Alison Marsden

All Publications

• Patient-specific computational flow simulation reveals significant differences in paravisceral aortic hemodynamics between fenestrated and branched endovascular aneurysm repair. JVS-vascular science Tran, K., Deslarzes-Dubuis, C., DeGlise, S., Kaladji, A., Yang, W., Marsden, A. L., Lee, J. T. 2024; 5: 100183

  Abstract

  Endovascular aneurysm repair with four-vessel fenestrated endovascular aneurysm repair (fEVAR) or branched endovascular aneurysm repair (bEVAR) currently represent the forefront of minimally invasive complex aortic aneurysm repair. This study sought to use patient-specific computational flow simulation (CFS) to assess differences in postoperative hemodynamic effects associated with fEVAR vs bEVAR.Patients from two institutions who underwent four-vessel fEVAR with the Cook Zenith Fenestrated platform and bEVAR with the Jotec E-xtra Design platform were retrospectively selected. Patients in both cohorts were treated for paravisceral and extent II, II, and V thoracoabdominal aortic aneurysms. Three-dimensional finite element volume meshes were created from preoperative and postoperative computed tomography scans. Boundary conditions were adjusted for body surface area, heart rate, and blood pressure. Pulsatile flow simulations were performed with equivalent boundary conditions between preoperative and postoperative states. Postoperative changes in hemodynamic parameters were compared between the fEVAR and bEVAR groups.Patient-specific CFS was performed on 20 patients (10 bEVAR, 10 fEVAR) with a total of 80 target vessels (40 renal, 20 celiac, 20 superior mesenteric artery stents). bEVAR was associated with a decrease in renal artery peak flow rate (-5.2% vs +2.0%; P < .0001) and peak pressure (-3.4 vs +0.1%; P < .0001) compared with fEVAR. Almost all renal arteries treated with bEVAR had a reduction in renal artery perfusion (n = 19 [95%]), compared with 35% (n = 7) treated with fEVAR. There were no significant differences in celiac or superior mesenteric artery perfusion metrics (P = .10-.27) between groups. Time-averaged wall shear stress in the paravisceral aorta and branches also varied significantly depending on endograft configuration, with bEVAR associated with large postoperative increases in renal artery (+47.5 vs +13.5%; P = .002) and aortic time-averaged wall shear stress (+200.1% vs -31.3%; P = .001) compared with fEVAR. Streamline analysis revealed areas of hemodynamic abnormalities associated with branched renal grafts which adopt a U-shaped geometry, which may explain the observed differences in postoperative changes in renal perfusion between bEVAR and fEVAR.bEVAR may be associated with subtle decreases in renal perfusion and a large increase in aortic wall shear stress compared with fEVAR. CFS is a novel tool for quantifying and visualizing the unique patient-specific hemodynamic effect of different complex EVAR strategies.This study used patient-specific CFS to compare postoperative hemodynamic effects of four-vessel fenestrated endovascular aneurysm repair (fEVAR) and branched endovascular aneurysm repair (bEVAR) in patients with complex aortic aneurysms. The findings indicate that bEVAR may result in subtle reductions in renal artery perfusion and a significant increase in aortic wall shear stress compared with fEVAR. These differences are clinically relevant, providing insights for clinicians choosing between these approaches. Understanding the patient-specific hemodynamic effects of complex EVAR strategies, as revealed by CFS, can aid in future personalized treatment decisions, and potentially reduce postoperative complications in aortic aneurysm repair.

  View details for DOI 10.1016/j.jvssci.2023.100183

  View details for PubMedID 38314201

  View details for PubMedCentralID PMC10832507

• FSGe: A fast and strongly-coupled 3D fluid-solid-growth interaction method COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Pfaller, M. R., Latorre, M., Schwarz, E. L., Gerosa, F. M., Szafron, J. M., Humphrey, J. D., Marsden, A. L. 2024; 431

  View details for DOI 10.1016/j.cma.2024.117259

  View details for Web of Science ID 001290187500001

• Investigation of a chronic single-stage sheep Fontan model. JTCVS open Kelly, J. M., Hu, Z., Takaesu, F., Watanabe, T., Storrs, J., Blais, B., Yuhara, S., Morrison, A., Nelson, K., Ulziibayar, A., Heuer, E., Anderson, C., Jimenez, M., Leland, J., Malbrue, R., Arsuaga-Zorrilla, C., Goodchild, L., Naguib, A., McKee, C., Varner, J., DeShetler, C., Spiess, J., Harrison, A., Boe, B., Armstrong, A. K., Salavitabar, A., Hor, K., Krishnamurthy, R., Yates, A. R., Shinoka, T., Carrillo, S. A., Davis, M. E., Marsden, A. L., Breuer, C. K. 2024; 21: 268-278

  Abstract

  Our goal was to conduct a hemodynamic analysis of a novel animal model of Fontan physiology. Poor late-term outcomes in Fontan patients are believed to arise from Fontan-induced hemodynamics, but the mechanisms remain poorly understood. Recent advances in surgical experimentation have resulted in the development of a chronic sheep model of Fontan physiology; however, detailed analysis of this model is lacking.We created a single-stage Fontan model in juvenile sheep with normal biventricular circulation. The superior vena cava was anastomosed to the main pulmonary artery, and the inferior vena cava was connected to the main pulmonary artery using an expanded polytetrafluoroethylene conduit. Longitudinal hemodynamics, including catheterization and magnetic resonance imaging were evaluated.Four out of 12 animals survived, with the longest surviving animal living 3 years after single-stage Fontan. We showed a significant era effect regarding survival (1 out of 8 and subsequently 3 out of 4 animals surviving beyond 2 months) attributed in large part to the procedural learning curve. Key characteristics of Fontan hemodynamics, namely systemic venous hypertension and low normal cardiac output, were observed. However, recapitulation of passive human Fontan hemodynamics is affected by volume loading of the right ventricle given an anatomic difference in sheep azygous venous anatomy draining to the coronary sinus.A significant learning curve exists to ensure long-term survival and future surgical modifications, including banding of the main pulmonary artery and ligation of the azygous to coronary sinus connection are promising strategies to improve the fidelity of model hemodynamics.

  View details for DOI 10.1016/j.xjon.2024.06.018

  View details for PubMedID 39534321

  View details for PubMedCentralID PMC11551305

• Deforming Patient-Specific Models of Vascular Anatomies to Represent Stent Implantation via Extended Position Based Dynamics. Cardiovascular engineering and technology Pham, J., Kong, F., James, D. L., Feinstein, J. A., Marsden, A. L. 2024

  Abstract

  Angioplasty with stent placement is a widely used treatment strategy for patients with stenotic blood vessels. However, it is often challenging to predict the outcomes of this procedure for individual patients. Image-based computational fluid dynamics (CFD) is a powerful technique for making these predictions. To perform CFD analysis of a stented vessel, a virtual model of the vessel must first be created. This model is typically made by manipulating two-dimensional contours of the vessel in its pre-stent state to reflect its post-stent shape. However, improper contour-editing can cause invalid geometric artifacts in the resulting mesh that then distort the subsequent CFD predictions. To address this limitation, we have developed a novel shape-editing method that deforms surface meshes of stenosed vessels to create stented models.Our method uses physics-based simulations via Extended Position Based Dynamics to guide these deformations. We embed an inflating stent inside a vessel and apply collision-generated forces to deform the vessel and expand its cross-section.We demonstrate that this technique is feasible and applicable for a wide range of vascular anatomies, while yielding clinically compatible results. We also illustrate the ability to parametrically vary the stented shape and create models allowing CFD analyses.Our stenting method will help clinicians predict the hemodynamic results of stenting interventions and adapt treatments to achieve target outcomes for patients. It will also enable generation of synthetic data for data-intensive applications, such as machine learning, to support cardiovascular research endeavors.

  View details for DOI 10.1007/s13239-024-00752-z

  View details for PubMedID 39354259

  View details for PubMedCentralID 1860348

• Personalized and uncertainty-aware coronary hemodynamics simulations: From Bayesian estimation to improved multi-fidelity uncertainty quantification. ArXiv Menon, K., Zanoni, A., Khan, O., Geraci, G., Nieman, K., Schiavazzi, D. E., Marsden, A. L. 2024

  Abstract

  Non-invasive simulations of coronary hemodynamics have improved clinical risk stratification and treatment outcomes for coronary artery disease, compared to relying on anatomical imaging alone. However, simulations typically use empirical approaches to distribute total coronary flow amongst the arteries in the coronary tree, which ignores patient variability, the presence of disease, and other clinical factors. Further, uncertainty in the clinical data often remains unaccounted for in the modeling pipeline.We present an end-to-end uncertainty-aware pipeline to (1) personalize coronary flow simulations by incorporating vessel-specific coronary flows as well as cardiac function; and (2) predict clinical and biomechanical quantities of interest with improved precision, while accounting for uncertainty in the clinical data.We assimilate patient-specific measurements of myocardial blood flow from clinical CT myocardial perfusion imaging to estimate branch-specific coronary artery flows. Simulated noise in the clinical data is used to estimate the joint posterior distributions of the model parameters using adaptive Markov Chain Monte Carlo sampling. Additionally, the posterior predictive distribution for the relevant quantities of interest is determined using a new approach combining multi-fidelity Monte Carlo estimation with non-linear, data-driven dimensionality reduction. This leads to improved correlations between high- and low-fidelity model outputs.Our framework accurately recapitulates clinically measured cardiac function as well as branch-specific coronary flows under measurement noise uncertainty. We observe substantial reductions in confidence intervals for estimated quantities of interest compared to single-fidelity Monte Carlo estimation and state-of-the-art multi-fidelity Monte Carlo methods. This holds especially true for quantities of interest that showed limited correlation between the low- and high-fidelity model predictions. In addition, the proposed multi-fidelity Monte Carlo estimators are significantly cheaper to compute than traditional estimators, under a specified confidence level or variance.The proposed pipeline for personalized and uncertainty-aware predictions of coronary hemodynamics is based on routine clinical measurements and recently developed techniques for CT myocardial perfusion imaging. The proposed pipeline offers significant improvements in precision and reduction in computational cost.

  View details for PubMedID 39279834

  View details for PubMedCentralID PMC11398544

• Improved multifidelity Monte Carlo estimators based on normalizing flows and dimensionality reduction techniques. Computer methods in applied mechanics and engineering Zanoni, A., Geraci, G., Salvador, M., Menon, K., Marsden, A. L., Schiavazzi, D. E. 2024; 429

  Abstract

  We study the problem of multifidelity uncertainty propagation for computationally expensive models. In particular, we consider the general setting where the high-fidelity and low-fidelity models have a dissimilar parameterization both in terms of number of random inputs and their probability distributions, which can be either known in closed form or provided through samples. We derive novel multifidelity Monte Carlo estimators which rely on a shared subspace between the high-fidelity and low-fidelity models where the parameters follow the same probability distribution, i.e., a standard Gaussian. We build the shared space employing normalizing flows to map different probability distributions into a common one, together with linear and nonlinear dimensionality reduction techniques, active subspaces and autoencoders, respectively, which capture the subspaces where the models vary the most. We then compose the existing low-fidelity model with these transformations and construct modified models with an increased correlation with the high-fidelity model, which therefore yield multifidelity estimators with reduced variance. A series of numerical experiments illustrate the properties and advantages of our approaches.

  View details for DOI 10.1016/j.cma.2024.117119

  View details for PubMedID 38912105

  View details for PubMedCentralID PMC11192502

• SDF4CHD: Generative modeling of cardiac anatomies with congenital heart defects. Medical image analysis Kong, F., Stocker, S., Choi, P. S., Ma, M., Ennis, D. B., Marsden, A. L. 2024; 97: 103293

  Abstract

  Congenital heart disease (CHD) encompasses a spectrum of cardiovascular structural abnormalities, often requiring customized treatment plans for individual patients. Computational modeling and analysis of these unique cardiac anatomies can improve diagnosis and treatment planning and may ultimately lead to improved outcomes. Deep learning (DL) methods have demonstrated the potential to enable efficient treatment planning by automating cardiac segmentation and mesh construction for patients with normal cardiac anatomies. However, CHDs are often rare, making it challenging to acquire sufficiently large patient cohorts for training such DL models. Generative modeling of cardiac anatomies has the potential to fill this gap via the generation of virtual cohorts; however, prior approaches were largely designed for normal anatomies and cannot readily capture the significant topological variations seen in CHD patients. Therefore, we propose a type- and shape-disentangled generative approach suitable to capture the wide spectrum of cardiac anatomies observed in different CHD types and synthesize differently shaped cardiac anatomies that preserve the unique topology for specific CHD types. Our DL approach represents generic whole heart anatomies with CHD type-specific abnormalities implicitly using signed distance fields (SDF) based on CHD type diagnosis. To capture the shape-specific variations, we then learn invertible deformations to morph the learned CHD type-specific anatomies and reconstruct patient-specific shapes. After training with a dataset containing the cardiac anatomies of 67 patients spanning 6 CHD types and 14 combinations of CHD types, our method successfully captures divergent anatomical variations across different types and the meaningful intermediate CHD states across the spectrum of related CHD diagnoses. Additionally, our method demonstrates superior performance in CHD anatomy generation in terms of CHD-type correctness and shape plausibility. It also exhibits comparable generalization performance when reconstructing unseen cardiac anatomies. Moreover, our approach shows potential in augmenting image-segmentation pairs for rarer CHD types to significantly enhance cardiac segmentation accuracy for CHDs. Furthermore, it enables the generation of CHD cardiac meshes for computational simulation, facilitating a systematic examination of the impact of CHDs on cardiac functions.

  View details for DOI 10.1016/j.media.2024.103293

  View details for PubMedID 39146700

• Digital twinning of cardiac electrophysiology for congenital heart disease. Journal of the Royal Society, Interface Salvador, M., Kong, F., Peirlinck, M., Parker, D. W., Chubb, H., Dubin, A. M., Marsden, A. L. 2024; 21 (215): 20230729

  Abstract

  In recent years, blending mechanistic knowledge with machine learning has had a major impact in digital healthcare. In this work, we introduce a computational pipeline to build certified digital replicas of cardiac electrophysiology in paediatric patients with congenital heart disease. We construct the patient-specific geometry by means of semi-automatic segmentation and meshing tools. We generate a dataset of electrophysiology simulations covering cell-to-organ level model parameters and using rigorous mathematical models based on differential equations. We previously proposed Branched Latent Neural Maps (BLNMs) as an accurate and efficient means to recapitulate complex physical processes in a neural network. Here, we employ BLNMs to encode the parametrized temporal dynamics of in silico 12-lead electrocardiograms (ECGs). BLNMs act as a geometry-specific surrogate model of cardiac function for fast and robust parameter estimation to match clinical ECGs in paediatric patients. Identifiability and trustworthiness of calibrated model parameters are assessed by sensitivity analysis and uncertainty quantification.

  View details for DOI 10.1098/rsif.2023.0729

  View details for PubMedID 38835246

• Effect of graft sizing in valve-sparing aortic root replacement for bicuspid aortic valve: The Goldilocks ratio. JTCVS techniques Choi, P. S., Sharir, A., Ono, Y., Shibata, M., Kaiser, A. D., Zhu, Y., Marsden, A. L., Woo, Y. J., Ma, M. R., Kim, J. B. 2024; 25: 1-7

  Abstract

  To investigate the effect of graft sizing on valve performance in valve-sparing aortic root replacement for bicuspid aortic valve.In addition to a diseased control model, 3 representative groups-free-edge length to aortic/graft diameter (FELAD) ratio <1.3, 1.5 to 1.64, and >1.7-were replicated in explanted porcine aortic roots (n = 3) using straight grafts sized respective to the native free-edge length. They were run on a validated ex vivo univentricular system under physiological parameters for 20 cycles. All groups were tested within the same aortic root to minimize inter-root differences. Outcomes included transvalvular gradient, regurgitation fraction, and orifice area. Linear mixed effects model and pairwise comparisons were employed to compare outcomes across groups.The diseased control had mean transvalvular gradient 10.9 ± 6.30 mm Hg, regurgitation fraction 32.5 ± 4.91%, and orifice area 1.52 ± 0.12 cm2. In ex vivo analysis, all repair groups had improved regurgitation compared with control (P < .001). FELAD <1.3 had the greatest amount of regurgitation among the repair groups (P < .001) and 1.5-1.64 the least (P < .001). FELAD <1.3 and >1.7 exhibited greater mean gradient compared with both control and 1.5 to 1.64 (P < .001). Among the repair groups, 1.5 to 1.64 had the largest orifice area, and >1.7 the smallest (P < .001).For a symmetric bicuspid aortic valve, performance after valve-sparing aortic root replacement shows a bimodal distribution across graft size. As the FELAD ratio departs from 1.5 to 1.64 in either direction, significant increases in transvalvular gradient are observed. FELAD <1.3 may also result in suboptimal improvement of baseline regurgitation.

  View details for DOI 10.1016/j.xjtc.2024.03.025

  View details for PubMedID 38899072

  View details for PubMedCentralID PMC11184666

• Quantification and Visualization of CT Myocardial Perfusion Imaging to Detect Ischemia-Causing Coronary Arteries. IEEE transactions on medical imaging Khan, M. O., Seresti, A. A., Menon, K., Marsden, A. L., Nieman, K. 2024; PP

  Abstract

  Coronary computed tomography angiography (cCTA) has poor specificity to identify coronary stenosis that limit blood flow to the myocardial tissue. Integration of dynamic CT myocardial perfusion imaging (CT-MPI) can potentially improve the diagnostic accuracy. We propose a method that integrates cCTA and CT-MPI to identify culprit coronary lesions that limit blood flow to the myocardium. Coronary arteries and left ventricle surfaces were segmented from cCTA and registered to CT-MPI. Myocardial blood flow (MBF) was derived from CT-MPI. A ray-casting approach was developed to project volumetric MBF onto the left ventricle surface. MBF volume were divided into coronary-specific territories based on proximity to the nearest coronary artery. MBF and normalized MBF were computed for the myocardium and each of the coronary artery. Projection of MBF onto cCTA allowed for direct visualization of perfusion defects. Normalized MBF had higher correlation with ischemic myocardial territory compared to MBF (MBF: R2=0.81 and Index MBF: R2=0.90). There were 18 vessels that showed angiographic disease (stenosis >50%); however, normalized MBF demonstrated only 5 coronary territories to be ischemic. These findings demonstrate that cCTA and CT-MPI can be integrated to visualize myocardial defects and detect culprit coronary arteries responsible for perfusion defects. These methods can allow for non-invasive detection of ischemia-causing coronary lesions and ultimately help guide clinicians to deliver more targeted coronary interventions.

  View details for DOI 10.1109/TMI.2024.3401552

  View details for PubMedID 38748525

• A mechanically consistent unified formulation for fluid-porous-structure-contact interaction COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Gerosa, F. M., Marsden, A. L. 2024; 425

  View details for DOI 10.1016/j.cma.2024.116942

  View details for Web of Science ID 001220236500001

• A mechanically consistent unified formulation for fluid-porous-structure-contact interaction. Computer methods in applied mechanics and engineering Gerosa, F. M., Marsden, A. L. 2024; 425

  Abstract

  Fluid-structure interaction with contact poses profound mathematical and numerical challenges, particularly when considering realistic contact scenarios and the influence of surface roughness. Computationally, contact introduces challenges in altering the fluid domain topology and preserving stress balance. This work introduces a new mathematical framework for a unified continuum description of fluid-porous-structure-contact interaction (FPSCI), leveraging the Navier-Stokes-Brinkman (NSB) equations to incorporate porous effects within the surface asperities in the contact region. Our approach maintains mechanical consistency during contact, circumventing issues associated with contact models and complex interface coupling conditions, allowing for the modeling of tangential creeping flows due to surface roughness. The unified continuum and variational multiscale formulation ensure robustness by enabling stable and unified integration of fluid, porous, and solid sub-problems. Computational efficiency and ease of implementation - key advantages of our approach - are demonstrated by solving two benchmark problems of a falling ball and an idealized heart valve. This research has broad implications for fields reliant on accurate fluid-structure interactions and promising advancements in modeling and numerical simulation techniques.

  View details for DOI 10.1016/j.cma.2024.116942

  View details for PubMedID 38826864

  View details for PubMedCentralID PMC11138479

• Cardiovascular fluid dynamics: a journey through our circulation FLOW Menon, K., Hu, Z., Marsden, A. L. 2024; 4

  View details for DOI 10.1017/flo.2024.5

  View details for Web of Science ID 001221235200001

• Personalized coronary and myocardial blood flow models incorporating CT perfusion imaging and synthetic vascular trees. Npj imaging Menon, K., Khan, M. O., Sexton, Z. A., Richter, J., Nguyen, P. K., Malik, S. B., Boyd, J., Nieman, K., Marsden, A. L. 2024; 2 (1): 9

  Abstract

  Computational simulations of coronary artery blood flow, using anatomical models based on clinical imaging, are an emerging non-invasive tool for personalized treatment planning. However, current simulations contend with two related challenges - incomplete anatomies in image-based models due to the exclusion of arteries smaller than the imaging resolution, and the lack of personalized flow distributions informed by patient-specific imaging. We introduce a data-enabled, personalized and multi-scale flow simulation framework spanning large coronary arteries to myocardial microvasculature. It includes image-based coronary anatomies combined with synthetic vasculature for arteries below the imaging resolution, myocardial blood flow simulated using Darcy models, and systemic circulation represented as lumped-parameter networks. We propose an optimization-based method to personalize multiscale coronary flow simulations by assimilating clinical CT myocardial perfusion imaging and cardiac function measurements to yield patient-specific flow distributions and model parameters. Using this proof-of-concept study on a cohort of six patients, we reveal substantial differences in flow distributions and clinical diagnosis metrics between the proposed personalized framework and empirical methods based purely on anatomy; these errors cannot be predicted a priori. This suggests virtual treatment planning tools would benefit from increased personalization informed by emerging imaging methods.

  View details for DOI 10.1038/s44303-024-00014-6

  View details for PubMedID 38706558

  View details for PubMedCentralID PMC11062925

• Hemodynamics and Wall Mechanics of Vascular Graft Failure. Arteriosclerosis, thrombosis, and vascular biology Szafron, J. M., Heng, E. E., Boyd, J., Humphrey, J. D., Marsden, A. L. 2024

  Abstract

  Blood vessels are subjected to complex biomechanical loads, primarily from pressure-driven blood flow. Abnormal loading associated with vascular grafts, arising from altered hemodynamics or wall mechanics, can cause acute and progressive vascular failure and end-organ dysfunction. Perturbations to mechanobiological stimuli experienced by vascular cells contribute to remodeling of the vascular wall via activation of mechanosensitive signaling pathways and subsequent changes in gene expression and associated turnover of cells and extracellular matrix. In this review, we outline experimental and computational tools used to quantify metrics of biomechanical loading in vascular grafts and highlight those that show potential in predicting graft failure for diverse disease contexts. We include metrics derived from both fluid and solid mechanics that drive feedback loops between mechanobiological processes and changes in the biomechanical state that govern the natural history of vascular grafts. As illustrative examples, we consider application-specific coronary artery bypass grafts, peripheral vascular grafts, and tissue-engineered vascular grafts for congenital heart surgery as each of these involves unique circulatory environments, loading magnitudes, and graft materials.

  View details for DOI 10.1161/ATVBAHA.123.318239

  View details for PubMedID 38572650

• IMPACT OF CARDIAC FIBER ORIENTATION ON ELECTRICAL DYSSYNCHRONY IN VENTRICULAR ECTOPY Perkins, S. J., Salvador, M., Hu, Z., Tikenogullari, O., Kong, F., Narayan, S. M., Marsden, A. ELSEVIER SCIENCE INC. 2024: 88

  View details for Web of Science ID 001324901500089

• IMPACT OF CARDIAC FIBER ORIENTATION ON ELECTRICAL DYSSYNCHRONY IN VENTRICULAR ECTOPY Perkins, S. J., Salvador, M., Hu, Z., Tikenogullari, O., Kong, F., Narayan, S. M., Marsden, A. ELSEVIER SCIENCE INC. 2024: 88

  View details for Web of Science ID 001291434300089

• A probabilistic neural twin for treatment planning in peripheral pulmonary artery stenosis. International journal for numerical methods in biomedical engineering Lee, J. D., Richter, J., Pfaller, M. R., Szafron, J. M., Menon, K., Zanoni, A., Ma, M. R., Feinstein, J. A., Kreutzer, J., Marsden, A. L., Schiavazzi, D. E. 2024: e3820

  Abstract

  The substantial computational cost of high-fidelity models in numerical hemodynamics has, so far, relegated their use mainly to offline treatment planning. New breakthroughs in data-driven architectures and optimization techniques for fast surrogate modeling provide an exciting opportunity to overcome these limitations, enabling the use of such technology for time-critical decisions. We discuss an application to the repair of multiple stenosis in peripheral pulmonary artery disease through either transcatheter pulmonary artery rehabilitation or surgery, where it is of interest to achieve desired pressures and flows at specific locations in the pulmonary artery tree, while minimizing the risk for the patient. Since different degrees of success can be achieved in practice during treatment, we formulate the problem in probability, and solve it through a sample-based approach. We propose a new offline-online pipeline for probabilistic real-time treatment planning which combines offline assimilation of boundary conditions, model reduction, and training dataset generation with online estimation of marginal probabilities, possibly conditioned on the degree of augmentation observed in already repaired lesions. Moreover, we propose a new approach for the parametrization of arbitrarily shaped vascular repairs through iterative corrections of a zero-dimensional approximant. We demonstrate this pipeline for a diseased model of the pulmonary artery tree available through the Vascular Model Repository.

  View details for DOI 10.1002/cnm.3820

  View details for PubMedID 38544354

• Tissue engineered vascular grafts are resistant to the formation of dystrophic calcification. Nature communications Turner, M. E., Blum, K. M., Watanabe, T., Schwarz, E. L., Nabavinia, M., Leland, J. T., Villarreal, D. J., Schwartzman, W. E., Chou, T. H., Baker, P. B., Matsumura, G., Krishnamurthy, R., Yates, A. R., Hor, K. N., Humphrey, J. D., Marsden, A. L., Stacy, M. R., Shinoka, T., Breuer, C. K. 2024; 15 (1): 2187

  Abstract

  Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.

  View details for DOI 10.1038/s41467-024-46431-4

  View details for PubMedID 38467617

  View details for PubMedCentralID 10224861

• A Modular Framework for Implicit 3D-0D Coupling in Cardiac Mechanics. Computer methods in applied mechanics and engineering Brown, A. L., Salvador, M., Shi, L., Pfaller, M. R., Hu, Z., Harold, K. E., Hsiai, T., Vedula, V., Marsden, A. L. 2024; 421

  Abstract

  In numerical simulations of cardiac mechanics, coupling the heart to a model of the circulatory system is essential for capturing physiological cardiac behavior. A popular and efficient technique is to use an electrical circuit analogy, known as a lumped parameter network or zero-dimensional (0D) fluid model, to represent blood flow throughout the cardiovascular system. Due to the strong physical interaction between the heart and the blood circulation, developing accurate and efficient numerical coupling methods remains an active area of research. In this work, we present a modular framework for implicitly coupling three-dimensional (3D) finite element simulations of cardiac mechanics to 0D models of blood circulation. The framework is modular in that the circulation model can be modified independently of the 3D finite element solver, and vice versa. The numerical scheme builds upon a previous work that combines 3D blood flow models with 0D circulation models (3D fluid - 0D fluid). Here, we extend it to couple 3D cardiac tissue mechanics models with 0D circulation models (3D structure - 0D fluid), showing that both mathematical problems can be solved within a unified coupling scheme. The effectiveness, temporal convergence, and computational cost of the algorithm are assessed through multiple examples relevant to the cardiovascular modeling community. Importantly, in an idealized left ventricle example, we show that the coupled model yields physiological pressure-volume loops and naturally recapitulates the isovolumic contraction and relaxation phases of the cardiac cycle without any additional numerical techniques. Furthermore, we provide a new derivation of the scheme inspired by the Approximate Newton Method of Chan (1985), explaining how the proposed numerical scheme combines the stability of monolithic approaches with the modularity and flexibility of partitioned approaches.

  View details for DOI 10.1016/j.cma.2024.116764

  View details for PubMedID 38523716

  View details for PubMedCentralID PMC10956732

• Non-invasive Estimation of Pressure Drop Across Aortic Coarctations: Validation of 0D and 3D Computational Models with In Vivo Measurements. Annals of biomedical engineering Nair, P. J., Pfaller, M. R., Dual, S. A., McElhinney, D. B., Ennis, D. B., Marsden, A. L. 2024

  Abstract

  Blood pressure gradient ([Formula: see text]) across an aortic coarctation (CoA) is an important measurement to diagnose CoA severity and gauge treatment efficacy. Invasive cardiac catheterization is currently the gold-standard method for measuring blood pressure. The objective of this study was to evaluate the accuracy of [Formula: see text] estimates derived non-invasively using patient-specific 0D and 3D deformable wall simulations. Medical imaging and routine clinical measurements were used to create patient-specific models of patients with CoA (N = 17). 0D simulations were performed first and used to tune boundary conditions and initialize 3D simulations. [Formula: see text] across the CoA estimated using both 0D and 3D simulations were compared to invasive catheter-based pressure measurements for validation. The 0D simulations were extremely efficient ([Formula: see text] 15 s computation time) compared to 3D simulations ([Formula: see text] 30 h computation time on a cluster). However, the 0D [Formula: see text] estimates, unsurprisingly, had larger mean errors when compared to catheterization than 3D estimates (12.1 ± 9.9 mmHg vs 5.3 ± 5.4 mmHg). In particular, the 0D model performance degraded in cases where the CoA was adjacent to a bifurcation. The 0D model classified patients with severe CoA requiring intervention (defined as [Formula: see text] [Formula: see text] 20 mmHg) with 76% accuracy and 3D simulations improved this to 88%. Overall, a combined approach, using 0D models to efficiently tune and launch 3D models, offers the best combination of speed and accuracy for non-invasive classification of CoA severity.

  View details for DOI 10.1007/s10439-024-03457-5

  View details for PubMedID 38341399

• Computational approaches for mechanobiology in cardiovascular development and diseases. Current topics in developmental biology Brown, A. L., Sexton, Z. A., Hu, Z., Yang, W., Marsden, A. L. 2024; 156: 19-50

  Abstract

  The cardiovascular development in vertebrates evolves in response to genetic and mechanical cues. The dynamic interplay among mechanics, cell biology, and anatomy continually shapes the hydraulic networks, characterized by complex, non-linear changes in anatomical structure and blood flow dynamics. To better understand this interplay, a diverse set of molecular and computational tools has been used to comprehensively study cardiovascular mechanobiology. With the continual advancement of computational capacity and numerical techniques, cardiovascular simulation is increasingly vital in both basic science research for understanding developmental mechanisms and disease etiologies, as well as in clinical studies aimed at enhancing treatment outcomes. This review provides an overview of computational cardiovascular modeling. Beginning with the fundamental concepts of computational cardiovascular modeling, it navigates through the applications of computational modeling in investigating mechanobiology during cardiac development. Second, the article illustrates the utility of computational hemodynamic modeling in the context of treatment planning for congenital heart diseases. It then delves into the predictive potential of computational models for elucidating tissue growth and remodeling processes. In closing, we outline prevailing challenges and future prospects, underscoring the transformative impact of computational cardiovascular modeling in reshaping cardiovascular science and clinical practice.

  View details for DOI 10.1016/bs.ctdb.2024.01.006

  View details for PubMedID 38556423

• Virtual shape-editing of patient-specific vascular models using Regularized Kelvinlets. IEEE transactions on bio-medical engineering Pham, J., Kong, F., James, D. L., Marsden, A. L. 2024; PP

  Abstract

  OBJECTIVE: Cardiovascular diseases, and the interventions performed to treat them, can lead to changes in the shape of patient vasculatures and their hemodynamics. Computational modeling and simulations of patient-specific vascular networks are increasingly used to quantify these hemodynamic changes, but they require modifying the shapes of the models. Existing methods to modify these shapes include editing 2D lumen contours prescribed along vessel centerlines and deforming meshes with geometry-based approaches. However, these methods can require extensive by-hand prescription of the desired shapes and often do not work robustly across a range of vascular anatomies. To overcome these limitations, we develop techniques to modify vascular models using physics-based principles that can automatically generate smooth deformations and readily apply them across different vascular anatomies.METHODS: We adapt Regularized Kelvinlets, analytical solutions to linear elastostatics, to perform elastic shape-editing of vascular models. The Kelvinlets are packaged into three methods that allow us to artificially create aneurysms, stenoses, and tortuosity.RESULTS: Our methods are able to generate such geometric changes across a wide range of vascular anatomies. We demonstrate their capabilities by creating sets of aneurysms, stenoses, and tortuosities with varying shapes and sizes on multiple patient-specific models.CONCLUSION: Our Kelvinlet-based deformers allow us to edit the shape of vascular models, regardless of their anatomical locations, and parametrically vary the size of the geometric changes.SIGNIFICANCE: These methods will enable researchers to more easily perform virtual-surgery-like deformations, computationally explore the impact of vascular shape on patient hemodynamics, and generate synthetic geometries for data-driven research.

  View details for DOI 10.1109/TBME.2024.3355307

  View details for PubMedID 38300772

• Computational Modelling of CRT in Congenital Heart Disease: Fantasy or the Future? Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology Chubb, H., Salvador, M., Marsden, A. L. 2024

  View details for DOI 10.1093/europace/euae027

  View details for PubMedID 38266146

• A modular framework for implicit 3D-0D coupling in cardiac mechanics COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Brown, A. L., Salvador, M., Shi, L., Pfaller, M. R., Hu, Z., Harold, K. E., Hsiai, T., Vedula, V., Marsden, A. L. 2024; 421

  View details for DOI 10.1016/j.cma.2024.116764

  View details for Web of Science ID 001170690900001

• Simulation-Based Design of Bicuspidization of the Aortic Valve. The Journal of thoracic and cardiovascular surgery Kaiser, A. D., Haidar, M. A., Choi, P. S., Sharir, A., Marsden, A. L., Ma, M. R. 2024

  Abstract

  Severe congenital aortic valve pathology in the growing patient remains a challenging clinical scenario. Bicuspidization of the diseased aortic valve has proven to be a promising repair technique with acceptable durability. However, most understanding of the procedure is empirical and retrospective. This work seeks to design the optimal gross morphology associated with surgical bicuspidization with simulations, based on the hypothesis that modifications to the free edge length cause or relieve stenosis.Model bicuspid valves were constructed with varying free edge lengths and gross morphology. Fluid-structure interaction simulations were conducted in a single patient-specific model geometry. The models were evaluated for primary targets of stenosis and regurgitation. Secondary targets were assessed and included qualitative hemodynamics, geometric height, effective height, orifice area and billow.Stenosis decreased with increasing free edge length and was pronounced with free edge length ≤1.3 times the annular diameter d. With free edge length 1.5d or greater, no stenosis occurred. All models were free of regurgitation. Substantial billow occurred with free edge length ≥1.7d.Free edge length ≥1.5d was required to avoid aortic stenosis in simulations. Cases with free edge length ≥1.7d showed excessive billow and other changes in gross morphology. Cases with free edge length 1.5-1.6d have a total free edge length approximately equal to the annular circumference and appeared optimal. These effects should be studied in vitro and in animal studies.

  View details for DOI 10.1016/j.jtcvs.2023.12.027

  View details for PubMedID 38211896

• Type and Shape Disentangled Generative Modeling for Congenital Heart Defects Kong, F., Marsden, A. L., Camara, O., Puyol-Anton, E., Sermesant, M., Suinesiaputra, A., Tao, Q., Wang, C., Young, A. SPRINGER INTERNATIONAL PUBLISHING AG. 2024: 196-208

  View details for DOI 10.1007/978-3-031-52448-6_19

  View details for Web of Science ID 001207832200019

• Branched Latent Neural Maps. Computer methods in applied mechanics and engineering Salvador, M., Marsden, A. L. 2024; 418 (Pt A)

  Abstract

  We introduce Branched Latent Neural Maps (BLNMs) to learn finite dimensional input-output maps encoding complex physical processes. A BLNM is defined by a simple and compact feedforward partially-connected neural network that structurally disentangles inputs with different intrinsic roles, such as the time variable from model parameters of a differential equation, while transferring them into a generic field of interest. BLNMs leverage latent outputs to enhance the learned dynamics and break the curse of dimensionality by showing excellent in-distribution generalization properties with small training datasets and short training times on a single processor. Indeed, their in-distribution generalization error remains comparable regardless of the adopted discretization during the testing phase. Moreover, the partial connections, in place of a fully-connected structure, significantly reduce the number of tunable parameters. We show the capabilities of BLNMs in a challenging test case involving biophysically detailed electrophysiology simulations in a biventricular cardiac model of a pediatric patient with hypoplastic left heart syndrome. The model includes a 1D Purkinje network for fast conduction and a 3D heart-torso geometry. Specifically, we trained BLNMs on 150 in silico generated 12-lead electrocardiograms (ECGs) while spanning 7 model parameters, covering cell-scale, organ-level and electrical dyssynchrony. Although the 12-lead ECGs manifest very fast dynamics with sharp gradients, after automatic hyperparameter tuning the optimal BLNM, trained in less than 3 hours on a single CPU, retains just 7 hidden layers and 19 neurons per layer. The resulting mean square error is on the order of 10-4 on an independent test dataset comprised of 50 additional electrophysiology simulations. In the online phase, the BLNM allows for 5000x faster real-time simulations of cardiac electrophysiology on a single core standard computer and can be employed to solve inverse problems via global optimization in a few seconds of computational time. This paper provides a novel computational tool to build reliable and efficient reduced-order models for digital twinning in engineering applications. The Julia implementation is publicly available under MIT License at https://github.com/StanfordCBCL/BLNM.jl.

  View details for DOI 10.1016/j.cma.2023.116499

  View details for PubMedID 37872974

  View details for PubMedCentralID PMC10588816

• Hemodynamic effects of entry and exit tear size in aortic dissection evaluated with in vitro magnetic resonance imaging and fluid-structure interaction simulation. Scientific reports Zimmermann, J., Bäumler, K., Loecher, M., Cork, T. E., Marsden, A. L., Ennis, D. B., Fleischmann, D. 2023; 13 (1): 22557

  Abstract

  Understanding the complex interplay between morphologic and hemodynamic features in aortic dissection is critical for risk stratification and for the development of individualized therapy. This work evaluates the effects of entry and exit tear size on the hemodynamics in type B aortic dissection by comparing fluid-structure interaction (FSI) simulations with in vitro 4D-flow magnetic resonance imaging (MRI). A baseline patient-specific 3D-printed model and two variants with modified tear size (smaller entry tear, smaller exit tear) were embedded into a flow- and pressure-controlled setup to perform MRI as well as 12-point catheter-based pressure measurements. The same models defined the wall and fluid domains for FSI simulations, for which boundary conditions were matched with measured data. Results showed exceptionally well matched complex flow patterns between 4D-flow MRI and FSI simulations. Compared to the baseline model, false lumen flow volume decreased with either a smaller entry tear (- 17.8 and - 18.5%, for FSI simulation and 4D-flow MRI, respectively) or smaller exit tear (- 16.0 and - 17.3%). True to false lumen pressure difference (initially 11.0 and 7.9 mmHg, for FSI simulation and catheter-based pressure measurements, respectively) increased with a smaller entry tear (28.9 and 14.6 mmHg), and became negative with a smaller exit tear (- 20.6 and - 13.2 mmHg). This work establishes quantitative and qualitative effects of entry or exit tear size on hemodynamics in aortic dissection, with particularly notable impact observed on FL pressurization. FSI simulations demonstrate acceptable qualitative and quantitative agreement with flow imaging, supporting its deployment in clinical studies.

  View details for DOI 10.1038/s41598-023-49942-0

  View details for PubMedID 38110526

  View details for PubMedCentralID PMC10728172

• A Fluid-Solid-Growth Solver for Cardiovascular Modeling. Computer methods in applied mechanics and engineering Schwarz, E. L., Pfaller, M. R., Szafron, J. M., Latorre, M., Lindsey, S. E., Breuer, C. K., Humphrey, J. D., Marsden, A. L. 2023; 417 (Pt B)

  Abstract

  We implement full, three-dimensional constrained mixture theory for vascular growth and remodeling into a finite element fluid-structure interaction (FSI) solver. The resulting "fluid-solid-growth" (FSG) solver allows long term, patient-specific predictions of changing hemodynamics, vessel wall morphology, tissue composition, and material properties. This extension from short term (FSI) to long term (FSG) simulations increases clinical relevance by enabling mechanobioloigcally-dependent studies of disease progression in complex domains.

  View details for DOI 10.1016/j.cma.2023.116312

  View details for PubMedID 38044957

• Digital twinning of cardiac electrophysiology for congenital heart disease. bioRxiv : the preprint server for biology Salvador, M., Kong, F., Peirlinck, M., Parker, D. W., Chubb, H., Dubin, A. M., Marsden, A. L. 2023

  Abstract

  In recent years, blending mechanistic knowledge with machine learning has had a major impact in digital healthcare. In this work, we introduce a computational pipeline to build certified digital replicas of cardiac electrophysiology in pediatric patients with congenital heart disease. We construct the patient-specific geometry by means of semi-automatic segmentation and meshing tools. We generate a dataset of electrophysiology simulations covering cell-to-organ level model parameters and utilizing rigorous mathematical models based on differential equations. We previously proposed Branched Latent Neural Maps (BLNMs) as an accurate and efficient means to recapitulate complex physical processes in a neural network. Here, we employ BLNMs to encode the parametrized temporal dynamics of in silico 12-lead electrocardiograms (ECGs). BLNMs act as a geometry-specific surrogate model of cardiac function for fast and robust parameter estimation to match clinical ECGs in pediatric patients. Identifiability and trustworthiness of calibrated model parameters are assessed by sensitivity analysis and uncertainty quantification.

