Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome.

BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

Biomechanical and transcriptional evidence that smooth muscle cell death drives an osteochondrogenic phenotype and severe proximal vascular disease in progeria.

Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.

A multi-scale computational model for the passive mechanical behavior of right ventricular myocardium.

We have previously demonstrated the importance of myofiber-collagen mechanical interactions in modeling the passive mechanical behavior of right ventricle free wall (RVFW) myocardium. To gain deeper insights into these coupling mechanisms, we developed a high-fidelity, micro-anatomically realistic 3D finite element model of right ventricle free wall (RVFW) myocardium by combining high-resolution imaging and supercomputer-based simulations. We first developed a representative tissue element (RTE) model at the sub-tissue scale by specializing the hyperelastic anisotropic structurally-based constitutive relations for myofibers and ECM collagen, and equi-biaxial and non-equibiaxial loading conditions were simulated using the open-source software FEniCS to compute the effective stress-strain response of the RTE. To estimate the model parameters of the RTE model, we first fitted a 'top-down' biaxial stress-strain behavior with our previous structurally based (tissue-scale) model, informed by the measured myofiber and collagen fiber composition and orientation distributions. Next, we employed a multi-scale approach to determine the tissue-level (5 x 5 x 0.7 mm specimen size) RVFW biaxial behavior via 'bottom-up' homogenization of the fitted RTE model, recapitulating the histologically measured myofiber and collagen orientation to the biaxial mechanical data. Our homogenization approach successfully reproduced the tissue-level mechanical behavior of our previous studies in all biaxial deformation modes, suggesting that the 3D micro-anatomical arrangement of myofibers and ECM collagen is indeed a primary mechanism driving myofiber-collagen interactions.

FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome.

BACKGROUND: Marfan syndrome, caused by mutations in the gene for fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM (extracellular matrix) remodeling are characteristic of both nonsyndromic and Marfan aneurysms. The ECM protein FN (fibronectin) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin α5ß1. We investigated the role of integrin α5-specific signals in Marfan mice in which the cytoplasmic domain of integrin α5 was replaced with that of integrin α2 (denoted α5/2 chimera). METHODS: We crossed α5/2 chimeric mice with Fbn1mgR/mgR mice (mgR model of Marfan syndrome) to evaluate the survival rate and pathogenesis of TAAs among wild-type, α5/2, mgR, and α5/2 mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs investigated molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. RESULTS: FN was elevated in the thoracic aortas from Marfan patients, in nonsyndromic aneurysms, and in mgR mice. The α5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, plating of wild-type SMCs on FN decreased contractile gene expression and activated inflammatory pathways whereas α5/2 SMCs were resistant. These effects correlated with increased NF-kB activation in cultured SMCs and mgR aortas, which was alleviated by the α5/2 mutation or NF-kB inhibition. CONCLUSIONS: FN-integrin α5 signaling is a significant driver of TAA in the mgR mouse model. This pathway thus warrants further investigation as a therapeutic target.

Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome.

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.

Perfluorocarbon nanodroplet size, acoustic vaporization, and inertial cavitation affected by lipid shell composition in vitro.

Perfluorocarbon nanodroplets (PFCnDs) are ultrasound contrast agents that phase-transition from liquid nanodroplets to gas microbubbles when activated by laser irradiation or insonated with an ultrasound pulse. The dynamics of PFCnDs can vary drastically depending on the nanodroplet composition, including the lipid shell properties. In this paper, we investigate the effect of varying the ratio of PEGylated to non-PEGylated phospholipids in the outer shell of PFCnDs on the acoustic nanodroplet vaporization (liquid to gas phase transition) and inertial cavitation (rapid collapse of the vaporized nanodroplets) dynamics in vitro when insonated with focused ultrasound. Nanodroplets with a high concentration of PEGylated lipids had larger diameters and exhibited greater variance in size distribution compared to nanodroplets with lower proportions of PEGylated lipids in the lipid shell. PFCnDs with a lipid shell composed of 50:50 PEGylated to non-PEGylated lipids yielded the highest B-mode image intensity and duration, as well as the greatest pressure difference between acoustic droplet vaporization onset and inertial cavitation onset. We demonstrate that slight changes in lipid shell composition of PFCnDs can significantly impact droplet phase transitioning and inertial cavitation dynamics. These findings can help guide researchers to fabricate PFCnDs with optimized compositions for their specific applications.

