An anatomically detailed arterial-venous network model. Cerebral and coronary circulation.

In recent years, several works have addressed the problem of modeling blood flow phenomena in veins, as a response to increasing interest in modeling pathological conditions occurring in the venous network and their connection with the rest of the circulatory system. In this context, one-dimensional models have proven to be extremely efficient in delivering predictions in agreement with in-vivo observations. Pursuing the increase of anatomical accuracy and its connection to physiological principles in haemodynamics simulations, the main aim of this work is to describe a novel closed-loop Anatomically-Detailed Arterial-Venous Network (ADAVN) model. An extremely refined description of the arterial network consisting of 2,185 arterial vessels is coupled to a novel venous network featuring high level of anatomical detail in cerebral and coronary vascular territories. The entire venous network comprises 189 venous vessels, 79 of which drain the brain and 14 are coronary veins. Fundamental physiological mechanisms accounting for the interaction of brain blood flow with the cerebro-spinal fluid and of the coronary circulation with the cardiac mechanics are considered. Several issues related to the coupling of arterial and venous vessels at the microcirculation level are discussed in detail. Numerical simulations are compared to patient records published in the literature to show the descriptive capabilities of the model. Furthermore, a local sensitivity analysis is performed, evidencing the high impact of the venous circulation on main cardiovascular variables.

A simple coronary blood flow model to study the collateral flow index.

In this work, we present a novel modeling framework to investigate the effects of collateral circulation into the coronary blood flow physiology. A prototypical model of the coronary tree, integrated with the concept of Collateral Flow Index (CFI), is employed to gain insight about the role of model parameters associated with the collateral circuitry, which results in physically-realizable solutions for specific CFI data. Then, we discuss the mathematical feasibility of pressure-derived CFI, anatomical implications and practical considerations involving the estimation of model parameters in collateral connections. A sensitivity analysis is carried out, and the investigation of the impact of the collateral circulation on FFR values is also addressed.

Coronary arterial geometry: A comprehensive comparison of two imaging modalities.

The characterization of vascular geometry is a fundamental step towards the correct interpretation of coronary artery disease. In this work, we report a comprehensive comparison of the geometry featured by coronary vessels as obtained from coronary computed tomography angiography (CCTA) and the combination of intravascular ultrasound (IVUS) with bi-plane angiography (AX) modalities. We analyzed 34 vessels from 28 patients with coronary disease, which were deferred to CCTA and IVUS procedures. We discuss agreement and discrepancies between several geometric indexes extracted from vascular geometries. Such an analysis allows us to understand to which extent the coronary vascular geometry can be reliable in the interpretation of geometric risk factors, and as a surrogate to characterize coronary artery disease.

Integrated cardiorespiratory system model with short timescale control mechanisms.

A compartmental model of the cardiorespiratory system featuring pulsatile blood flow and gas transport, as well as closed loop mechanisms of cardiorespiratory regulation is presented. Short timescale regulatory action includes baroreflex, peripheral and central chemoreflex feedback. The cardiorespiratory model is composed by compartments to describe blood flow and gas exchange in the major systemic and pulmonic regions. The control systems include formulations to afferent activity of arterial baroreceptor and peripheral and central chemoreceptors. Simulations described here include situations of hypoxia, hypercapnia, and hemorrhage. The overall responses of our simulations agree with physiological (experimental) and theoretical data. Our results suggest that the present model could be used to further understand the interplay among major regulatory mechanisms in the functioning of the cardiovascular and respiratory systems in cases of normal and abnormal physiological conditions.

On the anatomical definition of arterial networks in blood flow simulations: comparison of detailed and simplified models.

