Estimation of Regional Pulmonary Compliance in Idiopathic Pulmonary Fibrosis Based on Personalized Lung Poromechanical Modeling.

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed, and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure-volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly computed tomography (CT) images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of "effective", i.e., without considering the mixture porosity, or "rescaled," i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis.

Left Ventricular Torsion Obtained Using Equilibrated Warping in Patients with Repaired Tetralogy of Fallot.

Patients after surgical repair of Tetralogy of Fallot (rTOF) may suffer a decrease in left ventricular (LV) function. The aim of our study is to evaluate a novel method of assessing LV torsion in patients with rTOF, as an early indicator of systolic LV dysfunction. Motion tracking based on image registration regularized by the equilibrium gap principle, known as equilibrated warping, was employed to assess LV torsion. Seventy-six cases of rTOF and ten normal controls were included. The group of controls was assessed for reproducibility using both equilibrated warping and standard clinical tissue tracking software (CVI42, version 5.10.1, Calgary, Canada). Patients were dichotomized into two groups: normal vs. loss of torsion. Torsion by equilibrated warping was successfully obtained in 68 of 76 (89%) patients and 9 of 10 (90%) controls. For equilibrated warping, the intra- and interobserver coefficients of variation were 0.095 and 0.117, respectively, compared to 0.260 and 0.831 for tissue tracking by standard clinical software. The intra- and inter-observer intraclass correlation coefficients for equilibrated warping were 0.862 and 0.831, respectively, compared to 0.992 and 0.648 for tissue tracking. Loss of torsion was noted in 32 of the 68 (47%) patients with rTOF. There was no difference in LV or RV volumes or ejection fraction between these groups. The assessment of LV torsion by equilibrated warping is feasible and shows good reliability. Loss of torsion is common in patients with rTOF and its robust assessment might contribute into uncovering heart failure in an earlier stage.

Computational quantification of patient-specific changes in ventricular dynamics associated with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH (n = 12) and controls (n = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements. The optimized parameters were compared with clinical metrics to find usable indicators associated with the underlying mechanical changes. Peak contractility of the RV free wall (RVFW) γRVFW,max was found to be strongly correlated and had an inverse relationship with the RV and left ventricle (LV) end-diastolic volume ratio (i.e., RVEDV/LVEDV) (RVEDV/LVEDV)+ 0.44, R2 = 0.77). Correlation with RV ejection fraction (R2 = 0.50) and end-diastolic volume index (R2 = 0.40) were comparatively weaker. Patients with with RVEDV/LVEDV > 1.5 had 25% lower γRVFW,max (P < 0.05) than that of the control. On average, RVFW passive stiffness progressively increased with the degree of remodeling as indexed by RVEDV/LVEDV. These results suggest a mechanical basis of using RVEDV/LVEDV as a clinical index for delineating disease severity and estimating RVFW contractility in patients with PAH.NEW & NOTEWORTHY This article presents patient-specific data assimilation of a patient cohort and physical description of clinical observations.

Spin echo versus stimulated echo diffusion tensor imaging of the in vivo human heart.

PURPOSE: To compare signal-to-noise ratio (SNR) efficiency and diffusion tensor metrics of cardiac diffusion tensor mapping using acceleration-compensated spin-echo (SE) and stimulated echo acquisition mode (STEAM) imaging. METHODS: Diffusion weighted SE and STEAM sequences were implemented on a clinical 1.5 Tesla MR system. The SNR efficiency of SE and STEAM was measured (b = 50-450 s/mm(2) ) in isotropic agar, anisotropic diffusion phantoms and the in vivo human heart. Diffusion tensor analysis was performed on mean diffusivity, fractional anisotropy, helix and transverse angles. RESULTS: In the isotropic phantom, the ratio of SNR efficiency for SE versus STEAM, SNRt (SE/STEAM), was 2.84 ± 0.08 for all tested b-values. In the anisotropic diffusion phantom the ratio decreased from 2.75 ± 0.05 to 2.20 ± 0.13 with increasing b-value, similar to the in vivo decrease from 2.91 ± 0.43 to 2.30 ± 0.30. Diffusion tensor analysis revealed reduced deviation of helix angles from a linear transmural model and reduced transverse angle standard deviation for SE compared with STEAM. Mean diffusivity and fractional anisotropy were measured to be statistically different (P < 0.001) between SE and STEAM. CONCLUSION: Cardiac DTI using motion-compensated SE yields a 2.3-2.9× increase in SNR efficiency relative to STEAM and improved accuracy of tensor metrics. The SE method hence presents an attractive alternative to STEAM based approaches. Magn Reson Med 76:862-872, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Second-order motion-compensated spin echo diffusion tensor imaging of the human heart.