Neural operator learning of heterogeneous mechanobiological insults contributing to aortic aneurysms.

Thoracic aortic aneurysm (TAA) is a localized dilatation of the aorta that can lead to life-threatening dissection or rupture. In vivo assessments of TAA progression are largely limited to measurements of aneurysm size and growth rate. There is promise, however, that computational modelling of the evolving biomechanics of the aorta could predict future geometry and properties from initiating mechanobiological insults. We present an integrated framework to train a deep operator network (DeepONet)-based surrogate model to identify TAA contributing factors using synthetic finite-element-based datasets. For training, we employ a constrained mixture model of aortic growth and remodelling to generate maps of local aortic dilatation and distensibility for multiple TAA risk factors. We evaluate the performance of the surrogate model for insult distributions varying from fusiform (analytically defined) to complex (randomly generated). We propose two frameworks, one trained on sparse information and one on full-field greyscale images, to gain insight into a preferred neural operator-based approach. We show that this continuous learning approach can predict the patient-specific insult profile associated with any given dilatation and distensibility map with high accuracy, particularly when based on full-field images. Our findings demonstrate the feasibility of applying DeepONet to support transfer learning of patient-specific inputs to predict TAA progression.

Simulation of the 3D Hyperelastic Behavior of Ventricular Myocardium using a Finite-Element Based Neural-Network Approach.

High-fidelity cardiac models using attribute-rich finite element based models have been developed to a very mature stage. However, such finite-element based approaches remain time consuming, which have limited their clinical use. There remains a need for alternative methods for novel cardiac simulation methods of capable of high fidelity simulations in clinically relevant time frames. Surrogate models are one approach, which traditionally use a data-driven approach for training, requiring the generation of a sufficiently large number of simulation results as the training dataset. Alternatively, a physics-informed neural network can be trained by minimizing the PDE residuals or energy potentials. However, this approach does not provide for a general method to easily using existing finite element models. To address these challenges, we developed a hybrid approach that seamlessly bridged a neural network surrogate model with a differentiable finite element domain representation (NNFE). Given its importance in cardiac simulations, we applied this approach to simulations of the hyperelastic mechanical behavior of ventricular myocardium from recent 3D kinematic constitutive model (J Mech Behav Biomed Mater, 2020 doi: 10.1016/j.jmbbm.2019.103508). We utilized cuboidal domain and conducted numerical studies of individual myocardium specimens discretized by a finite element mesh and assigned with experimentally obtained myofiber architectures. Both parameterized Dirichlet and Neumann boundary conditions were studied. We developed a second-order Newton optimization method, instead of using stochastic gradient descent method, to train the neural network efficiently. The resulting trained neural network surrogate model demonstrated excellent agreement with the corresponding 'ground truth' finite element solutions over the entire physiological deformation range. More importantly, the NNFE approach provided a significantly decreased computational time for a range of finite element mesh sizes for online predictions. For example, as the finite element mesh sized increased from 2744 to 175615 elements the NNFE computational time increased from 0.1108 s to 0.1393 s, while the 'ground truth' FE model increased from 4.541 s to 719.9 s. These results suggests that NNFE run times can be significantly reduced compared with the traditional large-deformation based finite element solution methods. The trade off is to train the NNFE off-line within a range of anticipated physiological responses. However, training time would only have to be performed once before any number of application uses. Moreover, since the NNFE is an analytical function its computational performance will be amplified when the corresponding problem becomes more complex.

On the Three-Dimensional Mechanical Behavior of Human Breast Tissue.