The goal of this work is to assess the impact of vascular anatomy definition degree in the predictions of blood flow models of the arterial network. To this end, results obtained with an anatomically detailed network containing over 2000 vessels are systematically compared with those obtained with an anatomically simplified network containing the main 86 vessels, the latter being a truncated version of the former one. The comparison is performed quantitatively and qualitatively in terms of pressure and flow rate waveforms, wave intensity analysis and impedance analysis. Comparisons are performed under physiological conditions and for the case of common carotid artery occlusion. Mechanisms of blood flow delivery to the brain, as well as different blood flow steal phenomena, are unveiled in light of model predictions. Results show that detailed and simplified models are in reasonable agreement regarding the hemodynamics in larger vessels and in healthy scenarios. The anatomically detailed arterial network features improved predictive capabilities at peripheral vessels. Moreover, discrepancies between models are substantially accentuated in the case of anatomical variations or abnormal hemodynamic conditions. We conclude that physiologically meaningful agreement between models is obtained for normal hemodynamic conditions. This agreement rapidly deteriorates for abnormal blood flow conditions such as those caused by total arterial occlusion. Differences are even larger when modifications of the vascular anatomy are considered. This rational comparison allows us to gain insight into the need for anatomically detailed arterial networks when addressing complex hemodynamic interactions.

Coronary fractional flow reserve derived from intravascular ultrasound imaging: Validation of a new computational method of fusion between anatomy and physiology.

OBJECTIVES: To evaluate the diagnostic performance of a novel computational algorithm based on three-dimensional intravascular ultrasound (IVUS) imaging in estimating fractional flow reserve (IVUSFR ), compared to gold-standard invasive measurements (FFRINVAS ). BACKGROUND: IVUS provides accurate anatomical evaluation of the lumen and vessel wall and has been validated as a useful tool to guide percutaneous coronary intervention. However, IVUS poorly represents the functional status (i.e., flow-related information) of the imaged vessel. METHODS: Patients with known or suspected stable coronary disease scheduled for elective cardiac catheterization underwent FFRINVAS measurement and IVUS imaging in the same procedure to evaluate intermediate lesions. A processing methodology was applied on IVUS to generate a computational mesh condensing the geometric characteristics of the vessel. Computation of IVUSFR was obtained from patient-level morphological definition of arterial districts and from territory-specific boundary conditions. FFRINVAS measurements were dichotomized at the 0.80 threshold to define hemodynamically significant lesions. RESULTS: A total of 24 patients with 34 vessels were analyzed. IVUSFR significantly correlated (r = 0.79; P < 0.001) and showed good agreement with FFRINVAS , with a mean difference of -0.008 ± 0.067 (P = 0.47). IVUSFR presented an overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 91%, 89%, 92%, 80%, and 96%, respectively, to detect significant stenosis. CONCLUSION: The computational processing of IVUSFR is a new method that allows the evaluation of the functional significance of coronary stenosis in an accurate way, enriching the anatomical information of grayscale IVUS.

Mechanical Characterization of the Vessel Wall by Data Assimilation of Intravascular Ultrasound Studies.

Atherosclerotic plaque rupture and erosion are the most important mechanisms underlying the sudden plaque growth, responsible for acute coronary syndromes and even fatal cardiac events. Advances in the understanding of the culprit plaque structure and composition are already reported in the literature, however, there is still much work to be done toward in-vivo plaque visualization and mechanical characterization to assess plaque stability, patient risk, diagnosis and treatment prognosis. In this work, a methodology for the mechanical characterization of the vessel wall plaque and tissues is proposed based on the combination of intravascular ultrasound (IVUS) imaging processing, data assimilation and continuum mechanics models within a high performance computing (HPC) environment. Initially, the IVUS study is gated to obtain volumes of image sequences corresponding to the vessel of interest at different cardiac phases. These sequences are registered against the sequence of the end-diastolic phase to remove transversal and longitudinal rigid motions prescribed by the moving environment due to the heartbeat. Then, optical flow between the image sequences is computed to obtain the displacement fields of the vessel (each associated to a certain pressure level). The obtained displacement fields are regarded as observations within a data assimilation paradigm, which aims to estimate the material parameters of the tissues within the vessel wall. Specifically, a reduced order unscented Kalman filter is employed, endowed with a forward operator which amounts to address the solution of a hyperelastic solid mechanics model in the finite strain regime taking into account the axially stretched state of the vessel, as well as the effect of internal and external forces acting on the arterial wall. Due to the computational burden, a HPC approach is mandatory. Hence, the data assimilation and computational solid mechanics computations are parallelized at three levels: (i) a Kalman filter level; (ii) a cardiac phase level; and (iii) a mesh partitioning level. To illustrate the capabilities of this novel methodology toward the in-vivo analysis of patient-specific vessel constituents, mechanical material parameters are estimated using in-silico and in-vivo data retrieved from IVUS studies. Limitations and potentials of this approach are exposed and discussed.