PURPOSE: Myocardial microstructure has been challenging to probe in vivo. Spin echo-based diffusion-weighted sequences allow for single-shot acquisitions but are highly sensitive to cardiac motion. In this study, the use of second-order motion-compensated diffusion encoding was compared with first-order motion-compensated diffusion-weighted imaging during systolic contraction of the heart. METHODS: First- and second-order motion-compensated diffusion encoding gradients were incorporated into a triggered single-shot spin echo sequence. The effect of contractile motion on the apparent diffusion coefficients and tensor orientations was investigated in vivo from basal to apical level of the heart. RESULTS: Second-order motion compensation was found to increase the range of systolic trigger delays from 30%-55% to 15%-77% peak systole at the apex and from 25%-50% to 15%-79% peak systole at the base. Diffusion tensor analysis yielded more physiological transmural distributions when using second-order motion-compensated diffusion tensor imaging. CONCLUSION: Higher-order motion-compensated diffusion encoding decreases the sensitivity to cardiac motion, thereby enabling cardiac DTI over a wider range of time points during systolic contraction of the heart.

Patient-Specific Computational Analysis of Ventricular Mechanics in Pulmonary Arterial Hypertension.

Patient-specific biventricular computational models associated with a normal subject and a pulmonary arterial hypertension (PAH) patient were developed to investigate the disease effects on ventricular mechanics. These models were developed using geometry reconstructed from magnetic resonance (MR) images, and constitutive descriptors of passive and active mechanics in cardiac tissues. Model parameter values associated with ventricular mechanical properties and myofiber architecture were obtained by fitting the models with measured pressure-volume loops and circumferential strain calculated from MR images using a hyperelastic warping method. Results show that the peak right ventricle (RV) pressure was substantially higher in the PAH patient (65 mmHg versus 20 mmHg), who also has a significantly reduced ejection fraction (EF) in both ventricles (left ventricle (LV): 39% versus 66% and RV: 18% versus 64%). Peak systolic circumferential strain was comparatively lower in both the left ventricle (LV) and RV free wall (RVFW) of the PAH patient (LV: -6.8% versus -13.2% and RVFW: -2.1% versus -9.4%). Passive stiffness, contractility, and myofiber stress in the PAH patient were all found to be substantially increased in both ventricles, whereas septum wall in the PAH patient possessed a smaller curvature than that in the LV free wall. Simulations using the PAH model revealed an approximately linear relationship between the septum curvature and the transseptal pressure gradient at both early-diastole and end-systole. These findings suggest that PAH can induce LV remodeling, and septum curvature measurements may be useful in quantifying transseptal pressure gradient in PAH patients.

A Novel Method for Quantifying Smooth Regional Variations in Myocardial Contractility Within an Infarcted Human Left Ventricle Based on Delay-Enhanced Magnetic Resonance Imaging.