As the human breast undergoes complex, large-scale, fully three dimensional deformations in vivo, three-dimensional (3D) characterization of its mechanical behavior is fundamental to its diagnosis, treatment, and surgical modifications. Its anisotropic, heterogeneous fibrous structure results in complex behavior at both the tissue and organ levels. Mathematically modeling of this complex anisotropic behavior is thus critical to the proper simulation of the human breast. Yet, current breast tissue constitutive models do not account for these complexities, so that there is a pressing need for more detailed fully 3D analysis. To this end, we performed a full 3D kinematic mechanical evaluation of human fibroglandular and adipose breast tissues. We utilized our recently developed 3D kinematic numerical-experimental approach to acquire force-displacement data from both breast tissue subtypes. This was done by subjecting cuboidal test specimens, aligned to the anatomical axes,to both pure shear and simple compression loading paths. We then developed novel constitutive model that was able to simulate the unique anisotropic tension/compression behaviors observed. Constitutive model parameters were determined using a detailed finite element model of the experimental setup coupled to nonlinear optimization. We found that human breast tissues displayed complex anisotropic behavior, with strong, directionally dependent non-linearities. This was especially true for the fibroglandular tissue. The novel constitutive model was also able fully capture these behaviors, including states of combined tension and compression (i.e. in pure shear). The results of this study suggest that human breast tissue is complex in its mechanical response, exhibiting varying levels of anisotropy. Future studies will be required to link the observed anisotropy to the physical structure of the tissue, as well as mapping this heterogeneity and anisotropy across individuals.

A High-Fidelity 3D Micromechanical Model of Ventricular Myocardium.

Pulmonary arterial hypertension (PAH) imposes a pressure overload on the right ventricle (RV), leading to myofiber hypertrophy and remodeling of the extracellular collagen fiber network. While the macroscopic behavior of healthy and post-PAH RV free wall (RVFW) tissue has been studied previously, the mechanical microenvironment that drives remodeling events in the myofibers and the extracellular matrix (ECM) remains largely unexplored. We hypothesize that multiscale computational modeling of the heart, linking cellular-scale events to tissue-scale behavior, can improve our understanding of cardiac remodeling and better identify therapeutic targets. We have developed a high-fidelity microanatomically realistic model of ventricular myocardium, combining confocal microscopy techniques, soft tissue mechanics, and finite element modeling. We match our microanatomical model to the tissue-scale mechanical response of previous studies on biaxial properties of RVFW and examine the local myofiber-ECM interactions to study fiber-specific mechanics at the scale of individual myofibers. Through this approach, we determine that the interactions occurring at the tissue scale can be accounted for by accurately representing the geometry of the myofiber-collagen arrangement at the micro scale. Ultimately, models such as these can be used to link cellular-level adaptations with organ-level adaptations to lead to the development of patient-specific treatments for PAH.

The impact of myocardial compressibility on organ-level simulations of the normal and infarcted heart.

Myocardial infarction (MI) rapidly impairs cardiac contractile function and instigates maladaptive remodeling leading to heart failure. Patient-specific models are a maturing technology for developing and determining therapeutic modalities for MI that require accurate descriptions of myocardial mechanics. While substantial tissue volume reductions of 15-20% during systole have been reported, myocardium is commonly modeled as incompressible. We developed a myocardial model to simulate experimentally-observed systolic volume reductions in an ovine model of MI. Sheep-specific simulations of the cardiac cycle were performed using both incompressible and compressible tissue material models, and with synchronous or measurement-guided contraction. The compressible tissue model with measurement-guided contraction gave best agreement with experimentally measured reductions in tissue volume at peak systole, ventricular kinematics, and wall thickness changes. The incompressible model predicted myofiber peak contractile stresses approximately double the compressible model (182.8 kPa, 107.4 kPa respectively). Compensatory changes in remaining normal myocardium with MI present required less increase of contractile stress in the compressible model than the incompressible model (32.1%, 53.5%, respectively). The compressible model therefore provided more accurate representation of ventricular kinematics and potentially more realistic computed active contraction levels in the simulated infarcted heart. Our findings suggest that myocardial compressibility should be incorporated into future cardiac models for improved accuracy.

Real-time interleaved spectroscopic photoacoustic and ultrasound (PAUS) scanning with simultaneous fluence compensation and motion correction.

For over two decades photoacoustic imaging has been tested clinically, but successful human trials have been limited. To enable quantitative clinical spectroscopy, the fundamental issues of wavelength-dependent fluence variations and inter-wavelength motion must be overcome. Here we propose a real-time, spectroscopic photoacoustic/ultrasound (PAUS) imaging approach using a compact, 1-kHz rate wavelength-tunable laser. Instead of illuminating tissue over a large area, the fiber-optic delivery system surrounding an US array sequentially scans a narrow laser beam, with partial PA image reconstruction for each laser pulse. The final image is then formed by coherently summing partial images. This scheme enables (i) automatic compensation for wavelength-dependent fluence variations in spectroscopic PA imaging and (ii) motion correction of spectroscopic PA frames using US speckle tracking in real-time systems. The 50-Hz video rate PAUS system is demonstrated in vivo using a murine model of labelled drug delivery.

