Intravital Dynamic and Correlative Imaging of Mouse Livers Reveals Diffusion-Dominated Canalicular and Flow-Augmented Ductular Bile Flux.

BACKGROUND AND AIMS: Small-molecule flux in tissue microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely fluorescence loss after photoactivation and intravital arbitrary region image correlation spectroscopy. APPROACH AND RESULTS: The results challenge the prevailing "mechano-osmotic" theory of canalicular bile flow. After active transport across hepatocyte membranes, bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts is diffusion augmented by regulatable advection. Photoactivation of fluorescein bis-(5-carboxymethoxy-2-nitrobenzyl)-ether in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. CONCLUSIONS: The liver consists of a diffusion-dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow-augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

4D flow cardiovascular magnetic resonance recovery profiles following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR) allows comprehensive assessment of pulmonary artery (PA) flow dynamics. Few studies have characterized longitudinal changes in pulmonary flow dynamics and right ventricular (RV) recovery following a pulmonary endarterectomy (PEA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This can provide novel insights of RV and PA dynamics during recovery. We investigated the longitudinal trajectory of 4D flow metrics following a PEA including velocity, vorticity, helicity, and PA vessel wall stiffness. METHODS: Twenty patients with CTEPH underwent pre-PEA and > 6 months post-PEA CMR imaging including 4D flow CMR; right heart catheter measurements were performed in 18 of these patients. We developed a semi-automated pipeline to extract integrated 4D flow-derived main, left, and right PA (MPA, LPA, RPA) volumes, velocity flow profiles, and secondary flow profiles. We focused on secondary flow metrics of vorticity, volume fraction of positive helicity (clockwise rotation), and the helical flow index (HFI) that measures helicity intensity. RESULTS: Mean PA pressures (mPAP), total pulmonary resistance (TPR), and normalized RV end-systolic volume (RVESV) decreased significantly post-PEA (P < 0.002). 4D flow-derived PA volumes decreased (P < 0.001) and stiffness, velocity, and vorticity increased (P < 0.01) post-PEA. Longitudinal improvements from pre- to post-PEA in mPAP were associated with longitudinal decreases in MPA area (r = 0.68, P = 0.002). Longitudinal improvements in TPR were associated with longitudinal increases in the maximum RPA HFI (r=-0.85, P < 0.001). Longitudinal improvements in RVESV were associated with longitudinal decreases in MPA fraction of positive helicity (r = 0.75, P = 0.003) and minimum MPA HFI (r=-0.72, P = 0.005). CONCLUSION: We developed a semi-automated pipeline for analyzing 4D flow metrics of vessel stiffness and flow profiles. PEA was associated with changes in 4D flow metrics of PA flow profiles and vessel stiffness. Longitudinal analysis revealed that PA helicity was associated with pulmonary remodeling and RV reverse remodeling following a PEA.

Predicting the risk of post-hepatectomy portal hypertension using a digital twin: A clinical proof of concept.

BACKGROUND & AIMS: Despite improvements in medical and surgical techniques, post-hepatectomy liver failure (PHLF) remains the leading cause of postoperative death. High postoperative portal vein pressure (PPV) and portocaval gradient (PCG), which cannot be predicted by current tools, are the most important determinants of PHLF. Therefore, we aimed to evaluate a digital twin to predict the risk of postoperative portal hypertension (PHT). METHODS: We prospectively included 47 patients undergoing major hepatectomy. A mathematical (0D) model of the entire blood circulation was assessed and automatically calibrated from patient characteristics. Hepatic flows were obtained from preoperative flow MRI (n = 9), intraoperative flowmetry (n = 16), or estimated from cardiac output (n = 47). Resection was then simulated in these 3 groups and the computed PPV and PCG were compared to intraoperative data. RESULTS: Simulated post-hepatectomy pressures did not differ between the 3 groups, comparing well with collected data (no significant differences). In the entire cohort, the correlation between measured and simulated PPV values was good (r = 0.66, no adjustment to intraoperative events) or excellent (r = 0.75) after adjustment, as well as for PCG (respectively r = 0.59 and r = 0.80). The difference between simulated and measured post-hepatectomy PCG was ≤3 mmHg in 96% of cases. Four patients suffered from lethal PHLF for whom the model satisfactorily predicted their postoperative pressures. CONCLUSIONS: We demonstrated that a 0D model could correctly anticipate postoperative PHT, even using estimated hepatic flow rates as input data. If this major conceptual step is confirmed, this algorithm could change our practice toward more tailor-made procedures, while ensuring satisfactory outcomes. LAY SUMMARY: Post-hepatectomy portal hypertension is a major cause of liver failure and death, but no tool is available to accurately anticipate this potentially lethal complication for a given patient. Herein, we propose using a mathematical model to predict the portocaval gradient at the end of liver resection. We tested this model on a cohort of 47 patients undergoing major hepatectomy and demonstrated that it could modify current surgical decision-making algorithms.