  View details for DOI 10.1101/2023.11.27.568942

  View details for PubMedID 38076810

  View details for PubMedCentralID PMC10705388

• Learning reduced-order models for cardiovascular simulations with graph neural networks. Computers in biology and medicine Pegolotti, L., Pfaller, M. R., Rubio, N. L., Ding, K., Brugarolas Brufau, R., Darve, E., Marsden, A. L. 2023; 168: 107676

  Abstract

  Reduced-order models based on physics are a popular choice in cardiovascular modeling due to their efficiency, but they may experience loss in accuracy when working with anatomies that contain numerous junctions or pathological conditions. We develop one-dimensional reduced-order models that simulate blood flow dynamics using a graph neural network trained on three-dimensional hemodynamic simulation data. Given the initial condition of the system, the network iteratively predicts the pressure and flow rate at the vessel centerline nodes. Our numerical results demonstrate the accuracy and generalizability of our method in physiological geometries comprising a variety of anatomies and boundary conditions. Our findings demonstrate that our approach can achieve errors below 3% for pressure and flow rate, provided there is adequate training data. As a result, our method exhibits superior performance compared to physics-based one-dimensional models while maintaining high efficiency at inference time.

  View details for DOI 10.1016/j.compbiomed.2023.107676

  View details for PubMedID 38039892

• SDF4CHD: Generative Modeling of Cardiac Anatomies with Congenital Heart Defects. ArXiv Kong, F., Stocker, S., Choi, P. S., Ma, M., Ennis, D. B., Marsden, A. 2023

  Abstract

  Congenital heart disease (CHD) encompasses a spectrum of cardiovascular structural abnormalities, often requiring customized treatment plans for individual patients. Computational modeling and analysis of these unique cardiac anatomies can improve diagnosis and treatment planning and may ultimately lead to improved outcomes. Deep learning (DL) methods have demonstrated the potential to enable efficient treatment planning by automating cardiac segmentation and mesh construction for patients with normal cardiac anatomies. However, CHDs are often rare, making it challenging to acquire sufficiently large patient cohorts for training such DL models. Generative modeling of cardiac anatomies has the potential to fill this gap via the generation of virtual cohorts; however, prior approaches were largely designed for normal anatomies and cannot readily capture the significant topological variations seen in CHD patients. Therefore, we propose a type- and shape-disentangled generative approach suitable to capture the wide spectrum of cardiac anatomies observed in different CHD types and synthesize differently shaped cardiac anatomies that preserve the unique topology for specific CHD types. Our DL approach represents generic whole heart anatomies with CHD type-specific abnormalities implicitly using signed distance fields (SDF) based on CHD type diagnosis, which conveniently captures divergent anatomical variations across different types and represents meaningful intermediate CHD states. To capture the shape-specific variations, we then learn invertible deformations to morph the learned CHD type-specific anatomies and reconstruct patient-specific shapes. Our approach has the potential to augment the image-segmentation pairs for rarer CHD types for cardiac segmentation and generate cohorts of CHD cardiac meshes for computational simulation.

  View details for PubMedID 37961745

  View details for PubMedCentralID PMC10635288

• Longitudinal investigation of aortic dissection in mice with computational fluid dynamics. Computer methods in biomechanics and biomedical engineering Bäumler, K., Phillips, E. H., Grande Gutiérrez, N., Fleischmann, D., Marsden, A. L., Goergen, C. J. 2023: 1-14

  Abstract

  Predicting late adverse events in aortic dissections is challenging. One commonly observed risk factor is partial thrombosis of the false lumen. In this study we investigated false lumen thrombus progression over 7 days in four mice with angiotensin II-induced aortic dissection. We performed computational fluid dynamic simulations with subject-specific boundary conditions from velocity and pressure measurements. We investigated endothelial cell activation potential, mean velocity, thrombus formation potential, and other hemodynamic factors. Our findings support the hypothesis that flow stagnation is the predominant hemodynamic factor driving a large thrombus ratio in false lumina, particularly those with a single fenestration.

  View details for DOI 10.1080/10255842.2023.2274281

  View details for PubMedID 37897230

• Non-invasive estimation of pressure drop across aortic coarctations: validation of 0D and 3D computational models with in vivo measurements. medRxiv : the preprint server for health sciences Nair, P. J., Pfaller, M. R., Dual, S. A., McElhinney, D. B., Ennis, D. B., Marsden, A. L. 2023

  Abstract

  Blood pressure gradient (ΔP) across an aortic coarctation (CoA) is an important measurement to diagnose CoA severity and gauge treatment efficacy. Invasive cardiac catheterization is currently the gold-standard method for measuring blood pressure. The objective of this study was to evaluate the accuracy of ΔP estimates derived non-invasively using patient-specific 0D and 3D deformable wall simulations.Medical imaging and routine clinical measurements were used to create patient-specific models of patients with CoA (N=17). 0D simulations were performed first and used to tune boundary conditions and initialize 3D simulations. ΔP across the CoA estimated using both 0D and 3D simulations were compared to invasive catheter-based pressure measurements for validation.The 0D simulations were extremely efficient (~15 secs computation time) compared to 3D simulations (~30 hrs computation time on a cluster). However, the 0D ΔP estimates, unsurprisingly, had larger mean errors when compared to catheterization than 3D estimates (12.1 ± 9.9 mmHg vs 5.3 ± 5.4 mmHg). In particular, the 0D model performance degraded in cases where the CoA was adjacent to a bifurcation. The 0D model classified patients with severe CoA requiring intervention (defined as ΔP≥20 mmHg) with 76% accuracy and 3D simulations improved this to 88%.Overall, a combined approach, using 0D models to efficiently tune and launch 3D models, offers the best combination of speed and accuracy for non-invasive classification of CoA severity.

  View details for DOI 10.1101/2023.09.05.23295066

  View details for PubMedID 37732242

  View details for PubMedCentralID PMC10508787

• A computational growth and remodeling framework for adaptive and maladaptive pulmonary arterial hemodynamics. Biomechanics and modeling in mechanobiology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step toward predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1007/s10237-023-01744-z

  View details for PubMedID 37658985

• Personalized coronary and myocardial blood flow models incorporating CT perfusion imaging and synthetic vascular trees. medRxiv : the preprint server for health sciences Menon, K., Khan, M. O., Sexton, Z. A., Richter, J., Nieman, K., Marsden, A. L. 2023

  Abstract

  Computational simulations of coronary artery blood flow, using anatomical models based on clinical imaging, are an emerging non-invasive tool for personalized treatment planning. However, current simulations contend with two related challenges - incomplete anatomies in image-based models due to the exclusion of arteries smaller than the imaging resolution, and the lack of personalized flow distributions informed by patient-specific imaging. We introduce a data-enabled, personalized and multi-scale flow simulation framework spanning large coronary arteries to myocardial microvasculature. It includes image-based coronary models combined with synthetic vasculature for arteries below the imaging resolution, myocardial blood flow simulated using Darcy models, and systemic circulation represented as lumped-parameter networks. Personalized flow distributions and model parameters are informed by clinical CT myocardial perfusion imaging and cardiac function using surrogate-based optimization. We reveal substantial differences in flow distributions and clinical diagnosis metrics between the proposed personalized framework and empirical methods based on anatomy; these errors cannot be predicted a priori. This suggests virtual treatment planning tools would benefit from increased personalization informed by emerging imaging methods.

  View details for DOI 10.1101/2023.08.17.23294242

  View details for PubMedID 37645850

• Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing. ArXiv Sexton, Z. A., Hudson, A. R., Herrmann, J. E., Shiwarski, D. J., Pham, J., Szafron, J. M., Wu, S. M., Skylar-Scott, M., Feinberg, A. W., Marsden, A. 2023

  Abstract

  Our ability to produce human-scale bio-manufactured organs is critically limited by the need for vascularization and perfusion. For tissues of variable size and shape, including arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion has posed a major hurdle. Here, we introduce a model-driven design pipeline combining accelerated optimization methods for fast synthetic vascular tree generation and computational hemodynamics models. We demonstrate rapid generation, simulation, and 3D printing of synthetic vasculature in complex geometries, from small tissue constructs to organ scale networks. We introduce key algorithmic advances that all together accelerate synthetic vascular generation by more than 230 -fold compared to standard methods and enable their use in arbitrarily complex shapes through localized implicit functions. Furthermore, we provide techniques for joining vascular trees into watertight networks suitable for hemodynamic CFD and 3D fabrication. We demonstrate that organ-scale vascular network models can be generated in silico within minutes and can be used to perfuse engineered and anatomic models including a bioreactor, annulus, bi-ventricular heart, and gyrus. We further show that this flexible pipeline can be applied to two common modes of bioprinting with free-form reversible embedding of suspended hydrogels and writing into soft matter. Our synthetic vascular tree generation pipeline enables rapid, scalable vascular model generation and fluid analysis for bio-manufactured tissues necessary for future scale up and production.

  View details for PubMedID 37645046

  View details for PubMedCentralID PMC10462165

• Passive performance evaluation and validation of a viscous impeller pump for subpulmonary fontan circulatory support. Scientific reports Yang, W., Conover, T. A., Figliola, R. S., Giridharan, G. A., Marsden, A. L., Rodefeld, M. D. 2023; 13 (1): 12668

  Abstract

  Patients with single ventricle defects undergoing the Fontan procedure eventually face Fontan failure. Long-term cavopulmonary assist devices using rotary pump technologies are currently being developed as a subpulmonary power source to prevent and treat Fontan failure. Low hydraulic resistance is a critical safety requirement in the event of pump failure (0 RPM) as a modest 2 mmHg cavopulmonary pressure drop can compromise patient hemodynamics. The goal of this study is therefore to assess the passive performance of a viscous impeller pump (VIP) we are developing for Fontan patients, and validate flow simulations against in-vitro data. Two different blade heights (1.09 mm vs 1.62 mm) and a blank housing model were tested using a mock circulatory loop (MCL) with cardiac output ranging from 3 to 11 L/min. Three-dimensional flow simulations were performed and compared against MCL data. In-silico and MCL results demonstrated a pressure drop of < 2 mmHg at a cardiac output of 7 L/min for both blade heights. There was good agreement between simulation and MCL results for pressure loss (mean difference - 0.23 mmHg 95% CI [0.24-0.71]). Compared to the blank housing model, low wall shear stress area and oscillatory shear index on the pump surface were low, and mean washout times were within 2 s. This study demonstrated the low resistance characteristic of current VIP designs in the failed condition that results in clinically acceptable minimal pressure loss without increased washout time as compared to a blank housing model under normal cardiac output in Fontan patients.

  View details for DOI 10.1038/s41598-023-38559-y

  View details for PubMedID 37542111

  View details for PubMedCentralID 4505550

• Assessing Differences in Aortic Haemodynamics Between Two- Versus Four-Vessel Fenestrated Endovascular Aneurysm Repair using Patient-Specific Computational Flow Simulation. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery Tran, K., Kaladji, A., Yang, W., Marsden, A. L., Lee, J. T. 2023

  View details for DOI 10.1016/j.ejvs.2023.07.050

  View details for PubMedID 37536515

• Comparison of Immersed Boundary Simulations of Heart Valve Hemodynamics Against In Vitro 4D Flow MRI Data. Annals of biomedical engineering Kaiser, A. D., Schiavone, N. K., Elkins, C. J., McElhinney, D. B., Eaton, J. K., Marsden, A. L. 2023

  Abstract

  The immersed boundary (IB) method is a mathematical framework for fluid-structure interaction problems (FSI) that was originally developed to simulate flows around heart valves. Direct comparison of FSI simulations around heart valves against experimental data is challenging, however, due to the difficulty of performing robust and effective simulations, the complications of modeling a specific physical experiment, and the need to acquire experimental data that is directly comparable to simulation data. Such comparators are a necessary precursor for further formal validation studies of FSI simulations involving heart valves. In this work, we performed physical experiments of flow through a pulmonary valve in an in vitro pulse duplicator, and measured the corresponding velocity field using 4D flow MRI (4-dimensional flow magnetic resonance imaging). We constructed a computer model of this pulmonary artery setup, including modeling valve geometry and material properties via a technique called design-based elasticity, and simulated flow through it with the IB method. The simulated flow fields showed excellent qualitative agreement with experiments, excellent agreement on integral metrics, and reasonable relative error in the entire flow domain and on slices of interest. These results illustrate how to construct a computational model of a physical experiment for use as a comparator.

  View details for DOI 10.1007/s10439-023-03266-2

  View details for PubMedID 37378877

  View details for PubMedCentralID 6328065

• Effects of cardiac growth on electrical dyssynchrony in the single ventricle patient. Computer methods in biomechanics and biomedical engineering Tikenoğulları, O. Z., Peirlinck, M., Chubb, H., Dubin, A. M., Kuhl, E., Marsden, A. L. 2023: 1-17

  Abstract

  Single ventricle patients, including those with hypoplastic left heart syndrome (HLHS), typically undergo three palliative heart surgeries culminating in the Fontan procedure. HLHS is associated with high rates of morbidity and mortality, and many patients develop arrhythmias, electrical dyssynchrony, and eventually ventricular failure. However, the correlation between ventricular enlargement and electrical dysfunction in HLHS physiology remains poorly understood. Here we characterize the relationship between growth and electrophysiology in HLHS using computational modeling. We integrate a personalized finite element model, a volumetric growth model, and a personalized electrophysiology model to perform controlled in silico experiments. We show that right ventricle enlargement negatively affects QRS duration and interventricular dyssynchrony. Conversely, left ventricle enlargement can partially compensate for this dyssynchrony. These findings have potential implications on our understanding of the origins of electrical dyssynchrony and, ultimately, the treatment of HLHS patients.

  View details for DOI 10.1080/10255842.2023.2222203

  View details for PubMedID 37314141

• Improved Right Ventricular Energy Efficiency by 4-Dimensional Flow Magnetic Resonance Imaging After Harmony Valve Implantation. JACC. Advances Woo, J. P., Dong, M. L., Kong, F., McElhinney, D. B., Schiavone, N., Chan, F., Lui, G. K., Haddad, F., Bernstein, D., Marsden, A. 2023; 2 (3)

  View details for DOI 10.1016/j.jacadv.2023.100284

  View details for PubMedID 37691969

  View details for PubMedCentralID PMC10487049

• A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics. bioRxiv : the preprint server for biology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1101/2023.04.20.537714

  View details for PubMedID 37131683

  View details for PubMedCentralID PMC10153237

• Investigating the hemodynamics of Berlin Heart EXCOR support in Norwood patients across diverse clinical scenarios with computational modeling. Artificial organs Yuan, V., De Gaetano, F., Osouli, K., Marsden, A. L., Costantino, M. L. 2023

  Abstract

  Infants with single-ventricle (SV) physiology undergo the 3-stage Fontan surgery. Norwood patients, who have completed the first stage, face the highest interstage mortality. The Berlin Heart EXCOR (BH), a pediatric pulsatile ventricular assist device, has shown promise in supporting these patients. However, clinical questions regarding device configurations prevent optimal support.We developed a combined idealized mechanics-lumped parameter model of a Norwood patient and simulated two additional patient-specific cases: pulmonary hypertension (PH) and post-operative treatment with milrinone. We quantified the effects of BH support across different device volumes, rates, and inflow connections on patient hemodynamics and BH performance.Increasing device volume and rate increased cardiac output, but with unsubstantial changes in specific arterial oxygen content. We identified distinct SV-BH interactions that may impact patient myocardial health and contribute to poor clinical outcomes. Our results suggested BH settings for patients with PH and for patients treated post-operatively with milrinone.We present a computational model to characterize and quantify patient hemodynamics and BH support for infants with Norwood physiology. Our results emphasized that oxygen delivery does not increase with BH rate or volume, which may not meet patient needs and contribute to suboptimal clinical outcomes. Our findings demonstrated that an atrial BH may provide optimal cardiac loading for patients with diastolic dysfunction. Meanwhile, a ventricular BH decreased active stress in the myocardium, and countered the effects of milrinone. Patients with PH showed greater sensitivity to device volume. In this work, we demonstrate the adaptability of our model to analyze BH support across varied clinical situations.

  View details for DOI 10.1111/aor.14544

  View details for PubMedID 37042396

• Hemodynamic Effects of Entry and Exit Tear Size in Aortic Dissection Evaluated with In Vitro Magnetic Resonance Imaging and Fluid-Structure Interaction Simulation. ArXiv Zimmermann, J., Bäumler, K., Loecher, M., Cork, T. E., Marsden, A. L., Ennis, D. B., Fleischmann, D. 2023

  Abstract

  Understanding the complex interplay between morphologic and hemodynamic features in aortic dissection is critical for risk stratification and for the development of individualized therapy. This work evaluates the effects of entry and exit tear size on the hemodynamics in type B aortic dissection by comparing fluid-structure interaction (FSI) simulations with in vitro 4D-flow magnetic resonance imaging (MRI). A baseline patient-specific 3D-printed model and two variants with modified tear size (smaller entry tear, smaller exit tear) were embedded into a flow- and pressure-controlled setup to perform MRI as well as 12-point catheter-based pressure measurements. The same models defined the wall and fluid domains for FSI simulations, for which boundary conditions were matched with measured data. Results showed exceptionally well matched complex flow patterns between 4D-flow MRI and FSI simulations. Compared to the baseline model, false lumen flow volume decreased with either a smaller entry tear (-17.8 and -18.5 %, for FSI simulation and 4D-flow MRI, respectively) or smaller exit tear (-16.0 and -17.3 %). True to false lumen pressure difference (initially 11.0 and 7.9 mmHg, for FSI simulation and catheter-based pressure measurements, respectively) increased with a smaller entry tear (28.9 and 14.6 mmHg), and became negative with a smaller exit tear (-20.6 and -13.2 mmHg). This work establishes quantitative and qualitative effects of entry or exit tear size on hemodynamics in aortic dissection, with particularly notable impact observed on FL pressurization. FSI simulations demonstrate acceptable qualitative and quantitative agreement with flow imaging, supporting its deployment in clinical studies.

  View details for DOI 10.1161/HCI.0000000000000075

  View details for PubMedID 36994169

  View details for PubMedCentralID PMC10055490

• Predictors of Myocardial Ischemia in Patients with Kawasaki Disease: Insights from Patient-Specific Simulations of Coronary Hemodynamics. Journal of cardiovascular translational research Menon, K., Seo, J., Fukazawa, R., Ogawa, S., Kahn, A. M., Burns, J. C., Marsden, A. L. 2023

  Abstract

  Current treatments for patients with coronary aneurysms caused by Kawasaki disease (KD) are based primarily on aneurysm size. This ignores hemodynamic factors influencing myocardial ischemic risk. We performed patient-specific computational hemodynamics simulations for 15 KD patients, with parameters tuned to patients' arterial pressure and cardiac function. Ischemic risk was evaluated in 153 coronary arteries from simulated fractional flow reserve (FFR), wall shear stress, and residence time. FFR correlated weakly with aneurysm [Formula: see text]-scores (correlation coefficient, [Formula: see text]) but correlated better with the ratio of maximum-to-minimum aneurysmal lumen diameter ([Formula: see text]). FFR dropped more rapidly distal to aneurysms, and this correlated more with the lumen diameter ratio ([Formula: see text]) than [Formula: see text]-score ([Formula: see text]). Wall shear stress correlated better with the diameter ratio ([Formula: see text]), while residence time correlated more with [Formula: see text]-score ([Formula: see text]). Overall, the maximum-to-minimum diameter ratio predicted ischemic risk better than [Formula: see text]-score. Although FFR immediately distal to aneurysms was nonsignificant, its rapid rate of decrease suggests elevated risk.

  View details for DOI 10.1007/s12265-023-10374-w

  View details for PubMedID 36939959

• Beyond CFD: Emerging methodologies for predictive simulation in cardiovascular health and disease. Biophysics reviews Schwarz, E. L., Pegolotti, L., Pfaller, M. R., Marsden, A. L. 2023; 4 (1): 011301

  Abstract

  Physics-based computational models of the cardiovascular system are increasingly used to simulate hemodynamics, tissue mechanics, and physiology in evolving healthy and diseased states. While predictive models using computational fluid dynamics (CFD) originated primarily for use in surgical planning, their application now extends well beyond this purpose. In this review, we describe an increasingly wide range of modeling applications aimed at uncovering fundamental mechanisms of disease progression and development, performing model-guided design, and generating testable hypotheses to drive targeted experiments. Increasingly, models are incorporating multiple physical processes spanning a wide range of time and length scales in the heart and vasculature. With these expanded capabilities, clinical adoption of patient-specific modeling in congenital and acquired cardiovascular disease is also increasing, impacting clinical care and treatment decisions in complex congenital heart disease, coronary artery disease, vascular surgery, pulmonary artery disease, and medical device design. In support of these efforts, we discuss recent advances in modeling methodology, which are most impactful when driven by clinical needs. We describe pivotal recent developments in image processing, fluid-structure interaction, modeling under uncertainty, and reduced order modeling to enable simulations in clinically relevant timeframes. In all these areas, we argue that traditional CFD alone is insufficient to tackle increasingly complex clinical and biological problems across scales and systems. Rather, CFD should be coupled with appropriate multiscale biological, physical, and physiological models needed to produce comprehensive, impactful models of mechanobiological systems and complex clinical scenarios. With this perspective, we finally outline open problems and future challenges in the field.

  View details for DOI 10.1063/5.0109400

  View details for PubMedID 36686891

• Recent advances in quantifying the mechanobiology of cardiac development via computational modeling. Current opinion in biomedical engineering Brown, A. L., Gerosa, F. M., Wang, J., Hsiai, T., Marsden, A. L. 2023; 25

  Abstract

  Mechanical forces are essential for coordinating cardiac morphogenesis, but much remains to be discovered about the interactions between mechanical forces and the mechanotransduction pathways they activate. Due to the elaborate and fundamentally multi-physics and multi-scale nature of cardiac mechanobiology, a complete understanding requires multiple experimental and analytical techniques. We identify three fundamental tools used in the field to probe these interactions: high resolution imaging, genetic and molecular analysis, and computational modeling. In this review, we focus on computational modeling and present recent studies employing this tool to investigate the mechanobiological pathways involved with cardiac development. These works demonstrate that understanding the detailed spatial and temporal patterns of biomechanical forces is crucial to building a comprehensive understanding of mechanobiology during cardiac development, and that computational modeling is an effective and efficient tool for obtaining such detail. In this context, multidisciplinary studies combining all three tools present the most compelling results.

  View details for DOI 10.1016/j.cobme.2022.100428

  View details for PubMedID 36583220

  View details for PubMedCentralID PMC9794182

• Passive Performance Evaluation and Validation of a Viscous Impeller Pump for Subpulmonary Fontan Circulatory Support. Research square Yang, W., Conover, T. A., Figliola, R. S., Giridharan, G. A., Marsden, A. L., Rodefeld, M. D. 2023

  Abstract

  Patients with single ventricle defects undergoing the Fontan procedure eventually face Fontan failure. Long-term cavopulmonary assist devices using rotary pump technologies are currently being developed as a subpulmonary power source to prevent and treat Fontan failure. Low hydraulic resistance is a critical safety requirement in the event of pump failure (0 RPM) as a modest 2 mmHg cavopulmonary pressure drop can compromise patient hemodynamics. The goal of this study is therefore to assess the passive performance for a viscous impeller pump (VIP) we are developing for Fontan patients, and validate flow simulations against in-vitro data. Two different blade heights (1.09 mm vs 1.62 mm) and a blank housing model were tested using a mock circulatory loop (MCL) with cardiac output ranging from 3 to 11 L/min. Three-dimensional flow simulations were performed and compared against MCL data. In-silico and MCL results demonstrated a clinically insignificant pressure drop of $<$ 2 mmHg at a cardiac output of 7 L/min for both blade heights. There was good agreement between simulation and MCL results for pressure loss (mean difference -0.23 mmHg 95% CI [0.24 -0.71]). Compared to the blank housing model, low wall shear stress area and oscillatory shear index on the pump surface were low, and mean washout times were within 2 seconds. This study demonstrated the low resistance characteristic of current VIP designs in the failed condition that results in clinically acceptable minimal pressure loss with low risk of thrombosis.

  View details for DOI 10.21203/rs.3.rs-2584661/v1

  View details for PubMedID 36909557

  View details for PubMedCentralID PMC10002834

• Hemodynamic Effects of Entry Versus Exit Tear Size and Tissue Stiffness in Simulations of Aortic Dissection Baumler, K., Zimmermann, J., Ennis, D. B., Marsden, A. L., Fleischmann, D., Tavares, J. M., Bourauel, C., Geris, L., Slote, J. V. SPRINGER INTERNATIONAL PUBLISHING AG. 2023: 143-152

  View details for DOI 10.1007/978-3-031-10015-4_13

  View details for Web of Science ID 000876827700013

• Improved Right Ventricular Energy Efficiency by 4-Dimensional Flow Magnetic Resonance Imaging After Harmony Valve Implantation JACC:Advances Woo, J. P., Dong, M. L., Kong, F., McElhinney, D. B., Schiavone, N., Chan, F., Lui, G. K., Haddad, F., Bernstein, D., Marsden, A. 2023; 2 (3)

  View details for DOI 10.1016/j.jacadv.2023.100284

• A matched-pair case control study identifying hemodynamic predictors of cerebral aneurysm growth using computational fluid dynamics. Frontiers in physiology Weiss, A. J., Panduro, A. O., Schwarz, E. L., Sexton, Z. A., Lan, I. S., Geisbush, T. R., Marsden, A. L., Telischak, N. A. 2023; 14: 1300754

  Abstract

  Introduction: Initiation and progression of cerebral aneurysms is known to be driven by complex interactions between biological and hemodynamic factors, but the hemodynamic mechanism which drives aneurysm growth is unclear. We employed robust modeling and computational methods, including temporal and spatial convergence studies, to study hemodynamic characteristics of cerebral aneurysms and identify differences in these characteristics between growing and stable aneurysms. Methods: Eleven pairs of growing and non-growing cerebral aneurysms, matched in both size and location, were modeled from MRA and CTA images, then simulated using computational fluid dynamics (CFD). Key hemodynamic characteristics, including wall shear stress (WSS), oscillatory shear index (OSI), and portion of the aneurysm under low shear, were evaluated. Statistical analysis was then performed using paired Wilcoxon rank sum tests. Results: The portion of the aneurysm dome under 70% of the parent artery mean wall shear stress was higher in growing aneurysms than in stable aneurysms and had the highest significance among the tested metrics (p = 0.08). Other metrics of area under low shear had similar levels of significance. Discussion: These results align with previously observed hemodynamic trends in cerebral aneurysms, indicating a promising direction for future study of low shear area and aneurysm growth. We also found that mesh resolution significantly affected simulated WSS in cerebral aneurysms. This establishes that robust computational modeling methods are necessary for high fidelity results. Together, this work demonstrates that complex hemodynamics are at play within cerebral aneurysms, and robust modeling and simulation methods are needed to further study this topic.

  View details for DOI 10.3389/fphys.2023.1300754

  View details for PubMedID 38162830

• 4D flow cardiovascular magnetic resonance recovery profiles following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Dong, M. L., Azarine, A., Haddad, F., Amsallem, M., Kim, Y., Yang, W., Fadel, E., Aubrege, L., Loecher, M., Ennis, D., Pavec, J. L., Vignon-Clementel, I., Feinstein, J. A., Mercier, O., Marsden, A. L. 2022; 24 (1): 59

  Abstract

  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.

  View details for DOI 10.1186/s12968-022-00893-x

  View details for PubMedID 36372884

• High Shear Stress Decreases ERG Causing Endothelial to Mesenchymal Transition and Pulmonary Arterial Hypertension Shinohara, T., Moonen, J. A., Okamura, K., Szafron, J., Taylor, S., Isobe, S., Dong, M. L., Cao, A., Wang, L., Marsden, A. L., Korbelin, J., Rabinovitch, M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000890856901216

• svMorph: Interactive Geometry-Editing Tools for Virtual Patient-Specific Vascular Anatomies. Journal of biomechanical engineering Pham, J., Wyetzner, S., Pfaller, M., Parker, D., James, D., Marsden, A. 2022

  Abstract

  We propose svMorph, a framework for interactive virtual sculpting of patient-specific vascular anatomic models. Our framework includes three tools for the creation of tortuosity, aneurysms, and stenoses in tubular vascular geometries. These shape edits are performed via geometric operations on the surface mesh and vessel centerline curves of the input model. The tortuosity tool also uses the physics-based Oriented Particles method, coupled with linear blend skinning, to achieve smooth, elastic-like deformations. Our tools can be applied separately or in combination to produce simulation-suitable morphed models. They are also compatible with popular vascular modeling software, such as SimVascular. To illustrate our tools, we morph several image-based, patient-specific models to create a range of shape changes and simulate the resulting hemodynamics via three-dimensional, computational fluid dynamics. We also demonstrate the ability to quickly estimate the hemodynamic effects of the shape changes via automated generation of associated zero-dimensional lumped-parameter models.

  View details for DOI 10.1115/1.4056055

  View details for PubMedID 36282508

• Patient-Specific Computational Flow Simulation Reveals Significant Differences in Paravisceral Aortic Hemodynamics Between Fenestrated and Branched Endovascular Aneurysm Repair Tran, K., DeGlise, S., Deslarzes-Dubuis, C., Kaladji, A., Yang, W., Marsden, A., Lee, J. MOSBY-ELSEVIER. 2022: E83-E84

  View details for Web of Science ID 000868486600062

• How viscous is the beating heart?: Insights from a computational study. Computational mechanics Tikenoğulları, O. Z., Costabal, F. S., Yao, J., Marsden, A., Kuhl, E. 2022; 70 (3): 565-579

  Abstract

  Understanding tissue rheology is critical to accurately model the human heart. While the elastic properties of cardiac tissue have been extensively studied, its viscous properties remain an issue of ongoing debate. Here we adopt a viscoelastic version of the classical Holzapfel Ogden model to study the viscous timescales of human cardiac tissue. We perform a series of simulations and explore stress-relaxation curves, pressure-volume loops, strain profiles, and ventricular wall strains for varying viscosity parameters. We show that the time window for model calibration strongly influences the parameter identification. Using a four-chamber human heart model, we observe that, during the physiologically relevant time scales of the cardiac cycle, viscous relaxation has a negligible effect on the overall behavior of the heart. While viscosity could have important consequences in pathological conditions with compromised contraction or relaxation properties, we conclude that, for simulations within the physiological range of a human heart beat, we can reasonably approximate the human heart as hyperelastic.

  View details for DOI 10.1007/s00466-022-02180-z

  View details for PubMedID 37274842

  View details for PubMedCentralID PMC10237084

• Biodegradable external wrapping promotes favorable adaptation in an ovine vein graft model. Acta biomaterialia Ramachandra, A. B., Wang, H., Wnorowski, A., Schwarz, E. L., Pickering, J., Heiler, J. C., Lucian, H. J., Hironaka, C. E., Tran, N. A., Liu, Y., Khan, M. O., Obafemi, O., Tada, Y., Kahn, A. M., Sayed, N., Wu, J. C., Humphrey, J. D., Boyd, J., Marsden, A. L. 2022

  Abstract

  Vein grafts, the most commonly used conduits in multi-vessel coronary artery bypass grafting surgery, have high intermediate- and long-term failure rates. The abrupt and marked increase in hemodynamic loads on the vein graft is a known contributor to failure. Recent computational modeling suggests that veins can more successfully adapt to an increase in mechanical load if the rate of loading is gradual. Applying an external wrap or support at the time of surgery is one way to reduce the transmural load, and this approach has improved performance relative to an unsupported vein graft in several animal studies. Yet, a clinical trial in humans has shown benefits and drawbacks, and mechanisms by which an external wrap affects vein graft adaptation remain unknown. This study aims to elucidate such mechanisms using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, hemodynamics using computational fluid dynamics, structure using histology, and transcriptional changes using bulk RNA-sequencing in an ovine carotid-jugular interposition vein graft model, without and with an external biodegradable wrap that allows loads to increase gradually. We show that a biodegradable external wrap promotes luminal uniformity, physiological wall shear stress, and a consistent vein graft phenotype, namely, it prevents over-distension, over-thickening, intimal hyperplasia, and inflammation, and it preserves mechanotransduction. These mechanobiological insights into vein graft adaptation in the presence of an external support can inform computational growth and remodeling models of external support and facilitate design and manufacturing of next-generation external wrapping devices. STATEMENT OF SIGNIFICANCE: External mechanical support is emerging as a promising technology to prevent vein graft failure following coronary bypass graft surgery. While variants of this technology are currently under investigation in clinical trials, the fundamental mechanisms of adaptation remain poorly understood. We employ an ovine carotid-jugular interposition vein graft model, with and without an external biodegradable wrap to provide mechanical support, and probe vein graft adaptation using a multimodal experimental and computational data collection pipeline. We quantify morphometry using magnetic resonance imaging, mechanics using biaxial testing, fluid flow using computational fluid dynamics, vascular composition and structure using histology, and transcriptional changes using bulk RNA sequencing. We show that the wrap mitigates vein graft failure by promoting multiple adaptive mechanisms (across biological scales).

  View details for DOI 10.1016/j.actbio.2022.08.029

  View details for PubMedID 35995404

• Validation of the Reduced Unified Continuum Formulation Against In Vitro 4D-Flow MRI. Annals of biomedical engineering Lan, I. S., Liu, J., Yang, W., Zimmermann, J., Ennis, D. B., Marsden, A. L. 2022

  Abstract

  We previously introduced and verified the reduced unified continuum formulation for vascular fluid-structure interaction (FSI) against Womersley's deformable wall theory. Our present work seeks to investigate its performance in a patient-specific aortic setting in which assumptions of idealized geometries and velocity profiles are invalid. Specifically, we leveraged 2D magnetic resonance imaging (MRI) and 4D-flow MRI to extract high-resolution anatomical and hemodynamic information from an in vitro flow circuit embedding a compliant 3D-printed aortic phantom. To accurately reflect experimental conditions, we numerically implemented viscoelastic external tissue support, vascular tissue prestressing, and skew boundary conditions enabling in-plane vascular motion at each inlet and outlet. Validation of our formulation is achieved through close quantitative agreement in pressures, lumen area changes, pulse wave velocity, and early systolic velocities, as well as qualitative agreement in late systolic flow structures. Our validated suite of FSI techniques offers a computationally efficient approach for numerical simulation of vascular hemodynamics. This study is among the first to validate a cardiovascular FSI formulation against an in vitro flow circuit involving a compliant vascular phantom of complex patient-specific anatomy.

  View details for DOI 10.1007/s10439-022-03038-4

  View details for PubMedID 35963921

• Framework for patient-specific simulation of hemodynamics in heart failure with counterpulsation support. Frontiers in cardiovascular medicine Arduini, M., Pham, J., Marsden, A. L., Chen, I. Y., Ennis, D. B., Dual, S. A. 2022; 9: 895291

  Abstract

  Despite being responsible for half of heart failure-related hospitalizations, heart failure with preserved ejection fraction (HFpEF) has limited evidence-based treatment options. Currently, a substantial clinical issue is that the disease etiology is very heterogenous with no patient-specific treatment options. Modeling can provide a framework for evaluating alternative treatment strategies. Counterpulsation strategies have the capacity to improve left ventricular diastolic filling by reducing systolic blood pressure and augmenting the diastolic pressure that drives coronary perfusion. Here, we propose a framework for testing the effectiveness of a soft robotic extra-aortic counterpulsation strategy using a patient-specific closed-loop hemodynamic lumped parameter model of a patient with HFpEF. The soft robotic device prototype was characterized experimentally in a physiologically pressurized (50-150 mmHg) soft silicone vessel and modeled as a combination of a pressure source and a capacitance. The patient-specific model was created using open-source software and validated against hemodynamics obtained by imaging of a patient (male, 87 years, HR = 60 bpm) with HFpEF. The impact of actuation timing on the flows and pressures as well as systolic function was analyzed. Good agreement between the patient-specific model and patient data was achieved with relative errors below 5% in all categories except for the diastolic aortic root pressure and the end systolic volume. The most effective reduction in systolic pressure compared to baseline (147 vs. 141 mmHg) was achieved when actuating 350 ms before systole. In this case, flow splits were preserved, and cardiac output was increased (5.17 vs. 5.34 L/min), resulting in increased blood flow to the coronaries (0.15 vs. 0.16 L/min). Both arterial elastance (0.77 vs. 0.74 mmHg/mL) and stroke work (11.8 vs. 10.6 kJ) were decreased compared to baseline, however left atrial pressure increased (11.2 vs. 11.5 mmHg). A higher actuation pressure is associated with higher systolic pressure reduction and slightly higher coronary flow. The soft robotic device prototype achieves reduced systolic pressure, reduced stroke work, slightly increased coronary perfusion, but increased left atrial pressures in HFpEF patients. In future work, the framework could include additional physiological mechanisms, a larger patient cohort with HFpEF, and testing against clinically used devices.

  View details for DOI 10.3389/fcvm.2022.895291

  View details for PubMedID 35979018

  View details for PubMedCentralID PMC9376255

• Blood flow modeling reveals improved collateral artery performance during the regenerative period in mammalian hearts. Nature cardiovascular research Anbazhakan, S., Rios Coronado, P. E., Sy-Quia, A. N., Seow, L. W., Hands, A. M., Zhao, M., Dong, M. L., Pfaller, M. R., Amir, Z. A., Raftrey, B. C., Cook, C. K., D'Amato, G., Fan, X., Williams, I. M., Jha, S. K., Bernstein, D., Nieman, K., Pașca, A. M., Marsden, A. L., Horse, K. R. 2022; 1 (8): 775-790

  Abstract

  Collateral arteries bridge opposing artery branches, forming a natural bypass that can deliver blood flow downstream of an occlusion. Inducing coronary collateral arteries could treat cardiac ischemia, but more knowledge on their developmental mechanisms and functional capabilities is required. Here we used whole-organ imaging and three-dimensional computational fluid dynamics modeling to define spatial architecture and predict blood flow through collaterals in neonate and adult mouse hearts. Neonate collaterals were more numerous, larger in diameter and more effective at restoring blood flow. Decreased blood flow restoration in adults arose because during postnatal growth coronary arteries expanded by adding branches rather than increasing diameters, altering pressure distributions. In humans, adult hearts with total coronary occlusions averaged 2 large collaterals, with predicted moderate function, while normal fetal hearts showed over 40 collaterals, likely too small to be functionally relevant. Thus, we quantify the functional impact of collateral arteries during heart regeneration and repair-a critical step toward realizing their therapeutic potential.

  View details for DOI 10.1038/s44161-022-00114-9

  View details for PubMedID 37305211

  View details for PubMedCentralID PMC10256232

• Automated generation of 0D and 1D reduced-order models of patient-specific blood flow. International journal for numerical methods in biomedical engineering Pfaller, M. R., Pham, J., Verma, A., Pegolotti, L., Wilson, N. M., Parker, D. W., Yang, W., Marsden, A. L. 2022: e3639

  Abstract

  Three-dimensional (3D) cardiovascular fluid dynamics simulations typically require hours to days of computing time on a high-performance computing cluster. One-dimensional (1D) and lumped-parameter zero-dimensional (0D) models show great promise for accurately predicting blood bulk flow and pressure waveforms with only a fraction of the cost. They can also accelerate uncertainty quantification, optimization, and design parameterization studies. Despite several prior studies generating 1D and 0D models and comparing them to 3D solutions, these were typically limited to either 1D or 0D and a singular category of vascular anatomies. This work proposes a fully automated and openly available framework to generate and simulate 1D and 0D models from 3D patient-specific geometries, automatically detecting vessel junctions and stenosis segments. Our only input is the 3D geometry; we do not use any prior knowledge from 3D simulations. All computational tools presented in this work are implemented in the open-source software platform SimVascular. We demonstrate the reduced-order approximation quality against rigid-wall 3D solutions in a comprehensive comparison with N=72 publicly available models from various anatomies, vessel types, and disease conditions. Relative average approximation errors of flows and pressures typically ranged from 1% to 10% for both 1D and 0D models, measured at the outlets of terminal vessel branches. In general, 0D model errors were only slightly higher than 1D model errors despite requiring only a third of the 1D runtime. Automatically generated ROMs can significantly speed up model development and shift the computational load from high-performance machines to personal computers. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/cnm.3639

  View details for PubMedID 35875875

• Elucidating tricuspid Doppler signal interpolation and its implication for assessing pulmonary hypertension PULMONARY CIRCULATION Dual, S. A., Verdonk, C., Amsallem, M., Pham, J., Obasohan, C., Nataf, P., McElhinney, D. B., Arunamata, A., Kuznetsova, T., Zamanian, R., Feinstein, J. A., Marsden, A., Haddad, F. 2022; 12 (3): e12125

  Abstract

  Doppler echocardiography plays a central role in the assessment of pulmonary hypertension (PAH). We aim to improve quality assessment of systolic pulmonary arterial pressure (SPAP) by applying a cubic polynomial interpolation to digitized tricuspid regurgitation (TR) waveforms. Patients with PAH and advanced lung disease were divided into three cohorts: a derivation cohort (n = 44), a validation cohort (n = 71), an outlier cohort (n = 26), and a non-PAH cohort (n = 44). We digitized TR waveforms and analyzed normalized duration, skewness, kurtosis, and first and second derivatives of pressure. Cubic polynomial interpolation was applied to three physiology-driven phases: the isovolumic phase, ejection phase, and "shoulder" point phase. Coefficients of determination and a Bland-Altman analysis was used to assess bias between methods. The cubic polynomial interpolation of the TR waveform correlated strongly with expert read right ventricular systolic pressure (RVSP) with R 2 > 0.910 in the validation cohort. The biases when compared to invasive SPAP measured within 24 h were 6.03 [4.33; 7.73], -2.94 [1.47; 4.41], and -3.11 [-4.52; -1.71] mmHg, for isovolumic, ejection, and shoulder point interpolations, respectively. In the outlier cohort with more than 30% difference between echocardiographic estimates and invasive SPAP, cubic polynomial interpolation significantly reduced underestimation of RVSP. Cubic polynomial interpolation of the TR waveform based on isovolumic or early ejection phase may improve RVSP estimates.

