceflight is now becoming accessible to members of the public, many of whom would previously have been excluded owing to unsatisfactory fitness or the presence of cardiorespiratory diseases. While data exist on the effects of gravitational and acceleration (G) forces on human physiology, data on the effects of the aerospace environment in unselected members of the public, and particularly in those with clinically significant pathology, are limited. Although short in duration, these high acceleration forces can potentially either impair the experience or, more seriously, pose a risk to health in some individuals. Rather than expose individuals with existing pathology to G forces to collect data, computational modelling might be useful to predict the nature and severity of cardiovascular diseases that are of sufficient risk to restrict access, require modification, or suggest further investigation or training before flight. In this Review, we explore state-of-the-art, zero-dimensional, compartmentalized models of human cardiovascular pathophysiology that can be used to simulate the effects of acceleration forces, homeostatic regulation and ventilation-perfusion matching, using data generated by long-arm centrifuge facilities of the US National Aeronautics and Space Administration and the European Space Agency to risk stratify individuals and help to improve safety in commercial suborbital spaceflight., (© 2024. Springer Nature Limited.)

Background: Myocardial ischaemia results from insufficient coronary blood flow. Computed virtual fractional flow reserve (vFFR) allows quantification of proportional flow loss without the need for invasive pressure-wire testing. In the current study, we describe a novel, conductivity model of side branch flow, referred to as 'leak'. This leak model is a function of taper and local pressure, the latter of which may change radically when focal disease is present. This builds upon previous techniques, which either ignore side branch flow, or rely purely on anatomical factors. This study aimed to describe a new, conductivity model of side branch flow and compare this with established anatomical models., Methods and Results: The novel technique was used to quantify vFFR, distal absolute flow (Qd) and microvascular resistance (CMVR) in 325 idealised 1D models of coronary arteries, modelled from invasive clinical data. Outputs were compared to an established anatomical model of flow. The conductivity model correlated and agreed with the reference model for vFFR (r = 0.895, p < 0.0001; ＋0.02, 95% CI 0.00 to ＋ 0.22), Qd (r = 0.959, p < 0.0001; -5.2 mL/min, 95% CI -52.2 to ＋13.0) and CMVR (r = 0.624, p < 0.0001; ＋50 Woods Units, 95% CI -325 to ＋2549)., Conclusion: Agreement between the two techniques was closest for vFFR, with greater proportional differences seen for Qd and CMVR. The conductivity function assumes vessel taper was optimised for the healthy state and that CMVR was not affected by local disease. The latter may be addressed with further refinement of the technique or inferred from complementary image data. The conductivity technique may represent a refinement of current techniques for modelling coronary side-branch flow. Further work is needed to validate the technique against invasive clinical data., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This independent research was carried out at the National Institute for Health and Care Research (NIHR) Sheffield Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Increased coronary microvascular resistance (CMVR) is associated with coronary microvascular dysfunction (CMD). Although CMD is more common in women, sex-specific differences in CMVR have not been demonstrated previously., Aim: To compare CMVR between men and women being investigated for chest pain., Methods and Results: We used a computational fluid dynamics (CFD) model of human coronary physiology to calculate absolute CMVR based on invasive coronary angiographic images and pressures in 203 coronary arteries from 144 individual patients. CMVR was significantly higher in women than men (860 [650-1,205] vs. 680 [520-865] WU, Z  = -2.24, p  = 0.025). None of the other major subgroup comparisons yielded any differences in CMVR., Conclusion: CMVR was significantly higher in women compared with men. These sex-specific differences may help to explain the increased prevalence of CMD in women., Competing Interests: PM, JG, PL and DH are named as an inventors on a University of Sheffield patent that describes elements of the CFD method. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Taylor, Aubiniere-Robb, Gosling, Newman, Hose, Halliday, Lawford, Narracott, Gunn and Morris.)