Delineating Corneal Elastic Anisotropy in a Porcine Model Using Noncontact OCT Elastography and Ex Vivo Mechanical Tests.

Purpose: To compare noncontact acoustic microtapping (AµT) OCT elastography (OCE) with destructive mechanical tests to confirm corneal elastic anisotropy. Design: Ex vivo laboratory study with noncontact AµT-OCE followed by mechanical rheometry and extensometry. Participants: Inflated cornea of whole-globe porcine eyes (n = 9). Methods: A noncontact AµT transducer was used to launch propagating mechanical waves in the cornea that were imaged with phase-sensitive OCT at physiologically relevant controlled pressures. Reconstruction of both Young's modulus (E) and out-of-plane shear modulus (G) in the cornea from experimental data was performed using a nearly incompressible transversely isotropic (NITI) medium material model assuming spatial isotropy of corneal tensile properties. Corneal samples were excised and parallel plate rheometry was performed to measure shear modulus, G. Corneal samples were then subjected to strip extensometry to measure the Young's modulus, E. Main Outcome Measures: Strong corneal anisotropy was confirmed with both AµT-OCE and mechanical tests, with the Young's (E) and shear (G) moduli differing by more than an order of magnitude. These results show that AµT-OCE can quantify both moduli simultaneously with a noncontact, noninvasive, clinically translatable technique. Results: Mean of the OCE measured moduli were E = 12 ± 5 MPa and G = 31 ± 11 kPa at 5 mmHg and E = 20 ± 9 MPa and G = 61 ± 29 kPa at 20 mmHg. Tensile testing yielded a mean Young's modulus of 1 MPa - 20 MPa over a strain range of 1% to 7%. Shear storage and loss modulus (G'/G'') measured with rheometry was approximately 82/13 ± 12/4 kPa at 0.2 Hz and 133/29 ± 16/3 kPa at 16 Hz (0.1% strain). Conclusions: The cornea is confirmed to be a strongly anisotropic elastic material that cannot be characterized with a single elastic modulus. The NITI model is the simplest one that accounts for the cornea's incompressibility and in-plane distribution of lamellae. AµT-OCE has been shown to be the only reported noncontact, noninvasive method to measure both elastic moduli. Submillimeter spatial resolution and near real-time operation can be achieved. Quantifying corneal elasticity in vivo will enable significant innovation in ophthalmology, helping to develop personalized biomechanical models of the eye that can predict response to ophthalmic interventions.

Spatially localized sono-photoacoutic activation of phase-change contrast agents.

Sono-photoacoustic (SPA) activation lowers the threshold of phase-change contrast agents by timing a laser shot to coincide with the arrival of an acoustic wave at a region of interest. The combination of photothermal heating from optical absorption and negative pressure from the acoustic wave greatly reduces the droplet's combined vaporization threshold compared to using laser energy or acoustic energy alone. In previous studies, SPA imaging used a broadly illuminated optical pulse combined with plane wave acoustic pulses transmitted from a linear ultrasound array. Acoustic plane waves cover a wide lateral field of view, enabling direct visualization of the contrast agent distribution. In contrast, we demonstrate here that localized SPA activation is possible using electronically steered/focused ultrasound pulses. The focused SPA activation region is defined axially by the number of cycles in the acoustic pulse and laterally by the acoustic beam width. By reducing the spot size and enabling rapid electronic steering, complex activation patterns are possible, which may be particularly useful in therapeutic applications.

Nearly-incompressible transverse isotropy (NITI) of cornea elasticity: model and experiments with acoustic micro-tapping OCE.

The cornea provides the largest refractive power for the human visual system. Its stiffness, along with intraocular pressure (IOP), are linked to several pathologies, including keratoconus and glaucoma. Although mechanical tests can quantify corneal elasticity ex vivo, they cannot be used clinically. Dynamic optical coherence elastography (OCE), which launches and tracks shear waves to estimate stiffness, provides an attractive non-contact probe of corneal elasticity. To date, however, OCE studies report corneal moduli around tens of kPa, orders-of-magnitude less than those (few MPa) obtained by tensile/inflation testing. This large discrepancy impedes OCE's clinical adoption. Based on corneal microstructure, we introduce and fully characterize a nearly-incompressible transversely isotropic (NITI) model depicting corneal biomechanics. We show that the cornea must be described by at least two shear moduli, contrary to current single-modulus models, decoupling tensile and shear responses. We measure both as a function of IOP in ex vivo porcine cornea, obtaining values consistent with both tensile and shear tests. At pressures above 30 mmHg, the model begins to fail, consistent with non-linear changes in cornea at high IOP.