  View details for DOI 10.1002/pul2.12125

  View details for Web of Science ID 000843054900001

  View details for PubMedID 36016669

  View details for PubMedCentralID PMC9395694

• Controlled Comparison of Simulated Hemodynamics Across Tricuspid and Bicuspid Aortic Valves. Annals of biomedical engineering Kaiser, A. D., Shad, R., Schiavone, N., Hiesinger, W., Marsden, A. L. 2022

  Abstract

  Bicuspid aortic valve is the most common congenital heart defect, affecting 1-2% of the global population. Patients with bicuspid valves frequently develop dilation and aneurysms of the ascending aorta. Both hemodynamic and genetic factors are believed to contribute to dilation, yet the precise mechanism underlying this progression remains under debate. Controlled comparisons of hemodynamics in patients with different forms of bicuspid valve disease are challenging because of confounding factors, and simulations offer the opportunity for direct and systematic comparisons. Using fluid-structure interaction simulations, we simulate flows through multiple aortic valve models in a patient-specific geometry. The aortic geometry is based on a healthy patient with no known aortic or valvular disease, which allows us to isolate the hemodynamic consequences of changes to the valve alone. Four fully-passive, elastic model valves are studied: a tricuspid valve and bicuspid valves with fusion of the left- and right-, right- and non-, and non- and left-coronary cusps. The resulting tricuspid flow is relatively uniform, with little secondary or reverse flow, and little to no pressure gradient across the valve. The bicuspid cases show localized jets of forward flow, excess streamwise momentum, elevated secondary and reverse flow, and clinically significant levels of stenosis. Localized high flow rates correspond to locations of dilation observed in patients, with the location related to which valve cusps are fused. Thus, the simulations support the hypothesis that chronic exposure to high local flow contributes to localized dilation and aneurysm formation.

  View details for DOI 10.1007/s10439-022-02983-4

  View details for PubMedID 35748961

• Patient-specific fluid-structure simulations of anomalous aortic origin of right coronary arteries. JTCVS techniques Jiang, M. X., Khan, M. O., Ghobrial, J., Rogers, I. S., Pettersson, G. B., Blackstone, E. H., Marsden, A. L. 2022; 13: 144-162

  Abstract

  Objectives: Anomalous aortic origin of the right coronary artery (AAORCA) may cause ischemia and sudden death. However, the specific anatomic indications for surgery are unclear, so dobutamine-stress instantaneous wave-free ratio (iFR) is increasingly used. Meanwhile, advances in fluid-structure interaction (FSI) modeling can simulate the pulsatile hemodynamics and tissue deformation. We sought to evaluate the feasibility of simulating the resting and dobutamine-stress iFR in AAORCA using patient-specific FSI models and to visualize the mechanism of ischemia within the intramural geometry and associated lumen narrowing.Methods: We developed 6 patient-specific FSI models of AAORCA using SimVascular software. Three-dimensional geometries were segmented from coronary computed tomography angiography. Vascular outlets were coupled to lumped-parameter networks that included dynamic compression of the coronary microvasculature and were tuned to each patient's vitals and cardiac output.Results: All cases were interarterial, and 5 of 6 had an intramural course. Measured iFRs ranged from 0.95 to 0.98 at rest and 0.80 to 0.95 under dobutamine stress. After we tuned the distal coronary resistances to achieve a stress flow rate triple that at rest, the simulations adequately matched the measured iFRs (r=0.85, root-mean-square error=0.04). The intramural lumen remained narrowed with simulated stress and resulted in lower iFRs without needing external compression from the pulmonary root.Conclusions: Patient-specific FSI modeling of AAORCA is a promising, noninvasive method to assess the iFR reduction caused by intramural geometries and inform surgical intervention. However, the models' sensitivity to distal coronary resistance suggests that quantitative stress-perfusion imaging may augment virtual and invasive iFR studies.

  View details for DOI 10.1016/j.xjtc.2022.02.022

  View details for PubMedID 35711199

• How viscous is the beating heart? Insights from a computational study COMPUTATIONAL MECHANICS Tikenogullari, O., Costabal, F., Yao, J., Marsden, A., Kuhl, E. 2022

  View details for DOI 10.1007/s00466-022-02180-z

  View details for Web of Science ID 000799405900001

• A reduced unified continuum formulation for vascular fluid-structure interaction COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Lan, I. S., Liu, J., Yang, W., Marsden, A. L. 2022; 394

  View details for DOI 10.1016/j.cma.2022.114852

  View details for Web of Science ID 000821092400008

• Colocalization of Coronary Plaque with Wall Shear Stress in Myocardial Bridge Patients. Cardiovascular engineering and technology Khan, M. O., Nishi, T., Imura, S., Seo, J., Wang, H., Honda, Y., Nieman, K., Rogers, I. S., Tremmel, J. A., Boyd, J., Schnittger, I., Marsden, A. 2022

  Abstract

  PURPOSE: Patients with myocardial bridges (MBs) have a higher prevalence of atherosclerosis. Wall shear stress (WSS) has previously been correlated with plaque in coronary artery disease patients, but such correlations have not been investigated in symptomatic MB patients. The aim of this paper was to use a multi-scale computational fluid dynamics (CFD) framework to simulate hemodynamics in MB patient, and investigate the co-localization of WSS and plaque.METHODS: We identified N = 10 patients from a previously reported cohort of 50 symptomatic MB patients, all of whom had plaque in the proximal vessel. Dynamic 3D models were reconstructed from coronary computed tomography angiography (CCTA), intravascular ultrasound (IVUS) and catheter angiograms. CFD simulations were performed to compute WSS proximal to, within and distal to the MB. Plaque was quantified from IVUS images in 2 mm segments and registered to CFD model. Plaque area was compared to absolute and patient-normalized WSS.RESULTS: WSS was lower in the proximal segment compared to the bridge segment (6.1 ± 2.9 vs. 16.0 ± 7.1 dynes/cm2, p value < 0.01). Plaque area and plaque burden measured from IVUS peaked at 1-3 cm proximal to the MB entrance, coinciding with the first diagonal branch. Normalized WSS showed a statistically significant moderate correlation with plaque area (r = 0.41, p < 0.01).CONCLUSION: WSS may be obtained non-invasively in MB patients and provides a surrogate marker of plaque area. Using CFD, it may be possible to non-invasively assess the extent of plaque area, and identify patients who could benefit from frequent monitoring or medical management.

  View details for DOI 10.1007/s13239-022-00616-4

  View details for PubMedID 35296987

• Virtual Transcatheter Interventions for Peripheral Pulmonary Artery Stenosis in Williams and Alagille Syndromes. Journal of the American Heart Association Lan, I. S., Yang, W., Feinstein, J. A., Kreutzer, J., Collins, R. T., Ma, M., Adamson, G. T., Marsden, A. L. 2022: e023532

  Abstract

  Background Despite favorable outcomes of surgical pulmonary artery (PA) reconstruction, isolated proximal stenting of the central PAs is common clinical practice for patients with peripheral PA stenosis in association with Williams and Alagille syndromes. Given the technical challenges of PA reconstruction and the morbidities associated with transcatheter interventions, the hemodynamic consequences of all treatment strategies must be rigorously assessed. Our study aims to model, assess, and predict hemodynamic outcomes of transcatheter interventions in these patients. Methods and Results Isolated proximal and "extensive" interventions (stenting and/or balloon angioplasty of proximal and lobar vessels) were performed in silico on 6 patient-specific PA models. Autoregulatory adaptation of the cardiac output and downstream arterial resistance was modeled in response to intervention-induced hemodynamic perturbations. Postintervention computational fluid dynamics predictions were validated in 2 stented patients and quantitatively assessed in 4 surgical patients. Our computational methods accurately predicted postinterventional PA pressures, the primary indicators of success for treatment of peripheral PA stenosis. Proximal and extensive treatment achieved median reductions of 14% and 40% in main PA systolic pressure, 27% and 56% in pulmonary vascular resistance, and 10% and 45% in right ventricular stroke work, respectively. Conclusions In patients with Williams and Alagille syndromes, extensive transcatheter intervention is required to sufficiently reduce PA pressures and right ventricular stroke work. Transcatheter therapy was shown to be ineffective for long-segment stenosis and pales hemodynamically in comparison with published outcomes of surgical reconstruction. Regardless of the chosen strategy, a virtual treatment planning platform could identify lesions most critical for optimizing right ventricular afterload.

  View details for DOI 10.1161/JAHA.121.023532

  View details for PubMedID 35253446

• Comparison of Hemodynamic Changes Associated With Two-Versus Four-Vessel Fenestrated Endovascular Aneurysm Repair Using Patient-specific Computational Flow Modeling Tran, K., Kaladji, A., Yang, W., Marsden, A., Lee, J. MOSBY-ELSEVIER. 2022: E41-E42

  View details for Web of Science ID 000758691500053

• Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth. Communications medicine Blum, K. M., Zbinden, J. C., Ramachandra, A. B., Lindsey, S. E., Szafron, J. M., Reinhardt, J. W., Heitkemper, M., Best, C. A., Mirhaidari, G. J., Chang, Y., Ulziibayar, A., Kelly, J., Shah, K. V., Drews, J. D., Zakko, J., Miyamoto, S., Matsuzaki, Y., Iwaki, R., Ahmad, H., Daulton, R., Musgrave, D., Wiet, M. G., Heuer, E., Lawson, E., Schwarz, E., McDermott, M. R., Krishnamurthy, R., Krishnamurthy, R., Hor, K., Armstrong, A. K., Boe, B. A., Berman, D. P., Trask, A. J., Humphrey, J. D., Marsden, A. L., Shinoka, T., Breuer, C. K. 2022; 2: 3

  Abstract

  Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity.Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models.Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information.Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

  View details for DOI 10.1038/s43856-021-00063-7

  View details for PubMedID 35603301

• SimVascular Gateway for Education and Research Tran, J., Abeysinghe, E., LaDisa, J., Marsden, A., Pierce, M., ACM ASSOC COMPUTING MACHINERY. 2022

  View details for DOI 10.1145/3491418.3535162

  View details for Web of Science ID 001051711300067

• Numerical investigation of abdominal aortic aneurysm hemodynamics using the reduced unified continuum formulation for vascular fluid-structure interaction Forces in Mechanics Lan, I. S., Liu, J., Yang, W., Marsden, A. L. 2022; 7

  View details for DOI 10.1016/j.finmec.2022.100089

• A Mechanistic Lumped Parameter Model of the Berlin Heart EXCOR to Analyze Device Performance and Physiologic Interactions. Cardiovascular engineering and technology Yuan, V., Verma, A., Schiavone, N. K., Rosenthal, D. N., Marsden, A. L. 2022

  Abstract

  The Berlin Heart EXCOR (BH) is the only FDA-approved, extracorporeal pulsatile ventricular assist device (VAD) for infants and children with heart failure. Clinicians control four settings on the device-systolic and diastolic drive pressures, device pump rate, and systolic time as a percentage of the pump cycle. However, interactions between BH pneumatics and the native circulation remain poorly understood. Thus, establishing appropriate device size and settings can be challenging on a patient-to-patient basis.In this study we develop a novel lumped parameter network based on simplified device mechanics. We perform parametric studies to characterize device behavior, study interactions between the left ventricle (LV) and BH across different device settings, and develop patient-specific simulations. We then simulate the impact of changing device parameters for each of three patients.Increasing systolic pressure and systolic time increased device output. We identified previously unobserved cycle-to-cycle variations in LV-BH interactions that may impact patient health. Patient-specific simulations demonstrated the model's ability to replicate BH performance, captured trends in LV behavior after device implantation, and emphasized the importance of device rate and volume in optimizing BH efficiency.We present a novel, mechanistic model that can be readily adjusted to study a wide range of device settings and clinical scenarios. Physiologic interactions between the BH and the native LV produced large variability in cardiac loading. Our findings showed that operating the BH at a device rate greater than the patient's native heart decreases variability in physiological interactions between the BH and LV, increasing cardiac offloading while maintaining cardiac output. Device rates that are close to the resting heart rate may result in unfavorable cardiac loading conditions. Our work demonstrates the utility of our model to investigate BH performance for patient-specific physiologies.

  View details for DOI 10.1007/s13239-021-00603-1

  View details for PubMedID 34997556

• Computational simulations of the 4D micro-circulatory network in zebrafish tail amputation and regeneration. Journal of the Royal Society, Interface Roustaei, M., In Baek, K., Wang, Z., Cavallero, S., Satta, S., Lai, A., O'Donnell, R., Vedula, V., Ding, Y., Marsden, A. L., Hsiai, T. K. 2022; 19 (187): 20210898

  Abstract

  Wall shear stress (WSS) contributes to the mechanotransduction underlying microvascular development and regeneration. Using computational fluid dynamics, we elucidated the interplay between WSS and vascular remodelling in a zebrafish model of tail amputation and regeneration. The transgenic Tg (fli1:eGFP; Gata1:ds-red) zebrafish line was used to track the three-dimensional fluorescently labelled vascular endothelium for post-image segmentation and reconstruction of the fluid domain. Particle image velocimetry was used to validate the blood flow. Following amputation to the dorsal aorta and posterior cardinal vein (PCV), vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) along with increased WSS in the proximal segmental vessels (SVs) from amputation. Angiogenesis ensued at the tips of the amputated DLAV and PCV where WSS was minimal. At 2 days post amputation (dpa), vasodilation occurred in a pair of SVs proximal to amputation, followed by increased blood flow and WSS; however, in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the blood flow increased in the arterial SV proximal to amputation and through anastomosis with DLAV formed a loop with PCV. Thus, our in silico modelling revealed the interplay between WSS and microvascular adaptation to changes in WSS and blood flow to restore microcirculation following tail amputation.

  View details for DOI 10.1098/rsif.2021.0898

  View details for PubMedID 35167770

• Patient-specific changes in aortic hemodynamics is associated with thrombotic risk after fenestrated endovascular aneurysm repair with large diameter endografts. JVS-vascular science Tran, K., Feliciano, K. B., Yang, W., Schwarz, E. L., Marsden, A. L., Dalman, R. L., Lee, J. T. 2022; 3: 219-231

  Abstract

  Background: The durability of fenestrated endovascular aneurysm repair (fEVAR) has been threatened by thrombotic complications. In the present study, we used patient-specific computational fluid dynamic (CFD) simulation to investigate the effect of the endograft diameter on hemodynamics after fEVAR and explore the hypothesis that diameter-dependent alterations in aortic hemodynamics can predict for thrombotic events.Methods: A single-institutional retrospective study was performed of patients who had undergone fEVAR for juxtarenal aortic aneurysms. The patients were stratified into large diameter (34-36mm) and small diameter (24-26mm) endograft groups. Patient-specific CFD simulations were performed using three-dimensional paravisceral aortic models created from computed tomographic images with allometrically scaled boundary conditions. Aortic time-averaged wall shear stress (TAWSS) and residence time (RT) were computed and correlated with future thrombotic complications (eg, renal stent occlusion, development of significant intraluminal graft thrombus).Results: A total of 36 patients (14 with a small endograft and 22 with a large endograft) were included in the present study. The patients treated with large endografts had experienced a higher incidence of thrombotic complications compared with small endografts (45.5% vs 7.1%; P= .016). Large endografts were associated with a lower postoperative aortic TAWSS (1.45± 0.76dynes/cm2 vs 3.16± 1.24dynes/cm2; P< .001) and longer aortic RT (0.78± 0.30second vs 0.34± 0.08second; P< .001). In the large endograft group, a reduction >0.39dynes/cm2 in aortic TAWSS demonstrated discriminatory power for thrombotic complications (area under the receiver operating characteristic curve, 0.77). An increased aortic RT of ≥0.05second had similar accuracy for predicting thrombotic complications (area under the receiver operating characteristic curve, 0.78). The odds of thrombotic complications were significantly higher if patients had met the hemodynamic threshold changes in aortic TAWSS (odds ratio, 7.0; 95% confidence interval, 1.1-45.9) and RT (odds ratio, 8.0; 95% confidence interval, 1.13-56.8).Conclusions: Patient-specific CFD simulation of fEVAR in juxtarenal aortic aneurysms demonstrated significant endograft diameter-dependent differences in aortic hemodynamics. A postoperative reduction in TAWSS and an increased RT correlated with future thrombotic events after large-diameter endograft implantation. Patient-specific simulation of hemodynamics provides a novel method for thrombotic risk stratification after fEVAR.

  View details for DOI 10.1016/j.jvssci.2022.04.002

  View details for PubMedID 35647564

• Preoperative Computed Tomography Angiography Reveals Leaflet-Specific Calcification and Excursion Patterns in Aortic Stenosis. Circulation. Cardiovascular imaging Chen, I. Y., Vedula, V., Malik, S. B., Liang, T., Chang, A. Y., Chung, K. S., Sayed, N., Tsao, P. S., Giacomini, J. C., Marsden, A. L., Wu, J. C. 1800: CIRCIMAGING121012884

  Abstract

  BACKGROUND: Computed tomography-based evaluation of aortic stenosis (AS) by calcium scoring does not consider interleaflet differences in leaflet characteristics. Here, we sought to examine the functional implications of these differences.METHODS: We retrospectively reviewed the computed tomography angiograms of 200 male patients with degenerative calcific AS undergoing transcatheter aortic valve replacement and 20 male patients with normal aortic valves. We compared the computed tomography angiography (CTA)-derived aortic valve leaflet calcification load (AVLCCTA), appearance, and systolic leaflet excursion (LEsys) of individual leaflets. We performed computer simulations of normal valves to investigate how interleaflet differences in LEsys affect aortic valve area. We used linear regression to identify predictors of leaflet-specific calcification in patients with AS.RESULTS: In patients with AS, the noncoronary cusp (NCC) carried the greatest AVLCCTA (365.9 [237.3-595.4] Agatston unit), compared to the left coronary cusp (LCC, 278.5 [169.2-478.8] Agatston unit) and the right coronary cusp (RCC, 240.6 [137.3-439.0] Agatston unit; both P<0.001). However, LCC conferred the least LEsys (42.8 [38.8-49.0]) compared to NCC (44.8 [41.1-49.78], P=0.001) and RCC (47.7 [42.0-52.3], P<0.001) and was more often characterized as predominantly thickened (23.5%) compared to NCC (12.5%) and RCC (16.5%). Computer simulations of normal valves revealed greater reductions in aortic valve area following closures of NCC (-32.2 [-38.4 to -25.8]%) and RCC (-35.7 [-40.2 to -32.9]%) than LCC (-24.5 [-28.5 to -18.3]%; both P<0.001). By linear regression, the AVLCCTA of NCC and RCC, but not LCC, predicted LEsys (both P<0.001) in patients with AS. Both ostial occlusion and ostial height of the right coronary artery predicted AVLCCTA, RCC (P=0.005 and P=0.001).CONCLUSIONS: In male patients, the AVLCCTA of NCC and RCC contribute more to AS than that of LCC. LCC's propensity for noncalcific leaflet thickening and worse LEsys, however, should not be underestimated when using calcium scores to assess AS severity.

  View details for DOI 10.1161/CIRCIMAGING.121.012884

  View details for PubMedID 34915729

• Geometric uncertainty in patient-specific cardiovascular modeling with convolutional dropout networks COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Maher, G. D., Fleeter, C. M., Schiavazzi, D. E., Marsden, A. L. 2021; 386

  View details for DOI 10.1016/j.cma.2021.114038

  View details for Web of Science ID 000703985200002

• Geometric Uncertainty in Patient-Specific Cardiovascular Modeling with Convolutional Dropout Networks. Computer methods in applied mechanics and engineering Maher, G. D., Fleeter, C. M., Schiavazzi, D. E., Marsden, A. L. 2021; 386

  Abstract

  We propose a novel approach to generate samples from the conditional distribution of patient-specific cardiovascular models given a clinically aquired image volume. A convolutional neural network architecture with dropout layers is first trained for vessel lumen segmentation using a regression approach, to enable Bayesian estimation of vessel lumen surfaces. This network is then integrated into a path-planning patient-specific modeling pipeline to generate families of cardiovascular models. We demonstrate our approach by quantifying the effect of geometric uncertainty on the hemodynamics for three patient-specific anatomies, an aorto-iliac bifurcation, an abdominal aortic aneurysm and a sub-model of the left coronary arteries. A key innovation introduced in the proposed approach is the ability to learn geometric uncertainty directly from training data. The results show how geometric uncertainty produces coefficients of variation comparable to or larger than other sources of uncertainty for wall shear stress and velocity magnitude, but has limited impact on pressure. Specifically, this is true for anatomies characterized by small vessel sizes, and for local vessel lesions seen infrequently during network training.

  View details for DOI 10.1016/j.cma.2021.114038

  View details for PubMedID 34737480

  View details for PubMedCentralID PMC8562598

• A continuum and computational framework for viscoelastodynamics: I. Finite deformation linear models COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Liu, J., Latorre, M., Marsden, A. L. 2021; 385

  View details for DOI 10.1016/j.cma.2021.114059

  View details for Web of Science ID 000691817900002

• A design-based model of the aortic valve for fluid-structure interaction. Biomechanics and modeling in mechanobiology Kaiser, A. D., Shad, R., Hiesinger, W., Marsden, A. L. 2021

  Abstract

  This paper presents a new method for modeling the mechanics of the aortic valve and simulates its interaction with blood. As much as possible, the model construction is based on first principles, but such that the model is consistent with experimental observations. We require that tension in the leaflets must support a pressure, then derive a system of partial differential equations governing its mechanical equilibrium. The solution to these differential equations is referred to as the predicted loaded configuration; it includes the loaded leaflet geometry, fiber orientations and tensions needed to support the prescribed load. From this configuration, we derive a reference configuration and constitutive law. In fluid-structure interaction simulations with the immersed boundary method, the model seals reliably under physiological pressures and opens freely over multiple cardiac cycles. Further, model closure is robust to extreme hypo- and hypertensive pressures. Then, exploiting the unique features of this model construction, we conduct experiments on reference configurations, constitutive laws and gross morphology. These experiments suggest the following conclusions: (1) The loaded geometry, tensions and tangent moduli primarily determine model function. (2) Alterations to the reference configuration have little effect if the predicted loaded configuration is identical. (3) The leaflets must have sufficiently nonlinear material response to function over a variety of pressures. (4) Valve performance is highly sensitive to free edge length and leaflet height. These conclusions suggest appropriate gross morphology and material properties for the design of prosthetic aortic valves. In future studies, our aortic valve modeling framework can be used with patient-specific models of vascular or cardiac flow.

  View details for DOI 10.1007/s10237-021-01516-7

  View details for PubMedID 34549354

• Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease. PLoS computational biology Grande Gutierrez, N., Alber, M., Kahn, A. M., Burns, J. C., Mathew, M., McCrindle, B. W., Marsden, A. L. 2021; 17 (9): e1009331

  Abstract

  Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient.

  View details for DOI 10.1371/journal.pcbi.1009331

  View details for PubMedID 34491991

• Publisher Correction: Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients. NPJ Regenerative medicine Schwarz, E. L., Kelly, J. M., Blum, K. M., Hor, K. N., Yates, A. R., Zbinden, J. C., Verma, A., Lindsey, S. E., Ramachandra, A. B., Szafron, J. M., Humphrey, J. D., Shin'oka, T., Marsden, A. L., Breuer, C. K. 2021; 6 (1): 47

  View details for DOI 10.1038/s41536-021-00157-9

  View details for PubMedID 34385470

• Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients. NPJ Regenerative medicine Schwarz, E. L., Kelly, J. M., Blum, K. M., Hor, K. N., Yates, A. R., Zbinden, J. C., Verma, A., Lindsey, S. E., Ramachandra, A. B., Szafron, J. M., Humphrey, J. D., Shin'oka, T., Marsden, A. L., Breuer, C. K. 2021; 6 (1): 38

  Abstract

  In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

  View details for DOI 10.1038/s41536-021-00148-w

  View details for PubMedID 34294733

• Model order reduction of flow based on a modular geometrical approximation of blood vessels. Computer methods in applied mechanics and engineering Pegolotti, L., Pfaller, M. R., Marsden, A. L., Deparis, S. 2021; 380

  Abstract

  We are interested in a reduced order method for the efficient simulation of blood flow in arteries. The blood dynamics is modeled by means of the incompressible Navier-Stokes equations. Our algorithm is based on an approximated domain-decomposition of the target geometry into a number of subdomains obtained from the parametrized deformation of geometrical building blocks (e.g., straight tubes and model bifurcations). On each of these building blocks, we build a set of spectral functions by Proper Orthogonal Decomposition of a large number of snapshots of finite element solutions (offline phase). The global solution of the Navier-Stokes equations on a target geometry is then found by coupling linear combinations of these local basis functions by means of spectral Lagrange multipliers (online phase). Being that the number of reduced degrees of freedom is considerably smaller than their finite element counterpart, this approach allows us to significantly decrease the size of the linear system to be solved in each iteration of the Newton-Raphson algorithm. We achieve large speedups with respect to the full order simulation (in our numerical experiments, the gain is at least of one order of magnitude and grows inversely with respect to the reduced basis size), whilst still retaining satisfactory accuracy for most cardiovascular simulations.

  View details for DOI 10.1016/j.cma.2021.113762

  View details for PubMedID 34176992

• On the Periodicity of Cardiovascular Fluid Dynamics Simulations. Annals of biomedical engineering Pfaller, M. R., Pham, J., Wilson, N. M., Parker, D. W., Marsden, A. L. 2021

  Abstract

  Three-dimensional cardiovascular fluid dynamics simulations typically require computation of several cardiac cycles before they reach a periodic solution, rendering them computationally expensive. Furthermore, there is currently no standardized method to determine whether a simulation has yet reached that periodic state. In this work, we propose the use of an asymptotic error measurement to quantify the difference between simulation results and their ideal periodic state using open-loop lumped-parameter modeling. We further show that initial conditions are crucial in reducing computational time and develop an automated framework to generate appropriate initial conditions from a one-dimensional model of blood flow. We demonstrate the performance of our initialization method using six patient-specific models from the Vascular Model Repository. In our examples, our initialization protocol achieves periodic convergence within one or two cardiac cycles, leading to a significant reduction in computational cost compared to standard methods. All computational tools used in this work are implemented in the open-source software platform SimVascular. Automatically generated initial conditions have the potential to significantly reduce computation time in cardiovascular fluid dynamics simulations.

  View details for DOI 10.1007/s10439-021-02796-x

  View details for PubMedID 34169398

• Patient-Specific Computational Fluid Dynamics Reveal Localized Flow Patterns Predictive of Post-Left Ventricular Assist Device Aortic Incompetence. Circulation. Heart failure Shad, R., Kaiser, A. D., Kong, S., Fong, R., Quach, N., Bowles, C., Kasinpila, P., Shudo, Y., Teuteberg, J., Woo, Y. J., Marsden, A. L., Hiesinger, W. 2021: CIRCHEARTFAILURE120008034

  Abstract

  BACKGROUND: Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem.METHODS: Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients' aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver.RESULTS: The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm2 [95% CI, -0.51 to 1.85]; P=0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, -0.07 to 0.019]; P=0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm2; mean difference [95% CI, 0.15-0.39]; P<0.001), whereas oscillatory shear index was not significantly different between both groups (95% CI, -0.009 to 0.001; P=0.17).CONCLUSIONS: Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.008034

  View details for PubMedID 34139862

• RIGHT VENTRICULAR OUTFLOW TRACT AND PULMONARY ARTERY GEOMETRY IN PATIENTS WITH REPAIRED TETRALOGY OF FALLOT PRIOR TO PULMONARY VALVE REPLACEMENT-CHARACTERIZATION AND LONGITUDINAL ASSOCIATION WITH BIOPROSTHETIC VALVE FUNCTION Arana, V., Chan, F., Schiavone, N., Reddy, S., Hanley, F., Marsden, A., McElhinney, D. ELSEVIER SCIENCE INC. 2021: 1410

  View details for Web of Science ID 000647487501418

• Patient-specific computational fluid dynamic simulation for assessing hemodynamic changes following branched endovascular aneurysm repair: A pilot study Tran, K., Deslarzes, C., Marsden, A., Lee, J., Deglise, S. OXFORD UNIV PRESS. 2021

  View details for DOI 10.1093/bjs/znab202.068

  View details for Web of Science ID 000656262000069

• A unified continuum and variational multiscale formulation for fluids, solids, and fluid-structure interaction (vol 337, pg 549, 2018) COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Liu, J., Marsden, A. L. 2021; 375

  View details for DOI 10.1016/j.cma.2020.113520

  View details for Web of Science ID 000608741000001

• Fluid-structure interaction modeling of blood flow in the pulmonary arteries using the unified continuum and variational multiscale formulation (Rerpinted from vol 107, 103556, 2020) MECHANICS RESEARCH COMMUNICATIONS Liu, J., Yang, W., Lan, I. S., Marsden, A. L. 2021; 112

  View details for DOI 10.1016/j.mechrescom.2021.103704

  View details for Web of Science ID 000661385300007

• Computational evaluation of venous graft geometries in coronary artery bypass surgery. Seminars in thoracic and cardiovascular surgery Seo, J. n., Ramachandra, A. B., Boyd, J. n., Marsden, A. L., Kahn, A. M. 2021

  Abstract

  Cardiothoracic surgeons are faced with a choice of different revascularization techniques and diameters for saphenous vein grafts (SVG) in coronary artery bypass graft surgery (CABG). Using computational simulations, we virtually investigate the effect of SVG geometry on hemodynamics of both venous grafts and the target coronary arteries. We generated patient-specific three-dimensional anatomic models of CABG patients and quantified mechanical stimuli. We performed virtual surgery on three patient-specific models by modifying the geometry vein grafts to reflect single, Y, and sequential surgical configurations with SVG diameters ranging from 2 mm to 5 mm. Our study demonstrates that the coronary artery runoffs are relatively insensitive to the choice of SVG revascularization geometry. We observe a 10% increase in runoff when the SVG diameter is changed from 2 mm to 5 mm. The wall shear stress (WSS) of SVG increases dramatically when the diameter drops, following an inverse power scaling with diameter. For a fixed diameter, the average wall shear stress on the vein graft varies in ascending order as single, Y, and sequential graft in the patient cohort. The runoff to the target coronary arteries changes marginally due to the choice of graft configuration or diameter. The shear stress on the vein graft depends on both flow rate and diameter and follows an inverse power scaling consistent with a Poiseuille flow assumption. Given the similarity in runoff with different surgical configurations, choices of SVG geometries can be informed by propensity for graft failure using shear stress evaluations.

  View details for DOI 10.1053/j.semtcvs.2021.03.007

  View details for PubMedID 33711465

• Predictive Modeling of Secondary Pulmonary Hypertension in Left Ventricular Diastolic Dysfunction. Frontiers in physiology Harrod, K. K., Rogers, J. L., Feinstein, J. A., Marsden, A. L., Schiavazzi, D. E. 2021; 12: 666915

  Abstract

  Diastolic dysfunction is a common pathology occurring in about one third of patients affected by heart failure. This condition may not be associated with a marked decrease in cardiac output or systemic pressure and therefore is more difficult to diagnose than its systolic counterpart. Compromised relaxation or increased stiffness of the left ventricle induces an increase in the upstream pulmonary pressures, and is classified as secondary or group II pulmonary hypertension (2018 Nice classification). This may result in an increase in the right ventricular afterload leading to right ventricular failure. Elevated pulmonary pressures are therefore an important clinical indicator of diastolic heart failure (sometimes referred to as heart failure with preserved ejection fraction, HFpEF), showing significant correlation with associated mortality. However, accurate measurements of this quantity are typically obtained through invasive catheterization and after the onset of symptoms. In this study, we use the hemodynamic consistency of a differential-algebraic circulation model to predict pulmonary pressures in adult patients from other, possibly non-invasive, clinical data. We investigate several aspects of the problem, including the ability of model outputs to represent a sufficiently wide pathologic spectrum, the identifiability of the model's parameters, and the accuracy of the predicted pulmonary pressures. We also find that a classifier using the assimilated model parameters as features is free from the problem of missing data and is able to detect pulmonary hypertension with sufficiently high accuracy. For a cohort of 82 patients suffering from various degrees of heart failure severity, we show that systolic, diastolic, and wedge pulmonary pressures can be estimated on average within 8, 6, and 6 mmHg, respectively. We also show that, in general, increased data availability leads to improved predictions.

  View details for DOI 10.3389/fphys.2021.666915

  View details for PubMedID 34276397

• Computational simulation-derived hemodynamic and biomechanical properties of the pulmonary arterial tree early in the course of ventricular septal defects. Biomechanics and modeling in mechanobiology Dong, M. L., Lan, I. S., Yang, W., Rabinovitch, M., Feinstein, J. A., Marsden, A. L. 2021

  Abstract

  Untreated ventricular septal defects (VSDs) can lead to pulmonary arterial hypertension (PAH) characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, known as PAH associated with congenital heart disease (PAH-CHD). Though previous studies have investigated hemodynamic effects on vascular mechanobiology in late-stage PAH, hemodynamics leading to PAH-CHD initiation have not been fully quantified. We hypothesize that abnormal hemodynamics from left-to-right shunting in early stage VSDs affects PA biomechanical properties leading to PAH initiation. To model PA hemodynamics in healthy, small, moderate, and large VSD conditions prior to the onset of vascular remodeling, computational fluid dynamics simulations were performed using a 3D finite element model of a healthy 1-year-old's proximal PAs and a body-surface-area-scaled 0D distal PA tree. VSD conditions were modeled with increased pulmonary blood flow to represent degrees of left-to-right shunting. In the proximal PAs, pressure, flow, strain, and wall shear stress (WSS) increased with increasing VSD size; oscillatory shear index decreased with increasing VSD size in the larger PA vessels. WSS was higher in smaller diameter vessels and increased with VSD size, with the large VSD condition exhibiting WSS >100 dyn/cm[Formula: see text], well above values typically used to study dysfunctional mechanotransduction pathways in PAH. This study is the first to estimate hemodynamic and biomechanical metrics in the entire pediatric PA tree with VSD severity at the stage leading to PAH initiation and has implications for future studies assessing effects of abnormal mechanical stimuli on endothelial cells and vascular wall mechanics that occur during PAH-CHD initiation and progression.

  View details for DOI 10.1007/s10237-021-01519-4

  View details for PubMedID 34585299

• Standard CPR versus interposed abdominal compression CPR in shunted single ventricle patients: comparison using a lumped parameter mathematical model. Cardiology in the young Stromberg, D., Carvalho, K., Marsden, A., Mery, C. M., Immanuel, C., Mizrahi, M., Yang, W. 2021: 1-7

  Abstract

  Cardiopulmonary resuscitation (CPR) in the shunted single-ventricle population is associated with poor outcomes. Interposed abdominal compression-cardiopulmonary resuscitation, or IAC-CPR, is an adjunct to standard CPR in which pressure is applied to the abdomen during the recoil phase of chest compressions.A lumped parameter model that represents heart chambers and blood vessels as resistors and capacitors was used to simulate blood flow in both Blalock-Taussig-Thomas and Sano circulations. For standard CPR, a prescribed external pressure waveform was applied to the heart chambers and great vessels to simulate chest compressions. IAC-CPR was modelled by adding phasic compression pressure to the abdominal aorta. Differential equations for the model were solved by a Runge-Kutta method.In the Blalock-Taussig-Thomas model, mean pulmonary blood flow during IAC-CPR was 30% higher than during standard CPR; cardiac output increased 21%, diastolic blood pressure 16%, systolic blood pressure 8%, coronary perfusion pressure 17%, and coronary blood flow 17%. In the Sano model, pulmonary blood flow during IAC-CPR increased 150%, whereas cardiac output was improved by 13%, diastolic blood pressure 18%, systolic blood pressure 8%, coronary perfusion pressure 15%, and coronary blood flow 14%.In this model, IAC-CPR confers significant advantage over standard CPR with respect to pulmonary blood flow, cardiac output, blood pressure, coronary perfusion pressure, and coronary blood flow. These results support the notion that single-ventricle paediatric patients may benefit from adjunctive resuscitation techniques, and underscores the need for an in-vivo trial of IAC-CPR in children.

  View details for DOI 10.1017/S1047951121003917

  View details for PubMedID 34558399

• Patient-specific computational flow modelling for assessing hemodynamic changes following fenestrated endovascular aneurysm repair. JVS-vascular science Tran, K., Yang, W., Marsden, A., Lee, J. T., Stanford, C. 2021; 2: 53-69

  Abstract

  Objective: This study aimed to develop an accessible patient-specific computational flow modelling pipeline for evaluating the hemodynamic performance of fenestrated endovascular aneurysm repair (fEVAR), with the hypothesis that computational flow modelling can detect aortic branch hemodynamic changes associated with fEVAR graft implantation.Methods: Patients who underwent fEVAR for juxtarenal aortic aneurysms with the Cook ZFEN were retrospectively selected. Using open-source SimVascular software, preoperative and postoperative visceral aortic anatomy was manually segmented from computed tomography angiograms. Three-dimensional geometric models were then discretized into tetrahedral finite element meshes. Patient-specific pulsatile in-flow conditions were derived from known supraceliac aortic flow waveforms and adjusted for patient body surface area, average resting heart rate, and blood pressure. Outlet boundary conditions consisted of three-element Windkessel models approximated from physiologic flow splits. Rigid wall flow simulations were then performed on preoperative and postoperative models with the same inflow and outflow conditions. We used SimVascular's incompressible Navier-Stokes solver to perform blood flow simulations on a cluster using 72 cores.Results: Preoperative and postoperative flow simulations were performed for 10 patients undergoing fEVAR with a total of 30 target vessels (20 renal stents, 10 mesenteric scallops). Postoperative models required a higher mean number of mesh elements to reach mesh convergence (3.2 ± 1.8 * 106 vs 2.6 ± 1.1 * 106; P = .005) with a longer mean computational time (10.3 ± 6.3 hours vs 7.8 ± 3.5 hours; P = .04) compared with preoperative models. fEVAR was associated with small but statistically significant increases in mean peak proximal aortic arterial pressure (140.3 ± 11.0 mm Hg vs 136.9 ± 8.7 mm Hg; P = .02) and peak renal artery pressure (131.6 ± 14.8 mm Hg vs 128.9 ± 11.8 mm Hg; P = .04) compared with preoperative simulations. No differences were observed in peak pressure in the celiac, superior mesenteric, or distal aortic arteries (P = .17-.96). When measuring blood flow, the only observed difference was an increase in peak renal flow rate after fEVAR (17.5 ± 3.8 mL/s vs 16.9 ± 3.5 mL/s;P =.04). fEVAR was not associated with changes in the mean pressure or the mean flow rate in the celiac, superior mesenteric, or renal arteries (P = .06-.98). Stenting of the renal arteries did not induce significant changes time-averaged wall shear stress in the proximal renal artery (23.4 ± 8.1 dynes/cm2 vs 23.2 ± 8.4 dynes/cm2; P = .98) or distal renal artery (32.7 ± 13.9 dynes/cm2 vs 29.6 ± 11.8 dynes/cm2; P = .23). In addition, computational visualization of crosssectional velocity profiles revealed low flow disturbances associated with protrusion of renal graft fabric into the aortic lumen.Conclusions: In a pilot study involving a selective cohort of patients who underwent uncomplicated fEVAR, patient-specific flow modelling was a feasible method for assessing the hemodynamic performance of various two-vessel fenestrated device configurations and revealed subtle differences in computationally derived peak branch pressure and blood flow rates. Structural changes in aortic flow geometry after fEVAR do not seem to affect computationally estimated renovisceral branch perfusion or wall shear stress adversely. Additional studies with invasive angiography or phase contrast magnetic resonance imaging are required to clinically validate these findings.

  View details for DOI 10.1016/j.jvssci.2020.11.032

  View details for PubMedID 34258601

• On the impact of vessel wall stiffness on quantitative flow dynamics in a synthetic model of the thoracic aorta. Scientific reports Zimmermann, J. n., Loecher, M. n., Kolawole, F. O., Bäumler, K. n., Gifford, K. n., Dual, S. A., Levenston, M. n., Marsden, A. L., Ennis, D. B. 2021; 11 (1): 6703

  Abstract

  Aortic wall stiffening is a predictive marker for morbidity in hypertensive patients. Arterial pulse wave velocity (PWV) correlates with the level of stiffness and can be derived using non-invasive 4D-flow magnetic resonance imaging (MRI). The objectives of this study were twofold: to develop subject-specific thoracic aorta models embedded into an MRI-compatible flow circuit operating under controlled physiological conditions; and to evaluate how a range of aortic wall stiffness impacts 4D-flow-based quantification of hemodynamics, particularly PWV. Three aorta models were 3D-printed using a novel photopolymer material at two compliant and one nearly rigid stiffnesses and characterized via tensile testing. Luminal pressure and 4D-flow MRI data were acquired for each model and cross-sectional net flow, peak velocities, and PWV were measured. In addition, the confounding effect of temporal resolution on all metrics was evaluated. Stiffer models resulted in increased systolic pressures (112, 116, and 133 mmHg), variations in velocity patterns, and increased peak velocities, peak flow rate, and PWV (5.8-7.3 m/s). Lower temporal resolution (20 ms down to 62.5 ms per image frame) impacted estimates of peak velocity and PWV (7.31 down to 4.77 m/s). Using compliant aorta models is essential to produce realistic flow dynamics and conditions that recapitulated in vivo hemodynamics.