Registration Methods for IVUS: Transversal and Longitudinal Transducer Motion Compensation.

OBJECTIVE: Intravascular ultrasound (IVUS) is a fundamental imaging technique for atherosclerotic plaque assessment, interventionist guidance, and, ultimately, as a tissue characterization tool. The studies acquired by this technique present the spatial description of the vessel during the cardiac cycle. However, the study frames are not properly sorted. As gating methods deal with the cardiac phase classification of the frames, the gated studies lack motion compensation between vessel and catheter. In this study, we develop registration strategies to arrange the vessel data into its rightful spatial sequence. METHODS: Registration is performed by compensating longitudinal and transversal relative motion between vessel and catheter. Transversal motion is identified through maximum likelihood estimator optimization, while longitudinal motion is estimated by a neighborhood similarity estimator among the study frames. A strongly coupled implementation is proposed to compensate for both motion components at once. Loosely coupled implementations (DLT and DTL) decouple the registration process, resulting in more computationally efficient algorithms in detriment of the size of the set of candidate solutions. RESULTS AND CONCLUSIONS: The DTL outperforms DLT and coupled implementations in terms of accuracy by a factor of 1.9 and 1.4, respectively. Sensitivity analysis shows that perivascular tissue must be considered to obtain the best registration outcome. Evidences suggest that the method is able to measure axial strain along the vessel wall. SIGNIFICANCE: The proposed registration sorts the IVUS frames for spatial location, which is crucial for a correct interpretation of the vessel wall kinematics along the cardiac phases.

On the search of arterial geometry heritability.

BACKGROUND: Geometrical risk factors for CAD have been previously proposed before. To date, however, the effect of those factors is not conclusive, and remains as an open research field. Here, we hypothesize that some of these factors have a genetic component explaining inter-individual variability. OBJECTIVE: To detect heritability indicators of the coronary arterial geometry. MATERIALS AND METHODS: A patient sample of 48 individuals, consisting of 24 siblings, was used. Three dimensional geometry of the LAD, LCx and RCA were reconstructed from standard CCTA. Arterial models were characterized in terms of 20+ geometric descriptors (phenotypes). A comprehensive statistical analysis to detect potential heritability of such phenotypes was employed. Heritability was assessed by means of several statistical indexes. Finally, the association of phenotypes to stenotic lesion is also reported. RESULTS: The RCA scored positive indications for heritability in 15+ phenotypes, while the LAD in 10 and the LCx in only 3 phenotypes. Association between presence of lesion and phenotypes was higher in the LAD, 10+ phenotypes, while for the LCx only 2 phenotypes were significantly associated, and none association was found for the RCA. CONCLUSION: The RCA showed potential heritability for the largest number of phenotypes, followed by the LAD. The LCx presents the weaker association of morphology among siblings. Regarding lesion-geometry associations, the there are hints of an underlying relation in the LAD, the LCx featured a weaker association and the RCA showed none. This difference could be related to the different hemodynamic environments in these arteries.

On the effect of preload and pre-stretch on hemodynamic simulations: an integrative approach.