The study aimed to develop a pulmonary circulatory system capable of high-speed 3D reconstruction of valve leaflets to elucidate the local hemodynamic characteristics in the valved conduits with bulging sinuses. Then a simultaneous measurement system for leaflet structure and pressure and flow characteristics was designed to obtain valve leaflet dynamic behaviour with different conduit structures. An image preprocessing method was established to obtain the three leaflets behaviour simultaneously for one sequence with two leaflets images from each pair of three high-speed cameras. Firstly, the multi-digital image correlation analyses were performed, and then the valve leaflet structure was measured under the static condition with fixed opening angles in the water-filled visualization chamber and the pulsatile flow tests simulating paediatric pulmonary flow conditions in the different types of conduit structures; with or without bulging sinuses. The results showed the maximum 3D reconstruction error to be around 0.06 mm. In the steady flow test, the evaluation of opening angles under the different flow rates conditions was achieved. In the pulsatile flow test, each leaflet's opening and closing behaviours were successfully reconstructed simultaneously at the high-frequency recording rate of 960fps. Therefore, the system developed in this study confirms the design evaluation method of an ePTFE valved conduit behaviour with leaflet structures interacting with local fluid dynamics in the vicinity of valves. Clinical Relevance- The system reveals the bulging sinus effects on ePTFE valve leaflet motion by the 3D reconstruction using multi-camera high-speed sequential imaging in vitro.

Fractional flow reserve (FFR) is the current gold-standard invasive assessment of coronary artery disease (CAD). FFR reports coronary blood flow (CBF) as a fraction of a hypothetical and unknown normal value. Although used routinely to diagnose CAD and guide treatment, how accurately FFR predicts actual CBF changes remains unknown. Here we compared fractional CBF with the absolute CBF (aCBF in mL/min), measured with a computational method during standard angiography and pressure-wire assessment, on 203 diseased arteries (143 patients). We found a substantial correlation between the two measurements (r 0.89, Cohen's Kappa 0.71). Concordance between fractional and absolute CBF reduction was high when FFR was >0.80 (91%), but reduced when FFR was ≤0.80 (81%), 0.70-0.80 (68%) and, particularly 0.75-0.80 (62%). Discordance was associated with coronary microvascular resistance, vessel diameter and mass of myocardium subtended, all factors to which FFR is agnostic. Assessment of aCBF complements FFR, and may be valuable to assess CBF, particularly in cases within the FFR 'grey-zone'., Competing Interests: Competing interests The authors have no financial conflicts of interest. PDM, JPG, PJL and DRH are named as inventors on a University of Sheffield (UK) patent application describing the CFD method (VIRTU-Q. A method for determining volumetric blood flow. Patent application number 1813170.6).

Three dimensional (3D) coronary anatomy, reconstructed from coronary angiography (CA), is now being used as the basis to compute 'virtual' fractional flow reserve (vFFR), and thereby guide treatment decisions in patients with coronary artery disease (CAD). Reconstruction accuracy is therefore important. Yet the methods required remain poorly validated. Furthermore, the magnitude of vFFR error arising from reconstruction is unkown. We aimed to validate a method for 3D CA reconstruction and determine the effect this had upon the accuracy of vFFR. Clinically realistic coronary phantom models were created comprosing seven standard stenoses in aluminium and 15 patient-based 3D-printed, imaged with CA, three times, according to standard clinical protocols, yielding 66 datasets. Each was reconstructed using epipolar line projection and intersection. All reconstructions were compared against the real phantom models in terms of minimal lumen diameter, centreline and surface similarity. 3D-printed reconstructions (n = 45) and the reference files from which they were printed underwent vFFR computation, and the results were compared. The average error in reconstructing minimum lumen diameter (MLD) was 0.05 (± 0.03 mm) which was < 1% (95% CI 0.13-1.61%) compared with caliper measurement. Overall surface similarity was excellent (Hausdorff distance 0.65 mm). Errors in 3D CA reconstruction accounted for an error in vFFR of ± 0.06 (Bland Altman 95% limits of agreement). Errors arising from the epipolar line projection method used to reconstruct 3D coronary anatomy from CA are small but contribute to clinically relevant errors when used to compute vFFR., (© 2021. The Author(s).)