  View details for DOI 10.1038/s41598-021-86174-6

  View details for PubMedID 33758315

• In Vitro Assessment of Right Ventricular Outflow Tract Anatomy and Valve Orientation Effects on Bioprosthetic Pulmonary Valve Hemodynamics. Cardiovascular engineering and technology Schiavone, N. K., Elkins, C. J., McElhinney, D. B., Eaton, J. K., Marsden, A. L. 2021

  Abstract

  The congenital heart defect Tetralogy of Fallot (ToF) affects 1 in 2500 newborns annually in the US and typically requires surgical repair of the right ventricular outflow tract (RVOT) early in life, with variations in surgical technique leading to large disparities in RVOT anatomy among patients. Subsequently, often in adolescence or early adulthood, patients usually require surgical placement of a xenograft or allograft pulmonary valve prosthesis. Valve longevity is highly variable for reasons that remain poorly understood.This work aims to assess the performance of bioprosthetic pulmonary valves in vitro using two 3D printed geometries: an idealized case based on healthy subjects aged 11 to 13 years and a diseased case with a 150% dilation in vessel diameter downstream of the valve. Each geometry was studied with two valve orientations: one with a valve leaflet opening posterior, which is the native pulmonary valve position, and one with a valve leaflet opening anterior.Full three-dimensional, three-component, phase-averaged velocity fields were obtained in the physiological models using 4D flow MRI. Flow features, particularly vortex formation and reversed flow regions, differed significantly between the RVOT geometries and valve orientations. Pronounced asymmetry in streamwise velocity was present in all cases, while the diseased geometry produced additional asymmetry in radial flows. Quantitative integral metrics demonstrated increased secondary flow strength and recirculation in the rotated orientation for the diseased geometry.The compound effects of geometry and orientation on bioprosthetic valve hemodynamics illustrated in this study could have a crucial impact on long-term valve performance.

  View details for DOI 10.1007/s13239-020-00507-6

  View details for PubMedID 33452649

• A concurrent implementation of the surrogate management framework with application to cardiovascular shape optimization OPTIMIZATION AND ENGINEERING Verma, A., Wong, K., Marsden, A. L. 2020; 21 (4): 1487–1536

  View details for DOI 10.1007/s11081-020-09483-1

  View details for Web of Science ID 000575492000008

• Preoperative Computed Tomography Angiography Reveals Leaflet-specific Contribution to Aortic Stenosis Influenced by Local Coronary Factors Chen, I. Y., Vedula, V., Malik, S. B., Liang, T., Chung, K. S., Sayed, N., Tsao, P. S., Giacomini, J. C., Marsden, A. L., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/circ.142.suppl_3.16300

  View details for Web of Science ID 000607190404287

• Patient-specific Fluid Structure Interaction Simulations of Anomalous Origins of Right Coronary Arteries in Adults Correlate With Measured Instantaneous Wave-free Ratio Jiang, M. X., Khan, M. O., Ghobrial, J., Rogers, I. S., Blackstone, E. H., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000607190401455

• Semi-automated Analysis of Tricuspid Regurgitation Doppler Profile for Detection and Evaluation of Pulmonary Hypertension Dual, S. A., Amsallem, M., McElhinney, D., Zamanian, R., Feinstein, J., Haddad, F., Marsden, A. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000607190401378

• Cardiac Output and Valve Orientation Affect Blood Flow Patterns Local to Bioprosthetic Pulmonary Valves in Tetralogy of Fallot Schiavone, N., Elkins, C., McElhinney, D. B., Eaton, J. K., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000607190406033

• Validation of Wall Shear Stress Assessment in Non-invasive Coronary CTA versus Invasive Imaging: A Patient-Specific Computational Study. Annals of biomedical engineering Eslami, P., Hartman, E. M., Albaghadai, M., Karady, J., Jin, Z., Thondapu, V., Cefalo, N. V., Lu, M. T., Coskun, A., Stone, P. H., Marsden, A., Hoffmann, U., Wentzel, J. J. 2020

  Abstract

  Endothelial shear stress (ESS) identifies coronary plaques at high risk for progression and/or rupture leading to a future acute coronary syndrome. In this study an optimized methodology was developed to derive ESS, pressure drop and oscillatory shear index using computational fluid dynamics (CFD) in 3D models of coronary arteries derived from non-invasive coronary computed tomography angiography (CTA). These CTA-based ESS calculations were compared to the ESS calculations using the gold standard with fusion of invasive imaging and CTA. In 14 patients paired patient-specific CFD models based on invasive and non-invasive imaging of the left anterior descending (LAD) coronary arteries were created. Ten patients were used to optimize the methodology, and four patients to test this methodology. Time-averaged ESS (TAESS) was calculated for both coronary models applying patient-specific physiological data available at the time of imaging. For data analysis, each 3D reconstructed coronary artery was divided into 2mm segments and each segment was subdivided into 8 arcs (45°).TAESS and other hemodynamic parameters were averaged per segment as well as per arc. Furthermore, the paired segment- and arc-averaged TAESS were categorized into patient-specific tertiles (low, medium and high). In the ten LADs, used for optimization of the methodology, we found high correlations between invasively-derived and non-invasively-derived TAESS averaged over segments (n=263, r=0.86) as well as arcs (n=2104, r=0.85, p<0.001). The correlation was also strong in the four testing-patients with r=0.95 (n=117 segments, p=0.001) and r=0.93 (n=936 arcs, p=0.001).There was an overall high concordance of 78% of the three TAESS categories comparing both methodologies using the segment- and 76% for the arc-averages in the first ten patients. This concordance was lower in the four testing patients (64 and 64% in segment- and arc-averaged TAESS). Although the correlation and concordance were high for both patient groups, the absolute TAESS values averaged per segment and arc were overestimated using non-invasive vs. invasive imaging [testing patients: TAESS segment: 30.1(17.1-83.8) vs. 15.8(8.8-63.4) and TAESS arc: 29.4(16.2-74.7) vs 15.0(8.9-57.4) p<0.001]. We showed that our methodology can accurately assess the TAESS distribution non-invasively from CTA and demonstrated a good correlation with TAESS calculated using IVUS/OCT 3D reconstructed models.

  View details for DOI 10.1007/s10439-020-02631-9

  View details for PubMedID 33067688

• A note on the accuracy of the generalized-alpha scheme for the incompressible Navier-Stokes equations INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING Liu, J., Lan, I. S., Tikenogullari, O. Z., Marsden, A. L. 2020

  View details for DOI 10.1002/nme.6550

  View details for Web of Science ID 000576764000001

• Vascular adaptation in the presence of external support - A modeling study. Journal of the mechanical behavior of biomedical materials Ramachandra, A. B., Latorre, M., Szafron, J. M., Marsden, A. L., Humphrey, J. D. 2020; 110: 103943

  Abstract

  Vascular grafts have long been used to replace damaged or diseased vessels with considerable success, but a new approach is emerging where native vessels are merely supported, not replaced. Although external supports have been evaluated in diverse situations - ranging from aneurysmal disease to vein grafts or the Ross operation - optimal supports and procedures remain wanting. In this paper, we present a novel application of a growth and remodeling model well suited for parametrically exploring multiple designs of external supports while accounting for mechanobiological and immunobiological responses of the supported native vessel. These results suggest that a load bearing external support can reduce vessel thickening in response to pressure elevation. Results also suggest that the final adaptive state of the vessel depends on the structural stiffness of the support via a mechano-driven adaptation, although luminal encroachment may be a complication in the presence of chronic inflammation. Finally, the supported vessel can stiffen (structurally and materially) along circumferential and axial directions, which could have implications on overall hemodynamics and thus subsequent vascular remodeling. The proposed framework can provide valuable insights into vascular adaptation in the presence of external support, accelerate rational design, and aid translation of this emerging approach.

  View details for DOI 10.1016/j.jmbbm.2020.103943

  View details for PubMedID 32957235

• MULTIFIDELITY ESTIMATORS FOR CORONARY CIRCULATION MODELS UNDER CLINICALLY INFORMED DATA UNCERTAINTY. International journal for uncertainty quantification Seo, J., Fleeter, C., Kahn, A. M., Marsden, A. L., Schiavazzi, D. E. 2020; 10 (5): 449-466

  Abstract

  Numerical models are increasingly used for noninvasive diagnosis and treatment planning in coronary artery disease, where service-based technologies have proven successful in identifying hemodynamically significant and hence potentially dangerous vascular anomalies. Despite recent progress towards clinical adoption, many results in the field are still based on a deterministic characterization of blood flow, with no quantitative assessment of the variability of simulation outputs due to uncertainty from multiple sources. In this study, we focus on parameters that are essential to construct accurate patient-specific representations of the coronary circulation, such as aortic pressure waveform and intramyocardial pressure, and quantify how their uncertainty affects clinically relevant model outputs. We construct a deformable model of the left coronary artery subject to a prescribed inlet pressure and with open-loop outlet boundary conditions, treating fluid-structure interaction through an arbitrary-Lagrangian-Eulerian framework. Random input uncertainty is estimated directly from repeated clinical measurements from intracoronary catheterization and complemented by literature data. We also achieve significant computational cost reductions in uncertainty propagation thanks to multifidelity Monte Carlo estimators of the outputs of interest, leveraging the ability to generate, at practically no cost, one- and zero-dimensional low-fidelity representations of left coronary artery flow, with appropriate boundary conditions. The results demonstrate how the use of multifidelity control variate estimators leads to significant reductions in variance and accuracy improvements with respect to traditional Monte Carlo. In particular, the combination of three-dimensional hemodynamics simulations and zero-dimensional lumped parameter network models produces the best results, with only a negligible (less than 1%) computational overhead.

  View details for DOI 10.1615/int.j.uncertaintyquantification.2020033068

  View details for PubMedID 39525494

  View details for PubMedCentralID PMC11548888

• The nested block preconditioning technique for the incompressible Navier-Stokes equations with emphasis on hemodynamic simulations. Computer methods in applied mechanics and engineering Liu, J., Yang, W., Dong, M., Marsden, A. L. 2020; 367

  Abstract

  We develop a novel iterative solution method for the incompressible Navier-Stokes equations with boundary conditions coupled with reduced models. The iterative algorithm is designed based on the variational multiscale formulation and the generalized-α scheme. The spatiotemporal discretization leads to a block structure of the resulting consistent tangent matrix in the Newton-Raphson procedure. As a generalization of the conventional block preconditioners, a three-level nested block preconditioner is introduced to attain a better representation of the Schur complement, which plays a key role in the overall algorithm robustness and efficiency. This approach provides a flexible, algorithmic way to handle the Schur complement for problems involving multiscale and multiphysics coupling. The solution method is implemented and benchmarked against experimental data from the nozzle challenge problem issued by the US Food and Drug Administration. The robustness, efficiency, and parallel scalability of the proposed technique are then examined in several settings, including moderately high Reynolds number flows and physiological flows with strong resistance effect due to coupled downstream vasculature models. Two patient-specific hemodynamic simulations, covering systemic and pulmonary flows, are performed to further corroborate the efficacy of the proposed methodology.

  View details for DOI 10.1016/j.cma.2020.113122

  View details for PubMedID 32675836

  View details for PubMedCentralID PMC7365595

• Fluid-structure interaction modeling of blood flow in the pulmonary arteries using the unified continuum and variational multiscale formulation. Mechanics research communications Liu, J., Yang, W., Lan, I. S., Marsden, A. L. 2020; 107

  Abstract

  In this work, we present a computational fluid-structure interaction (FSI) study for a healthy patient-specific pulmonary arterial tree using the unified continuum and variational multiscale (VMS) formulation we previously developed. The unified framework is particularly well-suited for FSI, as the fluid and solid sub-problems are addressed in essentially the same manner and can thus be uniformly integrated in time with the generalized-alpha method. In addition, the VMS formulation provides a mechanism for large-eddy simulation in the fluid sub-problem and pressure stabilization in the solid sub-problem. The FSI problem is solved in a quasi-direct approach, in which the pressure and velocity in the unified continuum body are first solved, and the solid displacement is then obtained via a segregated algorithm and prescribed as a boundary condition for the mesh motion. Results of the pulmonary arterial FSI simulation are presented and compared against those of a rigid wall simulation.

  View details for DOI 10.1016/j.mechrescom.2020.103556

  View details for PubMedID 32773906

• Patient-Specific Computational Flow Modelling for Assessing Hemodynamic Changes Following Fenestrated Endovascular Aneurysm Repair Tran, K., Yang, W., Marsden, A., Lee, J. T. MOSBY-ELSEVIER. 2020: E182–E183

  View details for Web of Science ID 000544100700286

• Multilevel and multifidelity uncertainty quantification for cardiovascular hemodynamics. Computer methods in applied mechanics and engineering Fleeter, C. M., Geraci, G., Schiavazzi, D. E., Kahn, A. M., Marsden, A. L. 2020; 365

  Abstract

  Standard approaches for uncertainty quantification in cardiovascular modeling pose challenges due to the large number of uncertain inputs and the significant computational cost of realistic three-dimensional simulations. We propose an efficient uncertainty quantification framework utilizing a multilevel multifidelity Monte Carlo (MLMF) estimator to improve the accuracy of hemodynamic quantities of interest while maintaining reasonable computational cost. This is achieved by leveraging three cardiovascular model fidelities, each with varying spatial resolution to rigorously quantify the variability in hemodynamic outputs. We employ two low-fidelity models (zero- and one-dimensional) to construct several different estimators. Our goal is to investigate and compare the efficiency of estimators built from combinations of these two low-fidelity model alternatives and our high-fidelity three-dimensional models. We demonstrate this framework on healthy and diseased models of aortic and coronary anatomy, including uncertainties in material property and boundary condition parameters. Our goal is to demonstrate that for this application it is possible to accelerate the convergence of the estimators by utilizing a MLMF paradigm. Therefore, we compare our approach to single fidelity Monte Carlo estimators and to a multilevel Monte Carlo approach based only on three-dimensional simulations, but leveraging multiple spatial resolutions. We demonstrate significant, on the order of 10 to 100 times, reduction in total computational cost with the MLMF estimators. We also examine the differing properties of the MLMF estimators in healthy versus diseased models, as well as global versus local quantities of interest. As expected, global quantities such as outlet pressure and flow show larger reductions than local quantities, such as those relating to wall shear stress, as the latter rely more heavily on the highest fidelity model evaluations. Similarly, healthy models show larger reductions than diseased models. In all cases, our workflow coupling Dakota's MLMF estimators with the SimVascular cardiovascular modeling framework makes uncertainty quantification feasible for constrained computational budgets.

  View details for DOI 10.1016/j.cma.2020.113030

  View details for PubMedID 32336811

• The effects of clinically-derived parametric data uncertainty in patient-specific coronary simulations with deformable walls. International journal for numerical methods in biomedical engineering Seo, J., Schiavazzi, D. E., Kahn, A. M., Marsden, A. L. 2020

  Abstract

  Cardiovascular simulations are increasingly used for non-invasive diagnosis of cardiovascular disease, to guide treatment decisions, and in the design of medical devices. Quantitative assessment of the variability of simulation outputs due to input uncertainty is a key step toward further integration of cardiovascular simulations in the clinical workflow. In this study, we present uncertainty quantification in computational models of the coronary circulation to investigate the effect of uncertain parameters, including coronary pressure waveform, intramyocardial pressure, morphometry exponent, and the vascular wall Young's modulus. We employ a left coronary artery model with deformable vessel walls, simulated via an Arbitrary-Lagrangian-Eulerian framework for fluid-structure interaction, with a prescribed inlet pressure and open-loop lumped parameter network outlet boundary conditions. Stochastic modeling of the uncertain inputs is determined from intracoronary catheterization data or gathered from the literature. Uncertainty propagation is performed using several approaches including Monte Carlo, Quasi Monte Carlo sampling, stochastic collocation, and multiwavelet stochastic expansion. Variabilities in the quantities of interest, including branch pressure, flow, wall shear stress, and wall deformation are assessed. We find that uncertainty in inlet pressures and intramyocardial pressures significantly aect all resulting QoIs, while uncertainty in elastic modulus only affects the mechanical response of the vascular wall. Variability in the morphometry exponent used to distribute the total downstream vascular resistance to the single outlets, has little effect on coronary hemodynamics or wall mechanics. Finally, we compare convergence behaviors of statistics of QoIs using several uncertainty propagation methods on three model benchmark problems and the left coronary simulations. From the simulation results, we conclude that the multi-wavelet stochastic expansion shows superior accuracy and performance against Quasi Monte Carlo and stochastic collocation methods. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/cnm.3351

  View details for PubMedID 32419369

• Effect of Wall Elasticity on Hemodynamics and Wall Shear Stress in Patient-Specific Simulations in the Coronary Arteries JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Eslami, P., Tran, J., Jin, Z., Karady, J., Sotoodeh, R., Lu, M. T., Hoffmann, U., Marsden, A. 2020; 142 (2)

  View details for DOI 10.1115/1.4043722

  View details for Web of Science ID 000518552200014

• Fluid-structure interaction simulations of patient-specific aortic dissection. Biomechanics and modeling in mechanobiology Baumler, K., Vedula, V., Sailer, A. M., Seo, J., Chiu, P., Mistelbauer, G., Chan, F. P., Fischbein, M. P., Marsden, A. L., Fleischmann, D. 2020

  Abstract

  Credible computational fluid dynamic (CFD) simulations of aortic dissection are challenging, because the defining parallel flow channels-the true and the false lumen-are separated from each other by a more or less mobile dissection membrane, which is made up of a delaminated portion of the elastic aortic wall. We present a comprehensive numerical framework for CFD simulations of aortic dissection, which captures the complex interplay between physiologic deformation, flow, pressures, and time-averaged wall shear stress (TAWSS) in a patient-specific model. Our numerical model includes (1) two-way fluid-structure interaction (FSI) to describe the dynamic deformation of the vessel wall and dissection flap; (2) prestress and (3) external tissue support of the structural domain to avoid unphysiologic dilation of the aortic wall and stretching of the dissection flap; (4) tethering of the aorta by intercostal and lumbar arteries to restrict translatory motion of the aorta; and a (5) independently defined elastic modulus for the dissection flap and the outer vessel wall to account for their different material properties. The patient-specific aortic geometry is derived from computed tomography angiography (CTA). Three-dimensional phase contrast magnetic resonance imaging (4D flow MRI) and the patient's blood pressure are used to inform physiologically realistic, patient-specific boundary conditions. Our simulations closely capture the cyclical deformation of the dissection membrane, with flow simulations in good agreement with 4D flow MRI. We demonstrate that decreasing flap stiffness from [Formula: see text] to [Formula: see text] kPa (a) increases the displacement of the dissection flap from 1.4 to 13.4 mm, (b) decreases the surface area of TAWSS by a factor of 2.3, (c) decreases the mean pressure difference between true lumen and false lumen by a factor of 0.63, and (d) decreases the true lumen flow rate by up to 20% in the abdominal aorta. We conclude that the mobility of the dissection flap substantially influences local hemodynamics and therefore needs to be accounted for in patient-specific simulations of aortic dissection. Further research to accurately measure flap stiffness and its local variations could help advance future CFD applications.

  View details for DOI 10.1007/s10237-020-01294-8

  View details for PubMedID 31993829

• Multi-fidelity estimators for coronary artery circulation models under clinically-informed data uncertainty International Journal for Uncertainty Quantification Seo, J., Fleeter, C., Kahn, A. M., Marsden, A. L., Schiavazzi, D. E. 2020

  View details for DOI 10.1615/Int.J.UncertaintyQuantification.2020033068

• The nested block preconditioning technique for the incompressible Navier–Stokes equations with emphasis on hemodynamic simulations Computer Methods in Applied Mechanics and Engineering Liu, J., Yang, W., Dong, M., Marsden, A. L. 2020; 367

  View details for DOI 10.1016/j.cma.2020.113122

• Spontaneous reversal of stenosis in tissue-engineered vascular grafts. Science translational medicine Drews, J. D., Pepper, V. K., Best, C. A., Szafron, J. M., Cheatham, J. P., Yates, A. R., Hor, K. N., Zbinden, J. C., Chang, Y. C., Mirhaidari, G. J., Ramachandra, A. B., Miyamoto, S. n., Blum, K. M., Onwuka, E. A., Zakko, J. n., Kelly, J. n., Cheatham, S. L., King, N. n., Reinhardt, J. W., Sugiura, T. n., Miyachi, H. n., Matsuzaki, Y. n., Breuer, J. n., Heuer, E. D., West, T. A., Shoji, T. n., Berman, D. n., Boe, B. A., Asnes, J. n., Galantowicz, M. n., Matsumura, G. n., Hibino, N. n., Marsden, A. L., Pober, J. S., Humphrey, J. D., Shinoka, T. n., Breuer, C. K. 2020; 12 (537)

  Abstract

  We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

  View details for DOI 10.1126/scitranslmed.aax6919

  View details for PubMedID 32238576

• Integrated Image-Based Computational Fluid Dynamics Modeling Software as an Instructional Tool. Journal of biomechanical engineering Stevens Boster, K. n., Dong, M. n., Oakes, J. n., Bellini, C. n., Rayz, V. n., LaDisa, J. n., Parker, D. n., Wilson, N. n., Shadden, S. C., Marsden, A. n., Goergen, C. n. 2020

  Abstract

  Computational modeling of cardiovascular flows is becoming increasingly important in a range of biomedical applications, and understanding the fundamentals of computational modeling is important for engineering students. In addition to their purpose as research tools, integrated image-based computational fluid dynamics platforms can be used to teach the fundamental principles involved in computational modeling and generate interest in studying cardiovascular disease. We report the results of a study performed at five institutions designed to investigate the effectiveness of an integrated modeling platform as an instructional tool and describe "best practices" for using an integrated modeling platform in the classroom. Use of an integrated modeling platform as an instructional tool in nontraditional educational settings (workshops, study abroad programs, in outreach) is also discussed. Results of the study show statistically significant improvements in understanding after using the integrated modeling platform, suggesting such platforms can be effective tools for teaching fundamental cardiovascular computational modeling principles.

  View details for DOI 10.1115/1.4047479

  View details for PubMedID 32529203

• Low Wall Shear Stress Is Associated with Saphenous Vein Graft Stenosis in Patients with Coronary Artery Bypass Grafting. Journal of cardiovascular translational research Khan, M. O., Tran, J. S., Zhu, H. n., Boyd, J. n., Packard, R. R., Karlsberg, R. P., Kahn, A. M., Marsden, A. L. 2020

  Abstract

  Biomechanical forces may play a key role in saphenous vein graft (SVG) disease after coronary artery bypass graft (CABG) surgery. Computed tomography angiography (CTA) of 430 post-CABG patients were evaluated and 15 patients were identified with both stenosed and healthy SVGs for paired analysis. The stenosis was virtually removed, and detailed 3D models were reconstructed to perform patient-specific computational fluid dynamic (CFD) simulations. Models were processed to compute anatomic parameters, and hemodynamic parameters such as local and vessel-averaged wall shear stress (WSS), normalized WSS (WSS*), low shear area (LSA), oscillatory shear index (OSI), and flow rate. WSS* was significantly lower in pre-diseased SVG segments compared to corresponding control segments without disease (1.22 vs. 1.73, p = 0.012) and the area under the ROC curve was 0.71. No differences were observed in vessel-averaged anatomic or hemodynamic parameters between pre-stenosed and control whole SVGs. There are currently no clinically available tools to predict SVG failure post-CABG. CFD modeling has the potential to identify high-risk CABG patients who may benefit from more aggressive medical therapy and closer surveillance. Graphical Abstract.

  View details for DOI 10.1007/s12265-020-09982-7

  View details for PubMedID 32240496

• Exercise MRI highlights heterogeneity in cardiovascular mechanics among patients with Fontan circulation: proposed protocol for routine evaluation. Journal of thoracic disease Contijoch, F. n., Li, B. n., Yang, W. n., Silva-Sepulveda, J. A., Vodkin, I. n., Printz, B. n., Vavinskaya, V. n., Hegde, S. n., Marsden, A. n., El-Sabrout, H. n., Alshawabkeh, L. n., Moore, J. W., El-Said, H. n. 2020; 12 (3): 1204–12

  Abstract

  Single ventricle physiology and palliation via the Fontan operation lead to a series of cardiovascular changes. In addition, organs such as the kidneys and liver have been shown to experience insults and subsequent injury. This has led to routine surveillance of patients. We present findings from a small cohort of patients that was deeply phenotyped to illustrate the need for comprehensive evaluation. A cohort of four Fontan patients with fairly high cardiovascular function was recruited 5-10 years post-Fontan. Patients underwent a rigorous clinical work-up after which a research MRI scan was performed during which (I) data were obtained during exercise to evaluate changes in stroke volume during supine exercise and (II) magnetic resonance angiograms with phase-contrast images were obtained for computational modeling of flows through the Fontan circulation at rest. Clinical measures were consistent with a fairly homogeneous high function cohort (peak oxygen consumption >20 mL/kg/min, robust response to exercise, peak ventilatory efficiency below levels associated with heart failure, MR-derived ejection fraction >50%). Liver evaluation did not reveal clear signs of cirrhosis or extensive fibrosis. However, we observed considerable variability (27-162%) in the increase in stroke index with exercise [100%±64% increase, 53.9±17.4 mL/beat m2 (rest), 101.1±20.7 mL/beat m2, (exercise)]. Computational flow modeling at rest in two patients also showed marked differences in flow distribution and shear stress. We report marked differences in both changes in stroke index during an exercise MRI protocol as well as computational flow patterns at rest suggesting different compensation strategies may be associated with high functioning Fontan patients. The observed heterogeneity illustrates the need for deep phenotyping to capture patient-specific adaptive mechanisms.

  View details for DOI 10.21037/jtd.2019.09.59

  View details for PubMedID 32274201

  View details for PubMedCentralID PMC7139092

• Image-based scaling laws for somatic growth and pulmonary artery morphometry from infant- to adulthood. American journal of physiology. Heart and circulatory physiology Dong, M. L., Yang, W. n., Tamaresis, J. S., Chan, F. P., Zucker, E. J., Kumar, S. n., Rabinovitch, M. n., Marsden, A. L., Feinstein, J. A. 2020

  Abstract

  Pulmonary artery (PA) morphometry has been extensively explored in adults, with particular focus on intra-acinar arteries. However, scaling law relationships for length and diameter of extensive pre-acinar PAs by age have not been previously reported for in vivo human data. To understand pre-acinar PA growth spanning children to adults, we performed morphometric analyses of all PAs visible in the computed tomography (CT) and magnetic resonance (MR) images from a healthy subject cohort (n=16; age: 1-51 years; body surface area, BSA: 0.49-2.01 m2). Subject-specific anatomic PA models were constructed from CT and MR images, and morphometric information - diameter, length, tortuosity, bifurcation angle, and connectivity - was extracted and sorted into diameter-defined Strahler orders. Validation of Murray's law, describing optimal scaling exponents of radii for branching vessels, was performed to determine how closely PAs conform to this classical relationship. Using regression analyses of vessel diameters and lengths against orders and patient metrics (BSA, age, height), we found that diameters increased exponentially with order and allometrically with patient metrics, and length increased allometrically with patient metrics, albeit weakly. The average tortuosity index of all vessels was 0.026 ± 0.024, average bifurcation angle was 28.2º ± 15.1º, and average Murray's law exponent was 2.92 ± 1.07. We report a set of scaling laws for vessel diameter and length, along with other morphometric information. These provide an initial understanding of healthy structural pre-acinar PA development with age, which can be used for computational modeling studies and comparison with diseased PA anatomy.

  View details for DOI 10.1152/ajpheart.00123.2020

  View details for PubMedID 32618514

• Use of patient-specific computational models for optimization of aortic insufficiency after implantation of left ventricular assist device. The Journal of thoracic and cardiovascular surgery Kasinpila, P. n., Kong, S. n., Fong, R. n., Shad, R. n., Kaiser, A. D., Marsden, A. L., Woo, Y. J., Hiesinger, W. n. 2020

  Abstract

  Aortic incompetence (AI) is observed to be accelerated in the continuous-flow left ventricular assist device (LVAD) population and is related to increased mortality. Using computational fluid dynamics (CFD), we investigated the hemodynamic conditions related to the orientation of the LVAD outflow in these patients.We identified 10 patients with new aortic regurgitation, and 20 who did not, after LVAD implantation between 2009 and 2018. Three-dimensional models of patients' aortas were created from their computed tomography scans. The geometry of the LVAD outflow graft in relation to the aorta was quantified using azimuth angles (AA), polar angles (PAs), and distance from aortic root. The models were used to run CFD simulations, which calculated the pressures and wall shear stress (rWSS) exerted on the aortic root.The AA and PA were found to be similar. However, for combinations of high values of AA and low values of PA, there were no patients with AI. The distance from aortic root to the outflow graft was also smaller in patients who developed AI (3.39 ± 0.7 vs 4.07 ± 0.77 cm, P = .04). There was no significant difference in aortic root pressures in the 2 groups. The rWSS was greater in AI patients (4.60 ± 5.70 vs 2.37 ± 1.20 dyne/cm2, P < .001). Qualitatively, we observed a trend of greater perturbations, regions of high rWSS, and flow eddies in the AI group.Using CFD simulations, we demonstrated that patients who developed de novo AI have greater rWSS at the aortic root, and their outflow grafts were placed closer to the aortic roots than those patients without de novo AI.

  View details for DOI 10.1016/j.jtcvs.2020.04.164

  View details for PubMedID 32653292

• Neural Network Vessel Lumen Regression for Automated Lumen Cross-Section Segmentation in Cardiovascular Image-Based Modeling. Cardiovascular engineering and technology Maher, G. n., Parker, D. n., Wilson, N. n., Marsden, A. n. 2020

  Abstract

  We accelerate a pathline-based cardiovascular model building method by training machine learning models to directly predict vessel lumen surface points from computed tomography (CT) and magnetic resonance (MR) medical image data.We formulate vessel lumen detection as a regression task using a polar coordiantes representation.Neural networks trained with our regression formulation allow predictions to be made with significantly higher accuracy than existing methods that identify the vessel lumen through binary pixel classification. The regression formulation enables machine learning models to be trained end-to-end for vessel lumen detection without post-processing steps that reduce accuracy.By employing our models in a pathline-based cardiovascular model building pipeline we substantially reduce the manual segmentation effort required to build accurate cardiovascular models, and reduce the overall time required to perform patient-specific cardiovascular simulations. While our method is applied here for cardiovascular model building it is generally applicable to segmentation of tree-like and tubular structures from image data.

  View details for DOI 10.1007/s13239-020-00497-5

  View details for PubMedID 33179176

• An energy-stable mixed formulation for isogeometric analysis of incompressible hyper-elastodynamics. International journal for numerical methods in engineering Liu, J., Marsden, A. L., Tao, Z. 2019; 120 (8): 937-963

  Abstract

  We develop a mixed formulation for incompressible hyper-elastodynamics based on a continuum modeling framework recently developed in [41] and smooth generalizations of the Taylor-Hood element based on non-uniform rational B-splines (NURBS). This continuum formulation draws a link between computational fluid dynamics and computational solid dynamics. This link inspires an energy stability estimate for the spatial discretization, which favorably distinguishes the formulation from the conventional mixed formulations for finite elasticity. The inf-sup condition is utilized to provide a bound for the pressure field. The generalized-α method is applied for temporal discretization, and a nested block preconditioner is invoked for the solution procedure [42]. The inf-sup stability for different pairs of NURBS elements is elucidated through numerical assessment. The convergence rate of the proposed formulation with various combinations of mixed elements is examined by the manufactured solution method. The numerical scheme is also examined under compressive and tensile loads for isotropic and anisotropic hyperelastic materials. Finally, a suite of dynamic problems is numerically studied to corroborate the stability and conservation properties.

  View details for DOI 10.1002/nme.6165

  View details for PubMedID 32981972

  View details for PubMedCentralID PMC7517668

• Performance of preconditioned iterative linear solvers for cardiovascular simulations in rigid and deformable vessels. Computational mechanics Seo, J., Schiavazzi, D. E., Marsden, A. L. 2019; 64: 717-739

  Abstract

  Computing the solution of linear systems of equations is invariably the most time consuming task in the numerical solutions of PDEs in many fields of computational science. In this study, we focus on the numerical simulation of cardiovascular hemodynamics with rigid and deformable walls, discretized in space and time through the variational multiscale finite element method. We focus on three approaches: the problem agnostic generalized minimum residual (GMRES) and stabilized bi-conjugate gradient (BICGS) methods, and a recently proposed, problem specific, bi-partitioned (BIPN) method. We also perform a comparative analysis of several preconditioners, including diagonal, block-diagonal, incomplete factorization, multigrid, and resistance based methods. Solver performance and matrix characteristics (diagonal dominance, symmetry, sparsity, bandwidth and spectral properties) are first examined for an idealized cylindrical geometry with physiologic boundary conditions and then successively tested on several patient-specific anatomies representative of realistic cardiovascular simulation problems. Incomplete factorization preconditioners provide the best performance and results in terms of both strong and weak scalability. The BIPN method was found to outperform other methods in patient-specific models with rigid walls. In models with deformable walls, BIPN was outperformed by BICG with diagonal and Incomplete LU preconditioners.

  View details for DOI 10.1007/s00466-019-01678-3

  View details for PubMedID 31827310

  View details for PubMedCentralID PMC6905469

• Multiscale computational modeling of biomedical systems: current approaches and payoffs CURRENT OPINION IN BIOMEDICAL ENGINEERING Peirce-Cottler, S. M., Marsden, A. 2019; 11: A1-A3

  View details for DOI 10.1016/j.cobme.2019.12.001

  View details for Web of Science ID 000655273300001

• Accelerating cardiovascular model building with convolutional neural networks. Medical & biological engineering & computing Maher, G., Wilson, N., Marsden, A. 2019

  Abstract

  The objective of this work is to reduce the user effort required for 2D segmentation when building patient-specific cardiovascular models using the SimVascular cardiovascular modeling software package. The proposed method uses a fully convolutional neural network (FCNN) to generate 2D cardiovascular segmentations. Given vessel pathlines, the neural network generates 2D vessel enhancement images along the pathlines. Thereafter, vessel segmentations are extracted using the marching-squares algorithm, which are then used to construct 3D cardiovascular models. The neural network is trained using a novel loss function, tailored for partially labeled segmentation data. An automated quality control method is also developed, allowing promising segmentations to be selected. Compared with a threshold and level set algorithm, the FCNN method improved 2D segmentation accuracy across several metrics. The proposed quality control approach further improved the average DICE score by 25.8%. In tests with users of SimVascular, when using quality control, users accepted 80% of segmentations produced by the best performing FCNN. The FCNN cardiovascular model building method reduces the amount of manual segmentation effort required for patient-specific model construction, by as much as 73%. This leads to reduced turnaround time for cardiovascular simulations. While the method was used for cardiovascular model building, it is applicable to general tubular structures. Graphical Abstract Proposed FCNN-based cardiovascular model building pipeline. a.) Image data and vessel pathline supplied by the user. b.) Path information is used to extract image pixel intensities in plane perpendicular to the vessel path. c.) 2D images extracted along vessel pathlines are input to the FCNN. d.) FCNN acts on the input images to compute local vessel enhancement images. e.) Vessel enhancement images computed by the FCNN, the pixel values are between 0 and 1 indicating vessel tissue likelihood. f.) The marching-squares algorithm is appliedto each enhanced image to extract the central vessel segmentation. g.) 2D extracted vessel surface points overlayed on original input images. h.) The 2D vessel surface points are transformed back to 3D space. i.) 3D crosssectional vessel surfaces are interpolated along the pathline to form the final vessel model.

  View details for DOI 10.1007/s11517-019-02029-3

  View details for PubMedID 31446517

• An energy-stable mixed formulation for isogeometric analysis of incompressible hyperelastodynamics INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING Liu, J., Marsden, A. L., Tao, Z. 2019

  View details for DOI 10.1002/nme.6165

  View details for Web of Science ID 000478254600001

• Intracardiac 4D Flow MRI in Congenital Heart Disease: Recommendations on Behalf of the ISMRM Flow & Motion Study Group. Journal of magnetic resonance imaging : JMRI Zhong, L., Schrauben, E. M., Garcia, J., Uribe, S., Grieve, S. M., Elbaz, M. S., Barker, A. J., Geiger, J., Nordmeyer, S., Marsden, A., Carlsson, M., Tan, R., Garg, P., Westenberg, J. J., Markl, M., Ebbers, T. 2019

  Abstract

  LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019.

  View details for DOI 10.1002/jmri.26858

  View details for PubMedID 31317587

• Optimization of Tissue Engineered Vascular Graft Design Using Computational Modeling. Tissue engineering. Part C, Methods Szafron, J. M., B Ramachandra, A., Breuer, C. K., Marsden, A. L., Humphrey, J. D. 2019

  Abstract

  Tissue engineered vascular grafts hold great promise in many clinical applications, especially in pediatrics wherein growth potential is critical. A continuing challenge, however, is identification of optimal scaffold parameters for promoting favorable neovessel development. In particular, given the countless design parameters available, including those related to polymeric microstructure, material behavior, and degradation kinetics, the number of possible scaffold designs is almost limitless. Advances in computationally modeling the growth and remodeling of native blood vessels suggest that similar simulations could help reduce the search space for candidate scaffold designs in tissue engineering. Herein, we meld a computational model of in vivo neovessel formation with a surrogate management framework to identify optimal scaffold designs for use in the extra-cardiac Fontan circulation while comparing the utility of different objective functions. We show that evolving luminal radius and graft compliance can be matched to that of the native vein by the end of the simulation period with judicious combinations of scaffold parameters, though the inability to match these metrics at all times reveals constraints engendered by current materials. We emphasize further that there is yet a need to examine additional metrics, and combinations thereof, when seeking to optimize functionality and reduce the potential for adverse outcomes.

  View details for DOI 10.1089/ten.TEC.2019.0086

  View details for PubMedID 31218941

• Evolution of hemodynamic forces in the pulmonary tree with progressively worsening pulmonary arterial hypertension in pediatric patients BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Yang, W., Dong, M., Rabinovitch, M., Chan, F. P., Marsden, A. L., Feinstein, J. A. 2019; 18 (3): 779–96

  View details for DOI 10.1007/s10237-018-01114-0

  View details for Web of Science ID 000467394100015

• Contractile and hemodynamic forces coordinate Notch1b-mediated outflow tract valve formation JCI INSIGHT Hsu, J. J., Vedula, V., Baek, K., Chen, C., Chen, J., Chou, M., Lam, J., Subhedar, S., Wang, J., Ding, Y., Chang, C., Lee, J., Demer, L. L., Tintut, Y., Marsden, A. L., Hsiai, T. K. 2019; 4 (10)

  View details for DOI 10.1172/jci.insight.124460

  View details for Web of Science ID 000468146300006

• Effect of Wall Elasticity on Hemodynamics and Wall Shear Stress in Patient-Specific Simulations in the Coronary Arteries. Journal of biomechanical engineering Eslami, P., Tran, J., Jin, Z., Karady, J., Sotoodeh, R., Lu, M. T., Hoffmann, U., Marsden, A. 2019

  Abstract

  Wall shear stress (WSS) has been shown to be associated with myocardial infarction and progression of atherosclerosis. Wall elasticity is an important feature of hemodynamic modeling affecting WSS calculations. The objective of this study was to investigate the role of wall elasticity on WSS, and justify use of either rigid or elastic models in future studies. Digital anatomic models of the aorta and coronaries were created based on coronary computed tomography angiography (CCTA) in four patients. Hemodynamics were computed in rigid and elastic models using a finite element flow solver. WSS in five timepoints in the cardiac cycle and time averaged wall shear stress (TAWSS) were compared between the models at each 3mm subsegment and 4 arcs in cross sections along the centerlines of coronaries. In the left main, proximal left anterior descending, left circumflex and proximal right coronary artery of the elastic model, the mean percent radial increase were 5.95+/-1.25, 4.02+/-0.97, 4.08+/-0.94, 4.84+/-1.05%, respectively. WSS at each timepoint in the cardiac cycle had slightly different values, however when averaged over the cardiac cycle, there were negligible differences between the models. In both the subsegments (n=704) and sub-arc analysis, TAWSS in the two models were highly correlated (r=0.99) In investigation on the effect of coronary wall elasticity on WSS in CCTA-based models, the results of this study show no significant differences in TAWSS justifying using rigid wall models for future larger studies.

  View details for PubMedID 31074768

• A robust and efficient iterative method for hyper-elastodynamics with nested block preconditioning. Journal of computational physics Liu, J., Marsden, A. L. 2019; 383: 72-93

  Abstract

  We develop a robust and efficient iterative method for hyper-elastodynamics based on a novel continuum formulation recently developed in [1]. The numerical scheme is constructed based on the variational multiscale formulation and the generalized-α method. Within the nonlinear solution procedure, a block factorization is performed for the consistent tangent matrix to decouple the kinematics from the balance laws. Within the linear solution procedure, another block factorization is performed to decouple the mass balance equation from the linear momentum balance equations. A nested block preconditioning technique is proposed to combine the Schur complement reduction approach with the fully coupled approach. This preconditioning technique, together with the Krylov subspace method, constitutes a novel iterative method for solving hyper-elastodynamics. We demonstrate the efficacy of the proposed preconditioning technique by comparing with the SIMPLE preconditioner and the one-level domain decomposition preconditioner. Two representative examples are studied: the compression of an isotropic hyperelastic cube and the tensile test of a fully-incompressible anisotropic hyperelastic arterial wall model. The robustness with respect to material properties and the parallel performance of the preconditioner are examined.

