David De Wilde

Modeling the Impact of Partial Hepatectomy on the Hepatic Hemodynamics Using a Rat Model

Due to the growing shortage of donor livers, more patients are waiting for transplantation. Living donor liver transplantation may help expanding the donor pool, but is often confronted with the small-for-size syndrome. Since the hemodynamic effects of partial hepatectomy are not fully understood, we developed an electrical rat liver model to compare normal with resected liver hemodynamics. Detailed geometrical data and 3-D reconstructions of the liver vasculature of two rats were gathered by combining vascular corrosion casting, micro-CT scanning, and image processing. Data extrapolations allowed obtaining a total liver pressure- and flow-driven electrical analog. Subsequently, virtual resections led to 70%, 80%, or 90% partial hepatectomy models. Results demonstrated hyperperfusion effects such as portal hypertension and elevated lobe-specific portal venous flows (11, 12, and 24 mmHg, and 1.0-3.0, 1.8-3.5, and 7.4 ml/min for 70%, 80%, and 90% hepatectomy, respectively). Comparison of two 90% resection techniques demonstrated different total arterial flows (0.28 ml/min versus 0.61 ml/min), portal (24 mmHg versus 21 mmHg), and sinusoidal pressures (14 mmHg versus 9.5-12 mmHg), probably leading to better survival for lower portal and sinusoidal pressures. Toward the future, the models may be extrapolated to human livers and help us to optimize hepatectomy planning.

Assessment of shear stress related parameters in the carotid bifurcation using mouse-specific FSI simulations

The ApoE(-)(/)(-) mouse is a common small animal model to study atherosclerosis, an inflammatory disease of the large and medium sized arteries such as the carotid artery. It is generally accepted that the wall shear stress, induced by the blood flow, plays a key role in the onset of this disease. Wall shear stress, however, is difficult to derive from direct in vivo measurements, particularly in mice. In this study, we integrated in vivo imaging (micro-Computed Tomography-µCT and ultrasound) and fluid-structure interaction (FSI) modeling for the mouse-specific assessment of carotid hemodynamics and wall shear stress. Results were provided for 8 carotid bifurcations of 4 ApoE(-)(/)(-) mice. We demonstrated that accounting for the carotid elasticity leads to more realistic flow waveforms over the complete domain of the model due to volume buffering capacity in systole. The 8 simulated cases showed fairly consistent spatial distribution maps of time-averaged wall shear stress (TAWSS) and relative residence time (RRT). Zones with reduced TAWSS and elevated RRT, potential indicators of atherosclerosis-prone regions, were located mainly at the outer sinus of the external carotid artery. In contrast to human carotid hemodynamics, no flow recirculation could be observed in the carotid bifurcation region.

Shear Stress Metrics and Their Relation to Atherosclerosis: An In Vivo Follow-up Study in Atherosclerotic Mice

It is generally accepted that low and oscillatory wall shear stress favors the initiation and development of atherosclerosis. However, a quantitative analysis of the association between shear stress metrics at baseline and lesion prevalence at a later stage is challenging to perform in vivo on a within-subject basis. In this study, we assessed carotid hemodynamics and derived hemodynamic wall parameters from subject-specific fluid–structure interaction simulations in the left and right carotid arteries of 4 ApoE−/− mice prior to disease development. We then applied a point-by-point quantitative association (surrogate sample data analysis) between various established and more recent shear related parameters and the extent of macrophage infiltration at a later stage. We conclude that, for the atherosclerotic murine carotid bifurcation, (i) there is an association between hemodynamics and macrophage infiltration; (ii) this correlation is most apparent when assessed at the level of the entire carotid bifurcation; (iii) the strongest spatial correlation between hemodynamics and atherosclerosis development was found for the time averaged wall shear stress (negative correlation) and the relative residence time (positive correlation); (iv) aggregating the data leads to an overestimation of the correlation.

Vulnerable Plaque Detection and Quantification with Gold Particle-Enhanced Computed Tomography in Atherosclerotic Mouse Models