Cohort-based multiscale analysis of hemodynamic-driven growth and remodeling of the embryonic pharyngeal arch arteries.

Growth and remodeling of the primitive pharyngeal arch artery (PAA) network into the extracardiac great vessels is poorly understood but a major source of clinically serious malformations. Undisrupted blood flow is required for normal PAA development, yet specific relationships between hemodynamics and remodeling remain largely unknown. Meeting this challenge is hindered by the common reductionist analysis of morphology to single idealized models, where in fact structural morphology varies substantially. Quantitative technical tools that allow tracking of morphological and hemodynamic changes in a population-based setting are essential to advancing our understanding of morphogenesis. Here, we have developed a methodological pipeline from high-resolution nano-computed tomography imaging and live-imaging flow measurements to multiscale pulsatile computational models. We combine experimental-based computational models of multiple PAAs to quantify hemodynamic forces in the rapidly morphing Hamburger Hamilton (HH) stage HH18, HH24 and HH26 embryos. We identify local morphological variation along the PAAs and their association with specific hemodynamic changes. Population-level mechano-morphogenic variability analysis is a powerful strategy for identifying stage-specific regions of well and poorly tolerated morphological and/or hemodynamic variation that may protect or initiate cardiovascular malformations.

Indocyanine Green Fluorescence Imaging to Predict Graft Survival After Orthotopic Liver Transplantation: A Pilot Study.

The incidence of primary nonfunction (PNF) after liver transplantation (LT) remains a major concern with the increasing use of marginal grafts. Indocyanine green (ICG) fluorescence is an imaging technique used in hepatobiliary surgery and LT. Because few early predictors are available, we aimed to quantify in real time the fluorescence of grafts during LT to predict 3-month survival. After graft revascularization, ICG was intravenously injected, and then the fluorescence of the graft was captured with a near infrared camera and postoperatively quantified. A multiparametric modeling of the parenchymal fluorescence intensity (FI) curve was proposed, and a predictive model of graft survival was tested. Between July 2017 and May 2019, 76 LTs were performed, among which 6 recipients underwent retransplantation. No adverse effects of ICG injection were observed. The parameter a150 (temporal course of FI) was significantly higher in the re-LT group (0.022 seconds-1 (0.0011-0.059) versus 0.012 seconds-1 (0.0001-0.054); P = 0.01). This parameter was the only independent predictive factor of graft survival at 3 months (OR, 2.4; 95% CI, 1.05-5.50; P = 0.04). The best cutoff for the parameter a150 (0.0155 seconds-1 ) predicted the graft survival at 3 months with a sensitivity (Se) of 83.3% and a specificity (Spe) of 78.6% (area under the curve, 0.82; 95% CI, 0.67-0.98; P = 0.01). Quantitative assessment of intraoperative ICG fluorescence on the graft was feasible to predict graft survival at 3 months with a good Se and Spe. Further prospective studies should be undertaken to validate these results over larger cohorts and evaluate the clinical impact of this tool.

Kinetics of Hepatic Volume Evolution and Architectural Changes after Major Resection in a Porcine Model.

BACKGROUND: The hepatic volume gain following resection is essential for clinical recovery. Previous studies have focused on cellular regeneration. This study aims to explore the rate of hepatic regeneration of the porcine liver following major resection, highlighting estimates of the early microarchitectural changes that occur during the cellular regeneration. METHODS: Nineteen large white pigs had 75% resection with serial measurements of the hepatic volume, density, blood flow, and architectural changes. RESULTS: The growth rate initially was 45% per day, then rapidly decreased and was accompanied by a similar pattern of hepatic fat deposition. The architectural changes showed a significant increase in the Ki67 expression (p < 0.0001) in the days following resection with a peak on the 2nd day and nearly normalized on day 7. The expression of CD31 increased significantly on the 2nd and 3rd days compared to the pre-resection samples (p = 0.03). Hepatic artery flow per liver volume remained at baseline ranges during regeneration. Portal flow per liver volume increased after liver resection (p < 0.001), was still elevated on the 1st postoperative day, then decreased. Correlations were significantly negative between the hepatic volume increase on day 3 and the hepatic oxygen consumption and the net lactate production at the end of the procedure (r = -0.82, p = 0.01, and r = -0.70, p = 0.03). CONCLUSION: The volume increase in the first days - a fast process - is not explained by cellular proliferation alone. The liver/body weight ratio is back to 50% of the preoperative value after 3 days to close to 100% volume regain on days 10-15.