Aims: Ischaemic heart disease is the reduction of myocardial blood flow, caused by epicardial and/or microvascular disease. Both are common and prognostically important conditions, with distinct guideline-indicated management. Fractional flow reserve (FFR) is the current gold-standard assessment of epicardial coronary disease but is only a surrogate of flow and only predicts percentage flow changes. It cannot assess absolute (volumetric) flow or microvascular disease. The aim of this study was to develop and validate a novel method that predicts absolute coronary blood flow and microvascular resistance (MVR) in the catheter laboratory., Methods and Results: A computational fluid dynamics (CFD) model was used to predict absolute coronary flow (QCFD) and coronary MVR using data from routine invasive angiography and pressure-wire assessment. QCFD was validated in an in vitro flow circuit which incorporated patient-specific, three-dimensional printed coronary arteries; and then in vivo, in patients with coronary disease. In vitro, QCFD agreed closely with the experimental flow over all flow rates [bias +2.08 mL/min; 95% confidence interval (error range) -4.7 to +8.8 mL/min; R2 = 0.999, P < 0.001; variability coefficient <1%]. In vivo, QCFD and MVR were successfully computed in all 40 patients under baseline and hyperaemic conditions, from which coronary flow reserve (CFR) was also calculated. QCFD-derived CFR correlated closely with pressure-derived CFR (R2 = 0.92, P < 0.001). This novel method was significantly more accurate than Doppler-wire-derived flow both in vitro (±6.7 vs. ±34 mL/min) and in vivo (±0.9 vs. ±24.4 mmHg)., Conclusions: Absolute coronary flow and MVR can be determined alongside FFR, in absolute units, during routine catheter laboratory assessment, without the need for additional catheters, wires or drug infusions. Using this novel method, epicardial and microvascular disease can be discriminated and quantified. This comprehensive coronary physiological assessment may enable a new level of patient stratification and management., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Repair of dissected aorta requires remodeling the structure of the media. Modeling approaches specific to endovascular stenting for aortic dissection have been reported. We created a goat model of descending thoracic aortic dissection and reproduced its morphological characteristics in a mock circulatory system. The purpose of this study was to examine a newly developed aortic stent which was capable of installing to the aortic dissected lesion for biomedical hemodynamics point of view. In this study, we examined the changes in hemodynamics of dissected lesions and the amelioration by endovascular stent intervention. Firstly, we performed animal experiments with the dissected aorta and examined the effects of stenting on volumetric changes in the false lumen. Secondly, we made several types of 3-D stereolithographic dissected aortic models with silicone rubber membrane between the false and the true lumens. Then, the hemodynamic characteristics in each model were evaluated in the pulsatile flow conditions in a mock circulatory system. These modelling approaches enabled the quantitative examination of post-therapeutic effects of stenting followed by elucidating of hemodynamic changes in the vicinity of stents, which may follow the management of clinical amelioration of interventional treatment with aortic stenting.Clinical Relevance- This study represents a modelling approach of the dissected aorta for endovascular intervention using stenting followed by the examination of false lumen volumetric changes resulting in the deterioration of pressure increase in diseased lesions.

Endothelial cells (ECs) play a major role in the healing process following angioplasty to inhibit excessive neointima. This makes the process of EC healing after injury, in particular EC migration in a stented vessel, important for recovery of normal vessel function. In that context, we present a novel particle-based model of EC migration and validate it against in vitro experimental data. We have developed a particle-based model of EC migration under flow conditions in an in vitro vessel with obstacles. Cell movement in the model is a combination of random walks and directed movement along the local flow velocity vector. For model calibration, a set of experimental data for cell migration in a similarly shaped channel has been used. We have calibrated the model for a baseline case of a channel with no obstacles and then applied it to the case of a channel with ridges on the bottom surface, representative of stent strut geometry. We were able to closely reproduce the cell migration speed and angular distribution of their movement relative to the flow direction reported in vitro. The model also reproduces qualitative aspects of EC migration, such as entrapment of cells downstream from the flow-disturbing ridge. The model has the potential, after more extensive in vitro validation, to study the effect of variation in strut spacing and shape, through modification of the local flow, on EC migration. The results of this study support the hypothesis that EC migration is strongly affected by the direction and magnitude of local wall shear stress.