  View details for DOI 10.1016/j.jcp.2019.01.019

  View details for PubMedID 31595091

  View details for PubMedCentralID PMC6781635

• A robust and efficient iterative method for hyper-elastodynamics with nested block preconditioning JOURNAL OF COMPUTATIONAL PHYSICS Liu, J., Marsden, A. L. 2019; 383: 72–93

  View details for DOI 10.1016/j.jcp.2019.01.019

  View details for Web of Science ID 000459828700004

• Hemodynamic variables in aneurysms are associated with thrombotic risk in children with Kawasaki disease INTERNATIONAL JOURNAL OF CARDIOLOGY Gutierrez, N., Mathew, M., McCrindle, B., Tran, J. S., Kahn, A. M., Burns, J. C., Marsden, A. L. 2019; 281: 15–21

  View details for DOI 10.1016/j.ijcard.2019.01.092

  View details for Web of Science ID 000459490500003

• Patient-Specific Multiscale Modeling of the Assisted Bidirectional Glenn ANNALS OF THORACIC SURGERY Shang, J. K., Esmaily, M., Verma, A., Reinhartz, O., Figliola, R. S., Hsia, T., Feinstein, J. A., Marsden, A. L. 2019; 107 (4): 1232–40

  View details for DOI 10.1016/j.athoracsur.2018.10.024

  View details for Web of Science ID 000462308000057

• Uncertainty quantification of simulated biomechanical stimuli in coronary artery bypass grafts. Computer methods in applied mechanics and engineering Tran, J. S., Schiavazzi, D. E., Kahn, A. M., Marsden, A. L. 2019; 345: 402-428

  Abstract

  Coronary artery bypass graft surgery (CABG) is performed on more than 400,000 patients annually in the U.S. However, saphenous vein grafts (SVGs) implanted during CABG exhibit poor patency compared to arterial grafts, with failure rates up to 40% within 10 years after surgery. Differences in mechanical stimuli are known to play a role in driving maladaptation and have been correlated with endothelial damage and thrombus formation. As these quantities are difficult to measure in vivo, multi-scale coronary models offer a way to quantify them, while accounting for complex coronary physiology. However, prior studies have primarily focused on deterministic evaluations, without reporting variability in the model parameters due to uncertainty. This study aims to assess confidence in multi-scale predictions of wall shear stress and wall strain while accounting for uncertainty in peripheral hemodynamics and material properties. Boundary condition distributions are computed by assimilating uncertain clinical data, while spatial variations of vessel wall stiffness are obtained through approximation by a random field. We developed a stochastic submodeling approach to mitigate the computational burden of repeated multi-scale model evaluations to focus exclusively on the bypass grafts. This produces a two-level decomposition of quantities of interest into submodel contributions and full model/submodel discrepancies. We leverage these two levels in the context of forward uncertainty propagation using a previously proposed multi-resolution approach. The time- and space-averaged wall shear stress is well estimated with a coefficient of variation of <35%, but ignorance about the spatial distribution on the wall elastic modulus and thickness lead to large variations in an objective measure of wall strain, with coefficients of variation up to 100%. Sensitivity analysis reveals how the interactions between the flow and material parameters contribute to output variability.

  View details for DOI 10.1016/j.cma.2018.10.024

  View details for PubMedID 31223175

  View details for PubMedCentralID PMC6586227

• Uncertainty quantification of simulated biomechanical stimuli in coronary artery bypass grafts COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Tran, J. S., Schiavazzi, D. E., Kahn, A. M., Marsden, A. L. 2019; 345: 402–28

  View details for DOI 10.1016/j.cma.2018.10.024

  View details for Web of Science ID 000456953900018

• Hemodynamic variables in aneurysms are associated with thrombotic risk in children with Kawasaki disease. International journal of cardiology Grande Gutierrez, N., Mathew, M., McCrindle, B. W., Tran, J. S., Kahn, A. M., Burns, J. C., Marsden, A. L. 2019

  Abstract

  BACKGROUND: Thrombosis is a major adverse outcome associated with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD). Clinical guidelines recommend initiation of anticoagulation therapy with maximum CAA diameter (Dmax) ≥8 mm or Z-score ≥ 10. Here, we investigate the role of aneurysm hemodynamics as a superior method for thrombotic risk stratification in KD patients.METHODS AND RESULTS: We retrospectively studied ten KD patients with CAAs, including five patients who developed thrombosis. We constructed patient-specific anatomic models from cardiac magnetic resonance images and performed computational hemodynamic simulations using SimVascular. Our simulations incorporated pulsatile flow, deformable arterial walls and boundary conditions automatically tuned to match patient-specific arterial pressure and cardiac output. From simulation results, we derived local hemodynamic variables including time-averaged wall shear stress (TAWSS), low wall shear stress exposure, and oscillatory shear index (OSI). Local TAWSS was significantly lower in CAAs that developed thrombosis (1.2 ± 0.94 vs. 7.28 ± 9.77 dynes/cm2, p = 0.006) and the fraction of CAA surface area exposed to low wall shear stress was larger (0.69 ± 0.17 vs. 0.25 ± 0.26%, p = 0.005). Similarly, longer residence times were obtained in branches where thrombosis was confirmed (9.07 ± 6.26 vs. 2.05 ± 2.91 cycles, p = 0.004). No significant differences were found for OSI or anatomical measurements such us Dmax and Z-score. Assessment of thrombotic risk according to hemodynamic variables had higher sensitivity and specificity compared to standard clinical metrics (Dmax, Z-score).CONCLUSIONS: Hemodynamic variables can be obtained non-invasively via simulation and may provide improved thrombotic risk stratification compared to current diameter-based metrics, facilitating long-term clinical management of KD patients with persistent CAAs.

  View details for PubMedID 30728104

• Evolution of hemodynamic forces in the pulmonary tree with progressively worsening pulmonary arterial hypertension in pediatric patients. Biomechanics and modeling in mechanobiology Yang, W., Dong, M., Rabinovitch, M., Chan, F. P., Marsden, A. L., Feinstein, J. A. 2019

  Abstract

  Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling resulting in right ventricular (RV) dysfunction and ultimately RV failure. Mechanical stimuli acting on the vessel walls of the full pulmonary tree have not previously been comprehensively characterized. The goal of this study is to characterize wall shear stress (WSS) and strain in pediatric PAH patients at different stages of disease severity using computational patient-specific modeling. Computed tomography, magnetic resonance imaging and right heart catheterization data were collected and assimilated into pulmonary artery (PA) models for patients with and without PAH. Patients were grouped in three disease severity groups (control, moderate and severe) based on clinical evaluations. A finite element solver was employed to quantify hemodynamics and wall strains. To estimate WSS in the distal small PAs with diameters ranging from 50 to 500[Formula: see text], a morphometric tree model was created, with inputs coming from outlets of the 3D model. WSS in the proximal PAs decreased with disease severity (control 20.5 vs. moderate 15.8 vs. severe 6.3[Formula: see text], [Formula: see text]). Oscillatory shear index increased in the main pulmonary artery (MPA) with disease severity (0.13 vs. 0.13 vs. 0.2, [Formula: see text]). Wall strains measured by the first invariant of Green strain tensor decreased with disease severity (0.16 vs. 0.12 vs. 0.11, [Formula: see text]). Mean WSS for the distal PAs between 100 and 500[Formula: see text] significantly increased with disease severity (20 vs. 52 vs. 116 [Formula: see text], [Formula: see text]). In conclusion, 3D flow simulations showed that WSS is significantly decreased in the MPA with disease while the mathematical morphometric model suggested increased WSS in the distal small vessels. Computational models can reveal mechanical stimuli acting on vessel walls that may inform patient risk stratification and flow shear experiments.

  View details for PubMedID 30635853

• Contractile and hemodynamic forces coordinate Notch1b-mediated outflow tract valve formation. JCI insight Hsu, J. J., Vedula, V. n., Baek, K. I., Chen, C. n., Chen, J. n., Chou, M. I., Lam, J. n., Subhedar, S. n., Wang, J. n., Ding, Y. n., Chang, C. C., Lee, J. n., Demer, L. L., Tintut, Y. n., Marsden, A. L., Hsiai, T. K. 2019; 5

  Abstract

  Biomechanical forces and endothelial-to-mesenchymal transition (EndoMT) are known to mediate valvulogenesis. However, the relative contributions of myocardial contractile and hemodynamic shear forces remain poorly understood. We integrated 4-D light-sheet imaging of transgenic zebrafish models with moving-domain computational fluid dynamics to determine effects of changes in contractile forces and fluid wall shear stress (WSS) on ventriculobulbar (VB) valve development. Augmentation of myocardial contractility with isoproterenol increased both WSS and Notch1b activity in the developing outflow tract (OFT) and resulted in VB valve hyperplasia. Increasing WSS in the OFT, achieved by increasing blood viscosity through EPO mRNA injection, also resulted in VB valve hyperplasia. Conversely, decreasing myocardial contractility by Tnnt2a morpholino oligonucleotide (MO) administration, 2,3-butanedione monoxime treatment, or Plcγ1 inhibition completely blocked VB valve formation, which could not be rescued by increasing WSS or activating Notch. Decreasing WSS in the OFT, achieved by slowing heart rate with metoprolol or reducing viscosity with Gata1a MO, did not affect VB valve formation. Immunofluorescent staining with the mesenchymal marker, DM-GRASP, revealed that biomechanical force-mediated Notch1b activity is implicated in EndoMT to modulate valve morphology. Altogether, increases in WSS result in Notch1b- EndoMT-mediated VB valve hyperplasia, whereas decreases in contractility result in reduced Notch1b activity, absence of EndoMT, and VB valve underdevelopment. Thus, we provide developmental mechanotransduction mechanisms underlying Notch1b-mediated EndoMT in the OFT.

  View details for PubMedID 30973827

• Multiscale Modeling of Superior Cavopulmonary Circulation: Hemi-Fontan And Bidirectional Glenn Are Equivalent. Seminars in thoracic and cardiovascular surgery Kung, E. n., Corsini, C. n., Marsden, A. n., Vignon-Clementel, I. n., Pennati, G. n., Figliola, R. n., Hsia, T. Y. 2019

  Abstract

  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 were constructed to include detailed definition of the distal branch pulmonary arteries, 2) virtual hF and bG operations were performed to create two 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, i.e. power loss, and global systemic physiology can be quantified. In two 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 to 35%). In the remaining two 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 physiologic outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the two 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.

  View details for DOI 10.1053/j.semtcvs.2019.09.007

  View details for PubMedID 31520732

• Cavopulmonary assist: Long-term reversal of the Fontan paradox. The Journal of thoracic and cardiovascular surgery Rodefeld, M. D., Marsden, A. n., Figliola, R. n., Jonas, T. n., Neary, M. n., Giridharan, G. A. 2019

  Abstract

  Fontan circulatory inefficiency can be addressed by replacing the missing subpulmonary power source to reverse the Fontan paradox. An implantable cavopulmonary assist device is described that will simultaneously reduce systemic venous pressure and increase pulmonary arterial pressure, improving preload and cardiac output, in a univentricular Fontan circulation on a long-term basis.A rotary blood pump that was based on the von Karman viscous pump was designed for implantation into the total cavopulmonary connection (TCPC). It will impart modest pressure energy to augment Fontan flow without risk of obstruction. In the event of rotational failure, it is designed to default to a passive flow diverter. Pressure-flow performance was characterized in vitro in a Fontan mock circulatory loop with blood analog.The pump performed through the fully specified operating range, augmenting flow in all 4 directions of the TCPC. Pressure rise of 6 to 8 mm Hg was readily achieved, ranging to 14 mm Hg at highest speed (5600 rpm). Performance was consistent across a wide range of cardiac outputs. In stalled condition (0 rpm), there was no discernible pressure loss across the TCPC.A blood pump technology is described that can reverse the Fontan paradox and may permit a surgical strategy of long-term biventricular maintenance of a univentricular Fontan circulation. The technology is intended for Fontan failure in which right-sided circulatory inefficiencies predominate and ventricular systolic function is preserved. It may also apply before clinical Fontan failure as health maintenance to preempt the progression of Fontan disease.

  View details for DOI 10.1016/j.jtcvs.2019.06.112

  View details for PubMedID 31564543

• Expert recommendations on the assessment of wall shear stress in human coronary arteries: existing methodologies, technical considerations, and clinical applications. European heart journal Gijsen, F. n., Katagiri, Y. n., Barlis, P. n., Bourantas, C. n., Collet, C. n., Coskun, U. n., Daemen, J. n., Dijkstra, J. n., Edelman, E. n., Evans, P. n., van der Heiden, K. n., Hose, R. n., Koo, B. K., Krams, R. n., Marsden, A. n., Migliavacca, F. n., Onuma, Y. n., Ooi, A. n., Poon, E. n., Samady, H. n., Stone, P. n., Takahashi, K. n., Tang, D. n., Thondapu, V. n., Tenekecioglu, E. n., Timmins, L. n., Torii, R. n., Wentzel, J. n., Serruys, P. n. 2019

  View details for DOI 10.1093/eurheartj/ehz551

  View details for PubMedID 31566246

• Performance of preconditioned iterative linear solvers for cardiovascular simulations in rigid and deformable vessels. COMPUTATIONAL MECHANICS Seo, J., Schiavazzi, D. E., Marsden, A. L. 2019

  View details for DOI 10.1007/s00466-019-01678-3

• Simulating Developmental Cardiac Morphology in Virtual Reality Using a Deformable Image Registration Approach ANNALS OF BIOMEDICAL ENGINEERING Abiri, A., Ding, Y., Abiri, P., Packard, R., Vedula, V., Marsden, A., Kuo, C., Hsiai, T. K. 2018; 46 (12): 2177–88

  Abstract

  While virtual reality (VR) has potential in enhancing cardiovascular diagnosis and treatment, prerequisite labor-intensive image segmentation remains an obstacle for seamlessly simulating 4-dimensional (4-D, 3-D + time) imaging data in an immersive, physiological VR environment. We applied deformable image registration (DIR) in conjunction with 3-D reconstruction and VR implementation to recapitulate developmental cardiac contractile function from light-sheet fluorescence microscopy (LSFM). This method addressed inconsistencies that would arise from independent segmentations of time-dependent data, thereby enabling the creation of a VR environment that fluently simulates cardiac morphological changes. By analyzing myocardial deformation at high spatiotemporal resolution, we interfaced quantitative computations with 4-D VR. We demonstrated that our LSFM-captured images, followed by DIR, yielded average dice similarity coefficients of 0.92 ± 0.05 (n = 510) and 0.93 ± 0.06 (n = 240) when compared to ground truth images obtained from Otsu thresholding and manual segmentation, respectively. The resulting VR environment simulates a wide-angle zoomed-in view of motion in live embryonic zebrafish hearts, in which the cardiac chambers are undergoing structural deformation throughout the cardiac cycle. Thus, this technique allows for an interactive micro-scale VR visualization of developmental cardiac morphology to enable high resolution simulation for both basic and clinical science.

  View details for PubMedID 30112710

• Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH): Phase I: Segmentation CARDIOVASCULAR ENGINEERING AND TECHNOLOGY Berg, P., Voss, S., Saalfeld, S., Janiga, G., Bergersen, A. W., Valen-Sendstad, K., Bruening, J., Goubergrits, L., Spuler, A., Cancelliere, N. M., Steinman, D. A., Pereira, V. M., Chiu, T., Tsang, A., Chung, B., Cebral, J. R., Cito, S., Pallares, J., Copelli, G., Csippa, B., Paal, G., Fujimura, S., Takao, H., Hodis, S., Hille, G., Karmonik, C., Elias, S., Kellermann, K., Khan, M., Marsden, A. L., Morales, H. G., Piskin, S., Finol, E. A., Pravdivtseva, M., Rajabzadeh-Oghaz, H., Paliwal, N., Meng, H., Seshadhri, S., Howard, M., Shojima, M., Sugiyama, S., Niizuma, K., Sindeev, S., Frolov, S., Wagner, T., Brawanski, A., Qian, Y., Wu, Y., Carlson, K. D., Dragomir-Daescu, D., Beuing, O. 2018; 9 (4): 565–81

  Abstract

  Advanced morphology analysis and image-based hemodynamic simulations are increasingly used to assess the rupture risk of intracranial aneurysms (IAs). However, the accuracy of those results strongly depends on the quality of the vessel wall segmentation.To evaluate state-of-the-art segmentation approaches, the Multiple Aneurysms AnaTomy CHallenge (MATCH) was announced. Participants carried out segmentation in three anonymized 3D DSA datasets (left and right anterior, posterior circulation) of a patient harboring five IAs. Qualitative and quantitative inter-group comparisons were carried out with respect to aneurysm volumes and ostia. Further, over- and undersegmentation were evaluated based on highly resolved 2D images. Finally, clinically relevant morphological parameters were calculated.Based on the contributions of 26 participating groups, the findings reveal that no consensus regarding segmentation software or underlying algorithms exists. Qualitative similarity of the aneurysm representations was obtained. However, inter-group differences occurred regarding the luminal surface quality, number of vessel branches considered, aneurysm volumes (up to 20%) and ostium surface areas (up to 30%). Further, a systematic oversegmentation of the 3D surfaces was observed with a difference of approximately 10% to the highly resolved 2D reference image. Particularly, the neck of the ruptured aneurysm was overrepresented by all groups except for one. Finally, morphology parameters (e.g., undulation and non-sphericity) varied up to 25%.MATCH provides an overview of segmentation methodologies for IAs and highlights the variability of surface reconstruction. Further, the study emphasizes the need for careful processing of initial segmentation results for a realistic assessment of clinically relevant morphological parameters.

  View details for PubMedID 30191538

• Real-World Variability in the Prediction of Intracranial Aneurysm Wall Shear Stress: The 2015 International Aneurysm CFD Challenge CARDIOVASCULAR ENGINEERING AND TECHNOLOGY Valen-Sendstad, K., Bergersen, A. W., Shimogonya, Y., Goubergrits, L., Bruening, J., Pallares, J., Cito, S., Piskin, S., Pekkan, K., Geers, A. J., Larrabide, I., Rapaka, S., Mihalef, V., Fu, W., Qiao, A., Jain, K., Roller, S., Mardal, K., Kamakoti, R., Spirka, T., Ashton, N., Revell, A., Aristokleous, N., Houston, J., Tsuji, M., Ishida, F., Menon, P. G., Browne, L. D., Broderick, S., Shojima, M., Koizumi, S., Barbour, M., Aliseda, A., Morales, H. G., Lefevre, T., Hodis, S., Al-Smadi, Y. M., Tran, J. S., Marsden, A. L., Vaippummadhom, S., Einstein, G., Brown, A. G., Debus, K., Niizuma, K., Rashad, S., Sugiyama, S., Khan, M., Updegrove, A. R., Shadden, S. C., Cornelissen, B. W., Majoie, C. M., Berg, P., Saalfield, S., Kono, K., Steinman, D. A. 2018; 9 (4): 544–64

  Abstract

  Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline.3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters.A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability.Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters.

  View details for PubMedID 30203115

• Patient-Specific Multiscale Modeling of the Assisted Bidirectional Glenn. The Annals of thoracic surgery Shang, J. K., Esmaily, M., Verma, A., Reinhartz, O., Figliola, R. S., Hsia, T., Feinstein, J. A., Marsden, A. L. 2018

  Abstract

  BACKGROUND: First-stage palliation of neonates with single-ventricle physiology is associated with poor outcomes and challenging clinical management. Prior computational modeling and invitro experiments introduced the assisted bidirectional Glenn (ABG), which increased pulmonary flow and oxygenation over the bidirectional Glenn (BDG) and the systemic-to-pulmonary shunt in idealized models. In this study, we demonstrate that the ABG achieves similar performance in patient-specific models and assess the influence of varying shunt geometry.METHODS: In a small cohort of single-ventricle prestage 2 patients, we constructed three-dimensional in silico models and tuned lumped parameter networks to match clinical measurements. Each model was modified to produce virtual BDG and ABG surgeries. We simulated the hemodynamics of the stage 1 procedure, BDG, and ABG by using multiscale computational modeling, coupling a finite-element flow solver to the lumped parameter network. Two levels of pulmonary vascular resistances (PVRs) were investigated: baseline (low) PVR of the patients and doubled (high) PVR. The shunt nozzle diameter, anastomosis location, and shape were also manipulated.RESULTS: The ABG increased the pulmonary flow rate and pressure by 15% to 20%, which was accompanied by a rise in superior vena caval pressure (2 to 3 mm Hg) at both PVR values. Pulmonary flow rate and superior vena caval pressures were most sensitive to the shunt nozzle diameter.CONCLUSIONS: Patient-specific ABG performance was similar to prior idealized simulations and experiments, with good performance at lower PVR values in the range of measured clinical data. Larger shunt outlet diameters and lower PVR led to improved ABG performance.

  View details for PubMedID 30471273

• Computational Fluid Dynamics (BypassCFD) Trumps Anatomic Predictors of Saphenous Vein Graft Failure in CABG Patients Khan, M., Tran, J. S., Zhu, H., Packard, R. S., Karlsberg, R. P., Kahn, A., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619404279

• Contractile and Hemodynamic Forces Promote Cardiac Valve Development via Notch1b-Mediated Endothelial-to-Mesenchymal Transition Hsu, J. J., Vedula, V., Baek, K., Chen, C., Ding Yichen, Tintut, Y., Marsden, A. L., Hsiai, T. K. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619403448

• Pre-Operative Right Ventricular Outflow Tract and Pulmonary Artery Geometry Predicts Pulmonary Valve Replacement Outcomes in Patients With Tetralogy of Fallot Toro Arana, V., Chan, F., Shiavone, N., McElhinney, D., Reddy, S., Marsden, A. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619407405

• A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling (vol 13, e1005828, 2017) PLOS COMPUTATIONAL BIOLOGY Vedula, V., Lee, J., Xu, H., Kuo, C., Hsiai, T. K., Marsden, A. L. 2018; 14 (9): e1006482

  Abstract

  [This corrects the article DOI: 10.1371/journal.pcbi.1005828.].

  View details for DOI 10.1371/journal.pcbi.1006482

  View details for Web of Science ID 000450712200034

  View details for PubMedID 30222742

  View details for PubMedCentralID PMC6141061

• A unified continuum and variational multiscale formulation for fluids, solids, and fluid-structure interaction COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Liu, J., Marsden, A. L. 2018; 337: 549–97

  View details for DOI 10.1016/j.cma.2018.03.045

  View details for Web of Science ID 000433143200024

• A unified continuum and variational multiscale formulation for fluids, solids, and fluid-structure interaction. Computer methods in applied mechanics and engineering Liu, J., Marsden, A. L. 2018; 337: 549-597

  Abstract

  We develop a unified continuum modeling framework using the Gibbs free energy as the thermodynamic potential. This framework naturally leads to a pressure primitive variable formulation for the continuum body, which is well-behaved in both compressible and incompressible regimes. Our derivation also provides a rational justification of the isochoric-volumetric additive split of free energies in nonlinear elasticity. The variational multiscale analysis is performed for the continuum model to construct a foundation for numerical discretization. We first consider the continuum body instantiated as a hyperelastic material and develop a variational multiscale formulation for the hyper-elastodynamic problem. The generalized-α method is applied for temporal discretization. A segregated algorithm for the nonlinear solver, based on the original idea introduced in [107], is carefully analyzed. Second, we apply the new formulation to construct a novel unified formulation for fluid-solid coupled problems. The variational multiscale formulation is utilized for spatial discretization in both fluid and solid subdomains. The generalized-α method is applied for the whole continuum body, and optimal high-frequency dissipation is achieved in both fluid and solid subproblems. A new predictor multi-corrector algorithm is developed based on the segregated algorithm. The efficacy of the new formulations is examined in several benchmark problems. The results indicate that the proposed modeling and numerical methodologies constitute a promising technology for biomedical and engineering applications, particularly those necessitating incompressible models.

  View details for DOI 10.1016/j.cma.2018.03.045

  View details for PubMedID 30505038

  View details for PubMedCentralID PMC6261472

• Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation JCI INSIGHT Lee, J., Vedula, V., Baek, K., Chen, J., Hsu, J. J., Ding, Y., Chang, C., Kang, H., Small, A., Fei, P., Chuong, C., Li, R., Demer, L., Packard, R., Marsden, A. L., Hsiai, T. K. 2018; 3 (13)

  Abstract

  Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

  View details for PubMedID 29997298

• Right ventricular stroke work correlates with outcomes in pediatric pulmonary arterial hypertension PULMONARY CIRCULATION Yang, W., Marsden, A. L., Ogawa, M. T., Sakarovitch, C., Hall, K. K., Rabinovitch, M., Feinstein, J. A. 2018; 8 (3)

  View details for DOI 10.1177/2045894018780534

  View details for Web of Science ID 000434659100001

• Developmental Contractile Function Modulates Notch1b-Mediated Valvular Leaflet Development Hsu, J. J., Chen, J., Vedula, V., Chen, C., Lee, J., Tintut, Y., Demer, L. L., Marsden, A., Hsiai, T. K. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for DOI 10.1161/atvb.38.suppl_1.278

  View details for Web of Science ID 000497511500206

• Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair. World journal for pediatric & congenital heart surgery Verma, A., Esmaily, M., Shang, J., Figliola, R., Feinstein, J. A., Hsia, T. Y., Marsden, A. L. 2018; 9 (2): 157-170

  Abstract

  First-stage single-ventricle palliation is challenging to manage, and significant interstage morbidity and mortality remain. Prior computational and in vitro studies of the assisted bidirectional Glenn (ABG), a novel first-stage procedure that has shown potential for early conversion to a more stable augmented Glenn physiology, demonstrated increased pulmonary flow and oxygen delivery while decreasing cardiac work, as compared to conventional stage-1 alternatives. This study aims to identify optimal shunt designs for the ABG to improve pulmonary flow while maintaining or decreasing superior vena caval (SVC) pressure.A representative three-dimensional model of a neonatal bidirectional Glenn (BDG) was created, with a shunt connecting the innominate artery to the SVC. The shunt design was studied as a six-parameter constrained shape optimization problem. We simulated hemodynamics for each candidate designs using a multiscale finite element flow solver and compared performance against designs with taper-less shunts, the standalone BDG, and a simplified control volume model. Three values of pulmonary vascular resistance (PVR) of 2.3, 4.3, and 7.1 WUm2 were studied.Increases in pulmonary flow were generally accompanied by increases in SVC pressure, except at low PVR (2.3 WUm2), where the optimal shunt geometry achieved a 13% increase in pulmonary flow without incurring any increase in SVC pressure. Shunt outlet area was the most influential design parameter, while others had minimal effect.Assisted bidirectional Glenn performance is sensitive to PVR and shunt outlet diameter. An increase in pulmonary flow without a corresponding increase in SVC pressure is possible only when PVR is low.

  View details for DOI 10.1177/2150135117745026

  View details for PubMedID 29544408

• The future of biomedical engineering - Vascular bioengineering CURRENT OPINION IN BIOMEDICAL ENGINEERING Marsden, A. L., Truskey, G. A. 2018; 5: III-v

  View details for DOI 10.1016/j.cobme.2018.04.002

  View details for Web of Science ID 000655214700001

• Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis. Congenital heart disease Yang, W., Hanley, F. L., Chan, F. P., Marsden, A. L., Vignon-Clementel, I. E., Feinstein, J. A. 2018; 13 (2): 241-250

  Abstract

  Up to 90% of individuals with Alagille syndrome have congenital heart diseases. Peripheral pulmonary artery stenosis (PPS), resulting in right ventricular hypertension and pulmonary flow disparity, is one of the most common abnormalities, yet the hemodynamic effects are ill-defined, and optimal patient management and treatment strategies are not well established. The purpose of this pilot study is to use recently refined computational simulation in the setting of multiple surgical strategies, to examine the influence of pulmonary artery reconstruction on hemodynamics in this population.Based on computed tomography angiography and cardiac catheterization data, preoperative pulmonary artery models were constructed for 4 patients with Alagille syndrome with PPS (all male, age range: 0.6-2.9 years), and flow simulations with deformable walls were performed. Surgeon directed virtual surgery, mimicking the surgical procedure, was then performed to derive postoperative models. Postoperative simulation-derived hemodynamics and blood flow distribution were then compared with the clinical results.Simulations confirmed substantial resistance, resulting from preoperative severe ostial stenoses, and the use of newly developed adaptive outflow boundary conditions led to excellent agreement with in vivo measurements. Relief of PPS decreased pulmonary artery pressures and improved pulmonary flow distribution both in vivo and in silico with good correlation.Using adaptive outflow boundary conditions, computational simulations can estimate postoperative overall pulmonary flow distribution in patients with Alagille syndrome after pulmonary artery reconstruction. Obstruction relief along with pulmonary artery vasodilation determines postoperative pulmonary flow distribution and newer methods can incorporate these physiologic changes. Evolving blood flow simulations may be useful in surgical or transcatheter planning and in understanding the complex interplay among various obstructions in patients with peripheral pulmonary stenosis.

  View details for DOI 10.1111/chd.12556

  View details for PubMedID 29194961

• Benchmark problems for numerical treatment of backflow at open boundaries INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING Bertoglio, C., Caiazzo, A., Bazilevs, Y., Braack, M., Esmaily, M., Gravemeier, V., Marsden, A. L., Pironneau, O., Vignon-Clementel, I. E., Wall, W. A. 2018; 34 (2)

  View details for DOI 10.1002/cnm.2918

  View details for Web of Science ID 000424359400006

• A Re-Engineered Software Interface and Workflow for the Open-Source SimVascular Cardiovascular Modeling Package. Journal of biomechanical engineering Lan, H., Updegrove, A., Wilson, N. M., Maher, G. D., Shadden, S. C., Marsden, A. L. 2018; 140 (2)

  Abstract

  Patient-specific simulation plays an important role in cardiovascular disease research, diagnosis, surgical planning and medical device design, as well as education in cardiovascular biomechanics. simvascular is an open-source software package encompassing an entire cardiovascular modeling and simulation pipeline from image segmentation, three-dimensional (3D) solid modeling, and mesh generation, to patient-specific simulation and analysis. SimVascular is widely used for cardiovascular basic science and clinical research as well as education, following increased adoption by users and development of a GATEWAY web portal to facilitate educational access. Initial efforts of the project focused on replacing commercial packages with open-source alternatives and adding increased functionality for multiscale modeling, fluid-structure interaction (FSI), and solid modeling operations. In this paper, we introduce a major SimVascular (SV) release that includes a new graphical user interface (GUI) designed to improve user experience. Additional improvements include enhanced data/project management, interactive tools to facilitate user interaction, new boundary condition (BC) functionality, plug-in mechanism to increase modularity, a new 3D segmentation tool, and new computer-aided design (CAD)-based solid modeling capabilities. Here, we focus on major changes to the software platform and outline features added in this new release. We also briefly describe our recent experiences using SimVascular in the classroom for bioengineering education.

  View details for DOI 10.1115/1.4038751

  View details for PubMedID 29238826

  View details for PubMedCentralID PMC5816252

• Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair Optimization of the Assisted Bidirectional Glenn Procedure for First Stage Single Ventricle Repair Verma, A., Esmaily, M., Shang, J., Figliola, R., Feinstein, J., Hsia, T., Marsden, A. 2018; 9 (2): 157-170

  Abstract

  First-stage single-ventricle palliation is challenging to manage, and significant interstage morbidity and mortality remain. Prior computational and in vitro studies of the assisted bidirectional Glenn (ABG), a novel first-stage procedure that has shown potential for early conversion to a more stable augmented Glenn physiology, demonstrated increased pulmonary flow and oxygen delivery while decreasing cardiac work, as compared to conventional stage-1 alternatives. This study aims to identify optimal shunt designs for the ABG to improve pulmonary flow while maintaining or decreasing superior vena caval (SVC) pressure.A representative three-dimensional model of a neonatal bidirectional Glenn (BDG) was created, with a shunt connecting the innominate artery to the SVC. The shunt design was studied as a six-parameter constrained shape optimization problem. We simulated hemodynamics for each candidate designs using a multiscale finite element flow solver and compared performance against designs with taper-less shunts, the standalone BDG, and a simplified control volume model. Three values of pulmonary vascular resistance (PVR) of 2.3, 4.3, and 7.1 WUm2 were studied.Increases in pulmonary flow were generally accompanied by increases in SVC pressure, except at low PVR (2.3 WUm2), where the optimal shunt geometry achieved a 13% increase in pulmonary flow without incurring any increase in SVC pressure. Shunt outlet area was the most influential design parameter, while others had minimal effect.Assisted bidirectional Glenn performance is sensitive to PVR and shunt outlet diameter. An increase in pulmonary flow without a corresponding increase in SVC pressure is possible only when PVR is low.

  View details for DOI 10.1177/2150135117745026

• Right Ventricular Stroke Work Correlates with Outcomes in Pediatric Pulmonary Arterial Hypertension. Pulmonary circulation Yang, W., Marsden, A. L., Ogawa, M. T., Sakarovitch, C., Hall, K. K., Rabinovitch, M., Feinstein, J. A. 2018: 2045894018780534

  View details for PubMedID 29767574

• A re-engineered interface and workflow for the open source SimVascular cardiovascular modeling package A re-engineered interface and workflow for the open source SimVascular cardiovascular modeling package Lan, H., Updegrove, A., Wilson, N., Maher, G., Shadden, S., Marsden, A. 2018; 140 (2): 024501-024501-11

  Abstract

  Patient-specific simulation plays an important role in cardiovascular disease research, diagnosis, surgical planning and medical device design, as well as education in cardiovascular biomechanics. simvascular is an open-source software package encompassing an entire cardiovascular modeling and simulation pipeline from image segmentation, three-dimensional (3D) solid modeling, and mesh generation, to patient-specific simulation and analysis. SimVascular is widely used for cardiovascular basic science and clinical research as well as education, following increased adoption by users and development of a GATEWAY web portal to facilitate educational access. Initial efforts of the project focused on replacing commercial packages with open-source alternatives and adding increased functionality for multiscale modeling, fluid-structure interaction (FSI), and solid modeling operations. In this paper, we introduce a major SimVascular (SV) release that includes a new graphical user interface (GUI) designed to improve user experience. Additional improvements include enhanced data/project management, interactive tools to facilitate user interaction, new boundary condition (BC) functionality, plug-in mechanism to increase modularity, a new 3D segmentation tool, and new computer-aided design (CAD)-based solid modeling capabilities. Here, we focus on major changes to the software platform and outline features added in this new release. We also briefly describe our recent experiences using SimVascular in the classroom for bioengineering education.

  View details for DOI 10.1115/1.4038751

  View details for PubMedCentralID PMC5816252

• Spatiotemporal Variations in Intracardiac Shear Stress Differentially Modulate Trabeculation for Developmental Contractile Function Lee, J., Vedula, V., Ding, Y., Chen, J., Marsden, A., Hsiai, T. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000437035905411

• 4-D Light-Sheet Imaging and Moving-Domain Computation Reveal That Oscillatory Shear Index Mediates Endocardial Notch1b Signaling and Valve Development Hsu, J. J., Chen, J., Vedula, V., Lee, J., Ding, Y., Marsden, A. L., Hsiai, T. K. LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000437035905405

• Computational blood flow simulations in Kawasaki disease patients: Insight into coronary artery aneurysm hemodynamics. Global cardiology science & practice Grande Gutierrez, N., Kahn, A., Burns, J. C., Marsden, A. L. 2017; 2017 (3): e201729

  View details for PubMedID 29564350

• Assessment of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of Computerized Tomography Angiograms. The American journal of cardiology Grande Gutierrez, N., Shirinsky, O., Gagarina, N., Lyskina, G., Fukazawa, R., Ogawa, S., Burns, J. C., Marsden, A. L., Kahn, A. M. 2017; 120 (4): 556-562

  Abstract

  Patients with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend CAA diameter ≥8 mm as the criterion for initiating systemic anticoagulation. Transluminal attenuation gradient (TAG) analysis has been proposed as a noninvasive method for evaluating functional significance of coronary stenoses using computerized tomography angiography (CTA), but has not previously been used in CAA. We hypothesized that abnormal hemodynamics in CAA caused by KD could be quantified using TAG analysis. We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries and aneurysm geometry was characterized using maximum diameter, aneurysm shape index, and sphericity index. A total of 55 coronary arteries were analyzed, 25 of which had at least 1 aneurysmal region. TAG in aneurysmal arteries was significantly lower than in normal arteries (-23.5 ± 10.7 vs -10.5 ± 9.0, p = 0.00002). Aneurysm diameter, aneurysm shape index, and sphericity index were weakly correlated with TAG (r2 = 0.01, p = 0.6; r2 = 0.15, p = 0.06; r2 = 0.16, p = 0.04). This is the first application of TAG analysis to CAA caused by KD, and demonstrates significantly different TAG values in aneurysmal versus normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide hemodynamic information not available from anatomy alone. TAG represents a possible extension to standard CTA for KD patients who may improve thrombotic risk stratification and aid in clinical decision making.

  View details for DOI 10.1016/j.amjcard.2017.05.025

  View details for PubMedID 28666576

  View details for PubMedCentralID PMC6046216

• Gradual loading ameliorates maladaptation in computational simulations of vein graft growth and remodelling. Journal of the Royal Society, Interface Ramachandra, A. B., Humphrey, J. D., Marsden, A. L. 2017; 14 (130)

  Abstract

  Vein graft failure is a prevalent problem in vascular surgeries, including bypass grafting and arteriovenous fistula procedures in which veins are subjected to severe changes in pressure and flow. Animal and clinical studies provide significant insight, but understanding the complex underlying coupled mechanisms can be advanced using computational models. Towards this end, we propose a new model of venous growth and remodelling (G&R) based on a constrained mixture theory. First, we identify constitutive relations and parameters that enable venous adaptations to moderate perturbations in haemodynamics. We then fix these relations and parameters, and subject the vein to a range of combined loads (pressure and flow), from moderate to severe, and identify plausible mechanisms of adaptation versus maladaptation. We also explore the beneficial effects of gradual increases in load on adaptation. A gradual change in flow over 3 days plus an initial step change in pressure results in fewer maladaptations compared with step changes in both flow and pressure, or even a gradual change in pressure and flow over 3 days. A gradual change in flow and pressure over 8 days also enabled a successful venous adaptation for loads as severe as the arterial loads. Optimization is used to accelerate parameter estimation and the proposed framework is general enough to provide a good starting point for parameter estimations in G&R simulations.

  View details for DOI 10.1098/rsif.2016.0995

  View details for PubMedID 28566510

• Optimizing fluid-structure interaction systems with immersogeometric analysis and surrogate modeling: Application to a hydraulic arresting gear COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Wu, M. C., Kamensky, D., Wang, C., Herrema, A. J., Xu, F., Pigazzini, M. S., Verma, A., Marsden, A. L., Bazilevs, Y., Hsu, M. 2017; 316: 668-693

  View details for DOI 10.1016/j.cma.2016.09.032

  View details for Web of Science ID 000395952500029

• Patient-specific parameter estimation in single-ventricle lumped circulation models under uncertainty. International journal for numerical methods in biomedical engineering Schiavazzi, D. E., Baretta, A., Pennati, G., Hsia, T., Marsden, A. L. 2017; 33 (3)

  Abstract

  Computational models of cardiovascular physiology can inform clinical decision-making, providing a physically consistent framework to assess vascular pressures and flow distributions, and aiding in treatment planning. In particular, lumped parameter network (LPN) models that make an analogy to electrical circuits offer a fast and surprisingly realistic method to reproduce the circulatory physiology. The complexity of LPN models can vary significantly to account, for example, for cardiac and valve function, respiration, autoregulation, and time-dependent hemodynamics. More complex models provide insight into detailed physiological mechanisms, but their utility is maximized if one can quickly identify patient specific parameters. The clinical utility of LPN models with many parameters will be greatly enhanced by automated parameter identification, particularly if parameter tuning can match non-invasively obtained clinical data. We present a framework for automated tuning of 0D lumped model parameters to match clinical data. We demonstrate the utility of this framework through application to single ventricle pediatric patients with Norwood physiology. Through a combination of local identifiability, Bayesian estimation and maximum a posteriori simplex optimization, we show the ability to automatically determine physiologically consistent point estimates of the parameters and to quantify uncertainty induced by errors and assumptions in the collected clinical data. We show that multi-level estimation, that is, updating the parameter prior information through sub-model analysis, can lead to a significant reduction in the parameter marginal posterior variance. We first consider virtual patient conditions, with clinical targets generated through model solutions, and second application to a cohort of four single-ventricle patients with Norwood physiology. Copyright © 2016 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/cnm.2799

  View details for PubMedID 27155892

• SimVascular: An Open Source Pipeline for Cardiovascular Simulation. Annals of biomedical engineering Updegrove, A., Wilson, N. M., Merkow, J., Lan, H., Marsden, A. L., Shadden, S. C. 2017; 45 (3): 525-541

  Abstract

  Patient-specific cardiovascular simulation has become a paradigm in cardiovascular research and is emerging as a powerful tool in basic, translational and clinical research. In this paper we discuss the recent development of a fully open-source SimVascular software package, which provides a complete pipeline from medical image data segmentation to patient-specific blood flow simulation and analysis. This package serves as a research tool for cardiovascular modeling and simulation, and has contributed to numerous advances in personalized medicine, surgical planning and medical device design. The SimVascular software has recently been refactored and expanded to enhance functionality, usability, efficiency and accuracy of image-based patient-specific modeling tools. Moreover, SimVascular previously required several licensed components that hindered new user adoption and code management and our recent developments have replaced these commercial components to create a fully open source pipeline. These developments foster advances in cardiovascular modeling research, increased collaboration, standardization of methods, and a growing developer community.

  View details for DOI 10.1007/s10439-016-1762-8

  View details for PubMedID 27933407

• Superior performance of continuous over pulsatile flow ventricular assist devices in the single ventricle circulation: A computational study. Journal of biomechanics Schmidt, T., Rosenthal, D., Reinhartz, O., Riemer, K., He, F., Hsia, T., Marsden, A., Kung, E. 2017; 52: 48-54

  Abstract

  This study compares the physiological responses of systemic-to-pulmonary shunted single ventricle patients to pulsatile and continuous flow ventricular assist devices (VADs). Performance differences between pulsatile and continuous flow VADs have been clinically observed, but the underlying mechanism remains poorly understood. Six systemic-to-pulmonary shunted single ventricle patients (mean BSA=0.30m(2)) were computationally simulated using a lumped-parameter network tuned to match patient specific clinical data. A first set of simulations compared current clinical implementation of VADs in single ventricle patients. A second set modified pulsatile flow VAD settings with the goal to optimize cardiac output (CO). For all patients, the best-case continuous flow VAD CO was at least 0.99L/min greater than the optimized pulsatile flow VAD CO (p=0.001). The 25 and 50mL pulsatile flow VADs exhibited incomplete filling at higher heart rates that reduced CO as much as 9.7% and 37.3% below expectations respectively. Optimization of pulsatile flow VAD settings did not achieve statistically significant (p<0.05) improvement to CO. Results corroborate clinical experience that continuous flow VADs produce higher CO and superior ventricular unloading in single ventricle patients. Impaired filling leads to performance degradation of pulsatile flow VADs in the single ventricle circulation.