In this work, we address the simulation of three-dimensional arterial blood flow and its effect on the stress state of arterial walls. The novel contribution is the unprecedented combination of several modeling techniques to account for (1) the fact that known configurations for the arterial wall are in a preloaded state, (2) the compliance of the vessel segments, (3) proper boundary data over the non-physical interfaces resulting from the isolation of an arterial district from the rest of the arterial tree, (4) the presence of surrounding tissues in which the vessel is embedded and (5) residual stress state due to pre-stretch. Firstly, we formulate both the forward mechanical problem when the reference (zero-load) configuration is assumed to be known and, the preload problem arising when the known domain is a configuration at equilibrium with a certain load state (typically due to internal pressure and tethering forces). Then, two additional complexities are faced: the fluid-structure interaction problem that follows when the compliant vessels are coupled with the blood flow, and the introduction of non-physical boundaries coming from the artificial isolation of the arterial district from the original vessel. This, in turn, posses the problem of coupling dimensionally heterogeneous models to incorporate the effect of upstream and downstream systemic impedances. Additionally, a viscoelastic support on the external surface of the vessel is also incorporated. Two examples are presented to quantify in a physiologically consistent scenario the differences in simulation results when either considering or not the preload state of arterial walls. These computational simulations shed light on the validity of simplifying hypotheses in most hemodynamic models.

A high-order local time stepping finite volume solver for one-dimensional blood flow simulations: application to the ADAN model.

In recent years, the complexity of vessel networks for one-dimensional blood flow models has significantly increased, because of enhanced anatomical detail or automatic peripheral vasculature generation, for example. This fact, along with the application of these models in uncertainty quantification and parameter estimation poses the need for extremely efficient numerical solvers. The aim of this work is to present a finite volume solver for one-dimensional blood flow simulations in networks of elastic and viscoelastic vessels, featuring high-order space-time accuracy and local time stepping (LTS). The solver is built on (i) a high-order finite volume type numerical scheme, (ii) a high-order treatment of the numerical solution at internal vertexes of the network, often called junctions, and (iii) an accurate LTS strategy. The accuracy of the proposed methodology is verified by empirical convergence tests. Then, the resulting LTS scheme is applied to arterial networks of increasing complexity and spatial scale heterogeneity, with a number of one-dimensional segments ranging from a few tens up to several thousands and vessel lengths ranging from less than a millimeter up to tens of centimeters, in order to evaluate its computational cost efficiency. The proposed methodology can be extended to any other hyperbolic system for which network applications are relevant. Copyright © 2016 John Wiley & Sons, Ltd.

Improving Cardiac Phase Extraction in IVUS Studies by Integration of Gating Methods.

UNLABELLED:   GOAL: Coronary intravascular ultrasound (IVUS) is a fundamental imaging technique for atherosclerotic plaque assessment. However, volume-based data retrieved from IVUS studies can be misleading due to the artifacts generated by the cardiac motion, hindering diagnostic, and visualization of the vessel condition. Then, we propose an image-based gating method that improves the performance of the preexisting methods, delivering a gating in an appropriate time for clinical practice. METHODS: We propose a fully automatic method to synergically integrate motion signals from different gating methods to improve the cardiac phase estimation. Additionally, we present a local extrema identification method that provides a more accurate extraction of a cardiac phase and, also, a scheme for multiple phase extraction mandatory for elastography-type studies. RESULTS: A comparison with three state-of-the-art methods is performed over 61 in-vivo IVUS studies including a wide range of physiological situations. The results show that the proposed strategy offers: 1) a more accurate cardiac phase extraction; 2) a lower frame oversampling and/or omission in the extracted phase data (error of 1.492 ±0.977 heartbeats per study, mean ± SD); 3) a more accurate and robust heartbeat period detection with a Bland-Altman coefficient of reproducibility (RPC) of 0.23 s, while the second closest method presents an RPC of 0.36 s. SIGNIFICANCE: The integration of motion signals performed by our method shown an improvement of the gating accuracy and reliability.

An anatomically detailed arterial network model for one-dimensional computational hemodynamics.

