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.

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.

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.

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.

Assessing Early Cardiac Outflow Tract Adaptive Responses Through Combined Experimental-Computational Manipulations.

Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.

A whole lung in silico model to estimate age dependent particle dosimetry.

Anatomical and physiological changes alter airflow characteristics and aerosol distribution in the developing lung. Correlation between age and aerosol dosimetry is needed, specifically because youth are more susceptible to medication side effects. In this study, we estimate aerosol dosages (particle diameters of 1, 3, and 5 [Formula: see text]m) in a 3 month-old infant, a 6 year-old child, and a 36 year-old adult by performing whole lung subject-specific particle simulations throughout respiration. For 3 [Formula: see text]m diameter particles we estimate total deposition as 88, 73, and [Formula: see text] and the conducting versus respiratory deposition ratios as 4.0, 0.5, and 0.4 for the infant, child, and adult, respectively. Due to their lower tidal volumes and functional residual capacities the deposited mass is smaller while the tissue concentrations are larger in the infant and child subjects, compared to the adult. Furthermore, we find that dose cannot be predicted by simply scaling by tidal volumes. These results highlight the need for additional clinical and computational studies that investigate the efficiency of treatment, while optimizing dosage levels in order to alleviate side effects, in youth.

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.

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.

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.

Myocardial Perfusion Simulation for Coronary Artery Disease: A Coupled Patient-Specific Multiscale Model.

Patient-specific models of blood flow are being used clinically to diagnose and plan treatment for coronary artery disease. A remaining challenge is bridging scales from flow in arteries to the micro-circulation supplying the myocardium. Previously proposed models are descriptive rather than predictive and have not been applied to human data. The goal here is to develop a multiscale patient-specific model enabling blood flow simulation from large coronary arteries to myocardial tissue. Patient vasculatures are segmented from coronary computed tomography angiography data and extended from the image-based model down to the arteriole level using a space-filling forest of synthetic trees. Blood flow is modeled by coupling a 1D model of the coronary arteries to a single-compartment Darcy myocardium model. Simulated results on five patients with non-obstructive coronary artery disease compare overall well to [[Formula: see text]O][Formula: see text]O PET exam data for both resting and hyperemic conditions. Results on a patient with severe obstructive disease link coronary artery narrowing with impaired myocardial blood flow, demonstrating the model's ability to predict myocardial regions with perfusion deficit. This is the first report of a computational model for simulating blood flow from the epicardial coronary arteries to the left ventricle myocardium applied to and validated on human data.

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.

Multiscale Modeling of Superior Cavopulmonary Circulation: Hemi-Fontan and Bidirectional Glenn Are Equivalent.

Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis.

Verification of the coupled-momentum method with Womersley's Deformable Wall analytical solution.

In this paper, we perform a verification study of the Coupled-Momentum Method (CMM), a 3D fluid-structure interaction (FSI) model which uses a thin linear elastic membrane and linear kinematics to describe the mechanical behavior of the vessel wall. The verification of this model is done using Womersley's deformable wall analytical solution for pulsatile flow in a semi-infinite cylindrical vessel. This solution is, under certain premises, the analytical solution of the CMM and can thus be used for model verification. For the numerical solution, we employ an impedance boundary condition to define a reflection-free outflow boundary condition and thus mimic the physics of the analytical solution, which is defined on a semi-infinite domain. We first provide a rigorous derivation of Womersley's deformable wall theory via scale analysis. We then illustrate different characteristics of the analytical solution such as space-time wave periodicity and attenuation. Finally, we present the verification tests comparing the CMM with Womersley's theory.

A Cohort Longitudinal Study Identifies Morphology and Hemodynamics Predictors of Abdominal Aortic Aneurysm Growth.

Abdominal aortic aneurysms (AAA) are localized, commonly occurring aortic dilations. Following rupture only immediate treatment can prevent morbidity and mortality. AAA maximal diameter and growth are the current metrics to evaluate the associated risk and plan intervention. Although these criteria alone lack patient specificity, predicting their evolution would improve clinical decision. If the disease is known to be associated with altered morphology and blood flow, intraluminal thrombus deposit and clinical symptoms, the growth mechanisms are yet to be fully understood. In this retrospective longitudinal study of 138 scans, morphological analysis and blood flow simulations for 32 patients with clinically diagnosed AAAs and several follow-up CT-scans, are performed and compared to 9 control subjects. Several metrics stratify patients between healthy, low and high risk groups. Local correlations between hemodynamic metrics and AAA growth are also explored but due to their high inter-patient variability, do not explain AAA heterogeneous growth. Finally, high-risk predictors trained with successively clinical, morphological, hemodynamic and all data, and their link to the AAA evolution are built from supervise learning. Predictive performance is high for morphological, hemodynamic and all data, in contrast to clinical data. The morphology-based predictor exhibits an interesting effort-predictability tradeoff to be validated for clinical translation.

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.

Generation of Patient-Specific Cardiac Vascular Networks: A Hybrid Image-Based and Synthetic Geometric Model.

OBJECTIVE: In this paper, we propose an algorithm for the generation of a patient-specific cardiac vascular network starting from segmented epicardial vessels down to the arterioles. METHOD: We extend a tree generation method based on satisfaction of functional principles, named constrained constructive optimization, to account for multiple, competing vascular trees. The algorithm simulates angiogenesis under vascular volume minimization with flow-related and geometrical constraints adapting the simultaneous tree growths to patient priors. The generated trees fill the entire left ventricle myocardium up to the arterioles. RESULTS: From actual vascular tree models segmented from CT images, we generated networks with 6000 terminal segments for six patients. These networks contain between 33 and 62 synthetic trees. All vascular models match morphometry properties previously described. CONCLUSION AND SIGNIFICANCE: Image-based models derived from CT angiography are being used clinically to simulate blood flow in the coronary arteries of individual patients to aid in the diagnosis of disease and planning treatments. However, image resolution limits vessel segmentation to larger epicardial arteries. The generated model can be used to simulate the blood flow and derived quantities from the aorta into the myocardium. This is an important step for diagnosis and treatment planning of coronary artery disease.

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.