Background: Coronary artery restenosis is an important side effect of percutaneous coronary intervention. Computational models can be used to better understand this process. We report on an approach for validation of an in silico 3D model of in-stent restenosis in porcine coronary arteries and illustrate this approach by comparing the modelling results to in vivo data for 14 and 28 days post-stenting., Methods: This multiscale model includes single-scale models for stent deployment, blood flow and tissue growth in the stented vessel, including smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. The validation procedure uses data from porcine in vivo experiments, by simulating stent deployment using stent geometry obtained from micro computed tomography (micro-CT) of the stented vessel and directly comparing the simulation results of neointimal growth to histological sections taken at the same locations., Results: Metrics for comparison are per-strut neointimal thickness and per-section neointimal area. The neointimal area predicted by the model demonstrates a good agreement with the detailed experimental data. For 14 days post-stenting the relative neointimal area, averaged over all vessel sections considered, was 20 ± 3% in vivo and 22 ± 4% in silico. For 28 days, the area was 42 ± 3% in vivo and 41 ± 3% in silico., Conclusions: The approach presented here provides a very detailed, location-specific, validation methodology for in silico restenosis models. The model was able to closely match both histology datasets with a single set of parameters. Good agreement was obtained for both the overall amount of neointima produced and the local distribution. It should be noted that including vessel curvature and ECM production in the model was paramount to obtain a good agreement with the experimental data.

Ultrasound-based 2D speckle-tracking echocardiography (US-2D-STE) is increasingly used to assess the functionality of the heart. In particular, the analysis of cardiac strain plays an important role in the identification of several cardiovascular diseases. However, this imaging technique presents some limitations associated with its operating principle that result in low accuracy and reproducibility of the measurement. In this study, an experimental framework for multimodal strain imaging in an in vitro porcine heart was developed. Specifically, the aim of this work was to analyse displacement and strain in the heart by means of 3D digital image correlation (3D-DIC) and US-2D-STE. Over a single cardiac cycle, displacement values obtained from the two techniques were in strong correlation, although systematically larger displacements were observed with 3D-DIC. Notwithstanding an absolute comparison of the strain measurements was not possible to achieve between the two methods, maximum principal strain directions computed with 3D-DIC were consistent with the longitudinal and circumferential strain distribution measured with US-2D-STE. 3D-DIC confirmed its high repeatability in quantifying displacement and strain over multiple cardiac cycles, unlike US-2D-STE which is affected by accumulated errors over time (i.e. drift). To conclude, this study demonstrates the potential of 3D-DIC to perform dynamic measurement of displacement and strain during heart deformations and supports future applications of this method in ex vivo beating heart platforms, which replicate more fully the complex contraction of the heart., (Copyright © 2019. Published by Elsevier Ltd.)