Simulation platforms are increasingly becoming complementary tools for cutting-edge cardiovascular research. The interplay among structural properties of the arterial wall, morphometry, anatomy, wave propagation phenomena, and ultimately, cardiovascular diseases continues to be poorly understood. Accurate models are powerful tools to shed light on these open problems. We developed an anatomically detailed computational model of the arterial vasculature to conduct 1-D blood flow simulations to serve as simulation infrastructure to aid cardiovascular research. An average arterial vasculature of a man was outlined in 3-D space to serve as geometrical substrate for the mathematical model. The architecture of this model comprises almost every arterial vessel acknowledged in the medical/anatomical literature, with a resolution down to the luminal area of perforator arteries. Over 2000 arterial vessels compose the model. Anatomical, physiological, and mechanical considerations were employed for the set up of model parameters and to determine criteria for blood flow distribution. Computational fluid dynamics was used to simulate blood flow and wave propagation phenomena in such arterial network. A sensitivity analysis was developed to unveil the contributions of model parameters to the conformation of the pressure waveforms. In addition, parameters were modified to target model to a patient-specific scenario. On the light of the knowledge domain, we conclude that the present model features excellent descriptive and predictive capabilities in both patient-generic and patient-specific cases, presenting a new step toward integrating an unprecedented anatomical description, morphometric, and simulations data to help in understanding complex arterial blood flow phenomena and related cardiovascular diseases.

Blood flow distribution in an anatomically detailed arterial network model: criteria and algorithms.

Development of blood flow distribution criteria is a mandatory step toward developing computational models and numerical simulations of the systemic circulation. In the present work, we (i) present a systematic approach based on anatomical and physiological considerations to distribute the blood flow in a 1D anatomically detailed model of the arterial network and (ii) develop a numerical procedure to calibrate resistive parameters in terminal models in order to effectively satisfy such flow distribution. For the first goal, we merge data collected from the specialized medical literature with anatomical concepts such as vascular territories to determine blood flow supply to specific (encephalon, kidneys, etc.) and distributed (muscles, skin, etc.) organs. Overall, 28 entities representing the main specific organs are accounted for in the detailed description of the arterial topology that we use as model substrate. In turn, 116 vascular territories are considered as the basic blocks that compose the distributed organs throughout the whole body. For the second goal, Windkessel models are used to represent the peripheral beds, and the values of the resistive parameters are computed applying a Newton method to a parameter identification problem to guarantee the supply of the correct flow fraction to each terminal location according to the given criteria. Finally, it is shown that, by means of the criteria developed, and for a rather standard set of model parameters, the model predicts physiologically realistic pressure and flow waveforms.

Free and open-source software application for the evaluation of coronary computed tomography angiography images.

BACKGROUND: The standardization of images used in Medicine in 1993 was performed using the DICOM (Digital Imaging and Communications in Medicine) standard. Several tests use this standard and it is increasingly necessary to design software applications capable of handling this type of image; however, these software applications are not usually free and open-source, and this fact hinders their adjustment to most diverse interests. OBJECTIVE: To develop and validate a free and open-source software application capable of handling DICOM coronary computed tomography angiography images. METHODS: We developed and tested the ImageLab software in the evaluation of 100 tests randomly selected from a database. We carried out 600 tests divided between two observers using ImageLab and another software sold with Philips Brilliance computed tomography appliances in the evaluation of coronary lesions and plaques around the left main coronary artery (LMCA) and the anterior descending artery (ADA). To evaluate intraobserver, interobserver and intersoftware agreements, we used simple and kappa statistics agreements. RESULTS: The agreements observed between software applications were generally classified as substantial or almost perfect in most comparisons. CONCLUSION: The ImageLab software agreed with the Philips software in the evaluation of coronary computed tomography angiography tests, especially in patients without lesions, with lesions < 50% in the LMCA and < 70% in the ADA. The agreement for lesions > 70% in the ADA was lower, but this is also observed when the anatomical reference standard is used.

Software livre e de código aberto para avaliação de imagens de angiotomografia de coronárias / Free and open-source software application for the evaluation of coronary computed tomography angiography images