Heart failure is increasing at an alarming rate, making it a worldwide epidemic. As the population ages and life expectancy increases, this trend is not likely to change. Myocardial infarction (MI)-induced adverse left ventricular (LV) remodeling is responsible for nearly 70% of heart failure cases. The adverse remodeling process involves an extension of the border zone (BZ) adjacent to an MI, which is normally perfused but shows myofiber contractile dysfunction. To improve patient-specific modeling of cardiac mechanics, we sought to create a finite element model of the human LV with BZ and MI morphologies integrated directly from delayed-enhancement magnetic resonance (DE-MR) images. Instead of separating the LV into discrete regions (e.g., the MI, BZ, and remote regions) with each having a homogeneous myocardial material property, we assumed a functional relation between the DE-MR image pixel intensity and myocardial stiffness and contractility--we considered a linear variation of material properties as a function of DE-MR image pixel intensity, which is known to improve the accuracy of the model's response. The finite element model was then calibrated using measurements obtained from the same patient--namely, 3D strain measurements-using complementary spatial modulation of magnetization magnetic resonance (CSPAMM-MR) images. This led to an average circumferential strain error of 8.9% across all American Heart Association (AHA) segments. We demonstrate the utility of our method for quantifying smooth regional variations in myocardial contractility using cardiac DE-MR and CSPAMM-MR images acquired from a 78-yr-old woman who experienced an MI approximately 1 yr prior. We found a remote myocardial diastolic stiffness of C(0) = 0.102 kPa, and a remote myocardial contractility of T(max) = 146.9 kPa, which are both in the range of previously published normal human values. Moreover, we found a normalized pixel intensity range of 30% for the BZ, which is consistent with the literature. Based on these regional myocardial material properties, we used our finite element model to compute patient-specific diastolic and systolic LV myofiber stress distributions, which cannot be measured directly. One of the main driving forces for adverse LV remodeling is assumed to be an abnormally high level of ventricular wall stress, and many existing and new treatments for heart failure fundamentally attempt to normalize LV wall stress. Thus, our noninvasive method for estimating smooth regional variations in myocardial contractility should be valuable for optimizing new surgical or medical strategies to limit the chronic evolution from infarction to heart failure.

Applications of computational modeling in cardiac surgery.

Although computational modeling is common in many areas of science and engineering, only recently have advances in experimental techniques and medical imaging allowed this tool to be applied in cardiac surgery. Despite its infancy in cardiac surgery, computational modeling has been useful in calculating the effects of clinical devices and surgical procedures. In this review, we present several examples that demonstrate the capabilities of computational cardiac modeling in cardiac surgery. Specifically, we demonstrate its ability to simulate surgery, predict myofiber stress and pump function, and quantify changes to regional myocardial material properties. In addition, issues that would need to be resolved in order for computational modeling to play a greater role in cardiac surgery are discussed.

Using a micro-device with a deformable ceiling to probe stiffness heterogeneities within 3D cell aggregates.

Recent advances in the field of mechanobiology have led to the development of methods to characterise single-cell or monolayer mechanical properties and link them to their functional behaviour. However, there remains a strong need to establish this link for three-dimensional (3D) multicellular aggregates, which better mimic tissue function. Here we present a platform to actuate and observe many such aggregates within one deformable micro-device. The platform consists of a single polydimethylsiloxane piece cast on a 3D-printed mould and bonded to a glass slide or coverslip. It consists of a chamber containing cell spheroids, which is adjacent to air cavities that are fluidically independent. Controlling the air pressure in these air cavities leads to a vertical displacement of the chamber's ceiling. The device can be used in static or dynamic modes over time scales of seconds to hours, with displacement amplitudes from a fewµm to several tens of microns. Further, we show how the compression protocols can be used to obtain measurements of stiffness heterogeneities within individual co-culture spheroids, by comparing image correlations of spheroids at different levels of compression with finite element simulations. The labelling of the cells and their cytoskeleton is combined with image correlation methods to relate the structure of the co-culture spheroid with its mechanical properties at different locations. The device is compatible with various microscopy techniques, including confocal microscopy, which can be used to observe the displacements and rearrangements of single cells and neighbourhoods within the aggregate. The complete experimental and imaging platform can now be used to provide multi-scale measurements that link single-cell behaviour with the global mechanical response of the aggregates.