The quantitative assessment of cardiac strain is increasingly performed to provide valuable insights on heart function. Currently, the most frequently used technique in the clinic is ultrasound-based speckle tracking echocardiography (STE). However, verification and validation of this modality are still under investigation and further reference measurements are required to support this activity. The aim of this work was to enable these reference measurements using a dynamic beating heart simulator to ensure reproducible, controlled, and realistic haemodynamic conditions and to validate the reliability of optical-based three-dimensional digital image correlation (3D-DIC) for a dynamic full-field analysis of epicardial strain. Specifically, performance assessment of 3D-DIC was carried out by evaluating the accuracy and repeatability of the strain measurements across multiple cardiac cycles in a single heart and between five hearts. Moreover, the ability of this optical method to differentiate strain variations when different haemodynamic conditions were imposed in the same heart was examined. Strain measurements were successfully accomplished in a region of the lateral left ventricle surface. Results were highly repeatable over heartbeats and across hearts (intraclass correlation coefficient = 0.99), whilst strain magnitude was significantly different between hearts, due to change in anatomy and wall thickness. Within an individual heart, strain variations between different haemodynamic scenarios were greater than the estimated error of the measurement technique. This study demonstrated the feasibility of applying 3D-DIC in a dynamic passive heart simulator. Most importantly, non-contact measurements were obtained at a high spatial resolution (~ 1.5 mm) allowing resolution of local variation of strain on the epicardial surface during ventricular filling. The experimental framework developed in this paper provides detailed measurement of cardiac strains under controlled conditions, as a reference for validation of clinical cardiac strain imaging modalities., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic venous disease is defined as dysfunction of the venous system caused by incompetent venous valves with or without a proximal venous obstruction. Assessing the severity of the disease is challenging, since venous function is determined by various interacting hemodynamic factors. Mathematical models can relate these factors using physical laws and can thereby aid understanding of venous (patho-)physiology. To eventually use a mathematical model to support clinical decision making, first the model sensitivity needs to be determined. Therefore, the aim of this study is to assess the sensitivity of the venous valve model outputs to the relevant input parameters. Using a 1D pulse wave propagation model of the tibial vein including a venous valve, valve dynamics under head up tilt are simulated. A variance-based sensitivity analysis is performed based on generalized polynomial chaos expansion. Taking a global approach, individual parameter importance on the valve dynamics as well as importance of their interactions is determined. For the output related to opening state of the valve, the opening/closing pressure drop (dp valve,0 ) is found to be the most important parameter. The venous radius (r vein,0 ) is related to venous filling volume and is consequently most important for the output describing venous filling time. Finally, it is concluded that improved assessment of r vein,0 and dp valve,0 is most rewarding when simulating valve dynamics, as this results in the largest reduction in output uncertainty. In practice, this could be achieved using ultrasound imaging of the veins and fluid structure interaction simulations to characterize detailed valve dynamics, respectively., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The calf muscle pump is a mechanism which increases venous return and thereby compensates for the fluid shift towards the lower body during standing. During a muscle contraction, the embedded deep veins collapse and venous return increases. In the subsequent relaxation phase, muscle perfusion increases due to increased perfusion pressure, as the proximal venous valves temporarily reduce the distal venous pressure (shielding). The superficial and deep veins are connected via perforators, which contain valves allowing flow in the superficial-to-deep direction. The aim of this study is to investigate and quantify the physiological mechanisms of the calf muscle pump, including the effect of venous valves, hydrostatic pressure, and the superficial venous system. Using a one-dimensional pulse wave propagation model, a muscle contraction is simulated by increasing the extravascular pressure in the deep venous segments. The hemodynamics are studied in three different configurations: a single artery-vein configuration with and without valves and a more detailed configuration including a superficial vein. Proximal venous valves increase effective venous return by 53% by preventing reflux. Furthermore, the proximal valves shielding function increases perfusion following contraction. Finally, the superficial system aids in maintaining the perfusion during the contraction phase and reduces the refilling time by 37%., (© 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Purpose: To quantify variability of in vitro and in vivo measurement of 3D device geometry using 3D and biplanar imaging., Methods: Comparison of stent reconstruction is reported for in vitro coronary stent deployment (using micro-CT and optical stereo-photogrammetry) and in vivo pulmonary valve stent deformation (using 4DCT and biplanar fluoroscopy). Coronary stent strut length and inter-strut angle were compared in the fully deployed configuration. Local (inter-strut angle) and global (dog-boning ratio) measures of stent deformation were reported during stent deployment. Pulmonary valve stent geometry was assessed throughout the cardiac cycle by reconstruction of stent geometry and measurement of stent diameter., Results: Good agreement was obtained between methods for assessment of coronary stent geometry with maximum disagreement of +/- 0.03 mm (length) and +/- 3 degrees (angle). The stent underwent large, non-uniform, local deformations during balloon inflation, which did not always correlate with changes in stent diameter. Three-dimensional reconstruction of the pulmonary valve stent was feasible for all frames of the fluoroscopy and for 4DCT images, with good correlation between the diameters calculated from the two methods. The largest compression of the stent during the cardiac cycle was 6.98% measured from fluoroscopy and 7.92% from 4DCT, both in the most distal ring., Conclusions: Quantitative assessment of stent geometry reconstructed from biplanar imaging methods in vitro and in vivo has shown good agreement with geometry reconstructed from 3D techniques. As a result of their short image acquisition time, biplanar methods may have significant advantages in the measurement of dynamic 3D stent deformation.

The implantation of stents has been used to treat coronary artery stenosis for several decades. Although stenting is successful in restoring the vessel lumen and is a minimally invasive approach, the long-term outcomes are often compromised by in-stent restenosis (ISR). Animal models have provided insights into the pathophysiology of ISR and are widely used to evaluate candidate drug inhibitors of ISR. Such biological models allow the response of the vessel to stent implantation to be studied without the variation of lesion characteristics encountered in patient studies.This paper describes the development of complementary in silico models employed to improve the understanding of the biological response to stenting using a porcine model of restenosis. This includes experimental quantification using microCT imaging and histology and the use of this data to establish numerical models of restenosis. Comparison of in silico results with histology is used to examine the relationship between spatial localization of fluid and solid mechanics stimuli immediately post-stenting. Multi-scale simulation methods are employed to study the evolution of neointimal growth over time and the variation in the extent of neointimal hyperplasia within the stented region. Interpretation of model results through direct comparison with the biological response contributes to more detailed understanding of the pathophysiology of ISR, and suggests the focus for follow-up studies.In conclusion we outline the challenges which remain to both complete our understanding of the mechanisms responsible for restenosis and translate these models to applications in stent design and treatment planning at both population-based and patient-specific levels.