  View details for DOI 10.1016/j.jbiomech.2016.12.003

  View details for PubMedID 28038771

• A generalized multi-resolution expansion for uncertainty propagation with application to cardiovascular modeling COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Schiavazzi, D. E., Doostan, A., Iaccarino, G., Marsden, A. L. 2017; 314: 196-221

  Abstract

  Computational models are used in a variety of fields to improve our understanding of complex physical phenomena. Recently, the realism of model predictions has been greatly enhanced by transitioning from deterministic to stochastic frameworks, where the effects of the intrinsic variability in parameters, loads, constitutive properties, model geometry and other quantities can be more naturally included. A general stochastic system may be characterized by a large number of arbitrarily distributed and correlated random inputs, and a limited support response with sharp gradients or event discontinuities. This motivates continued research into novel adaptive algorithms for uncertainty propagation, particularly those handling high dimensional, arbitrarily distributed random inputs and non-smooth stochastic responses. In this work, we generalize a previously proposed multi-resolution approach to uncertainty propagation to develop a method that improves computational efficiency, can handle arbitrarily distributed random inputs and non-smooth stochastic responses, and naturally facilitates adaptivity, i.e., the expansion coefficients encode information on solution refinement. Our approach relies on partitioning the stochastic space into elements that are subdivided along a single dimension, or, in other words, progressive refinements exhibiting a binary tree representation. We also show how these binary refinements are particularly effective in avoiding the exponential increase in the multi-resolution basis cardinality and significantly reduce the regression complexity for moderate to high dimensional random inputs. The performance of the approach is demonstrated through previously proposed uncertainty propagation benchmarks and stochastic multi-scale finite element simulations in cardiovascular flow.

  View details for DOI 10.1016/j.cma.2016.09.024

  View details for Web of Science ID 000392782900012

  View details for PubMedCentralID PMC5568857

• Looks Do Matter! Aortic Arch Shape After Hypoplastic Left Heart Syndrome Palliation Correlates With Cavopulmonary Outcomes ANNALS OF THORACIC SURGERY Bruse, J. L., Cervi, E., McLeod, K., Biglino, G., Sermesant, M., Pennec, X., Taylor, A. M., Schievano, S., Hsia, T., MOCHA Collaborative Grp 2017; 103 (2): 645-654

  Abstract

  Aortic arch reconstruction after hypoplastic left heart syndrome (HLHS) palliation can vary widely in shape and dimensions between patients. Arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch three-dimensional shape features with functional and short-term outcome data after total cavopulmonary connection (TCPC).Aortic arch shape models of 37 patients with HLHS (age, 2.89 ± 0.99 years) were reconstructed from magnetic resonance data before TCPC completion. A novel, validated statistical shape analysis method was used to compute a three-dimensional anatomic mean shape from the cohort and calculate the deformation vectors of the mean shape toward each patient's specific anatomy. From these deformations, three-dimensional shape features most related to ventricular ejection fraction, indexed end-diastolic volume, and superior cavopulmonary pressure were extracted by partial least-square regression analysis. Shape patterns relating to intensive care unit and hospital lengths of stay after TCPC were assessed.Distinct deformation patterns, which result in an acutely mismatched aortic root and ascending aorta, and a gothic-like transverse arch, correlated with increased indexed end-diastolic volume and higher superior cavopulmonary pressure but not with ejection fraction. Specific arch morphology with pronounced transverse arch and descending aorta mismatch also correlated with longer intensive care unit and hospital lengths of stay after TCPC completion.Independent of hemodynamically important arch obstruction, altered aortic morphology in HLHS patients appears to have important associations with higher superior cavopulmonary pressure and with short-term outcomes after TCPC completion as highlighted by statistical shape analysis, which could act as adjunct to risk assessment in HLHS.

  View details for DOI 10.1016/j.athoracsur.2016.06.041

  View details for Web of Science ID 000397165400072

  View details for PubMedID 27592606

• Special Issue on Biological Systems Dedicated to William S. Klug COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Barbone, P., Budyn, E., Tepole, A., De, S., Ennis, D., Garikipati, K., Gerbeau, J., Gomez, H., Goriely, A., Healey, T., Hughes, T., Kuhl, E., Marsden, A., Masud, A., Nordsletten, D., Oberai, A., Oden, T., Ortiz, M., Perotti, L., Pinsky, P., Ponnaluri, A., Quarteroni, A., Sacks, M., Schiavazzi, D., Vignon-Clementel, I., Wall, W., Yankeelov, T., Zohdi, T. 2017; 314: 1-2

  View details for DOI 10.1016/j.cma.2016.11.027

  View details for Web of Science ID 000392782900001

• A generalized multi-resolution expansion for uncertainty propagation with application to cardiovascular modeling. Computer methods in applied mechanics and engineering Schiavazzi, D. E., Doostan, A., Iaccarino, G., Marsden, A. L. 2017; 314: 196-221

  Abstract

  Computational models are used in a variety of fields to improve our understanding of complex physical phenomena. Recently, the realism of model predictions has been greatly enhanced by transitioning from deterministic to stochastic frameworks, where the effects of the intrinsic variability in parameters, loads, constitutive properties, model geometry and other quantities can be more naturally included. A general stochastic system may be characterized by a large number of arbitrarily distributed and correlated random inputs, and a limited support response with sharp gradients or event discontinuities. This motivates continued research into novel adaptive algorithms for uncertainty propagation, particularly those handling high dimensional, arbitrarily distributed random inputs and non-smooth stochastic responses. In this work, we generalize a previously proposed multi-resolution approach to uncertainty propagation to develop a method that improves computational efficiency, can handle arbitrarily distributed random inputs and non-smooth stochastic responses, and naturally facilitates adaptivity, i.e., the expansion coefficients encode information on solution refinement. Our approach relies on partitioning the stochastic space into elements that are subdivided along a single dimension, or, in other words, progressive refinements exhibiting a binary tree representation. We also show how these binary refinements are particularly effective in avoiding the exponential increase in the multi-resolution basis cardinality and significantly reduce the regression complexity for moderate to high dimensional random inputs. The performance of the approach is demonstrated through previously proposed uncertainty propagation benchmarks and stochastic multi-scale finite element simulations in cardiovascular flow.

  View details for DOI 10.1016/j.cma.2016.09.024

  View details for PubMedID 28845061

  View details for PubMedCentralID PMC5568857

• How successful is successful? Aortic arch shape after successful aortic coarctation repair correlates with left ventricular function JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Brusc, J. L., Khushnood, A., McLeod, K., Biglino, G., Sermesant, M., Pennec, X., Taylor, A. M., Hsia, T., Schievano, S., Khambadkone, S., De Leval, M., Bove, E., Dorfman, A., Baker, G. H., Hlavacek, A., Migliavacca, F., Pennati, G., Dubini, G., Marsden, A., Vignon-Clementel, I., Figliola, R. 2017; 153 (2): 418-427

  Abstract

  Even after successful aortic coarctation repair, there remains a significant incidence of late systemic hypertension and other morbidities. Independently of residual obstruction, aortic arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch 3-dimensional shape features with functional data obtained from cardiac magnetic resonance scans.Three-dimensional aortic arch shape models of 53 patients (mean age, 22.3 ± 5.6 years) 12 to 38 years after aortic coarctation repair were reconstructed from cardiac magnetic resonance data. A novel validated statistical shape analysis method computed a 3-dimensional mean anatomic shape of all aortic arches and calculated deformation vectors of the mean shape toward each patient's arch anatomy. From these deformations, 3-dimensional shape features most related to left ventricular ejection fraction, indexed left ventricular end-diastolic volume, indexed left ventricular mass, and resting systolic blood pressure were extracted from the deformation vectors via partial least-squares regression.Distinct arch shape features correlated significantly with left ventricular ejection fraction (r = 0.42, P = .024), indexed left ventricular end-diastolic volume (r = 0.65, P < .001), and indexed left ventricular mass (r = 0.44, P = .014). Lower left ventricular ejection fraction, larger indexed left ventricular end-diastolic volume, and increased indexed left ventricular mass were identified with an aortic arch shape that has an elongated ascending aorta with a high arch height-to-width ratio, a relatively short proximal transverse arch, and a relatively dilated descending aorta. High blood pressure seemed to be linked to gothic arch shape features, but this did not achieve statistical significance.Independently of hemodynamically important arch obstruction or residual aortic coarctation, specific aortic arch shape features late after successful aortic coarctation repair seem to be associated with worse left ventricular function. Analyzing 3-dimensional shape information via statistical shape modeling can be an adjunct to long-term risk assessment in patients after aortic coarctation repair.

  View details for DOI 10.1016/j.jtcvs.2016.09.018

  View details for Web of Science ID 000396894200067

• Automated tuning for parameter identification and uncertainty quantification in multi-scale coronary simulations COMPUTERS & FLUIDS Tran, J. S., Schiavazzi, D. E., Ramachandra, A. B., Kahn, A. M., Marsden, A. L. 2017; 142: 128-138

  Abstract

  Atherosclerotic coronary artery disease, which can result in coronary artery stenosis, acute coronary artery occlusion, and eventually myocardial infarction, is a major cause of morbidity and mortality worldwide. Non-invasive characterization of coronary blood flow is important to improve understanding, prevention, and treatment of this disease. Computational simulations can now produce clinically relevant hemodynamic quantities using only non-invasive measurements, combining detailed three dimensional fluid mechanics with physiological models in a multiscale framework. These models, however, require specification of numerous input parameters and are typically tuned manually without accounting for uncertainty in the clinical data, hindering their application to large clinical studies. We propose an automatic, Bayesian, approach to parameter estimation based on adaptive Markov chain Monte Carlo sampling that assimilates non-invasive quantities commonly acquired in routine clinical care, quantifies the uncertainty in the estimated parameters and computes the confidence in local predicted hemodynamic indicators.

  View details for DOI 10.1016/j.compfluid.2016.05.015

  View details for PubMedID 28163340

• Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis Computational simulation of postoperative pulmonary flow distribution in Alagille patients with peripheral pulmonary artery stenosis Yang, W., Feinstein, J., Marsden, A., Vignon-Clementel, I. 2017; 00: 1–10

  View details for DOI 10.1111/chd.12556

• SimVascular as an Instructional Tool in the Classroom Goergen, C. J., Shadden, S. C., Marsden, A. L., IEEE IEEE. 2017

  View details for Web of Science ID 000426974900008

• A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling. PLoS computational biology Vedula, V. n., Lee, J. n., Xu, H. n., Kuo, C. J., Hsiai, T. K., Marsden, A. L. 2017; 13 (10): e1005828

  Abstract

  Blood flow and mechanical forces in the ventricle are implicated in cardiac development and trabeculation. However, the mechanisms of mechanotransduction remain elusive. This is due in part to the challenges associated with accurately quantifying mechanical forces in the developing heart. We present a novel computational framework to simulate cardiac hemodynamics in developing zebrafish embryos by coupling 4-D light sheet imaging with a stabilized finite element flow solver, and extract time-dependent mechanical stimuli data. We employ deformable image registration methods to segment the motion of the ventricle from high resolution 4-D light sheet image data. This results in a robust and efficient workflow, as segmentation need only be performed at one cardiac phase, while wall position in the other cardiac phases is found by image registration. Ventricular hemodynamics are then quantified by numerically solving the Navier-Stokes equations in the moving wall domain with our validated flow solver. We demonstrate the applicability of the workflow in wild type zebrafish and three treated fish types that disrupt trabeculation: (a) chemical treatment using AG1478, an ErbB2 signaling inhibitor that inhibits proliferation and differentiation of cardiac trabeculation; (b) injection of gata1a morpholino oligomer (gata1aMO) suppressing hematopoiesis and resulting in attenuated trabeculation; (c) weak-atriumm58 mutant (wea) with inhibited atrial contraction leading to a highly undeveloped ventricle and poor cardiac function. Our simulations reveal elevated wall shear stress (WSS) in wild type and AG1478 compared to gata1aMO and wea. High oscillatory shear index (OSI) in the grooves between trabeculae, compared to lower values on the ridges, in the wild type suggest oscillatory forces as a possible regulatory mechanism of cardiac trabeculation development. The framework has broad applicability for future cardiac developmental studies focused on quantitatively investigating the role of hemodynamic forces and mechanotransduction during morphogenesis.

  View details for PubMedID 29084212

• Computed Tomography Fractional Flow Reserve Can Identify Culprit Lesions in Aortoiliac Occlusive Disease Using Minimally Invasive Techniques ANNALS OF VASCULAR SURGERY Ward, E. P., Shiavazzi, D., Sood, D., Marsden, A., Lane, J., Owens, E., Barleben, A. 2017; 38: 151-157

  Abstract

  Currently, the gold standard diagnostic examination for significant aortoiliac lesions is angiography. Fractional flow reserve (FFR) has a growing body of literature in coronary artery disease as a minimally invasive diagnostic procedure. Improvements in numerical hemodynamics have allowed for an accurate and minimally invasive approach to estimating FFR, utilizing cross-sectional imaging. We aim to demonstrate a similar approach to aortoiliac occlusive disease (AIOD).A retrospective review evaluated 7 patients with claudication and cross-sectional imaging showing AIOD. FFR was subsequently measured during conventional angiogram with pull-back pressures in a retrograde fashion. To estimate computed tomography (CT) FFR, CT angiography (CTA) image data were analyzed using the SimVascular software suite to create a computational fluid dynamics model of the aortoiliac system. Inlet flow conditions were derived based on cardiac output, while 3-element Windkessel outlet boundary conditions were optimized to match the expected systolic and diastolic pressures, with outlet resistance distributed based on Murray's law. The data were evaluated with a Student's t-test and receiver operating characteristic curve.All patients had evidence of AIOD on CT and FFR was successfully measured during angiography. The modeled data were found to have high sensitivity and specificity between the measured and CT FFR (P = 0.986, area under the curve = 1). The average difference between the measured and calculated FFRs was 0.136, with a range from 0.03 to 0.30.CT FFR successfully identified aortoiliac lesions with significant pressure drops that were identified with angiographically measured FFR. CT FFR has the potential to provide a minimally invasive approach to identify flow-limiting stenosis for AIOD.

  View details for DOI 10.1016/j.avsg.2016.08.010

  View details for Web of Science ID 000396441100022

• Assessment of Coronary Artery Aneurysms Caused By Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of CT Angiograms Assessment of Coronary Artery Aneurysms Caused By Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of CT Angiograms Grande Gutierrez, N., Shirinsky, O., Gagarina, N., Lyskina, G., Fukazawa, R., Ogawa, S., Burns, J., Marsden, A., Kahn, A. 2017; 120 (4): 556–62

  Abstract

  Patients with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend CAA diameter ≥8 mm as the criterion for initiating systemic anticoagulation. Transluminal attenuation gradient (TAG) analysis has been proposed as a noninvasive method for evaluating functional significance of coronary stenoses using computerized tomography angiography (CTA), but has not previously been used in CAA. We hypothesized that abnormal hemodynamics in CAA caused by KD could be quantified using TAG analysis. We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries and aneurysm geometry was characterized using maximum diameter, aneurysm shape index, and sphericity index. A total of 55 coronary arteries were analyzed, 25 of which had at least 1 aneurysmal region. TAG in aneurysmal arteries was significantly lower than in normal arteries (-23.5 ± 10.7 vs -10.5 ± 9.0, p = 0.00002). Aneurysm diameter, aneurysm shape index, and sphericity index were weakly correlated with TAG (r2 = 0.01, p = 0.6; r2 = 0.15, p = 0.06; r2 = 0.16, p = 0.04). This is the first application of TAG analysis to CAA caused by KD, and demonstrates significantly different TAG values in aneurysmal versus normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide hemodynamic information not available from anatomy alone. TAG represents a possible extension to standard CTA for KD patients who may improve thrombotic risk stratification and aid in clinical decision making.

  View details for DOI 10.1016/j.amjcard.2017.05.025

  View details for PubMedCentralID PMC6046216

• Atlas-Based Ventricular Shape Analysis for Understanding Congenital Heart Disease. Progress in pediatric cardiology Farrar, G., Suinesiaputra, A., Gilbert, K., Perry, J. C., Hegde, S., Marsden, A., Young, A. A., Omens, J. H., McCulloch, A. D. 2016; 43: 61-69

  Abstract

  Congenital heart disease is associated with abnormal ventricular shape that can affect wall mechanics and may be predictive of long-term adverse outcomes. Atlas-based parametric shape analysis was used to analyze ventricular geometries of eight adolescent or adult single-ventricle CHD patients with tricuspid atresia and Fontans. These patients were compared with an "atlas" of non-congenital asymptomatic volunteers, resulting in a set of z-scores which quantify deviations from the control population distribution on a patient-by-patient basis. We examined the potential of these scores to: (1) quantify abnormalities of ventricular geometry in single ventricle physiologies relative to the normal population; (2) comprehensively quantify wall motion in CHD patients; and (3) identify possible relationships between ventricular shape and wall motion that may reflect underlying functional defects or remodeling in CHD patients. CHD ventricular geometries at end-diastole and end-systole were individually compared with statistical shape properties of an asymptomatic population from the Cardiac Atlas Project. Shape analysis-derived model properties, and myocardial wall motions between end-diastole and end-systole, were compared with physician observations of clinical functional parameters. Relationships between altered shape and altered function were evaluated via correlations between atlas-based shape and wall motion scores. Atlas-based shape analysis identified a diverse set of specific quantifiable abnormalities in ventricular geometry or myocardial wall motion in all subjects. Moreover, this initial cohort displayed significant relationships between specific shape abnormalities such as increased ventricular sphericity and functional defects in myocardial deformation, such as decreased long-axis wall motion. These findings suggest that atlas-based ventricular shape analysis may be a useful new tool in the management of patients with CHD who are at risk of impaired ventricular wall mechanics and chamber remodeling.

  View details for DOI 10.1016/j.ppedcard.2016.07.010

  View details for PubMedID 28082823

• Right Ventricular Stroke Work Correlates With Outcomes in Pediatric Pulmonary Arterial Hypertension (PAH) Patients Quality of Care and Outcomes Research Scientific Sessions Yang, W., Marsden, A. L., Ogawa, M. T., Phillips, K. K., Rabinovitch, M., Feinstein, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000396815607139

• Computed Tomography Fractional Flow Reserve Can Identify Culprit Lesions in Aortoiliac Occlusive Disease Using Minimally Invasive Techniques. Annals of vascular surgery Ward, E. P., Shiavazzi, D., Sood, D., Marsden, A., Lane, J., Owens, E., Barleben, A. 2016

  Abstract

  Currently, the gold standard diagnostic examination for significant aortoiliac lesions is angiography. Fractional flow reserve (FFR) has a growing body of literature in coronary artery disease as a minimally invasive diagnostic procedure. Improvements in numerical hemodynamics have allowed for an accurate and minimally invasive approach to estimating FFR, utilizing cross-sectional imaging. We aim to demonstrate a similar approach to aortoiliac occlusive disease (AIOD).A retrospective review evaluated 7 patients with claudication and cross-sectional imaging showing AIOD. FFR was subsequently measured during conventional angiogram with pull-back pressures in a retrograde fashion. To estimate computed tomography (CT) FFR, CT angiography (CTA) image data were analyzed using the SimVascular software suite to create a computational fluid dynamics model of the aortoiliac system. Inlet flow conditions were derived based on cardiac output, while 3-element Windkessel outlet boundary conditions were optimized to match the expected systolic and diastolic pressures, with outlet resistance distributed based on Murray's law. The data were evaluated with a Student's t-test and receiver operating characteristic curve.All patients had evidence of AIOD on CT and FFR was successfully measured during angiography. The modeled data were found to have high sensitivity and specificity between the measured and CT FFR (P = 0.986, area under the curve = 1). The average difference between the measured and calculated FFRs was 0.136, with a range from 0.03 to 0.30.CT FFR successfully identified aortoiliac lesions with significant pressure drops that were identified with angiographically measured FFR. CT FFR has the potential to provide a minimally invasive approach to identify flow-limiting stenosis for AIOD.

  View details for DOI 10.1016/j.avsg.2016.08.010

  View details for PubMedID 27575305

• Patient-Specific Simulations Reveal Significant Differences in Mechanical Stimuli in Venous and Arterial Coronary Grafts. Journal of cardiovascular translational research Ramachandra, A. B., Kahn, A. M., Marsden, A. L. 2016; 9 (4): 279-290

  Abstract

  Mechanical stimuli are key to understanding disease progression and clinically observed differences in failure rates between arterial and venous grafts following coronary artery bypass graft surgery. We quantify biologically relevant mechanical stimuli, not available from standard imaging, in patient-specific simulations incorporating non-invasive clinical data. We couple CFD with closed-loop circulatory physiology models to quantify biologically relevant indices, including wall shear, oscillatory shear, and wall strain. We account for vessel-specific material properties in simulating vessel wall deformation. Wall shear was significantly lower (p = 0.014*) and atheroprone area significantly higher (p = 0.040*) in venous compared to arterial grafts. Wall strain in venous grafts was significantly lower (p = 0.003*) than in arterial grafts while no significant difference was observed in oscillatory shear index. Simulations demonstrate significant differences in mechanical stimuli acting on venous vs. arterial grafts, in line with clinically observed graft failure rates, offering a promising avenue for stratifying patients at risk for graft failure.

  View details for DOI 10.1007/s12265-016-9706-0

  View details for PubMedID 27447176

• On a sparse pressure-flow rate condensation of rigid circulation models. Journal of biomechanics Schiavazzi, D. E., Hsia, T. Y., Marsden, A. L. 2016; 49 (11): 2174-2186

  Abstract

  Cardiovascular simulation has shown potential value in clinical decision-making, providing a framework to assess changes in hemodynamics produced by physiological and surgical alterations. State-of-the-art predictions are provided by deterministic multiscale numerical approaches coupling 3D finite element Navier Stokes simulations to lumped parameter circulation models governed by ODEs. Development of next-generation stochastic multiscale models whose parameters can be learned from available clinical data under uncertainty constitutes a research challenge made more difficult by the high computational cost typically associated with the solution of these models. We present a methodology for constructing reduced representations that condense the behavior of 3D anatomical models using outlet pressure-flow polynomial surrogates, based on multiscale model solutions spanning several heart cycles. Relevance vector machine regression is compared with maximum likelihood estimation, showing that sparse pressure/flow rate approximations offer superior performance in producing working surrogate models to be included in lumped circulation networks. Sensitivities of outlets flow rates are also quantified through a Sobol׳ decomposition of their total variance encoded in the orthogonal polynomial expansion. Finally, we show that augmented lumped parameter models including the proposed surrogates accurately reproduce the response of multiscale models they were derived from. In particular, results are presented for models of the coronary circulation with closed loop boundary conditions and the abdominal aorta with open loop boundary conditions.

  View details for DOI 10.1016/j.jbiomech.2015.11.028

  View details for PubMedID 26671219

  View details for PubMedCentralID PMC4884557

• A statistical shape modelling framework to extract 3D shape biomarkers from medical imaging data: assessing arch morphology of repaired coarctation of the aorta BMC MEDICAL IMAGING Bruse, J. L., McLeod, K., Biglino, G., Ntsinjana, H. N., Capelli, C., Hsia, T., Sermesant, M., Pennec, X., Taylor, A. M., Schievano, S., Modeling Congenital Hearts Allianc 2016; 16: 40

  Abstract

  Medical image analysis in clinical practice is commonly carried out on 2D image data, without fully exploiting the detailed 3D anatomical information that is provided by modern non-invasive medical imaging techniques. In this paper, a statistical shape analysis method is presented, which enables the extraction of 3D anatomical shape features from cardiovascular magnetic resonance (CMR) image data, with no need for manual landmarking. The method was applied to repaired aortic coarctation arches that present complex shapes, with the aim of capturing shape features as biomarkers of potential functional relevance. The method is presented from the user-perspective and is evaluated by comparing results with traditional morphometric measurements.Steps required to set up the statistical shape modelling analyses, from pre-processing of the CMR images to parameter setting and strategies to account for size differences and outliers, are described in detail. The anatomical mean shape of 20 aortic arches post-aortic coarctation repair (CoA) was computed based on surface models reconstructed from CMR data. By analysing transformations that deform the mean shape towards each of the individual patient's anatomy, shape patterns related to differences in body surface area (BSA) and ejection fraction (EF) were extracted. The resulting shape vectors, describing shape features in 3D, were compared with traditionally measured 2D and 3D morphometric parameters.The computed 3D mean shape was close to population mean values of geometric shape descriptors and visually integrated characteristic shape features associated with our population of CoA shapes. After removing size effects due to differences in body surface area (BSA) between patients, distinct 3D shape features of the aortic arch correlated significantly with EF (r = 0.521, p = .022) and were well in agreement with trends as shown by traditional shape descriptors.The suggested method has the potential to discover previously unknown 3D shape biomarkers from medical imaging data. Thus, it could contribute to improving diagnosis and risk stratification in complex cardiac disease.

  View details for DOI 10.1186/s12880-016-0142-z

  View details for Web of Science ID 000377578000001

  View details for PubMedID 27245048

  View details for PubMedCentralID PMC4894556

• Uncertainty quantification in virtual surgery hemodynamics predictions for single ventricle palliation INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING Schiavazzi, D. E., Arbia, G., Baker, C., Hlavacek, A. M., Hsia, T. Y., Marsden, A. L., Vignon-Clementel, I. E. 2016; 32 (3)

  Abstract

  The adoption of simulation tools to predict surgical outcomes is increasingly leading to questions about the variability of these predictions in the presence of uncertainty associated with the input clinical data. In the present study, we propose a methodology for full propagation of uncertainty from clinical data to model results that, unlike deterministic simulation, enables estimation of the confidence associated with model predictions. We illustrate this problem in a virtual stage II single ventricle palliation surgery example. First, probability density functions (PDFs) of right pulmonary artery (PA) flow split ratio and average pulmonary pressure are determined from clinical measurements, complemented by literature data. Starting from a zero-dimensional semi-empirical approximation, Bayesian parameter estimation is used to find the distributions of boundary conditions that produce the expected PA flow split and average pressure PDFs as pre-operative model results. To reduce computational cost, this inverse problem is solved using a Kriging approximant. Second, uncertainties in the boundary conditions are propagated to simulation predictions. Sparse grid stochastic collocation is employed to statistically characterize model predictions of post-operative hemodynamics in models with and without PA stenosis. The results quantify the statistical variability in virtual surgery predictions, allowing for placement of confidence intervals on simulation outputs.

  View details for DOI 10.1002/cnm.2737

  View details for Web of Science ID 000372155900001

  View details for PubMedID 26217878

• Multiscale modelling of single-ventricle hearts for clinical decision support: a Leducq Transatlantic Network of Excellence EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Hsia, T., Figliola, R., Modeling Congenital Hearts Allianc 2016; 49 (2): 365-368

  View details for DOI 10.1093/ejcts/ezv368

  View details for Web of Science ID 000371819300006

  View details for PubMedID 26489838

• Respiration Increases Ventricular Filling at Rest and Exercise via Pulmonary Compliance: A Clinical and Computational Modeling Study Kung, E., Van De Bruaene, A., Claessen, G., La Gerche, A., Marsden, A., De Meester, P., Devroe, S., Bogaert, J., Claus, P., Heidbuchel, H., Budts, W., Gewillig, M. LIPPINCOTT WILLIAMS & WILKINS. 2015

  View details for Web of Science ID 000209846307121

• Assessment of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of Coronary CT Angiograms Gutierrez, N., Shirinsky, O., Gagarina, N. V., Lyskina, G. A., Fukazawa, R., Ogawa, S., Burns, J. C., Marsden, A. L., Kahn, A. M. LIPPINCOTT WILLIAMS & WILKINS. 2015

  View details for Web of Science ID 000209846303122

• Computational modeling and engineering in pediatric and congenital heart disease. Current opinion in pediatrics Marsden, A. L., Feinstein, J. A. 2015; 27 (5): 587-596

  Abstract

  Recent methodological advances in computational simulations are enabling increasingly realistic simulations of hemodynamics and physiology, driving increased clinical utility. We review recent developments in the use of computational simulations in pediatric and congenital heart disease, describe the clinical impact in modeling in single-ventricle patients, and provide an overview of emerging areas.Multiscale modeling combining patient-specific hemodynamics with reduced order (i.e., mathematically and computationally simplified) circulatory models has become the de-facto standard for modeling local hemodynamics and 'global' circulatory physiology. We review recent advances that have enabled faster solutions, discuss new methods (e.g., fluid structure interaction and uncertainty quantification), which lend realism both computationally and clinically to results, highlight novel computationally derived surgical methods for single-ventricle patients, and discuss areas in which modeling has begun to exert its influence including Kawasaki disease, fetal circulation, tetralogy of Fallot (and pulmonary tree), and circulatory support.Computational modeling is emerging as a crucial tool for clinical decision-making and evaluation of novel surgical methods and interventions in pediatric cardiology and beyond. Continued development of modeling methods, with an eye towards clinical needs, will enable clinical adoption in a wide range of pediatric and congenital heart diseases.

  View details for DOI 10.1097/MOP.0000000000000269

  View details for PubMedID 26262579

• In Vitro Assessment of the Assisted Bidirectional Glenn Procedure for Stage One Single Ventricle Repair. Cardiovascular engineering and technology Zhou, J., Esmaily-Moghadam, M., Conover, T. A., Hsia, T., Marsden, A. L., Figliola, R. S. 2015; 6 (3): 256-267

  Abstract

  This in vitro study compares the hemodynamic performance of the Norwood and the Glenn circulations to assess the performance of a novel assisted bidirectional Glenn (ABG) procedure for stage one single ventricle surgery. In the ABG, the flow in a bidirectional Glenn procedure is assisted by injection of a high-energy flow stream from the systemic circulation using an aorta-caval shunt with nozzle. The aim is to explore experimentally the potential of the ABG as a surgical alternative to current surgical practice. The experiments are directly compared against previously published numerical simulations. A multiscale mock circulatory system was used to measure the hemodynamic performance of the three circulations. For each circulation, the system was tested using both low and high values of pulmonary vascular resistance. Resulting parameters measured were: pressure and flow rate at left/right pulmonary artery and superior vena cava (SVC). Systemic oxygen delivery (OD) was calculated. A parametric study of the ratio of ABG nozzle to shunt diameter was done. We report time-based comparisons with numerical simulations for the three surgical variants tested. The ABG circulation demonstrated an increase of 30-38% in pulmonary flow with a 2-3.7 mmHg increase in SVC pressure compared to the Glenn and a 4-14% higher systemic OD than either the Norwood or the Glenn. The nozzle/shunt diameter ratio affected the local hemodynamics. These experimental results agreed with those of the numerical model: mean flow values were not significantly different (p > 0.05) while mean pressures were comparable within 1.2 mmHg. The results verify the approaches providing two tools to study this complicated circulation. Using a realistic experimental model we demonstrate the performance of a novel surgical procedure with potential to improve patient hemodynamics in early palliation of the univentricular circulation.

  View details for DOI 10.1007/s13239-015-0232-z

  View details for PubMedID 26577359

• Integration of Clinical Data Collected at Different Times for Virtual Surgery in Single Ventricle Patients: A Case Study ANNALS OF BIOMEDICAL ENGINEERING Corsini, C., Baker, C., Baretta, A., Biglino, G., Hlavacek, A. M., Hsia, T., Kung, E., Marsden, A., Migliavacca, F., Vignon-Clementel, I., Pennati, G. 2015; 43 (6): 1310-1320

  Abstract

  Newborns with single ventricle physiology are usually palliated with a multi-staged procedure. When cardiovascular complications e.g., collateral vessel formation occur during the inter-stage periods, further treatments are required. An 8-month-old patient, who underwent second stage (i.e., bi-directional Glenn, BDG) surgery at 4 months, was diagnosed with a major veno-venous collateral vessel (VVC) which was endovascularly occluded to improve blood oxygen saturations. Few clinical data were collected at 8 months, whereas at 4 months a more detailed data set was available. The aim of this study is threefold: (i) to show how to build a patient-specific model describing the hemodynamics in the presence of VVC, using patient-specific clinical data collected at different times; (ii) to use this model to perform virtual VVC occlusion for quantitative hemodynamics prediction; and (iii) to compare predicted hemodynamics with post-operative measurements. The three-dimensional BDG geometry, resulting from the virtual surgery on the first stage model, was coupled with a lumped parameter model (LPM) of the 8-month patient's circulation. The latter was developed by scaling the 4-month LPM to account for changes in vascular impedances due to growth and adaptation. After virtual VVC closure, the model confirmed the 2 mmHg BDG pressure increase, as clinically observed, suggesting the importance of modeling vascular adaptation following the BDG procedure.

  View details for DOI 10.1007/s10439-014-1113-6

  View details for Web of Science ID 000355924000005

  View details for PubMedID 25344350

• Computational Modeling of Pathophysiologic Responses to Exercise in Fontan Patients ANNALS OF BIOMEDICAL ENGINEERING Kung, E., Perry, J. C., Davis, C., Migliavacca, F., Pennati, G., Giardini, A., Hsia, T., Marsden, A. 2015; 43 (6): 1335-1347

  Abstract

  Reduced exercise capacity is nearly universal among Fontan patients. Although many factors have emerged as possible contributors, the degree to which each impacts the overall hemodynamics is largely unknown. Computational modeling provides a means to test hypotheses of causes of exercise intolerance via precisely controlled virtual experiments and measurements. We quantified the physiological impacts of commonly encountered, clinically relevant dysfunctions introduced to the exercising Fontan system via a previously developed lumped-parameter model of Fontan exercise. Elevated pulmonary arterial pressure was observed in all cases of dysfunction, correlated with lowered cardiac output (CO), and often mediated by elevated atrial pressure. Pulmonary vascular resistance was not the most significant factor affecting exercise performance as measured by CO. In the absence of other dysfunctions, atrioventricular valve insufficiency alone had significant physiological impact, especially under exercise demands. The impact of isolated dysfunctions can be linearly summed to approximate the combined impact of several dysfunctions occurring in the same system. A single dominant cause of exercise intolerance was not identified, though several hypothesized dysfunctions each led to variable decreases in performance. Computational predictions of performance improvement associated with various interventions should be weighed against procedural risks and potential complications, contributing to improvements in routine patient management protocol.

  View details for DOI 10.1007/s10439-014-1131-4

  View details for Web of Science ID 000355924000007

  View details for PubMedID 25260878

  View details for PubMedCentralID PMC4376649

• Multiscale Modeling of Cardiovascular Flows for Clinical Decision Support APPLIED MECHANICS REVIEWS Marsden, A. L., Esmaily-Moghadam, M. 2015; 67 (3)

  View details for DOI 10.1115/1.4029909

  View details for Web of Science ID 000360285400004

• Thrombotic Risk Assessment in Kawasaki Disease Patients with Coronary Artery Aneurysms using Transluminal Attenuation Gradient Analysis Gutierrez, N., Kahn, A. M., Shirinsky, O., Lyskina, G. A., Fukazawa, R., Ogawa, S., Burns, J. C., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2015

  View details for Web of Science ID 000381411800491

• Thrombotic Risk Assessment in Kawasaki Disease Patients with Coronary Artery Aneurysms using Transluminal Attenuation Gradient Analysis Gutierrez, N., Kahn, A. M., Shirinsky, O., Lyskina, G. A., Fukazawa, R., Ogawa, S., Burns, J. C., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2015

  View details for Web of Science ID 000381411800355

• Distribution of aerosolized particles in healthy and emphysematous rat lungs: Comparison between experimental and numerical studies JOURNAL OF BIOMECHANICS Oakes, J. M., Marsden, A. L., Grandmont, C., Darquenne, C., Vignon-Clementel, I. E. 2015; 48 (6): 1147-1157

  Abstract

  In silico models of airflow and particle deposition in the lungs are increasingly used to determine the therapeutic or toxic effects of inhaled aerosols. While computational methods have advanced significantly, relatively few studies have directly compared model predictions to experimental data. Furthermore, few prior studies have examined the influence of emphysema on particle deposition. In this work we performed airflow and particle simulations to compare numerical predictions to data from our previous aerosol exposure experiments. Employing an image-based 3D rat airway geometry, we first compared steady flow simulations to coupled 3D-0D unsteady simulations in the healthy rat lung. Then, in 3D-0D simulations, the influence of emphysema was investigated by matching disease location to the experimental study. In both the healthy unsteady and steady simulations, good agreement was found between numerical predictions of aerosol delivery and experimental deposition data. However, deposition patterns in the 3D geometry differed between the unsteady and steady cases. On the contrary, satisfactory agreement was not found between the numerical predictions and experimental data for the emphysematous lungs. This indicates that the deposition rate downstream of the 3D geometry is likely proportional to airflow delivery in the healthy lungs, but not in the emphysematous lungs. Including small airway collapse, variations in downstream airway size and tissue properties, and tracking particles throughout expiration may result in a more favorable agreement in future studies.

  View details for DOI 10.1016/j.jbiomech.2015.01.004

  View details for PubMedID 25682537

• A bi-partitioned iterative algorithm for solving linear systems arising from incompressible flow problems COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Esmaily-Moghadam, M., Bazilevs, Y., Marsden, A. L. 2015; 286: 40-62

  View details for DOI 10.1016/j.cma.2014.11.033

  View details for Web of Science ID 000349857700003

• Does TCPC power loss really affect exercise capacity? Reply HEART Khiabani, R. H., Whitehead, K. K., Han, D., Restrepo, M., Tang, E., Bethel, J., Paridon, S. M., Fogel, M. A., Yoganathan, A. P. 2015; 101 (7): 575–76

  View details for DOI 10.1136/heartjnl-2015-307484

  View details for Web of Science ID 000350352200018

  View details for PubMedID 25673526

• THE ASSISTED BIDIRECTIONAL GLENN: AN IN VITRO AND IN SILICO STUDY OF A SURGICAL APPROACH FOR FIRST STAGE SINGLE VENTRICLE HEART PALLIATION Figliola, R., Esmaily-Moghadam, M., Zhou, J., Hsia, T., Marsden, A. ELSEVIER SCIENCE INC. 2015: A518

  View details for DOI 10.1016/S0735-1097(15)60518-6

  View details for Web of Science ID 000375328800519

• Hemodynamic effects of left pulmonary artery stenosis after superior cavopulmonary connection: A patient-specific multiscale modeling study JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Schiavazzi, D. E., Kung, E. O., Marsden, A. L., Baker, C., Pennati, G., Hsia, T., Hlavacek, A., Dorfman, A. L. 2015; 149 (3): 689-?

  Abstract

  Currently, no quantitative guidelines have been established for treatment of left pulmonary artery (LPA) stenosis. This study aims to quantify the effects of LPA stenosis on postoperative hemodynamics for single-ventricle patients undergoing stage II superior cavopulmonary connection (SCPC) surgery, using a multiscale computational approach.Image data from 6 patients were segmented to produce 3-dimensional models of the pulmonary arteries before stage II surgery. Pressure and flow measurements were used to tune a 0-dimensional model of the entire circulation. Postoperative geometries were generated through stage II virtual surgery; varying degrees of LPA stenosis were applied using mesh morphing and hemodynamics assessed through coupled 0-3-dimensional simulations. To relate metrics of stenosis to clinical classifications, pediatric cardiologists and surgeons ranked the degrees of stenosis in the models. The effects of LPA stenosis were assessed based on left-to-right pulmonary artery flow split ratios, mean pressure drop across the stenosis, cardiac pressure-volume loops, and other clinically relevant parameters.Stenosis of >65% of the vessel diameter was required to produce a right pulmonary artery:LPA flow split <30%, and/or a mean pressure drop of >3.0 mm Hg, defined as clinically significant changes.The effects of <65% stenosis on SCPC hemodynamics and physiology were minor and may not justify the increased complexity of adding LPA arterioplasty to the SCPC operation. However, in the longer term, pulmonary augmentation may affect outcomes of the Fontan completion surgery, as pulmonary artery distortion is a risk factor that may influence stage III physiology.

  View details for DOI 10.1016/j.jtcvs.2014.12.040

  View details for Web of Science ID 000351930600025

  View details for PubMedID 25659189

• Computational Simulation of the Adaptive Capacity of Vein Grafts in Response to Increased Pressure JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Ramachandra, A. B., Sankaran, S., Humphrey, J. D., Marsden, A. L. 2015; 137 (3)

  Abstract

  Vein maladaptation, leading to poor long-term patency, is a serious clinical problem in patients receiving coronary artery bypass grafts (CABGs) or undergoing related clinical procedures that subject veins to elevated blood flow and pressure. We propose a computational model of venous adaptation to altered pressure based on a constrained mixture theory of growth and remodeling (G&R). We identify constitutive parameters that optimally match biaxial data from a mouse vena cava, then numerically subject the vein to altered pressure conditions and quantify the extent of adaptation for a biologically reasonable set of bounds for G&R parameters. We identify conditions under which a vein graft can adapt optimally and explore physiological constraints that lead to maladaptation. Finally, we test the hypothesis that a gradual, rather than a step, change in pressure will reduce maladaptation. Optimization is used to accelerate parameter identification and numerically evaluate hypotheses of vein remodeling.