A two-scale Weibull approach to the failure of porous ceramic structures made by robocasting: possibilities and limits.

This paper introduces our approach to modeling the mechanical behavior of cellular ceramics, through the example of calcium phosphate scaffolds made by robocasting for bone-tissue engineering. The Weibull theory is used to deal with the scaffolds' constitutive rods statistical failure, and the Sanchez-Palencia theory of periodic homogenization is used to link the rod- and scaffold-scales. Uniaxial compression of scaffolds and three-point bending of rods were performed to calibrate and validate the model. If calibration based on rod-scale data leads to over-conservative predictions of scaffold's properties (as rods' successive failures are not taken into account), we show that, for a given rod diameter, calibration based on scaffold-scale data leads to very satisfactory predictions for a wide range of rod spacing, i.e. of scaffold porosity, as well as for different loading conditions. This work establishes the proposed model as a reliable tool for understanding and optimizing cellular ceramics' mechanical properties.

On the structural origin of the anisotropy in the myocardium: Multiscale modeling and analysis.

Due to structural heterogeneities within the tissue, the myocardium displays an orthotropic material behavior. However, the link between the microstructure and the macroscopic mechanical properties is still not fully established. In particular, if it is admitted that the cardiomyocyte organization induces a transversely isotropic symmetry, the relative role in the observed orthotropic symmetry of cardiomyocyte orientation variation and perimysium collagen "sheetlet" structure, two mechanisms occurring at different scales, is still a matter of debate. In order to shed light on this question, we designed a multiscale model of the myocardium, bridging the cell, sheetlet and tissue scales. More precisely, we compared the macroscopic anisotropy obtained by homogenization of different mesostructures consisting in cardiomyocytes and extracellular collageneous layers, also taking into account the variation of cardiomyocyte and sheetlet orientations on the macroscale, to available experimental data. This study confirms the importance of sheetlets layers in assuring the tissue's anisotropic response, as cardiomyocytes-only mesostructures cannot reproduce the observed anisotropy. Moreover, our model shows the existence of a size effect in the myocardial tissue shear properties, which will require further experimental analysis.

Reduced left ventricular dynamics modeling based on a cylindrical assumption.

Biomechanical modeling and simulation is expected to play a significant role in the development of the next generation tools in many fields of medicine. However, full-order finite element models of complex organs such as the heart can be computationally very expensive, thus limiting their practical usability. Therefore, reduced models are much valuable to be used, for example, for pre-calibration of full-order models, fast predictions, real-time applications, and so forth. In this work, focused on the left ventricle, we develop a reduced model by defining reduced geometry & kinematics while keeping general motion and behavior laws, allowing to derive a reduced model where all variables & parameters have a strong physical meaning. More specifically, we propose a reduced ventricular model based on cylindrical geometry & kinematics, which allows to describe the myofiber orientation through the ventricular wall and to represent contraction patterns such as ventricular twist, two important features of ventricular mechanics. Our model is based on the original cylindrical model of Guccione, McCulloch, & Waldman (1991); Guccione, Waldman, & McCulloch (1993), albeit with multiple differences: we propose a fully dynamical formulation, integrated into an open-loop lumped circulation model, and based on a material behavior that incorporates a fine description of contraction mechanisms; moreover, the issue of the cylinder closure has been completely reformulated; our numerical approach is novel aswell, with consistent spatial (finite element) and time discretizations. Finally, we analyze the sensitivity of the model response to various numerical and physical parameters, and study its physiological response.

Comparison of optimization parametrizations for regional lung compliance estimation using personalized pulmonary poromechanical modeling.

Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) or post-COVID-19 pulmonary fibrosis, are progressive and severe diseases characterized by an irreversible scarring of interstitial tissues that affects lung function. Despite many efforts, these diseases remain poorly understood and poorly treated. In this paper, we propose an automated method for the estimation of personalized regional lung compliances based on a poromechanical model of the lung. The model is personalized by integrating routine clinical imaging data - namely computed tomography images taken at two breathing levels in order to reproduce the breathing kinematic-notably through an inverse problem with fully personalized boundary conditions that is solved to estimate patient-specific regional lung compliances. A new parametrization of the inverse problem is introduced in this paper, based on the combined estimation of a personalized breathing pressure in addition to material parameters, improving the robustness and consistency of estimation results. The method is applied to three IPF patients and one post-COVID-19 patient. This personalized model could help better understand the role of mechanics in pulmonary remodeling due to fibrosis; moreover, patient-specific regional lung compliances could be used as an objective and quantitative biomarker for improved diagnosis and treatment follow up for various interstitial lung diseases.

A quasi-static poromechanical model of the lungs.

The lung vital function of providing oxygen to the body heavily relies on its mechanical behavior and the interaction with its complex environment. In particular, the large compliance and the porosity of the pulmonary tissue are critical for lung inflation and air inhalation, and the diaphragm, the pleura, the rib cage and intercostal muscles all play a role in delivering and controlling the breathing driving forces. In this paper, we introduce a novel poromechanical model of the lungs. The constitutive law is derived within a general poromechanics theory via the formulation of lung-specific assumptions, leading to a hyperelastic potential reproducing the volume response of the pulmonary mixture to a change of pressure. Moreover, physiological boundary conditions are formulated to account for the interaction of the lungs with their surroundings, including a following pressure and bilateral frictionless contact. A strategy is established to estimate the unloaded configuration from a given loaded state, with a particular focus on ensuring a positive porosity. Finally, we illustrate through several realistic examples the relevance of our model and its potential clinical applications.

Quantification of left ventricular strain and torsion by joint analysis of 3D tagging and cine MR images.

Cardiovascular magnetic resonance (CMR) imaging is the gold standard for the non-invasive assessment of left-ventricular (LV) function. Prognostic value of deformation metrics extracted directly from regular SSFP CMR images has been shown by numerous studies in the clinical setting, but with some limitations to detect torsion of the myocardium. Tagged CMR introduces trackable features in the myocardium that allow for the assessment of local myocardial deformation, including torsion; it is, however, limited in the quantification of radial strain, which is a decisive metric for assessing the contractility of the heart. In order to improve SSFP-only and tagged-only approaches, we propose to combine the advantages of both image types by fusing global shape motion obtained from SSFP images with the local deformation obtained from tagged images. To this end, tracking is first performed on SSFP images, and subsequently, the resulting motion is utilized to mask and track tagged data. Our implementation is based on a recent finite element-based motion tracking tool with mechanical regularization. Joint SSFP and tagged images registration performance is assessed based on deformation metrics including LV strain and twist using human and in-house porcine datasets. Results show that joint analysis of SSFP and 3DTAG images provides better quantification of LV strain and twist as either data source alone.

In-silico study of accuracy and precision of left-ventricular strain quantification from 3D tagged MRI.

Cardiac Magnetic Resonance Imaging (MRI) allows quantifying myocardial tissue deformation and strain based on the tagging principle. In this work, we investigate accuracy and precision of strain quantification from synthetic 3D tagged MRI using equilibrated warping. To this end, synthetic biomechanical left-ventricular tagged MRI data with varying tag distance, spatial resolution and signal-to-noise ratio (SNR) were generated and processed to quantify errors in radial, circumferential and longitudinal strains relative to ground truth. Results reveal that radial strain is more sensitive to image resolution and noise than the other strain components. The study also shows robustness of quantifying circumferential and longitudinal strain in the presence of geometrical inconsistencies of 3D tagged data. In conclusion, our study points to the need for higher-resolution 3D tagged MRI than currently available in practice in order to achieve sufficient accuracy of radial strain quantification.

A 3D personalized cardiac myocyte aggregate orientation model using MRI data-driven low-rank basis functions.