This paper presents a quantitative assessment of uncertainty for the 3D reconstruction of stents. This study investigates a CP stent (Numed, USA) used in congenital heart disease applications with a focus on the variance in measurements of stent geometry. The stent was mounted on a model of patient implantation site geometry, reconstructed from magnetic resonance images, and imaged using micro-computed tomography (CT), conventional CT, biplane fluoroscopy and optical stereo-photogrammetry. Image data were post-processed to retrieve the 3D stent geometry. Stent strut length, separation angle and cell asymmetry were derived and repeatability was assessed for each technique along with variation in relation to μCT data, assumed to represent the gold standard. The results demonstrate the performance of biplanar reconstruction methods is comparable with volumetric CT scans in evaluating 3D stent geometry. Uncertainty on the evaluation of strut length, separation angle and cell asymmetry using biplanar fluoroscopy is of the order ±0.2mm, 3° and 0.03, respectively. These results support the use of biplanar fluoroscopy for in vivo measurement of 3D stent geometry and provide quantitative assessment of uncertainty in the measurement of geometric parameters., (Copyright © 2014 IPEM. Published by Elsevier Ltd. All rights reserved.)

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.

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.

This paper describes the use of diverse software tools in cardiovascular applications. These tools were primarily developed in the field of engineering and the applications presented push the boundaries of the software to address events related to venous and arterial valve closure, exploration of dynamic boundary conditions or the inclusion of multi-scale boundary conditions from protein to organ levels. The future of cardiovascular research and the challenges that modellers and clinicians face from validation to clinical uptake are discussed from an end-user perspective.

This paper presents a validated model of calf compression with an external pressure cuff as used for deep vein thrombosis. Magnetic resonance (MR) images of calf geometry were used to generate subject-specific finite-element (FE) models of the calf cross section. Ultrasound images of deep vessel collapse obtained through a water-filled cuff were used to validate model behavior. Calf/cuff pressure interface measurements were applied to the FE model and the resulting tissue deformation was compared with MR image in normal volunteers (three females, four males, age range 20-55) using two distinct cuffs. MR observations and the model results showed good qualitative agreement. A similar reduction in cross-sectional area of the posterior tibial veins was obtained under both symmetric compression (89%) and asymmetric compression (81%), but greater compression of the anterior tibial veins was achieved with symmetric compression. The need to account for the effective compressibility of the calf tissue suggests that external measurements of the calf tissue deformation will not accurately predict deep vessel collapse. These results have implications for the modification of venous haemodynamics by such systems and could help to improve cuff design.

Background: It is widely accepted that venous valves play an important role in reducing the pressure applied to the veins under dynamic load conditions, such as the act of standing up. This understanding is, however, qualitative and not quantitative. The purpose of this paper is to quantify the pressure shielding effect and its variation with a number of system parameters., Methods: A one-dimensional mathematical model of a collapsible tube, with the facility to introduce valves at any position, was used. The model has been exercised to compute transient pressure and flow distributions along the vein under the action of an imposed gravity field (standing up)., Results: A quantitative evaluation of the effect of a valve, or valves, on the shielding of the vein from peak transient pressure effects was undertaken. The model used reported that a valve decreased the dynamic pressures applied to a vein when gravity is applied by a considerable amount., Conclusion: The model has the potential to increase understanding of dynamic physical effects in venous physiology, and ultimately might be used as part of an interventional planning tool.

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.

Intermittent pneumatic compression (IPC) is widely used for deep vein thrombosis (DVT) prophylaxis. The technique involves periodic inflation of a compression cuff around a limb, which acts to simulate the muscle pump mechanism, encouraging venous blood flow. However, there is uncertainty regarding the relationship between compression, vascular effects and clinical outcomes. This study investigates calf compression provided by four IPC cuffs with different air bladder configurations. Interface pressure between the cuff and the skin surface is measured and magnetic resonance (MR) images are obtained showing the calf cross section before and during compression. The data will be used to inform numerical simulations of IPC, leading to increased understanding of the implications of cuff design in relation to IPC and DVT prophylaxis.