Modulating Portal Hemodynamics With Vascular Ring Allows Efficient Regeneration After Partial Hepatectomy in a Porcine Model.

OBJECTIVE: To investigate safety and efficacy of temporary portal hemodynamics modulation with a novel percutaneously adjustable vascular ring (MID-AVR) onto a porcine model of 75% hepatectomy. BACKGROUND: Postoperative liver failure is a leading cause of mortality after major hepatectomy. Portal flow modulation is an increasingly accepted concept to prevent postoperative liver failure. Nonetheless, the current strategies have shortcomings. METHODS: Resection was performed under hemodynamic monitoring in 17 large, white pigs allocated into 2 groups. Eight pigs had ring around the portal vein for 3 days with the aim of reducing changes in hemodynamics due to hepatectomy. Analysis of hemodynamics, laboratory, and histopathological parameters was performed. RESULTS: Percutaneous inflation, deflation, and removal of the MID-AVR were safe. Two (25%) pigs in the MID-AVR group and 4 (45%) controls died before day 3 (P = NS). A moderate increase of portal flow rate per liver mass after resection was associated with better survival (P = 0.017). The portocaval pressure gradient was lower after hepatectomy in the MID-AVR group (P = 0.001). Postoperative serum bilirubin levels were lower in the MID-AVR group (P = 0.007 at day 5). In the MID-AVR group, the Ki67 index was significantly higher on day 3 (P = 0.043) and the architectural derangement was lower (P < 0.05). Morphometric quantification of the bile canaliculi revealed a significantly lower number of intersection branches (P < 0.05) and intersection nodes (P < 0.001) on day 7 compared with the preoperative specimen, in the control group. These differences were not found in the ring group. CONCLUSIONS: MID-AVR is safe for portal hemodynamics modulation. It might improve liver regeneration by protecting liver microarchitecture.

Transit time ultrasound perivascular flow probe technology is superior to MR imaging on hepatic blood flow measurement in a porcine model.

BACKGROUND: The hepatic hemodynamics is an essential parameter in surgical planning as well as in various disease processes. The transit time ultrasound (TTUS) perivascular flow probe technology is widely used in clinical practice to evaluate the hepatic inflow, yet invasive. The phase-contrast-MRI (PC-MRI) is not invasive and potentially applicable in assessing the hepatic blood flow. In the present study, we compared the hepatic inflow rates using the PC-MRI and the TTUS probe, and evaluated their predictive value of post-hepatectomy adverse events. METHODS: Eighteen large white pigs were anaesthetized for PC-MRI and approximately 75% hepatic resection was performed under a unified protocol. The blood flow was measured in the hepatic artery (Qha), the portal vein (Qpv), and the aorta above the celiac trunk (Qca) using PC-MRI, and was compared to the TTUS probe. The Bland-Altman method was conducted and a partial least squares regression (PLS) model was implemented. RESULTS: The mean Qpv measured in PC-MRI was 0.55 ±â€¯0.12 L/min, and in the TTUS probe was 0.74 ±â€¯0.17 L/min. Qca was 1.40 ±â€¯0.47 L/min in the PC-MRI and 2.00 ±â€¯0.60 L/min in the TTUS probe. Qha was 0.17 ±â€¯0.10 L/min in the PC-MRI, and 0.13 ±â€¯0.06 L/min in the TTUS probe. The Bland-Altman method revealed that the estimated bias of Qca in the PC-MRI was 32% (95% CI: -49% to 15%); Qha 17% (95% CI: -15% to 51%); and Qpv 40% (95% CI: -62% to 18%). The TTUS probe had a higher weight in predicting adverse outcomes after 75% resection compared to the PC-MRI (ß= 0.35 and 0.43 vs ß = 0.22 and 0.07, for tissue changes and premature death, respectively). CONCLUSIONS: There is a tendency of the PC-MRI to underestimate the flow measured by the TTUS probes. The TTUS probe measures are more predictive of relevant post-hepatectomy outcomes.

Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data.

We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue organization processes. Importantly, calibrating the model with two nutriment-rich growth conditions, the outcome for two nutriment-poor growth conditions could be predicted. As the final model is however quite complex, incorporating many mechanisms, space, time, and stochastic processes, parameter identification is a challenge. This calls for more efficient strategies of imaging and image analysis, as well as of parameter identification in stochastic agent-based simulations.

Simplified technique for 75% and 90% hepatic resection with hemodynamic monitoring in a large white swine model.

BACKGROUND: Accurate measuring of the hepatic hemodynamic parameters in humans is inconvenient. Swine has been a favorite surgical model for the study of liver conditions due to many similarities with human livers. However, pigs cannot tolerate pedicle clamping and to reduce bleeding during resection a simplified technique is required. The aim of this study is to present a simplified technique for different percentages of hepatic resection in a porcine model. METHODS: Twenty-two consecutive large white pigs were operated with 75% and 90% liver resection. Computarized tomography liver volumetry is performed before and after surgery. In both types of surgery, hemodynamic monitoring was performed using a specialized apparatus. RESULTS: Resections were performed in both groups successfully. The residual volume in the planned 75% was 235 ± 77 mL and 118 ± 119 mL in the planned 90% resection. For 75% resection, the portal flow was reduced after resection by 8.13 ± 28%, which might be part of systemic circulatory depression. However, the portal pressure increased by 20.1 ± 51%. The hepatic artery flow decreased by 63.86 ± 26.3% as well as the pressure by 5 ± 28%. The central venous pressure at the start of surgery was 3.34 ± 1.9 mm Hg and 2.8 ± 2.2 mm Hg at the end of surgery. The portacaval pressure gradient was 4.4 ± 2.9 mm Hg at the beginning of surgery and was 5.9 ± 2.8 mm Hg at the end of surgery. For 90% resection, the portal flow decreased by 33.6 ± 12.6% and the pressure increased by 104 ± 58%. The hepatic artery flow decreased by 88 ± 7%, and the pressure decreased by 5 ± 14.8%. The central venous pressure was 3.5 ± 1.7 mm Hg before resection and 3 ± 2.5 mm Hg after resection. The portacaval pressure gradient was 3.8 ± 1.1 mm Hg before resection and 8 ± 3.7 mm Hg after resection. The mean anesthesia time was 6.6 ± 1.05 h and 6.9 ± 0.5 h for 75% and 90% resection, respectively. The mean operative time was 4.6 ± 0.9 h and 5 ± 0.7 h for 75% and 90% resections, respectively. The mean time for hepatectomy was 1.23 ± 0.76 h and 2.4 ± 0.1 h for 75% and 90% resection, respectively. The mean time consumed in the measurements was 2.28 ± 1.4 h and 1.1 ± 0.3 h for 75% and 90% resections, respectively. The mean volume of aspirated fluid and blood in the 75% resection was 1062 ± 512 mL, while it was 1050 ± 354 mL in 90% resections. CONCLUSIONS: The hereby described technique is simple and easily applicable for major liver resection in a porcine model. Portal flow decreases after 90% resection more than in 75% due to the relative reduction of remnant hepatic mass. There was a larger increase in portal pressure following 90% compared to 75% resection. The hepatic artery flow decreases more in 90% than in 75% resections.

Numerical blood flow simulation in surgical corrections: what do we need for an accurate analysis?