FUNDAMENTO: A estandardização do padrão de imagens utilizada dentro da medicina foi realizada em 1993 por meio do padrão DICOM (Digital Imaging and Communications in Medicine). Diversos exames utilizam esse padrão e cada vez mais são necessários softwares capazes de manipular esse tipo de imagem, porém esses softwares geralmente não têm o formato livre e de código aberto, e isso dificulta o seu ajuste para os mais diferentes interesses. OBJETIVO: Desenvolver e validar um software livre e de código aberto capaz de manipular imagens DICOM de exames de angiotomografia de coronárias. MÉTODOS: Desenvolvemos e testamos o software intitulado ImageLab na avaliação de 100 exames selecionados de forma randômica por meio de um banco de dados. Foram realizadas 600 análises divididas por dois observadores utilizando o ImageLab e um outro software comercializado junto a aparelhos de tomografia computadorizada Philips Brilliance, na avaliação da presença de lesões e placas coronarianas nos territórios do Tronco da Coronária Esquerda (TCE) e na Artéria Descendente Anterior (ADA). Para avaliar as concordâncias intraobservador, interobservadores e intersoftware, utilizamos concordância simples e estatística Kappa. RESULTADOS: As concordâncias observadas entre os softwares foram em geral classificadas como substancial ou quase perfeitas na maioria das comparações. CONCLUSÃO: O software ImageLab concordou com o software Philips na avaliação de exames de angiotomografia de coronárias especialmente em pacientes sem lesões, com lesões inferiores a 50% no TCE e inferiores a 70% na ADA. A concordância para lesão >70% na ADA foi menor, porém isso também é observado quando se utiliza o padrão de referência anatômico.

BACKGROUND: The standardization of images used in Medicine in 1993 was performed using the DICOM (Digital Imaging and Communications in Medicine) standard. Several tests use this standard and it is increasingly necessary to design software applications capable of handling this type of image; however, these software applications are not usually free and open-source, and this fact hinders their adjustment to most diverse interests. OBJECTIVE: To develop and validate a free and open-source software application capable of handling DICOM coronary computed tomography angiography images. METHODS: We developed and tested the ImageLab software in the evaluation of 100 tests randomly selected from a database. We carried out 600 tests divided between two observers using ImageLab and another software sold with Philips Brilliance computed tomography appliances in the evaluation of coronary lesions and plaques around the left main coronary artery (LMCA) and the anterior descending artery (ADA). To evaluate intraobserver, interobserver and intersoftware agreements, we used simple and kappa statistics agreements. RESULTS: The agreements observed between software applications were generally classified as substantial or almost perfect in most comparisons. CONCLUSION: The ImageLab software agreed with the Philips software in the evaluation of coronary computed tomography angiography tests, especially in patients without lesions, with lesions < 50% in the LMCA and < 70% in the ADA. The agreement for lesions > 70% in the ADA was lower, but this is also observed when the anatomical reference standard is used.

A cellular automata-based mathematical model for thymocyte development.

Intrathymic T cell development is an important process necessary for the normal formation of cell-mediated immune responses. Importantly, such a process depends on interactions of developing thymocytes with cellular and extracellular elements of the thymic microenvironment. Additionally, it includes a series of oriented and tunely regulated migration events, ultimately allowing mature cells to cross endothelial barriers and leave the organ. Herein we built a cellular automata-based mathematical model for thymocyte migration and development. The rules comprised in this model take into account the main stages of thymocyte development, two-dimensional sections of the normal thymic microenvironmental network, as well as the chemokines involved in intrathymic cell migration. Parameters of our computer simulations with further adjusted to results derived from previous experimental data using sub-lethally irradiated mice, in which thymus recovery can be evaluated. The model fitted with the increasing numbers of each CD4/CD8-defined thymocyte subset. It was further validated since it fitted with the times of permanence experimentally ascertained in each CD4/CD8-defined differentiation stage. Importantly, correlations using the whole mean volume of young normal adult mice revealed that the numbers of cells generated in silico with the mathematical model fall within the range of total thymocyte numbers seen in these animals. Furthermore, simulations made with a human thymic epithelial network using the same mathematical model generated similar profiles for temporal evolution of thymocyte developmental stages. Lastly, we provided in silico evidence that the thymus architecture is important in the thymocyte development, since changes in the epithelial network result in different theoretical profiles for T cell development/migration. This model likely can be used to predict thymocyte evolution following therapeutic strategies designed for recovery of the thymus in diseases coursing with thymus involution, such as some primary immunodeficiencies, acute infections, and malnutrition.