Cardiac myocyte aggregate orientation has a strong impact on cardiac electrophysiology and mechanics. Studying the link between structural characteristics, strain, and stresses over the cardiac cycle and cardiac function requires a full volumetric representation of the microstructure. In this work, we exploit the structural similarity across hearts to extract a low-rank representation of predominant myocyte orientation in the left ventricle from high-resolution magnetic resonance ex-vivo cardiac diffusion tensor imaging (cDTI) in porcine hearts. We compared two reduction methods, Proper Generalized Decomposition combined with Singular Value Decomposition and Proper Orthogonal Decomposition. We demonstrate the existence of a general set of basis functions of aggregated myocyte orientation which defines a data-driven, personalizable, parametric model featuring higher flexibility than existing atlas and rule-based approaches. A more detailed representation of microstructure matching the available patient data can improve the accuracy of personalized computational models. Additionally, we approximate the myocyte orientation of one ex-vivo human heart and demonstrate the feasibility of transferring the basis functions to humans.

Biomechanical Modeling to Inform Pulmonary Valve Replacement in Tetralogy of Fallot Patients After Complete Repair.

BACKGROUND: A biomechanical model of the heart can be used to incorporate multiple data sources (electrocardiography, imaging, invasive hemodynamics). The purpose of this study was to use this approach in a cohort of patients with tetralogy of Fallot after complete repair (rTOF) to assess comparative influences of residual right ventricular outflow tract obstruction (RVOTO) and pulmonary regurgitation on ventricular health. METHODS: Twenty patients with rTOF who underwent percutaneous pulmonary valve replacement (PVR) and cardiovascular magnetic resonance imaging were included in this retrospective study. Biomechanical models specific to individual patient and physiology (before and after PVR) were created and used to estimate the RV myocardial contractility. The ability of models to capture post-PVR changes of right ventricular (RV) end-diastolic volume (EDV) and effective flow in the pulmonary artery (Qeff) was also compared with expected values. RESULTS: RV contractility before PVR (mean 66 ± 16 kPa, mean ± standard deviation) was increased in patients with rTOF compared with normal RV (38-48 kPa) (P < 0.05). The contractility decreased significantly in all patients after PVR (P < 0.05). Patients with predominantly RVOTO demonstrated greater reduction in contractility (median decrease 35%) after PVR than those with predominant pulmonary regurgitation (median decrease 11%). The model simulated post-PVR decreased EDV for the majority and suggested an increase of Qeff-both in line with published data. CONCLUSIONS: This study used a biomechanical model to synthesize multiple clinical inputs and give an insight into RV health. Individualized modeling allows us to predict the RV response to PVR. Initial data suggest that residual RVOTO imposes greater ventricular work than isolated pulmonary regurgitation.

Microstructural deformation observed by Mueller polarimetry during traction assay on myocardium samples.

Despite recent advances, the myocardial microstructure remains imperfectly understood. In particular, bundles of cardiomyocytes have been observed but their three-dimensional organisation remains debated and the associated mechanical consequences unknown. One of the major challenges remains to perform multiscale observations of the mechanical response of the heart wall. For this purpose, in this study, a full-field Mueller polarimetric imager (MPI) was combined, for the first time, with an in-situ traction device. The full-field MPI enables to obtain a macroscopic image of the explored tissue, while providing detailed information about its structure on a microscopic scale. Specifically it exploits the polarization of the light to determine various biophysical quantities related to the tissue scattering or anisotropy properties. Combined with a mechanical traction device, the full-field MPI allows to measure the evolution of such biophysical quantities during tissue stretch. We observe separation lines on the tissue, which are associated with a fast variation of the fiber orientation, and have the size of cardiomyocyte bundles. Thus, we hypothesize that these lines are the perimysium, the collagen layer surrounding these bundles. During the mechanical traction, we observe two mechanisms simultaneously. On one hand, the azimuth shows an affine behavior, meaning the orientation changes according to the tissue deformation, and showing coherence in the tissue. On the other hand, the separation lines appear to be resistant in shear and compression but weak against traction, with a forming of gaps in the tissue.