BACKGROUND: Computational fluid dynamics has been increasingly used in congenital heart surgery to simulate pathophysiological blood flow, investigate surgical options, or design medical devices. Several commercial and research computational or numerical codes have been developed. They present different approaches to numerically solve the blood flow equations, raising the question whether these numerical codes are equally reliable to achieve accurate simulation results. Accordingly, we sought to examine the influence of numerical code selection in several complex congenital cardiac operations. MATERIAL AND METHODS: The main steps of blood flow simulations are detailed (geometrical mesh, boundary conditions, and solver numerical methods) for congenital cardiac operations of increasing complexity. The first case tests different numerical solutions against an analytical, or exact, solution. In the second case, the three-dimensional domain is a patient-specific superior cavopulmonary anastomosis. As an analytical solution does not exist in such a complex geometry, different numerical solutions are compared. Finally, a realistic case of a systemic-to-pulmonary shunt is presented with both geometrically and physiologically challenging conditions. For all, solutions from a commercially available code and an open-source research code are compared. RESULTS: In the first case, as the mesh or solver numerical method is refined, the simulation results for both codes converged to the analytical solution. In the second example, velocity differences between the two codes are greater when the resolution of the mesh were lower and less refined. The third case with realistic anatomy reveals that the pulsatile complex flow is very similar for both codes. CONCLUSIONS: The precise setup of the numerical cases has more influence on the results than the choice of numerical codes. The need for detailed construction of the numerical model that requires high computational cost depends on the precision needed to answer the biomedical question at hand and should be assessed for each problem on a combination of clinically relevant patient-specific geometry and physiological conditions.

Optimization of a Y-graft design for improved hepatic flow distribution in the fontan circulation.

Single ventricle heart defects are among the most serious congenital heart diseases, and are uniformly fatal if left untreated. Typically, a three-staged surgical course, consisting of the Norwood, Glenn, and Fontan surgeries is performed, after which the superior vena cava (SVC) and inferior vena cava (IVC) are directly connected to the pulmonary arteries (PA). In an attempt to improve hemodynamic performance and hepatic flow distribution (HFD) of Fontan patients, a novel Y-shaped graft has recently been proposed to replace the traditional tube-shaped extracardiac grafts. Previous studies have demonstrated that the Y-graft is a promising design with the potential to reduce energy loss and improve HFD. However these studies also found suboptimal Y-graft performance in some patient models. The goal of this work is to determine whether performance can be improved in these models through further design optimization. Geometric and hemodynamic factors that influence the HFD have not been sufficiently investigated in previous work, particularly for the Y-graft. In this work, we couple Lagrangian particle tracking to an optimal design framework to study the effects of boundary conditions and geometry on HFD. Specifically, we investigate the potential of using a Y-graft design with unequal branch diameters to improve hepatic distribution under a highly uneven RPA/LPA flow split. As expected, the resulting optimal Y-graft geometry largely depends on the pulmonary flow split for a particular patient. The unequal branch design is demonstrated to be unnecessary under most conditions, as it is possible to achieve the same or better performance with equal-sized branches. Two patient-specific examples show that optimization-derived Y-grafts effectively improve the HFD, compared to initial nonoptimized designs using equal branch diameters. An instance of constrained optimization shows that energy efficiency slightly increases with increasing branch size for the Y-graft, but that a smaller branch size is preferred when a proximal anastomosis is needed to achieve optimal HFD.

Sensitivity Analysis of a Mathematical Model Simulating the Post-Hepatectomy Hemodynamics Response.

Recently a lumped-parameter model of the cardiovascular system was proposed to simulate the hemodynamics response to partial hepatectomy and evaluate the risk of portal hypertension (PHT) due to this surgery. Model parameters are tuned based on each patient data. This work focuses on a global sensitivity analysis (SA) study of such model to better understand the main drivers of the clinical outputs of interest. The analysis suggests which parameters should be considered patient-specific and which can be assumed constant without losing in accuracy in the predictions. While performing the SA, model outputs need to be constrained to physiological ranges. An innovative approach exploits the features of the polynomial chaos expansion method to reduce the overall computational cost. The computed results give new insights on how to improve the calibration of some model parameters. Moreover the final parameter distributions enable the creation of a virtual population available for future works. Although this work is focused on partial hepatectomy, the pipeline can be applied to other cardiovascular hemodynamics models to gain insights for patient-specific parameterization and to define a physiologically relevant virtual population.

A proof-of-concept pipeline to guide evaluation of tumor tissue perfusion by dynamic contrast-agent imaging: Direct simulation and inverse tracer-kinetic procedures.