Recently, an apolipoprotein E-deficient (ApoE-/-) mouse model with a mutation (C1039G+/-) in the fibrillin-1 (Fbn1) gene (ApoE-/-Fbn1C1039G+/- mouse model) was developed showing vulnerable atherosclerotic plaques, prone to rupture, in contrast to the ApoE-/- mouse model, where mainly stable plaques are present. One indicator of plaque vulnerability is the level of macrophage infiltration. Therefore, this study aimed to measure and quantify in vivo the macrophage infiltration related to plaque development and progression. For this purpose, 5-weekly consecutive gold nanoparticle-enhanced micro-computed tomography (microCT) scans were acquired. Histology confirmed that the presence of contrast agent coincided with the presence of macrophages. Based on the microCT scans, regions of the artery wall with contrast agent present were calculated and visualized in three dimensions. From this information, the contrast-enhanced area and contrast-enhanced centerline length were calculated for the branches of the carotid bifurcation (common, external, and internal carotid arteries). Statistical analysis showed a more rapid development and a larger extent of plaques in the ApoE-/-Fbn1C1039G+/- compared to the ApoE-/- mice. Regional differences between the branches were also observable and quantifiable. We developed and applied a methodology based on gold particle-enhanced microCT to visualize the presence of macrophages in atherosclerotic plaques in vivo.Recently, an apolipoprotein E–deficient (ApoE−/−) mouse model with a mutation (C1039G+/−) in the fibrillin-1 (Fbn1) gene (ApoE−/−Fbn1C1039G+/− mouse model) was developed showing vulnerable atherosclerotic plaques, prone to rupture, in contrast to the ApoE−/− mouse model, where mainly stable plaques are present. One indicator of plaque vulnerability is the level of macrophage infiltration. Therefore, this study aimed to measure and quantify in vivo the macrophage infiltration related to plaque development and progression. For this purpose, 5-weekly consecutive gold nanoparticle–enhanced micro–computed tomography (microCT) scans were acquired. Histology confirmed that the presence of contrast agent coincided with the presence of macrophages. Based on the microCT scans, regions of the artery wall with contrast agent present were calculated and visualized in three dimensions. From this information, the contrast-enhanced area and contrast-enhanced centerline length were calculated for the branches of the carotid bifurcation (common, external, and internal carotid arteries). Statistical analysis showed a more rapid development and a larger extent of plaques in the ApoE−/−Fbn1C1039G+/− compared to the ApoE−/− mice. Regional differences between the branches were also observable and quantifiable. We developed and applied a methodology based on gold particle–enhanced microCT to visualize the presence of macrophages in atherosclerotic plaques in vivo.

The influence of anesthesia and fluid-structure interaction on simulated shear stress patterns in the carotid bifurcation of mice

BACKGROUND Low and oscillatory wall shear stresses (WSS) near aortic bifurcations have been linked to the onset of atherosclerosis. In previous work, we calculated detailed WSS patterns in the carotid bifurcation of mice using a Fluid-structure interaction (FSI) approach. We subsequently fed the animals a high-fat diet and linked the results of the FSI simulations to those of atherosclerotic plaque location on a within-subject basis. However, these simulations were based on boundary conditions measured under anesthesia, while active mice might experience different hemodynamics. Moreover, the FSI technique for mouse-specific simulations is both time- and labor-intensive, and might be replaced by simpler and easier Computational Fluid Dynamics (CFD) simulations. The goal of the current work was (i) to compare WSS patterns based on anesthesia conditions to those representing active resting and exercising conditions; and (ii) to compare WSS patterns based on FSI simulations to those based on steady-state and transient CFD simulations. METHODS For each of the 3 computational techniques (steady state CFD, transient CFD, FSI) we performed 5 simulations: 1 for anesthesia, 2 for conscious resting conditions and 2 more for conscious active conditions. The inflow, pressure and heart rate were scaled according to representative in vivo measurements obtained from literature. RESULTS When normalized by the maximal shear stress value, shear stress patterns were similar for the 3 computational techniques. For all activity levels, steady state CFD led to an overestimation of WSS values, while FSI simulations yielded a clear increase in WSS reversal at the outer side of the sinus of the external carotid artery that was not visible in transient CFD-simulations. Furthermore, the FSI simulations in the highest locomotor activity state showed a flow recirculation zone in the external carotid artery that was not present under anesthesia. This recirculation went hand in hand with locally increased WSS reversal. CONCLUSIONS Our data show that FSI simulations are not necessary to obtain normalized WSS patterns, but indispensable to assess the oscillatory behavior of the WSS in mice. Flow recirculation and WSS reversal at the external carotid artery may occur during high locomotor activity while they are not present under anesthesia. These phenomena might thus influence plaque formation to a larger extent than what was previously assumed.

Electrical Analog Models to Simulate the Impact of Partial Hepatectomy on Hepatic Hemodynamics

Due to the growing shortage of donor livers, more patients are waiting for liver transplantation. Efforts to expand the donor pool include the use of living donor liver transplantation (LDLT) and split liver transplantation. LDLT involves a healthy person undergoing a partial hepatectomy to donate a part of his liver to a patient with severe liver failure. Afterwards, the regenerative capacity of the organ allows the livers of both donor and recipient to regrow to normal liver masses. The procedure is not without risk as serious complications may occur (such as cholestasis, ascites, gastrointestinal bleeding and renal impairment). An inadequate liver mass compared to the body mass may result in the small-for-size syndrome (SFSS). In both donor and recipient, LDLT may lead to portal hypertension associated with the elevated intrahepatic resistance of a smaller liver, and an increased portal venous (PV) inflow per gram of liver tissue compared to the total liver before resection. Excessive hyperperfusion and shear stress may damage the sinusoidal endothelial cells and lead to graft dysfunction.Copyright