The level of restenosis following coronary artery stenting may be related to the deployed stent geometry. This study investigated the influence of two balloon folding patterns (;C' and ;S' shaped) on stent deployment. In vitro stent expansion showed ;S' shape folding produced more uniform expansion than ;C' shape folding. A numerical contact model (NCM) was developed to study the detail of load transfer between balloon and stent. Finite element analysis of the Palmaz-Schatz 204C stent provided a composite non-linear material model for the NCM. Agreement between the predicted final stent geometry and experimental results was strongly dependent on the frictional coefficient between the stent and balloon. We conclude that non-uniform contact may contribute to the asymmetry of deployed stents reported clinically.

Stresses in a prosthetic heart valve at closure are determined by its geometrical and structural characteristics, by the mechanical support environment, and by the momentum of the valve leaflets or occluder and of the blood at the instant of closure. The mass of blood to be arrested is significantly greater than that of the leaflets or occluder, and is therefore likely to dominate the closure impulse. The kinetic energy of the blood must be transduced into potential energy in the structural components (valve leaflets, aortic root and aorta). This paper presents a methodology for computation and parameterisation of the blood momentum associated with a valve in the aortic position. It is suggested that the influence of physiological parameters, such as systolic waveform and systemic impedance, on the closure characteristics can be investigated based on the fluid dynamic implications. Detailed results are presented for a single leaflet mechanical valve (Bjork-Shiley 60 degrees Convexo-Concave). It is demonstrated that a simple analytical method can yield results that might be adequate for the purposes of valve design.

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.

Balloon-expandable stents are used routinely in the treatment of coronary artery disease. Their effectiveness is limited by the occurrence of restenosis. Previous studies have suggested that the level of restenosis may be related to the deployed stent geometry, and in particular to the symmetry of the deployment profile. It is suggested that the symmetry of deployment might be influenced by the folding pattern of the balloon on which the stent is delivered. This paper describes a stereo-photogrammetric system for the three-dimensional reconstruction of stent geometry during expansion, including appropriate specification and calibration procedures. Calibration testing of the system indicated an accuracy of +/-0.05 mm in the reconstruction of the position of a point on the stent surface. Methods for processing the 3D data are described, including a technique for quantitatively differentiating between results from two alternative balloon folding patterns. This study may aid future balloon and stent design with respect to the optimization of stent deployment characteristics.

Fluid-solid interaction is a primary feature of cardiovascular flows. There is increasing interest in the numerical solution of these systems as the extensive computational resource required for such studies becomes available. One form of coupling is an external weak coupling of separate solid and fluid mechanics codes. Information about the stress tensor and displacement vector at the wetted boundary is passed between the codes, and an iterative scheme is employed to move towards convergence of these parameters at each time step. This approach has the attraction that separate codes with the most extensive functionality for each of the separate phases can be selected, which might be important in the context of the complex rheology and contact mechanics that often feature in cardiovascular systems. Penrose and Staples describe a weak coupling of CFX for computational fluid mechanics to ANSYS for solid mechanics, based on a simple Jacobi iteration scheme. It is important to validate the coupled numerical solutions. An extensive analytical study of flow in elastic-walled tubes was carried out by Womersley in the late 1950s. This paper describes the performance of the coupling software for the straight elastic-walled tube, and compares the results with Womersley's analytical solutions. It also presents preliminary results demonstrating the application of the coupled software in the context of a stented vessel.

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 (5.8 ohm m at birth to 20.9 ohm m 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.

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 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. 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.

The insertion of vein grafts into the arterial circulation may contribute to vessel wall thickening and accelerated atherosclerosis, a common feature of late vein graft failure. We aimed to develop a model suitable for investigation of the effects of altered haemodynamics on human saphenous vein following its implantation into the arterial circulation. Segments of human saphenous vein obtained from patients undergoing coronary artery bypass surgery were sutured at each end to PTFE and placed into a flow system. Pressure and flow rates to stimulate the arterial and venous systems were achieved. A theoretical model of the flow chamber was created and computational fluid dynamics software (FLOTRAN, Swanson Analysis Systems) was used to determine the flow profile within the model. In summary, a flow model has been developed to investigate the effect of altered haemodynamics on the molecular and pathological changes that occur in vein grafts incorporated into the arterial circulation.