Dynamic contrast-enhanced (DCE) perfusion imaging has shown great potential to non-invasively assess cancer development and its treatment by their characteristic tissue signatures. Different tracer kinetics models are being applied to estimate tissue and tumor perfusion parameters from DCE perfusion imaging. The goal of this work is to provide an in silico model-based pipeline to evaluate how these DCE imaging parameters may relate to the true tissue parameters. As histology data provides detailed microstructural but not functional parameters, this work can also help to better interpret such data. To this aim in silico vasculatures are constructed and the spread of contrast agent in the tissue is simulated. As a proof of principle we show the evaluation procedure of two tracer kinetic models from in silico contrast-agent perfusion data after a bolus injection. Representative microvascular arterial and venous trees are constructed in silico. Blood flow is computed in the different vessels. Contrast-agent input in the feeding artery, intra-vascular transport, intra-extravascular exchange and diffusion within the interstitial space are modeled. From this spatiotemporal model, intensity maps are computed leading to in silico dynamic perfusion images. Various tumor vascularizations (architecture and function) are studied and show spatiotemporal contrast imaging dynamics characteristic of in vivo tumor morphotypes. The Brix II also called 2CXM, and extended Tofts tracer-kinetics models common in DCE imaging are then applied to recover perfusion parameters that are compared with the ground truth parameters of the in silico spatiotemporal models. The results show that tumor features can be well identified for a certain permeability range. The simulation results in this work indicate that taking into account space explicitly to estimate perfusion parameters may lead to significant improvements in the perfusion interpretation of the current tracer-kinetics models.

Optimization of shunt placement for the Norwood surgery using multi-domain modeling.

An idealized systemic-to-pulmonary shunt anatomy is parameterized and coupled to a closed loop, lumped parameter network (LPN) in a multidomain model of the Norwood surgical anatomy. The LPN approach is essential for obtaining information on global changes in cardiac output and oxygen delivery resulting from changes in local geometry and physiology. The LPN is fully coupled to a custom 3D finite element solver using a semi-implicit approach to model the heart and downstream circulation. This closed loop multidomain model is then integrated with a fully automated derivative-free optimization algorithm to obtain optimal shunt geometries with variable parameters of shunt diameter, anastomosis location, and angles. Three objective functions: (1) systemic; (2) coronary; and (3) combined systemic and coronary oxygen deliveries are maximized. Results show that a smaller shunt diameter with a distal shunt-brachiocephalic anastomosis is optimal for systemic oxygen delivery, whereas a more proximal anastomosis is optimal for coronary oxygen delivery and a shunt between these two anatomies is optimal for both systemic and coronary oxygen deliveries. Results are used to quantify the origin of blood flow going through the shunt and its relationship with shunt geometry. Results show that coronary artery flow is directly related to shunt position.

Multiscale modelling of Potts shunt as a potential palliative treatment for suprasystemic idiopathic pulmonary artery hypertension: a paediatric case study.

Potts shunt (PS) was suggested as palliation for patients with suprasystemic pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. PS, however, can result in poorly understood mortality. Here, a patient-specific geometrical multiscale model of PAH physiology and PS is developed for a paediatric PAH patient with stent-based PS. In the model, 7.6mm-diameter PS produces near-equalisation of the aortic and PA pressures and [Formula: see text] (oxygenated vs deoxygenated blood flow) ratio of 0.72 associated with a 16% decrease of left ventricular (LV) output and 18% increase of RV output. The flow from LV to aortic arch branches increases by 16%, while LV contribution to the lower body flow decreases by 29%. Total flow in the descending aorta (DAo) increases by 18% due to RV contribution through the PS with flow into the distal PA branches decreasing. PS induces 18% increase of RV work due to its larger stroke volume pumped against lower afterload. Nonetheless, larger RV work does not lead to increased RV end-diastolic volume. Three-dimensional flow assessment demonstrates the PS jet impinging with a high velocity and wall shear stress on the opposite DAo wall with the most of the shunt flow being diverted to the DAo. Increasing the PS diameter from 5mm up to 10mm results in a nearly linear increase in post-operative shunt flow and a nearly linear decrease in shunt pressure-drop. In conclusion, this model reasonably represents patient-specific haemodynamics pre- and post-creation of the PS, providing insights into physiology of this complex condition, and presents a predictive tool that could be useful for clinical decision-making regarding suitability for PS in PAH patients with drug-resistant suprasystemic PAH.

Comparative study of viscoelastic arterial wall models in nonlinear one-dimensional finite element simulations of blood flow.