  View details for DOI 10.1115/1.4029021

  View details for Web of Science ID 000350572600010

  View details for PubMedID 25376151

  View details for PubMedCentralID PMC4321118

• Simulations Reveal Adverse Hemodynamics in Patients With Multiple Systemic to Pulmonary Shunts JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Esmaily-Moghadam, M., Murtuza, B., Hsia, T., Marsden, A. 2015; 137 (3)

  Abstract

  For newborns diagnosed with pulmonary atresia or severe pulmonary stenosis leading to insufficient pulmonary blood flow, cyanosis can be mitigated with placement of a modified Blalock-Taussig shunt (MBTS) between the innominate and pulmonary arteries. In some clinical scenarios, patients receive two systemic-to-pulmonary connections, either by leaving the patent ductus arteriosus (PDA) open or by adding an additional central shunt (CS) in conjunction with the MBTS. This practice has been motivated by the thinking that an additional source of pulmonary blood flow could beneficially increase pulmonary flow and provide the security of an alternate pathway in case of thrombosis. However, there have been clinical reports of premature shunt occlusion when more than one shunt is employed, leading to speculation that multiple shunts may in fact lead to unfavorable hemodynamics and increased mortality. In this study, we hypothesize that multiple shunts may lead to undesirable flow competition, resulting in increased residence time (RT) and elevated risk of thrombosis, as well as pulmonary overcirculation. Computational fluid dynamics-based multiscale simulations were performed to compare a range of shunt configurations and systematically quantify flow competition, pulmonary circulation, and other clinically relevant parameters. In total, 23 cases were evaluated by systematically changing the PDA/CS diameter, pulmonary vascular resistance (PVR), and MBTS position and compared by quantifying oxygen delivery (OD) to the systemic and coronary beds, wall shear stress (WSS), oscillatory shear index (OSI), WSS gradient (WSSG), and RT in the pulmonary artery (PA), and MBTS. Results showed that smaller PDA/CS diameters can lead to flow conditions consistent with increased thrombus formation due to flow competition in the PA, and larger PDA/CS diameters can lead to insufficient OD due to pulmonary hyperfusion. In the worst case scenario, it was found that multiple shunts can lead to a 160% increase in RT and a 10% decrease in OD. Based on the simulation results presented in this study, clinical outcomes for patients receiving multiple shunts should be critically investigated, as this practice appears to provide no benefit in terms of OD and may actually increase thrombotic risk.

  View details for DOI 10.1115/1.4029429

  View details for Web of Science ID 000350572600002

  View details for PubMedID 25531794

  View details for PubMedCentralID PMC4321115

• The assisted bidirectional Glenn: A novel surgical approach for first-stage single-ventricle heart palliation JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Esmaily-Moghadam, M., Hsia, T., Marsden, A. L. 2015; 149 (3): 699-705

  Abstract

  Outcomes after a modified Blalock-Taussig shunt (mBTS) in neonates with single-ventricle physiology remain unsatisfactory. However, initial palliation with a superior cavopulmonary connection, such as a bidirectional Glenn (BDG), is discouraged, owing to potential for inadequate pulmonary blood flow (PBF). We tested the feasibility of a novel surgical approach, adopting the engineering concept of an ejector pump, whereby the flow in the BDG is "assisted" by injection of a high-energy flow stream from the systemic circulation.Realistic 3-dimensional models of the neonatal mBTS and BDG circulations were created. The "assisted" bidirectional Glenn (ABG) consisted of a shunt between the right innominate artery and the superior vena cava (SVC), with a 1.5-mm clip near the SVC anastomosis to create a Venturi effect. The 3 models were coupled to a validated hydraulic circulation model, and 2 pulmonary vascular resistance (PVR) values (7 and 2.3 Wood units) were simulated.The ABG provided the highest systemic oxygen saturation and oxygen delivery at both PVR levels. In addition to achieving higher PBF than the BDG, the ABG produced a lower single-ventricular workload than mBTS. SVC pressure was highest in the ABG model (ABG: 15; Glenn: 11; mBTS: 3 mm Hg; PVR = 7 Wood units), but at low PVR, the SVC pressure was significantly lower (ABG: 8; Glenn: 6; mBTS: <3 mm Hg).Adopting the principle of an ejector pump, with additional flow directed into the SVC in a BDG, the ABG appears to increase PBF with a modest increase in SVC and pulmonary arterial pressure. Although multiscale modeling results demonstrate the conceptual feasibility of the ABG circulation, further technical refinement and investigations are necessary, especially in an appropriate animal model.

  View details for DOI 10.1016/j.jtcvs.2014.10.035

  View details for Web of Science ID 000351930600027

  View details for PubMedID 25454920

• Flow simulations and validation for the first cohort of patients undergoing the Y-graft Fontan procedure JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Yang, W., Chan, F. P., Reddy, V. M., Marsden, A. L., Feinstein, J. A. 2015; 149 (1): 247-255

  Abstract

  In this study, with the use of computational fluid dynamics, we evaluate the postoperative hemodynamic performance of the first cohort of patients undergoing a handcrafted Y-graft Fontan procedure and validate simulation predictions of hepatic blood flow distribution against in vivo clinical data.An 18-12 × 2-mm handcrafted Y-graft modification of the Fontan procedure was performed in 6 patients. Early (at the time of discharge) and 6-month postoperative 3-dimensional magnetic resonance imaging data were collected. Patient-specific models were constructed for flow simulations.Hepatic blood flow distribution varied among patients. Lung perfusion data (n = 3) showed good agreement with simulations. Postoperative asymmetry in hepatic blood flow distribution was reduced 6 months postoperatively. In 1 patient, low wall shear stress was found in the left limb of the Y-graft, corresponding to the location of subsequent thrombosis in the patient.The credibility and accuracy of simulation-based predictions of postoperative hepatic flow distribution for the Fontan surgery have been validated by in vivo lung perfusion data. The performance of the Y-graft design is highly patient-specific. The anastomosis location is likely the most important factor influencing hepatic blood flow distribution. Although the development of thrombosis is multifactorial, the occurrence in 1 patient suggests that simulations should not solely consider the hepatic blood flow distribution but also aim to avoid low wall shear stress in the limbs.

  View details for DOI 10.1016/j.jtcvs.2014.08.069

  View details for PubMedID 25439766

• Structural Edge Detection for Cardiovascular Modeling Merkow, J., Tu, Z., Kriegman, D., Marsden, A., Navab, N., Hornegger, J., Wells, W. M., Frangi, A. F. SPRINGER INT PUBLISHING AG. 2015: 735–42

  View details for DOI 10.1007/978-3-319-24574-4_88

  View details for Web of Science ID 000365963800088

• Creating Shape Templates for Patient Specific Biventricular Modeling in Congenital Heart Disease Gilbert, K., Farrar, G., Cowan, B. R., Suinesiaputra, A., Occleshaw, C., Pontre, B., Perry, J., Hegde, S., Marsden, A., Omens, J., McCulloch, A., Young, A. A., IEEE IEEE. 2015: 679–82

  Abstract

  Survival rates for infants with congenital heart disease (CHD) are improving, resulting in a growing population of adults with CHD. However, the analysis of left and right ventricular function is very time-consuming owing to the variety of congenital morphologies. Efficient customization of patient geometry and function depends on high quality shape templates specifically designed for the application. In this paper, we combine a method for creating finite element shape templates with an interactive template customization to patient MRI examinations. This enables different templates to be chosen depending on patient morphology. To demonstrate this pipeline, a new biventricular template with 162 elements was created and tested in place of an existing 82-element template. The method was able to provide fast interactive biventricular analysis with 0.31 sec per edit response time. The new template was customized to 13 CHD patients with similar biventricular topology, showing improved performance over the previous template and good agreement with clinical indices.

  View details for Web of Science ID 000371717200172

  View details for PubMedID 26736353

  View details for PubMedCentralID PMC5797697

• Does TCPC power loss really affect exercise capacity? Heart (British Cardiac Society) Kung, E. n., Marsden, A. n., Baker, C. n., Giardini, A. n., Figliola, R. n., Hsia, T. Y. 2015; 101 (7): 575

  View details for PubMedID 25586155

• Effect of respiration on cardiac filling at rest and during exercise in Fontan patients: A clinical and computational modeling study. International journal of cardiology. Heart & vasculature Van De Bruaene, A. n., Claessen, G. n., La Gerche, A. n., Kung, E. n., Marsden, A. n., De Meester, P. n., Devroe, S. n., Bogaert, J. n., Claus, P. n., Heidbuchel, H. n., Budts, W. n., Gewillig, M. n. 2015; 9: 100–108

  View details for PubMedID 28785717

• Impact of data distribution on the parallel performance of iterative linear solvers with emphasis on CFD of incompressible flows COMPUTATIONAL MECHANICS Esmaily-Moghadam, M., Bazilevs, Y., Marsden, A. L. 2015; 55 (1): 93-103

  View details for DOI 10.1007/s00466-014-1084-3

  View details for Web of Science ID 000347290800006

• Technical feasibility and intermediate outcomes of using a handcrafted, area-preserving, bifurcated Y-graft modification of the Fontan procedure JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Martin, M. H., Feinstein, J. A., Chan, F. P., Marsden, A. L., Yang, W., Reddy, V. M. 2015; 149 (1): 239-U381

  Abstract

  To demonstrate the technical feasibility and describe intermediate outcomes for the initial patients undergoing handcrafted, area-preserving, Y-graft modification of the Fontan procedure.A retrospective review of a pilot study was undertaken to describe preoperative, intraoperative, and postoperative results.Six patients underwent successful procedures and remain alive 3 to 4 years later. The median age at operation was 3.3 years, and median weight was 13.2 kg. Five operations were done without cardiopulmonary bypass and no intraoperative pressure gradients were found. Five patients were extubated by postoperative day 1, Fontan pressures were 12 to 14 mm Hg, transpulmonary gradients were 6 to 8 mm Hg, and no renal or hepatic function abnormalities were found. Length of stay was 10 to 64 days. One patient required venovenous extracorporeal membrane oxygenation for previously undiagnosed plastic bronchitis (64-day stay); another required reoperation for an incidentally diagnosed aortic thrombus (44-day stay). One patient had occlusion of a Y-graft limb noted on magnetic resonance imaging follow-up at 3 months. Catheterization showed excellent hemodynamic parameters and no Fontan obstruction. Occlusion was believed to be due to right-sided pulmonary arteriovenous malformations and widely discrepant flow (80%) to the right lung leading to low flow in the left limb.The area-preserving, bifurcated Y-graft Fontan modification is technically feasible and shows excellent intermediate outcomes. Additional study is required to determine whether the advantages seen in the computational models will be realized in patients over the long-term, and to optimize patient selection for each of the various Fontan options now available.

  View details for DOI 10.1016/j.jtcvs.2014.08.058

  View details for Web of Science ID 000350550100068

  View details for PubMedID 25439786

• Technical feasibility and intermediate outcomes of using a handcrafted, area-preserving, bifurcated Y-graft modification of the Fontan procedure. journal of thoracic and cardiovascular surgery Martin, M. H., Feinstein, J. A., Chan, F. P., Marsden, A. L., Yang, W., Reddy, V. M. 2015; 149 (1): 239-45 e1

  Abstract

  To demonstrate the technical feasibility and describe intermediate outcomes for the initial patients undergoing handcrafted, area-preserving, Y-graft modification of the Fontan procedure.A retrospective review of a pilot study was undertaken to describe preoperative, intraoperative, and postoperative results.Six patients underwent successful procedures and remain alive 3 to 4 years later. The median age at operation was 3.3 years, and median weight was 13.2 kg. Five operations were done without cardiopulmonary bypass and no intraoperative pressure gradients were found. Five patients were extubated by postoperative day 1, Fontan pressures were 12 to 14 mm Hg, transpulmonary gradients were 6 to 8 mm Hg, and no renal or hepatic function abnormalities were found. Length of stay was 10 to 64 days. One patient required venovenous extracorporeal membrane oxygenation for previously undiagnosed plastic bronchitis (64-day stay); another required reoperation for an incidentally diagnosed aortic thrombus (44-day stay). One patient had occlusion of a Y-graft limb noted on magnetic resonance imaging follow-up at 3 months. Catheterization showed excellent hemodynamic parameters and no Fontan obstruction. Occlusion was believed to be due to right-sided pulmonary arteriovenous malformations and widely discrepant flow (80%) to the right lung leading to low flow in the left limb.The area-preserving, bifurcated Y-graft Fontan modification is technically feasible and shows excellent intermediate outcomes. Additional study is required to determine whether the advantages seen in the computational models will be realized in patients over the long-term, and to optimize patient selection for each of the various Fontan options now available.

  View details for DOI 10.1016/j.jtcvs.2014.08.058

  View details for PubMedID 25439786

• Novel 4-Dimensional Optical Technique to Elucidate Hemodynamic Shear Forces and Initiation of Trabeculation During Cardiac Morphogenesis Lee, J., Fei, P., Jen, N., Beebe, T., Ho, C., Marsden, A., Chi, N., Hsiai, T. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000209790205198

• High Death and Re-Intervention Rate in Neonatal Modified Blalock-Taussig Shunts With Concomitant Patent Dutus Artertiosus: Mechanistic Insights Into Competitive Flow and Pulmonary Overcirculation Murtuza, B., Moghadam, M., Marsden, A. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000209790205158

• In-vitro and Computational Study of the Assisted Bidirectional Glenn Procedure for Initial Palliation of Single Ventricle Physiology Esmaily-Moghadam, M., Zhou, J., Hsia, T., Figliola, R., Marsden, A. LIPPINCOTT WILLIAMS & WILKINS. 2014

  View details for Web of Science ID 000209790205152

• ST and ALE-VMS methods for patient-specific cardiovascular fluid mechanics modeling MATHEMATICAL MODELS & METHODS IN APPLIED SCIENCES Takizawa, K., Bazilevs, Y., Tezduyar, T. E., Long, C. C., Marsden, A. L., Schjodt, K. 2014; 24 (12)

  View details for DOI 10.1142/S0218202514500250

  View details for Web of Science ID 000341008600003

• Thrombotic risk stratification using computational modeling in patients with coronary artery aneurysms following Kawasaki disease BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Sengupta, D., Kahn, A. M., Kung, E., Moghadam, M. E., Shirinsky, O., Lyskina, G. A., Burns, J. C., Marsden, A. L. 2014; 13 (6): 1261-1276

  Abstract

  Kawasaki disease (KD) is the leading cause of acquired heart disease in children and can result in life-threatening coronary artery aneurysms in up to 25 % of patients. These aneurysms put patients at risk of thrombus formation, myocardial infarction, and sudden death. Clinicians must therefore decide which patients should be treated with anticoagulant medication, and/or surgical or percutaneous intervention. Current recommendations regarding initiation of anticoagulant therapy are based on anatomy alone with historical data suggesting that patients with aneurysms [Formula: see text]8 mm are at greatest risk of thrombosis. Given the multitude of variables that influence thrombus formation, we postulated that hemodynamic data derived from patient-specific simulations would more accurately predict risk of thrombosis than maximum diameter alone. Patient-specific blood flow simulations were performed on five KD patients with aneurysms and one KD patient with normal coronary arteries. Key hemodynamic and geometric parameters, including wall shear stress, particle residence time, and shape indices, were extracted from the models and simulations and compared with clinical outcomes. Preliminary fluid structure interaction simulations with radial expansion were performed, revealing modest differences in wall shear stress compared to the rigid wall case. Simulations provide compelling evidence that hemodynamic parameters may be a more accurate predictor of thrombotic risk than aneurysm diameter alone and motivate the need for follow-up studies with a larger cohort. These results suggest that a clinical index incorporating hemodynamic information be used in the future to select patients for anticoagulant therapy.

  View details for DOI 10.1007/s10237-014-0570-z

  View details for PubMedID 24722951

• Shape optimization of pulsatile ventricular assist devices using FSI to minimize thrombotic risk COMPUTATIONAL MECHANICS Long, C. C., Marsden, A. L., Bazilevs, Y. 2014; 54 (4): 921-932

  View details for DOI 10.1007/s00466-013-0967-z

  View details for Web of Science ID 000341835300004

• A Simulation Protocol for Exercise Physiology in Fontan Patients Using a Closed Loop Lumped-Parameter Model (vol 136, 081007, 2014) JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Kung, E., Pennati, G., Migliavacca, F., Hsia, T., Figliola, R., Marsden, A., Giardini, A. 2014; 136 (10)

  View details for DOI 10.1115/1.4028108

  View details for Web of Science ID 000341298400014

• Computation of residence time in the simulation of pulsatile ventricular assist devices COMPUTATIONAL MECHANICS Long, C. C., Esmaily-Moghadam, M., Marsden, A. L., Bazilevs, Y. 2014; 54 (4): 911-919

  View details for DOI 10.1007/s00466-013-0931-y

  View details for Web of Science ID 000341835300003

• USNCTAM perspectives on mechanics in medicine JOURNAL OF THE ROYAL SOCIETY INTERFACE Bao, G., Bazilevs, Y., Chung, J., Decuzzi, P., Espinosa, H. D., Ferrari, M., Gao, H., Hossain, S. S., Hughes, T. J., Kamm, R. D., Liu, W. K., Marsden, A., Schrefler, B. 2014; 11 (97)

  Abstract

  Over decades, the theoretical and applied mechanics community has developed sophisticated approaches for analysing the behaviour of complex engineering systems. Most of these approaches have targeted systems in the transportation, materials, defence and energy industries. Applying and further developing engineering approaches for understanding, predicting and modulating the response of complicated biomedical processes not only holds great promise in meeting societal needs, but also poses serious challenges. This report, prepared for the US National Committee on Theoretical and Applied Mechanics, aims to identify the most pressing challenges in biological sciences and medicine that can be tackled within the broad field of mechanics. This echoes and complements a number of national and international initiatives aiming at fostering interdisciplinary biomedical research. This report also comments on cultural/educational challenges. Specifically, this report focuses on three major thrusts in which we believe mechanics has and will continue to have a substantial impact. (i) Rationally engineering injectable nano/microdevices for imaging and therapy of disease. Within this context, we discuss nanoparticle carrier design, vascular transport and adhesion, endocytosis and tumour growth in response to therapy, as well as uncertainty quantification techniques to better connect models and experiments. (ii) Design of biomedical devices, including point-of-care diagnostic systems, model organ and multi-organ microdevices, and pulsatile ventricular assistant devices. (iii) Mechanics of cellular processes, including mechanosensing and mechanotransduction, improved characterization of cellular constitutive behaviour, and microfluidic systems for single-cell studies.

  View details for DOI 10.1098/rsif.2014.0301

  View details for PubMedID 24872502

• A Simulation Protocol for Exercise Physiology in Fontan Patients Using a Closed Loop Lumped-Parameter Model JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Kung, E., Pennati, G., Migliavacca, F., Hsia, T., Figliola, R., Marsden, A., Giardini, A. 2014; 136 (8)

  Abstract

  Reduced exercise capacity is nearly universal among Fontan patients, though its etiology is not yet fully understood. While previous computational studies have attempted to model Fontan exercise, they did not fully account for global physiologic mechanisms nor directly compare results against clinical and physiologic data.In this study, we developed a protocol to simulate Fontan lower-body exercise using a closed-loop lumped-parameter model describing the entire circulation. We analyzed clinical exercise data from a cohort of Fontan patients, incorporated previous clinical findings from literature, quantified a comprehensive list of physiological changes during exercise, translated them into a computational model of the Fontan circulation, and designed a general protocol to model Fontan exercise behavior. Using inputs of patient weight, height, and if available, patient-specific reference heart rate (HR) and oxygen consumption, this protocol enables the derivation of a full set of parameters necessary to model a typical Fontan patient of a given body-size over a range of physiologic exercise levels.In light of previous literature data and clinical knowledge, the model successfully produced realistic trends in physiological parameters with exercise level. Applying this method retrospectively to a set of clinical Fontan exercise data, direct comparison between simulation results and clinical data demonstrated that the model successfully reproduced the average exercise response of a cohort of typical Fontan patients.This work is intended to offer a foundation for future advances in modeling Fontan exercise, highlight the needs in clinical data collection, and provide clinicians with quantitative reference exercise physiologies for Fontan patients.

  View details for DOI 10.1115/1.4027271

  View details for Web of Science ID 000338507000007

  View details for PubMedID 24658635

• In Vitro Validation of Patient-Specific Hemodynamic Simulations in Coronary Aneurysms Caused by Kawasaki Disease. Cardiovascular engineering and technology Kung, E., Kahn, A. M., Burns, J. C., Marsden, A. 2014; 5 (2): 189-201

  Abstract

  To perform experimental validation of computational fluid dynamics (CFD) applied to patient specific coronary aneurysm anatomy of Kawasaki disease. We quantified hemodynamics in a patient-specific coronary artery aneurysm physical phantom under physiologic rest and exercise flow conditions. Using phase contrast MRI (PCMRI), we acquired 3-component flow velocity at two slice locations in the aneurysms. We then performed numerical simulations with the same geometry and inflow conditions, and performed qualitative and quantitative comparisons of velocities between experimental measurements and simulation results. We observed excellent qualitative agreement in flow pattern features. The quantitative spatially and temporally varying differences in velocity between PCMRI and CFD were proportional to the flow velocity. As a result, the percent discrepancy between simulation and experiment was relatively constant regardless of flow velocity variations. Through 1D and 2D quantitative comparisons, we found a 5-17% difference between measured and simulated velocities. Additional analysis assessed wall shear stress differences between deformable and rigid wall simulations. This study demonstrated that CFD produced good qualitative and quantitative predictions of velocities in a realistic coronary aneurysm anatomy under physiological flow conditions. The results provide insights on factors that may influence the level of agreement, and a set of in vitro experimental data that can be used by others to compare against CFD simulation results. The findings of this study increase confidence in the use of CFD for investigating hemodynamics in the specialized anatomy of coronary aneurysms. This provides a basis for future hemodynamics studies in patient-specific models of Kawasaki disease.

  View details for PubMedID 25050140

• In Vitro Validation of Patient-Specific Hemodynamic Simulations in Coronary Aneurysms Caused by Kawasaki Disease CARDIOVASCULAR ENGINEERING AND TECHNOLOGY Kung, E., Kahn, A. M., Burns, J. C., Marsden, A. 2014; 5 (2): 189-201

  Abstract

  To perform experimental validation of computational fluid dynamics (CFD) applied to patient specific coronary aneurysm anatomy of Kawasaki disease. We quantified hemodynamics in a patient-specific coronary artery aneurysm physical phantom under physiologic rest and exercise flow conditions. Using phase contrast MRI (PCMRI), we acquired 3-component flow velocity at two slice locations in the aneurysms. We then performed numerical simulations with the same geometry and inflow conditions, and performed qualitative and quantitative comparisons of velocities between experimental measurements and simulation results. We observed excellent qualitative agreement in flow pattern features. The quantitative spatially and temporally varying differences in velocity between PCMRI and CFD were proportional to the flow velocity. As a result, the percent discrepancy between simulation and experiment was relatively constant regardless of flow velocity variations. Through 1D and 2D quantitative comparisons, we found a 5-17% difference between measured and simulated velocities. Additional analysis assessed wall shear stress differences between deformable and rigid wall simulations. This study demonstrated that CFD produced good qualitative and quantitative predictions of velocities in a realistic coronary aneurysm anatomy under physiological flow conditions. The results provide insights on factors that may influence the level of agreement, and a set of in vitro experimental data that can be used by others to compare against CFD simulation results. The findings of this study increase confidence in the use of CFD for investigating hemodynamics in the specialized anatomy of coronary aneurysms. This provides a basis for future hemodynamics studies in patient-specific models of Kawasaki disease.

  View details for DOI 10.1007/s13239-014-0184-8

  View details for Web of Science ID 000209839700006

  View details for PubMedCentralID PMC4103185

• Computational models of aortic coarctation in hypoplastic left heart syndrome: Considerations on validation of a detailed 3D model INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS Biglino, G., Corsini, C., Schievano, S., Dubini, G., Giardini, A., Hsia, T., Pennati, G., Taylor, A. M., MOCHA Collaborative Grp 2014; 37 (5): 371-381

  Abstract

  Reliability of computational models for cardiovascular investigations strongly depends on their validation against physical data. This study aims to experimentally validate a computational model of complex congenital heart disease (i.e., surgically palliated hypoplastic left heart syndrome with aortic coarctation) thus demonstrating that hemodynamic information can be reliably extrapolated from the model for clinically meaningful investigations.A patient-specific aortic arch model was tested in a mock circulatory system and the same flow conditions were re-created in silico, by setting an appropriate lumped parameter network (LPN) attached to the same three-dimensional (3D) aortic model (i.e., multi-scale approach). The model included a modified Blalock-Taussig shunt and coarctation of the aorta. Different flow regimes were tested as well as the impact of uncertainty in viscosity.Computational flow and pressure results were in good agreement with the experimental signals, both qualitatively, in terms of the shape of the waveforms, and quantitatively (mean aortic pressure 62.3 vs. 65.1 mmHg, 4.8% difference; mean aortic flow 28.0 vs. 28.4% inlet flow, 1.4% difference; coarctation pressure drop 30.0 vs. 33.5 mmHg, 10.4% difference), proving the reliability of the numerical approach. It was observed that substantial changes in fluid viscosity or using a turbulent model in the numerical simulations did not significantly affect flows and pressures of the investigated physiology. Results highlighted how the non-linear fluid dynamic phenomena occurring in vitro must be properly described to ensure satisfactory agreement.This study presents methodological considerations for using experimental data to preliminarily set up a computational model, and then simulate a complex congenital physiology using a multi-scale approach.

  View details for DOI 10.5301/ijao.5000332

  View details for Web of Science ID 000339531000004

  View details for PubMedID 24968194

• Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments ANNALS OF BIOMEDICAL ENGINEERING Oakes, J. M., Marsden, A. L., Grandmont, C., Shadden, S. C., Darquenne, C., Vignon-Clementel, I. E. 2014; 42 (4): 899-914

  Abstract

  Image-based in silico modeling tools provide detailed velocity and particle deposition data. However, care must be taken when prescribing boundary conditions to model lung physiology in health or disease, such as in emphysema. In this study, the respiratory resistance and compliance were obtained by solving an inverse problem; a 0D global model based on healthy and emphysematous rat experimental data. Multi-scale CFD simulations were performed by solving the 3D Navier-Stokes equations in an MRI-derived rat geometry coupled to a 0D model. Particles with 0.95 μm diameter were tracked and their distribution in the lung was assessed. Seven 3D-0D simulations were performed: healthy, homogeneous, and five heterogeneous emphysema cases. Compliance (C) was significantly higher (p = 0.04) in the emphysematous rats (C = 0.37 ± 0.14 cm(3)/cmH2O) compared to the healthy rats (C = 0.25 ± 0.04 cm(3)/cmH2O), while the resistance remained unchanged (p = 0.83). There were increases in airflow, particle deposition in the 3D model, and particle delivery to the diseased regions for the heterogeneous cases compared to the homogeneous cases. The results highlight the importance of multi-scale numerical simulations to study airflow and particle distribution in healthy and diseased lungs. The effect of particle size and gravity were studied. Once available, these in silico predictions may be compared to experimental deposition data.

  View details for DOI 10.1007/s10439-013-0954-8

  View details for Web of Science ID 000333010900018

  View details for PubMedID 24318192

  View details for PubMedCentralID PMC4092242

• Recent advances in computational methodology for simulation of mechanical circulatory assist devices WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE Marsden, A. L., Bazilevs, Y., Long, C. C., Behr, M. 2014; 6 (2): 169-188

  Abstract

  Ventricular assist devices (VADs) provide mechanical circulatory support to offload the work of one or both ventricles during heart failure. They are used in the clinical setting as destination therapy, as bridge to transplant, or more recently as bridge to recovery to allow for myocardial remodeling. Recent developments in computational simulation allow for detailed assessment of VAD hemodynamics for device design and optimization for both children and adults. Here, we provide a focused review of the recent literature on finite element methods and optimization for VAD simulations. As VAD designs typically fall into two categories, pulsatile and continuous flow devices, we separately address computational challenges of both types of designs, and the interaction with the circulatory system with three representative case studies. In particular, we focus on recent advancements in finite element methodology that have increased the fidelity of VAD simulations. We outline key challenges, which extend to the incorporation of biological response such as thrombosis and hemolysis, as well as shape optimization methods and challenges in computational methodology.

  View details for DOI 10.1002/wsbm.1260

  View details for PubMedID 24449607

• Optimization in Cardiovascular Modeling ANNUAL REVIEW OF FLUID MECHANICS, VOL 46 Marsden, A. L. 2014; 46: 519-546

  View details for DOI 10.1146/annurev-fluid-010313-141341

  View details for Web of Science ID 000329820100021

• Patient-specific hemodynamic simulations in a group of patients with coronary artery aneurysms caused by Kawasaki Disease Sengupta, D., Burns, J. C., Kahn, A., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389200150

• AN EFFICIENT PRECONDITIONER FOR LINEAR SYSTEM SOLUTION IN MULTI-DOMAIN MODELING OF THE CIRCULATORY SYSTEM Moghadam, M., Bazilevs, Y., Hsia, T., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389200170

• AN AUTOMATED SIMULATION PROTOCOL FOR EXERCISE PHYSIOLOGY IN FONTAN PATIENTS USING A CLOSED-LOOP LUMPED-PARAMETER MODEL Kung, E., Giardini, A., Migliavacca, F., Pennati, G., Hsia, T., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389200243

• GROWTH AND REMODELING OF VEIN GRAFT IN AN ARTERIAL ENVIRONMENT: PARAMETER ESTIMATION AND SENSITIVITY ANALYSIS Ramachandra, A. B., Sankaran, S., Humphrey, J. D., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389300038

• A HEMI FONTAN OPERATION PERFORMED BY AN ENGINEER: CONSIDERATIONS ON VIRTUAL SURGERY Biglino, G., Kung, E., Dorfman, A., Taylor, A. M., Bove, E., Marsden, A., Hsia, T., Schievano, S., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389300128

• A PUBLIC REPOSITORY OF IMAGE-BASED COMPUTATIONAL MODELS AND PATIENT-SPECIFIC BLOOD FLOW SIMULATION RESULTS Wilson, N. M., Ortiz, A. K., Johnson, A. B., Feinstein, J. A., LaDisa, J. F., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2014

  View details for Web of Science ID 000359389200185

• An integrated approach to patient-specific predictive modeling for single ventricle heart palliation COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING Corsini, C., Baker, C., Kung, E., Schievano, S., Arbia, G., Baretta, A., Biglino, G., Migliavacca, F., Dubini, G., Pennati, G., Marsden, A., Vignon-Clementel, I., Taylor, A., Hsia, T., Dorfman, A. 2014; 17 (14): 1572-1589

  Abstract

  In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient-specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre-operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient-specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi-scale modeling.

  View details for DOI 10.1080/10255842.2012.758254

  View details for Web of Science ID 000337528400005

  View details for PubMedID 23343002

  View details for PubMedCentralID PMC4242799

• Numerical blood flow simulation in surgical corrections: what do we need for an accurate analysis? JOURNAL OF SURGICAL RESEARCH Arbia, G., Corsini, C., Moghadam, M. E., Marsden, A. L., Migliavacca, F., Pennati, G., Hsia, T., Vignon-Clementel, I. E. 2014; 186 (1): 44-55

  Abstract

  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.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.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.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.

  View details for DOI 10.1016/j.jss.2013.07.037

  View details for Web of Science ID 000328628800007

  View details for PubMedID 23993199

• Fluid-structure interaction simulation of pulsatile ventricular assist devices COMPUTATIONAL MECHANICS Long, C. C., Marsden, A. L., Bazilevs, Y. 2013; 52 (5): 971-981

  View details for DOI 10.1007/s00466-013-0858-3

  View details for Web of Science ID 000325810300001

• A new preconditioning technique for implicitly coupled multidomain simulations with applications to hemodynamics COMPUTATIONAL MECHANICS Esmaily-Moghadam, M., Bazilevs, Y., Marsden, A. L. 2013; 52 (5): 1141-1152

  View details for DOI 10.1007/s00466-013-0868-1

  View details for Web of Science ID 000325810300011

• A non-discrete method for computation of residence time in fluid mechanics simulations PHYSICS OF FLUIDS Esmaily-Moghadam, M., Hsia, T., Marsden, A. L. 2013; 25 (11)

  Abstract

  Cardiovascular simulations provide a promising means to predict risk of thrombosis in grafts, devices, and surgical anatomies in adult and pediatric patients. Although the pathways for platelet activation and clot formation are not yet fully understood, recent findings suggest that thrombosis risk is increased in regions of flow recirculation and high residence time (RT). Current approaches for calculating RT are typically based on releasing a finite number of Lagrangian particles into the flow field and calculating RT by tracking their positions. However, special care must be taken to achieve temporal and spatial convergence, often requiring repeated simulations. In this work, we introduce a non-discrete method in which RT is calculated in an Eulerian framework using the advection-diffusion equation. We first present the formulation for calculating residence time in a given region of interest using two alternate definitions. The physical significance and sensitivity of the two measures of RT are discussed and their mathematical relation is established. An extension to a point-wise value is also presented. The methods presented here are then applied in a 2D cavity and two representative clinical scenarios, involving shunt placement for single ventricle heart defects and Kawasaki disease. In the second case study, we explored the relationship between RT and wall shear stress, a parameter of particular importance in cardiovascular disease.

  View details for DOI 10.1063/1.4819142

  View details for Web of Science ID 000329184100003

  View details for PubMedCentralID PMC3765298

• Simulation based planning of surgical interventions in pediatric cardiology PHYSICS OF FLUIDS Marsden, A. L. 2013; 25 (10)

  View details for DOI 10.1063/1.4825031

  View details for Web of Science ID 000326642800003

• Simulation based planning of surgical interventions in pediatric cardiology. Physics of fluids (Woodbury, N.Y. : 1994) Marsden, A. L. 2013; 25 (10): 101303

  Abstract

  Hemodynamics plays an essential role in the progression and treatment of cardiovascular disease. However, while medical imaging provides increasingly detailed anatomical information, clinicians often have limited access to hemodynamic data that may be crucial to patient risk assessment and treatment planning. Computational simulations can now provide detailed hemodynamic data to augment clinical knowledge in both adult and pediatric applications. There is a particular need for simulation tools in pediatric cardiology, due to the wide variation in anatomy and physiology in congenital heart disease patients, necessitating individualized treatment plans. Despite great strides in medical imaging, enabling extraction of flow information from magnetic resonance and ultrasound imaging, simulations offer predictive capabilities that imaging alone cannot provide. Patient specific simulations can be used for in silico testing of new surgical designs, treatment planning, device testing, and patient risk stratification. Furthermore, simulations can be performed at no direct risk to the patient. In this paper, we outline the current state of the art in methods for cardiovascular blood flow simulation and virtual surgery. We then step through pressing challenges in the field, including multiscale modeling, boundary condition selection, optimization, and uncertainty quantification. Finally, we summarize simulation results of two representative examples from pediatric cardiology: single ventricle physiology, and coronary aneurysms caused by Kawasaki disease. These examples illustrate the potential impact of computational modeling tools in the clinical setting.

  View details for DOI 10.1063/1.4825031

  View details for PubMedID 24255590

  View details for PubMedCentralID PMC3820639

• Moving Domain Computational Fluid Dynamics to Interface with an Embryonic Model of Cardiac Morphogenesis PLOS ONE Lee, J., Moghadam, M. E., Kung, E., Cao, H., Beebe, T., Miller, Y., Roman, B. L., Lien, C., Chi, N. C., Marsden, A. L., Hsiai, T. K. 2013; 8 (8)

  Abstract

  Peristaltic contraction of the embryonic heart tube produces time- and spatial-varying wall shear stress (WSS) and pressure gradients (∇P) across the atrioventricular (AV) canal. Zebrafish (Danio rerio) are a genetically tractable system to investigate cardiac morphogenesis. The use of Tg(fli1a:EGFP) (y1) transgenic embryos allowed for delineation and two-dimensional reconstruction of the endocardium. This time-varying wall motion was then prescribed in a two-dimensional moving domain computational fluid dynamics (CFD) model, providing new insights into spatial and temporal variations in WSS and ∇P during cardiac development. The CFD simulations were validated with particle image velocimetry (PIV) across the atrioventricular (AV) canal, revealing an increase in both velocities and heart rates, but a decrease in the duration of atrial systole from early to later stages. At 20-30 hours post fertilization (hpf), simulation results revealed bidirectional WSS across the AV canal in the heart tube in response to peristaltic motion of the wall. At 40-50 hpf, the tube structure undergoes cardiac looping, accompanied by a nearly 3-fold increase in WSS magnitude. At 110-120 hpf, distinct AV valve, atrium, ventricle, and bulbus arteriosus form, accompanied by incremental increases in both WSS magnitude and ∇P, but a decrease in bi-directional flow. Laminar flow develops across the AV canal at 20-30 hpf, and persists at 110-120 hpf. Reynolds numbers at the AV canal increase from 0.07±0.03 at 20-30 hpf to 0.23±0.07 at 110-120 hpf (p< 0.05, n=6), whereas Womersley numbers remain relatively unchanged from 0.11 to 0.13. Our moving domain simulations highlights hemodynamic changes in relation to cardiac morphogenesis; thereby, providing a 2-D quantitative approach to complement imaging analysis.

  View details for DOI 10.1371/journal.pone.0072924

  View details for Web of Science ID 000324403200035

  View details for PubMedID 24009714

  View details for PubMedCentralID PMC3751826

• A modular numerical method for implicit 0D/3D coupling in cardiovascular finite element simulations JOURNAL OF COMPUTATIONAL PHYSICS Moghadam, M. E., Vignon-Clementel, I. E., Figliola, R., Marsden, A. L. 2013; 244: 63-79

  View details for DOI 10.1016/j.jcp.2012.07.035

  View details for Web of Science ID 000319456900005

• Lagrangian analysis of hemodynamics data from FSI simulation INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING Duvernois, V., Marsden, A. L., Shadden, S. C. 2013; 29 (4): 445-461

  Abstract

  We present the computation of lagrangian-based flow characterization measures for time-dependent, deformable-wall, finite-element blood flow simulations. Applicability of the algorithm is demonstrated in a fluid-structure interaction simulation of blood flow through a total cavopulmonary connection (Fontan procedure), and results are compared with a rigid-vessel simulation. Specifically, we report on several important lagrangian-based measures including flow distributions, finite-time Lyapunov exponent fields, particle residence time, and exposure time calculations. Overall, strong similarity in lagrangian measures of the flow between deformable and rigid-vessel models was observed.

  View details for DOI 10.1002/cnm.2523

  View details for Web of Science ID 000317311700001

  View details for PubMedID 23559551

  View details for PubMedCentralID PMC3875314

• SPATIAL DISTRIBUTION OF AEROSOLS IN HEALTHY RAT LUNGS: FINDINGS FROM NUMERICAL AND EXPERIMENTAL MODELS Oakes, J. M., Darquenne, C., Grandmont, C., Scadeng, M., Breen, E., Vignon-Clementel, I., Marsden, A. L. MARY ANN LIEBERT INC. 2013: A35

  View details for Web of Science ID 000317040000096

• An efficient framework for optimization and parameter sensitivity analysis in arterial growth and remodeling computations COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Sankaran, S., Humphrey, J. D., Marsden, A. L. 2013; 256: 200-210

  Abstract

  Computational models for vascular growth and remodeling (G&R) are used to predict the long-term response of vessels to changes in pressure, flow, and other mechanical loading conditions. Accurate predictions of these responses are essential for understanding numerous disease processes. Such models require reliable inputs of numerous parameters, including material properties and growth rates, which are often experimentally derived, and inherently uncertain. While earlier methods have used a brute force approach, systematic uncertainty quantification in G&R models promises to provide much better information. In this work, we introduce an efficient framework for uncertainty quantification and optimal parameter selection, and illustrate it via several examples. First, an adaptive sparse grid stochastic collocation scheme is implemented in an established G&R solver to quantify parameter sensitivities, and near-linear scaling with the number of parameters is demonstrated. This non-intrusive and parallelizable algorithm is compared with standard sampling algorithms such as Monte-Carlo. Second, we determine optimal arterial wall material properties by applying robust optimization. We couple the G&R simulator with an adaptive sparse grid collocation approach and a derivative-free optimization algorithm. We show that an artery can achieve optimal homeostatic conditions over a range of alterations in pressure and flow; robustness of the solution is enforced by including uncertainty in loading conditions in the objective function. We then show that homeostatic intramural and wall shear stress is maintained for a wide range of material properties, though the time it takes to achieve this state varies. We also show that the intramural stress is robust and lies within 5% of its mean value for realistic variability of the material parameters. We observe that prestretch of elastin and collagen are most critical to maintaining homeostasis, while values of the material properties are most critical in determining response time. Finally, we outline several challenges to the G&R community for future work. We suggest that these tools provide the first systematic and efficient framework to quantify uncertainties and optimally identify G&R model parameters.

  View details for DOI 10.1016/j.cma.2012.12.013

  View details for Web of Science ID 000316509400014

  View details for PubMedCentralID PMC3635687

• Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge. Journal of biomechanical engineering Steinman, D. A., Hoi, Y., Fahy, P., Morris, L., Walsh, M. T., Aristokleous, N., Anayiotos, A. S., Papaharilaou, Y., Arzani, A., Shadden, S. C., Berg, P., Janiga, G., Bols, J., Segers, P., Bressloff, N. W., Cibis, M., Gijsen, F. H., Cito, S., Pallarés, J., Browne, L. D., Costelloe, J. A., Lynch, A. G., Degroote, J., Vierendeels, J., Fu, W., Qiao, A., Hodis, S., Kallmes, D. F., Kalsi, H., Long, Q., Kheyfets, V. O., Finol, E. A., Kono, K., Malek, A. M., Lauric, A., Menon, P. G., Pekkan, K., Esmaily Moghadam, M., Marsden, A. L., Oshima, M., Katagiri, K., Peiffer, V., Mohamied, Y., Sherwin, S. J., Schaller, J., Goubergrits, L., Usera, G., Mendina, M., Valen-Sendstad, K., Habets, D. F., Xiang, J., Meng, H., Yu, Y., Karniadakis, G. E., Shaffer, N., Loth, F. 2013; 135 (2): 021016-?

  Abstract

  Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

  View details for DOI 10.1115/1.4023382

  View details for PubMedID 23445061

• Predictive modeling of the virtual Hemi-Fontan operation for second stage single ventricle palliation: Two patient-specific cases JOURNAL OF BIOMECHANICS Kung, E., Baretta, A., Baker, C., Arbia, G., Biglino, G., Corsini, C., Schievano, S., Vignon-Clementel, I. E., Dubini, G., Pennati, G., Taylor, A., Dorfman, A., Hlavacek, A. M., Marsden, A. L., Hsia, T., Migliavacca, F. 2013; 46 (2): 423-429

  Abstract

  Single ventricle hearts are congenital cardiovascular defects in which the heart has only one functional pumping chamber. The treatment for these conditions typically requires a three-staged operative process where Stage 1 is typically achieved by a shunt between the systemic and pulmonary arteries, and Stage 2 by connecting the superior venous return to the pulmonary circulation. Surgically, the Stage 2 circulation can be achieved through a procedure called the Hemi-Fontan, which reconstructs the right atrium and pulmonary artery to allow for an enlarged confluence with the superior vena cava. Based on pre-operative data obtained from two patients prior to Stage 2 surgery, we developed two patient-specific multi-scale computational models, each including the 3D geometrical model of the surgical junction constructed from magnetic resonance imaging, and a closed-loop systemic lumped-parameter network derived from clinical measurements. "Virtual" Hemi-Fontan surgery was performed on the 3D model with guidance from clinical surgeons, and a corresponding multi-scale simulation predicts the patient's post-operative hemodynamic and physiologic conditions. For each patient, a post-operative active scenario with an increase in the heart rate (HR) and a decrease in the pulmonary and systemic vascular resistance (PVR and SVR) was also performed. Results between the baseline and this "active" state were compared to evaluate the hemodynamic and physiologic implications of changing conditions. Simulation results revealed a characteristic swirling vortex in the Hemi-Fontan in both patients, with flow hugging the wall along the SVC to Hemi-Fontan confluence. One patient model had higher levels of swirling, recirculation, and flow stagnation. However, in both models, the power loss within the surgical junction was less than 13% of the total power loss in the pulmonary circulation, and less than 2% of the total ventricular power. This implies little impact of the surgical junction geometry on the SVC pressure, cardiac output, and other systemic parameters. In contrast, varying HR, PVR, and SVR led to significant changes in theses clinically relevant global parameters. Adopting a work-flow of customized virtual planning of the Hemi-Fontan procedure with patient-specific data, this study demonstrates the ability of multi-scale modeling to reproduce patient specific flow conditions under differing physiological states. Results demonstrate that the same operation performed in two different patients can lead to different hemodynamic characteristics, and that modeling can be used to uncover physiologic changes associated with different clinical conditions.

  View details for DOI 10.1016/j.jbiomech.2012.10.023

  View details for PubMedID 23174419

• Optimization of a Y-Graft Design for Improved Hepatic Flow Distribution in the Fontan Circulation JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Yang, W., Feinstein, J. A., Shadden, S. C., Vignon-Clementel, I. E., Marsden, A. L. 2013; 135 (1)

  Abstract

  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.

  View details for DOI 10.1115/1.4023089

  View details for PubMedID 23363213

• Patient-Specific Multiscale Modeling of Blood Flow for Coronary Artery Bypass Graft Surgery ANNALS OF BIOMEDICAL ENGINEERING Sankaran, S., Moghadam, M. E., Kahn, A. M., Tseng, E. E., Guccione, J. M., Marsden, A. L. 2012; 40 (10): 2228-2242

  Abstract

  We present a computational framework for multiscale modeling and simulation of blood flow in coronary artery bypass graft (CABG) patients. Using this framework, only CT and non-invasive clinical measurements are required without the need to assume pressure and/or flow waveforms in the coronaries and we can capture global circulatory dynamics. We demonstrate this methodology in a case study of a patient with multiple CABGs. A patient-specific model of the blood vessels is constructed from CT image data to include the aorta, aortic branch vessels (brachiocephalic artery and carotids), the coronary arteries and multiple bypass grafts. The rest of the circulatory system is modeled using a lumped parameter network (LPN) 0 dimensional (0D) system comprised of resistances, capacitors (compliance), inductors (inertance), elastance and diodes (valves) that are tuned to match patient-specific clinical data. A finite element solver is used to compute blood flow and pressure in the 3D (3 dimensional) model, and this solver is implicitly coupled to the 0D LPN code at all inlets and outlets. By systematically parameterizing the graft geometry, we evaluate the influence of graft shape on the local hemodynamics, and global circulatory dynamics. Virtual manipulation of graft geometry is automated using Bezier splines and control points along the pathlines. Using this framework, we quantify wall shear stress, wall shear stress gradients and oscillatory shear index for different surgical geometries. We also compare pressures, flow rates and ventricular pressure-volume loops pre- and post-bypass graft surgery. We observe that PV loops do not change significantly after CABG but that both coronary perfusion and local hemodynamic parameters near the anastomosis region change substantially. Implications for future patient-specific optimization of CABG are discussed.

  View details for DOI 10.1007/s10439-012-0579-3

  View details for Web of Science ID 000308638400012

  View details for PubMedID 22539149

  View details for PubMedCentralID PMC3570226

• Respiratory effects on hemodynamics in patient-specific CFD models of the Fontan circulation under exercise conditions EUROPEAN JOURNAL OF MECHANICS B-FLUIDS Baretta, A., Corsini, C., Marsden, A. L., Vignon-Clementel, I. E., Hsia, T., Dubini, G., Migliavacca, F., Pennati, G. 2012; 35: 61-69

  View details for DOI 10.1016/j.euromechflu.2012.01.012

  View details for Web of Science ID 000306039700010

• Image-based modeling of hemodynamics in coronary artery aneurysms caused by Kawasaki disease BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Sengupta, D., Kahn, A. M., Burns, J. C., Sankaran, S., Shadden, S. C., Marsden, A. L. 2012; 11 (6): 915-932

  Abstract

  Kawasaki Disease (KD) is the leading cause of acquired pediatric heart disease. A subset of KD patients develops aneurysms in the coronary arteries, leading to increased risk of thrombosis and myocardial infarction. Currently, there are limited clinical data to guide the management of these patients, and the hemodynamic effects of these aneurysms are unknown. We applied patient-specific modeling to systematically quantify hemodynamics and wall shear stress in coronary arteries with aneurysms caused by KD. We modeled the hemodynamics in the aneurysms using anatomic data obtained by multi-detector computed tomography (CT) in a 10-year-old male subject who suffered KD at age 3 years. The altered hemodynamics were compared to that of a reconstructed normal coronary anatomy using our subject as the model. Computer simulations using a robust finite element framework were used to quantify time-varying shear stresses and particle trajectories in the coronary arteries. We accounted for the cardiac contractility and the microcirculation using physiologic downstream boundary conditions. The presence of aneurysms in the proximal coronary artery leads to flow recirculation, reduced wall shear stress within the aneurysm, and high wall shear stress gradients at the neck of the aneurysm. The wall shear stress in the KD subject (2.95-3.81 dynes/sq cm) was an order of magnitude lower than the normal control model (17.10-27.15 dynes/sq cm). Particle residence times were significantly higher, taking 5 cardiac cycles to fully clear from the aneurysmal regions in the KD subject compared to only 1.3 cardiac cycles from the corresponding regions of the normal model. In this novel quantitative study of hemodynamics in coronary aneurysms caused by KD, we documented markedly abnormal flow patterns that are associated with increased risk of thrombosis. This methodology has the potential to provide further insights into the effects of aneurysms in KD and to help risk stratify patients for appropriate medical and surgical interventions.

  View details for DOI 10.1007/s10237-011-0361-8

  View details for PubMedID 22120599

• Identification of Hemodynamically Optimal Coronary Stent Designs Based on Vessel Caliber IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Gundert, T. J., Marsden, A. L., Yang, W., Marks, D. S., LaDisa, J. F. 2012; 59 (7): 1992-2002

  Abstract

  Coronary stent design influences local patterns of wall shear stress (WSS) that are associated with neointimal growth, restenosis, and the endothelialization of stent struts. The number of circumferentially repeating crowns N(C) for a given stent design is often modified depending on the target vessel caliber, but the hemodynamic implications of altering N(C) have not previously been studied. In this investigation, we analyzed the relationship between vessel diameter and the hemodynamically optimal N(C) using a derivative-free optimization algorithm coupled with computational fluid dynamics. The algorithm computed the optimal vessel diameter, defined as minimizing the area of stent-induced low WSS, for various configurations (i.e., N(C)) of a generic slotted-tube design and designs that resemble commercially available stents. Stents were modeled in idealized coronary arteries with a vessel diameter that was allowed to vary between 2 and 5 mm. The results indicate that the optimal vessel diameter increases for stent configurations with greater N(C), and the designs of current commercial stents incorporate a greater N(C) than hemodynamically optimal stent designs. This finding suggests that reducing the N(C) of current stents may improve the hemodynamic environment within stented arteries and reduce the likelihood of excessive neointimal growth and thrombus formation.

  View details for DOI 10.1109/TBME.2012.2196275

  View details for Web of Science ID 000305622100022

  View details for PubMedID 22547450

• Rat airway morphometry measured from in situ MRI-based geometric models JOURNAL OF APPLIED PHYSIOLOGY Oakes, J. M., Scadeng, M., Breen, E. C., Marsden, A. L., Darquenne, C. 2012; 112 (11): 1921-1931

  Abstract

  Rodents have been widely used to study the environmental or therapeutic impact of inhaled particles. Knowledge of airway morphometry is essential in assessing geometric influence on aerosol deposition and in developing accurate lung models of aerosol transport. Previous morphometric studies of the rat lung performed ex situ provided high-resolution measurements (50-125 μm). However, it is unclear how the overall geometry of these casts might have differed from the natural in situ appearance. In this study, four male Wistar rat (268 ± 14 g) lungs were filled sequentially with perfluorocarbon and phosphate-buffered saline before being imaged in situ in a 7-T magnetic resonance (MR) scanner at a resolution of 0.2 × 0.2 × 0.27 mm. Airway length, diameter, gravitational, bifurcation, and rotational angles were measured for the first four airway generations from 3D geometric models built from the MR images. Minor interanimal variability [expressed by the relative standard deviation RSD (=SD/mean)] was found for length (0.18 ± 0.07), diameter (0.15 ± 0.15), and gravitational angle (0.12 ± 0.06). One rat model was extended to 16 airway generations. Organization of the airways using a diameter-defined Strahler ordering method resulted in lower interorder variability than conventional generation-based grouping for both diameter (RSD = 0.12 vs. 0.42) and length (0.16 vs. 0.67). Gravitational and rotational angles averaged 82.9 ± 37.9° and 53.6 ± 24.1°, respectively. Finally, the major daughter branch bifurcated at a smaller angle (19.3 ± 14.6°) than the minor branch (60.5 ± 19.4°). These data represent the most comprehensive set of rodent in situ measurements to date and can be used readily in computational studies of lung function and aerosol exposure.

  View details for DOI 10.1152/japplphysiol.00018.2012

  View details for Web of Science ID 000304810500015

  View details for PubMedID 22461437

  View details for PubMedCentralID PMC3379152

• Fluid-structure interaction simulations of the Fontan procedure using variable wall properties INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING Long, C. C., Hsu, M., Bazilevs, Y., Feinstein, J. A., Marsden, A. L. 2012; 28 (5): 513-527

  Abstract

  Children born with single ventricle heart defects typically undergo a staged surgical procedure culminating in a total cavopulmonary connection (TCPC) or Fontan surgery. The goal of this work was to perform physiologic, patient-specific hemodynamic simulations of two post-operative TCPC patients by using fluid-structure interaction (FSI) simulations. Data from two patients are presented, and post-op anatomy is reconstructed from MRI data. Respiration rate, heart rate, and venous pressures are obtained from catheterization data, and inflow rates are obtained from phase contrast MRI data and are used together with a respiratory model. Lumped parameter (Windkessel) boundary conditions are used at the outlets. We perform FSI simulations by using an arbitrary Lagrangian-Eulerian finite element framework to account for motion of the blood vessel walls in the TCPC. This study is the first to introduce variable elastic properties for the different areas of the TCPC, including a Gore-Tex conduit. Quantities such as wall shear stresses and pressures at critical locations are extracted from the simulation and are compared with pressure tracings from clinical data as well as with rigid wall simulations. Hepatic flow distribution and energy efficiency are also calculated and compared for all cases. There is little effect of FSI on pressure tracings, hepatic flow distribution, and time-averaged energy efficiency. However, the effect of FSI on wall shear stress, instantaneous energy efficiency, and wall motion is significant and should be considered in future work, particularly for accurate prediction of thrombus formation.

  View details for DOI 10.1002/cnm.1485

  View details for Web of Science ID 000303441300002

• Optimization of Shunt Placement for the Norwood Surgery Using Multi-Domain Modeling JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Moghadam, M. E., Migliavacca, F., Vignon-Clementel, I. E., Hsia, T., Marsden, A. L. 2012; 134 (5)

  Abstract

  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.

  View details for DOI 10.1115/1.4006814

  View details for PubMedID 22757490

• Hepatic blood flow distribution and performance in conventional and novel Y-graft Fontan geometries: A case series computational fluid dynamics study JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Yang, W., Vignon-Clementel, I. E., Troianowski, G., Reddy, V. M., Feinstein, J. A., Marsden, A. L. 2012; 143 (5): 1086-1097

  Abstract

  A novel Y-shaped baffle has been proposed for the Fontan operation with promising initial results. However, previous studies have relied either on idealized models or a single patient-specific model. The objective of this study is to comprehensively compare the hemodynamic performance and hepatic blood flow distribution of the Y-graft Fontan baffle with 2 current designs using multiple patient-specific models.Y-shaped and tube-shaped grafts were virtually implanted into 5 patient-specific Glenn models forming 3 types of Fontan geometries: Y-graft, T-junction, and offset. Unsteady flow simulations were performed at rest and at varying exercise conditions. The hepatic flow distribution between the right and left lungs was carefully quantified using a particle tracking method. Other physiologically relevant parameters such as energy dissipation, superior vena cava pressure, and wall shear stress were evaluated.The Fontan geometry significantly influences the hepatic flow distribution. The Y-graft design improves the hepatic flow distribution effectively in 4 of 5 patients, whereas the T-junction and offset designs may skew as much as 97% of hepatic flow to 1 lung in 2 cases. Sensitivity studies show that changes in pulmonary flow split can affect the hepatic flow distribution dramatically but that some Y-graft and T-junction designs are relatively less sensitive than offset designs. The Y-graft design offers moderate improvements over the traditional designs in power loss and superior vena cava pressure in all patients.The Y-graft Fontan design achieves overall superior hemodynamic performance compared with traditional designs. However, the results emphasize that no one-size-fits-all solution is available that will universally benefit all patients and that designs should be customized for individual patients before clinical application.

  View details for DOI 10.1016/j.jtcvs.2011.06.042

  View details for PubMedID 21962841

• Hypoplastic Left Heart Syndrome Current Considerations and Expectations JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Feinstein, J. A., Benson, D. W., Dubin, A. M., Cohen, M. S., Maxey, D. M., Mahle, W. T., Pahl, E., Villafane, J., Bhatt, A. B., Peng, L. F., Johnson, B. A., Marsden, A. L., Daniels, C. J., Rudd, N. A., Caldarone, C. A., Mussatto, K. A., Morales, D. L., Ivy, D. D., Gaynor, J. W., Tweddell, J. S., Deal, B. J., Furck, A. K., Rosenthal, G. L., Ohye, R. G., Ghanayem, N. S., Cheatham, J. P., Tworetzky, W., Martin, G. R. 2012; 59 (1): S1-S42

  Abstract

  In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients.

  View details for DOI 10.1016/j.jacc.2011.09.022

  View details for PubMedID 22192720

• COMPARISON OF CLINICAL AND SIMULATION RESULTS FOR THE STANFORD Y-GRAFT FONTAN PILOT TRIAL ASME Summer Bioengineering Conference (SBC) Yang, W., Feinstein, J. A., Reddy, V. M., Chan, F. P., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2012: 463–464

  View details for Web of Science ID 000325036600231

• In Vitro Study of the Norwood Palliation: A Patient-Specific Mock Circulatory System ASAIO JOURNAL Biglino, G., Giardini, A., Baker, C., Figliola, R. S., Hsia, T., Taylor, A. M., Schievano, S., MOCHA Collaborative Grp 2012; 58 (1): 25-31

  Abstract

  The aim of this study was to build a mock circulatory system replicating in vitro the hemodynamics following the Norwood procedure and testing patient-specific anatomies focusing on the effect of aortic coarctation. Three anatomies were reconstructed from magnetic resonance images and rapid prototyped with transparent rigid resin. The models presented varying degrees of coarctation (none, moderate, and severe). A Blalock-Taussing (BT) shunt was modeled in all phantoms, which were inserted into a mock circulation. The single ventricle was simulated using a Berlin Heart driven with a PC-controlled piston. Resistive and compliant elements were implemented, creating a lumped parameter network. Pressure was measured at three locations: the transverse aortic arch, just after the aortic isthmus, and further downstream in the thoracic aorta. Volume distribution was derived from the instantaneous flow measurements at three outlets: upper body, lower body, and BT shunt. The combination of three-dimensional (3D) detailed anatomy and lumped parameter network effectively renders the circuit a multiscale in vitro model that successfully reproduces physiologic pressure signals. The pressure results highlight the larger pressure drop caused by coarctation and show the effect of pressure recovery. Results also suggest a reduction of flow to the lower body with increasing severity of coarctation, to the advantage of upper body and pulmonary circulation.

  View details for DOI 10.1097/MAT.0b013e3182396847

  View details for Web of Science ID 000298643200006

  View details for PubMedID 22210648

• Toward a Computational Steering Framework for Large-Scale Composite Structures Based on Continually and Dynamically Injected Sensor Data Bazilevs, Y., Marsden, A. L., di Scalea, F., Majumdar, A., Tatineni, M., Ali, H., Shi, Y., Khazanchi, D., Lees, M., VanAlbada, G. D., Dongarra, J., Sloot, P. M. ELSEVIER SCIENCE BV. 2012: 1149-1158

  View details for DOI 10.1016/j.procs.2012.04.124

  View details for Web of Science ID 000306288400122

• CFD CHALLENGE: CEREBRAL ANEURYSM SIMULATIONS USING AN IN-HOUSE FINITE ELEMENT SOLVER Moghadam, M., Wilson, N., Bazilevs, Y., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2012: 159-160

  View details for Web of Science ID 000325036600080

• STUDY OF MULTIPLE SYSTEMIC-TO-PULMONARY SHUNTS IN SINGLE VENTRICLE HEARTS Moghadam, M., Hsia, T., Murtuza, B., Marsden, A., ASME AMER SOC MECHANICAL ENGINEERS. 2012: 599-600

  View details for Web of Science ID 000325036600299

• MULTISCALE MODEL OF AIRFLOW IN HEALTHY AND EMPHYSEMA RAT LUNGS Oakes, J. M., Marsden, A. L., Grandmont, C., Darquenne, C., Vignon-Clementel, I. E., ASME AMER SOC MECHANICAL ENGINEERS. 2012: 1263-1264

  View details for Web of Science ID 000325036600631

• A PUBLIC REPOSITORY OF IMAGE-BASED COMPUTATIONAL MODELS FOR PATIENT-SPECIFIC BLOOD FLOW SIMULATION ASME Summer Bioengineering Conference (SBC) Wilson, N. M., Ortiz, A. K., Johnson, A. B., Arko, F. R., Feinstein, J. A., LaDisa, J. F., Marsden, A. AMER SOC MECHANICAL ENGINEERS. 2012: 969–970

  View details for Web of Science ID 000325036600484

• Immersive Volume Rendering of Blood Vessels Long, G., Kim, H., Marsden, A., Bazilevs, Y., Schulze, J. P., McDowall, I. E., Dolinsky, M. SPIE-INT SOC OPTICAL ENGINEERING. 2012

  View details for DOI 10.1117/12.909729

  View details for Web of Science ID 000302551600018

• Optimization of Computationally Expensive Simulations with Gaussian Processes and Parameter Uncertainty: Application to Cardiovascular Surgery Xie, J., Frazier, P. I., Sankaran, S., Marsden, A., Elmohamed, S., IEEE IEEE. 2012: 406–13

  View details for Web of Science ID 000320654000056

• Optimization of Cardiovascular Stent Design Using Computational Fluid Dynamics JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Gundert, T. J., Marsden, A. L., Yang, W., LaDisa, J. F. 2012; 134 (1)

  Abstract

  Coronary stent design affects the spatial distribution of wall shear stress (WSS), which can influence the progression of endothelialization, neointimal hyperplasia, and restenosis. Previous computational fluid dynamics (CFD) studies have only examined a small number of possible geometries to identify stent designs that reduce alterations in near-wall hemodynamics. Based on a previously described framework for optimizing cardiovascular geometries, we developed a methodology that couples CFD and three-dimensional shape-optimization for use in stent design. The optimization procedure was fully-automated, such that solid model construction, anisotropic mesh generation, CFD simulation, and WSS quantification did not require user intervention. We applied the method to determine the optimal number of circumferentially repeating stent cells (N(C)) for slotted-tube stents with various diameters and intrastrut areas. Optimal stent designs were defined as those minimizing the area of low intrastrut time-averaged WSS. Interestingly, we determined that the optimal value of N(C) was dependent on the intrastrut angle with respect to the primary flow direction. Further investigation indicated that stent designs with an intrastrut angle of approximately 40 deg minimized the area of low time-averaged WSS regardless of vessel size or intrastrut area. Future application of this optimization method to commercially available stent designs may lead to stents with superior hemodynamic performance and the potential for improved clinical outcomes.

  View details for DOI 10.1115/1.4005542

  View details for Web of Science ID 000302582100002

  View details for PubMedID 22482657

• Virtual surgeries in patients with congenital heart disease: a multi-scale modelling test case PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES BARETTA, A., Corsini, C., Yang, W., Vignon-Clementel, I. E., Marsden, A. L., Feinstein, J. A., Hsia, T., Dubini, G., Migliavacca, F., Pennati, G. 2011; 369 (1954): 4316-4330

  Abstract

  The objective of this work is to perform a virtual planning of surgical repairs in patients with congenital heart diseases--to test the predictive capability of a closed-loop multi-scale model. As a first step, we reproduced the pre-operative state of a specific patient with a univentricular circulation and a bidirectional cavopulmonary anastomosis (BCPA), starting from the patient's clinical data. Namely, by adopting a closed-loop multi-scale approach, the boundary conditions at the inlet and outlet sections of the three-dimensional model were automatically calculated by a lumped parameter network. Successively, we simulated three alternative surgical designs of the total cavopulmonary connection (TCPC). In particular, a T-junction of the venae cavae to the pulmonary arteries (T-TCPC), a design with an offset between the venae cavae (O-TCPC) and a Y-graft design (Y-TCPC) were compared. A multi-scale closed-loop model consisting of a lumped parameter network representing the whole circulation and a patient-specific three-dimensional finite volume model of the BCPA with detailed pulmonary anatomy was built. The three TCPC alternatives were investigated in terms of energetics and haemodynamics. Effects of exercise were also investigated. Results showed that the pre-operative caval flows should not be used as boundary conditions in post-operative simulations owing to changes in the flow waveforms post-operatively. The multi-scale approach is a possible solution to overcome this incongruence. Power losses of the Y-TCPC were lower than all other TCPC models both at rest and under exercise conditions and it distributed the inferior vena cava flow evenly to both lungs. Further work is needed to correlate results from these simulations with clinical outcomes.

  View details for DOI 10.1098/rsta.2011.0130

  View details for Web of Science ID 000295458900010

  View details for PubMedID 21969678

• A comparison of outlet boundary treatments for prevention of backflow divergence with relevance to blood flow simulations COMPUTATIONAL MECHANICS Moghadam, M. E., Bazilevs, Y., Hsia, T., Vignon-Clementel, I. E., Marsden, A. L. 2011; 48 (3): 277-291

  View details for DOI 10.1007/s00466-011-0599-0

  View details for Web of Science ID 000294346200004

• Towards inverse modeling of turbidity currents: The inverse lock-exchange problem COMPUTERS & GEOSCIENCES Lesshafft, L., Meiburg, E., Kneller, B., Marsden, A. 2011; 37 (4): 521-529

  View details for DOI 10.1016/j.cageo.2010.09.015

  View details for Web of Science ID 000289332000012

• A Stochastic Collocation Method for Uncertainty Quantification and Propagation in Cardiovascular Simulations JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Sankaran, S., Marsden, A. L. 2011; 133 (3)

  Abstract

  Simulations of blood flow in both healthy and diseased vascular models can be used to compute a range of hemodynamic parameters including velocities, time varying wall shear stress, pressure drops, and energy losses. The confidence in the data output from cardiovascular simulations depends directly on our level of certainty in simulation input parameters. In this work, we develop a general set of tools to evaluate the sensitivity of output parameters to input uncertainties in cardiovascular simulations. Uncertainties can arise from boundary conditions, geometrical parameters, or clinical data. These uncertainties result in a range of possible outputs which are quantified using probability density functions (PDFs). The objective is to systemically model the input uncertainties and quantify the confidence in the output of hemodynamic simulations. Input uncertainties are quantified and mapped to the stochastic space using the stochastic collocation technique. We develop an adaptive collocation algorithm for Gauss-Lobatto-Chebyshev grid points that significantly reduces computational cost. This analysis is performed on two idealized problems--an abdominal aortic aneurysm and a carotid artery bifurcation, and one patient specific problem--a Fontan procedure for congenital heart defects. In each case, relevant hemodynamic features are extracted and their uncertainty is quantified. Uncertainty quantification of the hemodynamic simulations is done using (a) stochastic space representations, (b) PDFs, and (c) the confidence intervals for a specified level of confidence in each problem.

  View details for DOI 10.1115/1.4003259

  View details for Web of Science ID 000287096100001

  View details for PubMedID 21303177

• The impact of uncertainty on shape optimization of idealized bypass graft models in unsteady flow PHYSICS OF FLUIDS Sankaran, S., Marsden, A. L. 2010; 22 (12)

  View details for DOI 10.1063/1.3529444

  View details for Web of Science ID 000285770200005

• A primer on computational simulation in congenital heart disease for the clinician PROGRESS IN PEDIATRIC CARDIOLOGY Vignon-Clementel, I. E., Marsden, A. L., Feinstein, J. A. 2010; 30 (1-2): 3–13

  View details for DOI 10.1016/j.ppedcard.2010.09.002

  View details for Web of Science ID 000213519300002

• Introduction PROGRESS IN PEDIATRIC CARDIOLOGY Feinstein, J. A., Marsden, A. 2010; 30 (1-2): 1

  View details for DOI 10.1016/j.ppedcard.2010.09.001

  View details for Web of Science ID 000213519300001

• Imaging and patient-specific simulations for the Fontan surgery: current methodologies and clinical applications. Progress in pediatric cardiology de Zélicourt, D. A., Marsden, A., Fogel, M. A., Yoganathan, A. P. 2010; 30 (1-2): 31-44

  View details for PubMedID 25620865

• A method for stochastic constrained optimization using derivative-free surrogate pattern search and collocation JOURNAL OF COMPUTATIONAL PHYSICS Sankaran, S., Audet, C., Marsden, A. L. 2010; 229 (12): 4664-4682

  View details for DOI 10.1016/j.jcp.2010.03.005

  View details for Web of Science ID 000277944400013

• A New Multiparameter Approach to Computational Simulation for Fontan Assessment and Redesign CONGENITAL HEART DISEASE Marsden, A. L., Reddy, V. M., Shadden, S. C., Chan, F. P., Taylor, C. A., Feinstein, J. A. 2010; 5 (2): 104-117

  Abstract

  Despite an abundance of prior Fontan simulation articles, there have been relatively few clinical advances that are a direct result of computational methods. We address a few key limitations of previous Fontan simulations as a step towards increasing clinical relevance. Previous simulations have been limited in scope because they have primarily focused on a single energy loss parameter. We present a multi-parameter approach to Fontan modeling that establishes a platform for clinical decision making and comprehensive evaluation of proposed interventions.Time-dependent, 3-D blood flow simulations were performed on six patient-specific Fontan models. Key modeling advances include detailed pulmonary anatomy, catheterization-derived pressures, and MRI-derived flow with respiration. The following performance parameters were used to rank patients at rest and simulated exercise from best to worst performing: energy efficiency, inferior and superior vena cava (IVC, SVC) pressures, wall shear stress, and IVC flow distribution.Simulated pressures were well matched to catheterization data, but low Fontan pressure did not correlate with high efficiency. Efficiency varied from 74% to 96% at rest, and from 63% to 91% with exercise. Distribution of IVC flow ranged from 88%/12% (LPA/RPA) to 53%/47%. A "transcatheter" virtual intervention demonstrates the utility of computation in evaluating interventional strategies, and is shown to result in increased energy efficiency.A multiparameter approach demonstrates that each parameter results in a different ranking of Fontan performance. Ranking patients using energy efficiency does not correlate with the ranking using other parameters of presumed clinical importance. As such, current simulation methods that evaluate energy dissipation alone are not sufficient for a comprehensive evaluation of new Fontan designs.

  View details for DOI 10.1111/j.1747-0803.2010.00383.x

  View details for Web of Science ID 000289417500004

  View details for PubMedID 20412482

• Constrained optimization of an idealized Y-shaped baffle for the Fontan surgery at rest and exercise COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Yang, W., Feinstein, J. A., Marsden, A. L. 2010; 199 (33-36): 2135-2149

  View details for DOI 10.1016/j.cma.2010.03.012

  View details for Web of Science ID 000279365100005

• Patient-specific hemodynamic simulations in coronary artery aneurysms caused by Kawasaki Disease Sengupta, D., Burns, J. C., Kahn, A., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2010: 575-576

  View details for Web of Science ID 000290705300288

• A COMPUTATIONAL TECHNIQUE FOR ROBUST OPTIMIZATION OF CARDIOVASCULAR BYPASS GRAFT SURGERIES Sankaran, S., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2010: 613-614

  View details for Web of Science ID 000290705300307

• IMAGE-BASED MORPHOMETRY AND AIRFLOW SIMULATION IN RAT LUNGS Oakes, J. M., Marsden, A. L., Scadeng, M., Darquenne, C., ASME AMER SOC MECHANICAL ENGINEERS. 2010: 655-656

  View details for Web of Science ID 000290705300328

• CFD SIMULATION OF FLOW MIXING IN THE VERTOBROBASILAR SYSTEM Bockman, M. D., Kansagra, A. P., Wong, E. C., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2010: 679-680

  View details for Web of Science ID 000290705300340

• VIRTUAL DESIGN FOR THE FONTAN PROCEDURE: FROM IDEALIZED TO PATIENT SPECIFIC MODELS USING CFD AND DERIVATIVE-FREE OPTIMIZATION 12th ASME Summer Bioengineering Conference Yang, W., Troianowski, G., Birolleau, A., Vignon-Clementel, I., Feinstein, J. A., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2010: 425–426

  View details for Web of Science ID 000290705300213

• A COMPUTATIONAL FRAMEWORK FOR OPTIMIZATION AND UNCERTAINTY QUANTIFICATION IN SURGICAL DESIGN FOR PEDIATRIC CARDIOLOGY 12th ASME Summer Bioengineering Conference Marsden, A. L., Yang, W., Sankaran, S., Feinstein, J. A. AMER SOC MECHANICAL ENGINEERS. 2010: 249–250

  View details for Web of Science ID 000290705300125

• Computational fluid-structure interaction: methods and application to a total cavopulmonary connection COMPUTATIONAL MECHANICS Bazilevs, Y., Hsu, M., Benson, D. J., Sankaran, S., Marsden, A. L. 2009; 45 (1): 77-89

  View details for DOI 10.1007/s00466-009-0419-y

  View details for Web of Science ID 000270428100006

• Recent Advances in the Application of Computational Mechanics to the Diagnosis and Treatment of Cardiovascular Disease REVISTA ESPANOLA DE CARDIOLOGIA del Alamo, J. C., Marsden, A. L., Lasheras, J. C. 2009; 62 (7): 781–805

  Abstract

  During the last 30 years, research into the pathogenesis and progression of cardiovascular disease has had to employ a multidisciplinary approach involving a wide range of subject areas, from molecular and cell biology to computational mechanics and experimental solid and fluid mechanics. In general, research was driven by the need to provide answers to questions of critical importance for disease management. Ongoing improvements in the spatial resolution of medical imaging equipment coupled to an exponential growth in the capacity, flexibility and speed of computational techniques have provided a valuable opportunity for numerical simulations and complex experimental techniques to make a contribution to improving the diagnosis and clinical management of many forms of cardiovascular disease. This paper contains a review of recent progress in the numerical simulation of cardiovascular mechanics, focusing on three particular areas: patient-specific modeling and the optimization of surgery in pediatric cardiology, evaluating the risk of rupture in aortic aneurysms, and noninvasive characterization of intraventricular flow in the management of heart failure.

  View details for DOI 10.1016/S0300-8932(09)71692-6

  View details for Web of Science ID 000267550300010

  View details for PubMedID 19709514

  View details for PubMedCentralID PMC6089365

• Evaluation of a novel Y-shaped extracardiac Fontan baffle using computational fluid dynamics JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Marsden, A. L., Bernstein, A. J., Reddy, V. M., Shadden, S. C., Spilker, R. L., Chan, F. P., Taylor, C. A., Feinstein, J. A. 2009; 137 (2): 394-U187

  Abstract

  The objective of this work is to evaluate the hemodynamic performance of a new Y-graft modification of the extracardiac conduit Fontan operation. The performance of the Y-graft design is compared to two designs used in current practice: a t-junction connection of the venae cavae and an offset between the inferior and superior venae cavae.The proposed design replaces the current tube grafts used to connect the inferior vena cava to the pulmonary arteries with a Y-shaped graft. Y-graft hemodynamics were evaluated at rest and during exercise with a patient-specific model from magnetic resonance imaging data together with computational fluid dynamics. Four clinically motivated performance measures were examined: Fontan pressures, energy efficiency, inferior vena cava flow distribution, and wall shear stress. Two variants of the Y-graft were evaluated: an "off-the-shelf" graft with 9-mm branches and an "area-preserving" graft with 12-mm branches.Energy efficiency of the 12-mm Y-graft was higher than all other models at rest and during exercise, and the reduction in efficiency from rest to exercise was improved by 38%. Both Y-graft designs reduced superior vena cava pressures during exercise by as much as 5 mm Hg. The Y-graft more equally distributed the inferior vena cava flow to both lungs, whereas the offset design skewed 70% of the flow to the left lung. The 12-mm graft resulted in slightly larger regions of low wall shear stress than other models; however, minimum shear stress values were similar.The area-preserving 12-mm Y-graft is a promising modification of the Fontan procedure that should be clinically evaluated. Further work is needed to correlate our performance metrics with clinical outcomes, including exercise intolerance, incidence of protein-losing enteropathy, and thrombus formation.

  View details for DOI 10.1016/j.jtcvs.2008.06.043

  View details for Web of Science ID 000262919000020

  View details for PubMedID 19185159

• OPTIMIZATION OF AN IDEALIZED Y-GRAFT FOR THE FONTAN PROCEDURE USING CFD AND A DERIVATIVE-FREE OPTIMIZATION ALGORITHM ASME Summer Bioengineering Conference Yang, W., Feinstein, J. A., Reddy, V. M., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2009: 449–450

  View details for Web of Science ID 000280089000225

• A COMPUTATIONAL INVESTIGATION OF MURRAY'S LAW USING 3-D NAVIER STOKES SOLUTIONS AND DERIVATIVE FREE OPTIMIZATION Sengupta, D., Marsden, A. L., ASME AMER SOC MECHANICAL ENGINEERS. 2009: 473-474

  View details for Web of Science ID 000280089000237

• A COMPUTATIONAL TECHNIQUE FOR UNCERTAINTY QUANTIFICATION AND ROBUST DESIGN IN CARDIOVASCULAR SYSTEMS ASME Summer Bioengineering Conference Sankaran, S., Feinstein, J. A., Marsden, A. L. AMER SOC MECHANICAL ENGINEERS. 2009: 17–18

  View details for Web of Science ID 000280089000009

• Generation of optimal artificial neural networks using a pattern search algorithm: Application to approximation of chemical systems NEURAL COMPUTATION Ihme, M., Marsden, A. L., Pitsch, H. 2008; 20 (2): 573-601

  Abstract

  A pattern search optimization method is applied to the generation of optimal artificial neural networks (ANNs). Optimization is performed using a mixed variable extension to the generalized pattern search method. This method offers the advantage that categorical variables, such as neural transfer functions and nodal connectivities, can be used as parameters in optimization. When used together with a surrogate, the resulting algorithm is highly efficient for expensive objective functions. Results demonstrate the effectiveness of this method in optimizing an ANN for the number of neurons, the type of transfer function, and the connectivity among neurons. The optimization method is applied to a chemistry approximation of practical relevance. In this application, temperature and a chemical source term are approximated as functions of two independent parameters using optimal ANNs. Comparison of the performance of optimal ANNs with conventional tabulation methods demonstrates equivalent accuracy by considerable savings in memory storage. The architecture of the optimal ANN for the approximation of the chemical source term consists of a fully connected feedforward network having four nonlinear hidden layers and 117 synaptic weights. An equivalent representation of the chemical source term using tabulation techniques would require a 500 x 500 grid point discretization of the parameter space.

  View details for PubMedID 18045024

• A computational framework for derivative-free optimization of cardiovascular geometries COMPUTER METHODS IN APPLIED MECHANICS AND ENGINEERING Marsden, A. L., Feinstein, J. A., Taylor, C. A. 2008; 197 (21-24): 1890-1905

  View details for DOI 10.1016/j.cma.2007.12.009

  View details for Web of Science ID 000254931400004

• Large differences in efficiency among Fontan patients demonstrated in patient specific models of blood flow simulations 80th Annual Scientific Session of the American-Heart-Association (AHA) Marsden, A. L., Bernstein, A. J., Spilker, R. L., Chan, F. P., Taylor, C. A., Feinstein, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2007: 480–80

  View details for Web of Science ID 000250394302214

• Trailing-edge noise reduction using derivative-free optimization and large-eddy simulation JOURNAL OF FLUID MECHANICS Marsden, A. L., Wang, M., Dennis, J. E., Moin, P. 2007; 572: 13-36

  View details for DOI 10.1017/S0022112006003235

  View details for Web of Science ID 000244434700002

• Effects of exercise and respiration on hemodynamic efficiency in CFD simulations of the total cavopulmonary connection ANNALS OF BIOMEDICAL ENGINEERING Marsden, A. L., Vignon-Clementel, I. E., Chan, F. P., Feinstein, J. A., Taylor, C. A. 2007; 35 (2): 250-263

  Abstract

  Congenital heart defects with a single functional ventricle, such as hypoplastic left heart syndrome and tricuspid atresia, require a staged surgical approach to separate the systemic and pulmonary circulations. Ultimately, the venous or pulmonary side of the heart is bypassed by directly connecting the vena cava to the pulmonary arteries with a modified t-shaped junction. The Fontan procedure (total cavopulmonary connection, TCPC) completes this process of separation. To date, computational fluid dynamics (CFD) simulations in this low pressure, passive flow, intrathoracic system have neglected the presumed important effects of respiration on physiology and higher "stress" states such as with exercise have never been considered. We hypothesize that incorporating effects of respiration and exercise would provide more realistic estimates of TCPC performance. Time-dependent, 3D blood flow simulations are performed by a custom finite element solver for two patient-specific Fontan models with a novel respiration model, developed to generate physiologic time-varying flow conditions. Blood flow features, pressure, and energy efficiency are analyzed at rest and with increasing flow rates to simulate exercise conditions. The simulations produce realistic pressure and flow data, comparable to that measured by catheterization and echocardiography, and demonstrate substantial increases in energy dissipation (i.e. decreased performance) with exercise and respiration due to increasing intensity of small scale vortices in the flow. As would be expected, these changes are highly dependent on patient-specific anatomy and Fontan geometry. We propose that respiration and exercise should be incorporated into TCPC CFD simulations to provide increasingly realistic evaluations of TCPC performance.

  View details for DOI 10.1007/s10439-006-9224-3

  View details for PubMedID 17171509

• Evaluation of hemodynamic efficiency in a new "Y-graft" design for the Fontan operation ASME Summer Bioengineering Conference Bernstein, A. J., Marsden, A. L., Spilker, R. L., Reddy, V. M., Taylor, C. A., Feinstein, J. A. AMER SOC MECHANICAL ENGINEERS. 2007: 473–474

  View details for Web of Science ID 000252105700237

• Suppression of vortex-shedding noise via derivative-free shape optimization PHYSICS OF FLUIDS Marsden, A. L., Wang, M., Dennis, J. E., Moin, P. 2004; 16 (10): L83-L86

  View details for DOI 10.1063/1.1786551

  View details for Web of Science ID 000223822300001

• Optimal aeroacoustic shape design using the surrogate management framework OPTIMIZATION AND ENGINEERING Marsden, A. L., Wang, M., Dennis, J. E., Moin, P. 2004; 5 (2): 235-262

  View details for Web of Science ID 000227173000008

• Construction of commutative filters for LES on unstructured meshes JOURNAL OF COMPUTATIONAL PHYSICS Marsden, A. L., Vasilyev, O. V., Moin, P. 2002; 175 (2): 584-603

  View details for DOI 10.1006/jcph.2001.6958

  View details for Web of Science ID 000173796900010