It is well known that blood vessels exhibit viscoelastic properties, which are modeled in the literature with different mathematical forms and experimental bases. The wide range of existing viscoelastic wall models may produce significantly different blood flow, pressure, and vessel deformation solutions in cardiovascular simulations. In this paper, we present a novel comparative study of two different viscoelastic wall models in nonlinear one-dimensional (1D) simulations of blood flow. The viscoelastic models are from papers by Holenstein et al. in 1980 (model V1) and Valdez-Jasso et al. in 2009 (model V2). The static elastic or zero-frequency responses of both models are chosen to be identical. The nonlinear 1D blood flow equations incorporating wall viscoelasticity are solved using a space-time finite element method and the implementation is verified with the Method of Manufactured Solutions. Simulation results using models V1, V2 and the common static elastic model are compared in three application examples: (i) wave propagation study in an idealized vessel with reflection-free outflow boundary condition; (ii) carotid artery model with nonperiodic boundary conditions; and (iii) subject-specific abdominal aorta model under rest and simulated lower limb exercise conditions. In the wave propagation study the damping and wave speed were largest for model V2 and lowest for the elastic model. In the carotid and abdominal aorta studies the most significant differences between wall models were observed in the hysteresis (pressure-area) loops, which were larger for V2 than V1, indicating that V2 is a more dissipative model. The cross-sectional area oscillations over the cardiac cycle were smaller for the viscoelastic models compared to the elastic model. In the abdominal aorta study, differences between constitutive models were more pronounced under exercise conditions than at rest. Inlet pressure pulse for model V1 was larger than the pulse for V2 and the elastic model in the exercise case. In this paper, we have successfully implemented and verified two viscoelastic wall models in a nonlinear 1D finite element blood flow solver and analyzed differences between these models in various idealized and physiological simulations, including exercise. The computational model of blood flow presented here can be utilized in further studies of the cardiovascular system incorporating viscoelastic wall properties.

Computational simulations for aortic coarctation: representative results from a sampling of patients.

Treatments for coarctation of the aorta (CoA) can alleviate blood pressure (BP) gradients (Δ), but long-term morbidity still exists that can be explained by altered indices of hemodynamics and biomechanics. We introduce a technique to increase our understanding of these indices for CoA under resting and nonresting conditions, quantify their contribution to morbidity, and evaluate treatment options. Patient-specific computational fluid dynamics (CFD) models were created from imaging and BP data for one normal and four CoA patients (moderate native CoA: Δ12 mmHg, severe native CoA: Δ25 mmHg and postoperative end-to-end and end-to-side patients: Δ0 mmHg). Simulations incorporated vessel deformation, downstream vascular resistance and compliance. Indices including cyclic strain, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were quantified. Simulations replicated resting BP and blood flow data. BP during simulated exercise for the normal patient matched reported values. Greatest exercise-induced increases in systolic BP and mean and peak ΔBP occurred for the moderate native CoA patient (SBP: 115 to 154 mmHg; mean and peak ΔBP: 31 and 73 mmHg). Cyclic strain was elevated proximal to the coarctation for native CoA patients, but reduced throughout the aorta after treatment. A greater percentage of vessels was exposed to subnormal TAWSS or elevated OSI for CoA patients. Local patterns of these indices reported to correlate with atherosclerosis in normal patients were accentuated by CoA. These results apply CFD to a range of CoA patients for the first time and provide the foundation for future progress in this area.

Simulation of a detoxifying organ function: Focus on hemodynamics modeling and convection-reaction numerical simulation in microcirculatory networks.

When modeling a detoxifying organ function, an important component is the impact of flow on the metabolism of a compound of interest carried by the blood. We here study the effects of red blood cells (such as the Fahraeus-Lindqvist effect and plasma skimming) on blood flow in typical microcirculatory components such as tubes, bifurcations and entire networks, with particular emphasis on the liver as important representative of detoxifying organs. In one of the plasma skimming models, under certain conditions, oscillations between states are found and analyzed in a methodical study to identify their causes and influencing parameters. The flow solution obtained is then used to define the velocity at which a compound would be transported. A convection-reaction equation is studied to simulate the transport of a compound in blood and its uptake by the surrounding cells. Different types of signal sharpness have to be handled depending on the application to address different temporal compound concentration profiles. To permit executing the studied models numerically stable and accurate, we here extend existing transport schemes to handle converging bifurcations, and more generally multi-furcations. We study the accuracy of different numerical schemes as well as the effect of reactions and of the network itself on the bolus shape. Even though this study is guided by applications in liver micro-architecture, the proposed methodology is general and can readily be applied to other capillary network geometries, hence to other organs or to bioengineered network designs.