How hydrogel inclusions modulate the local mechanical response in early and fully formed post-infarcted myocardium.

Expansion of myocardium after myocardial infarction (MI) has long been identified as the primary mechanism that drives adverse left ventricular (LV) remodeling towards heart failure and death. Direct injection of hydrogels into the myocardium to mechanically constrain the infarct has demonstrated promise in limiting its remodeling and expansion. Despite early successes, there remain open questions in the determination of optimal hydrogel therapies, key application characteristics for which include injected polymer volume, stiffness, and spatial placement. Addressing these questions is complicated by the substantial variations in infarct type and extent, as well as limited understanding of the underlying mechanisms. Herein, we present an investigation on how hydrogel inclusions affect the effective tissue-level stiffness and strain fields in myocardium using full three-dimensional (3D) finite element simulations at early and late post-MI time points. We calibrated our simulations to triaxial mechanical and structural measurements of cuboidal LV myocardial specimens of post-infarcted myocardium, 0 and 4 weeks post-MI, injected with a dual-crosslinking hyaluronic acid-based hydrogel. Simulations included multiple deformation modes that spanned the anticipated physiological range in order to assess the effects of variations in inclusion size, location, and modulus on tissue-level myocardial mechanics. We observed significant local stiffening in the hydrogel-injected specimens that was highly dependent on the volume and mechanical properties of the injected hydrogel. Simulations revealed that the primary effect of the injections under physiological loading was a reduction in myocardial strain. This result suggests that hydrogel injections reduce infarct expansion by limiting the peak strains over the cardiac cycle. Overall, our study indicated that modulation of local effective tissue stiffness and corresponding strain reduction are governed by the volume and stiffness of the hydrogel, but relatively insensitive to its transmural placement. These findings provide important insights into mechanisms for ameliorating post-MI remodeling, as well as guidance for the future design of post-MI therapies.

On the in vivo systolic compressibility of left ventricular free wall myocardium in the normal and infarcted heart.

Although studied for many years, there remain continued gaps in our fundamental understanding of cardiac kinematics, such as the nature and extent of heart wall volumetric changes that occur over the cardiac cycle. Such knowledge is especially important for accurate in silico simulations of cardiac pathologies and in the development of novel therapies for their treatment. A prime example is myocardial infarction (MI), which induces profound, regionally variant maladaptive remodeling of the left ventricle (LV) wall. To address this problem, we conducted an in vivo fiduciary marker-based study in an established ovine model of MI to generate detailed, time-evolving transmural in vivo volumetric measurements of LV free wall deformations in the normal state, as well as up to 12 h post-MI. This was accomplished using a transmural array of sonomicrometry crystals that acquired fiducial positions at ∼250 Hz with a positional accuracy of ∼0.1 mm, covering the entire infarct, border, and remote zones. A convex-hull method was used to directly calculate the Jacobian J(t)=Δv(t)/ΔVED from sonocrystal positions over the entire cardiac cycle, where ΔV is the volume of each convex polyhedral at end diastole (ED) (typically ∼1 cc). We demonstrated significant in vivo compressibility in normal functioning LV free wall myocardium, with JES=0.85±0.07 at end systole (ES). We also observed substantial regional variations, with the largest reduction in local myocardial tissue volume during systole in the base region accompanied by substantial transmural gradients. These patterns changed profoundly following loss of perfusion post-MI, with the apical region showing the greatest loss of volume reduction at ES. To verify that the sonocrystals did not affect local volumetric measurements, JES measures were also verified by non-invasive magnetic resonance imaging, exhibiting very similar changes in regional volume. We note that while our estimates of regional compressibility were in close agreement with the values previously reported for large animals, ranging from 5% to 20%, the direct, comprehensive measurements of wall compressibility presented herein improved on the limitations of previous reports. These limitations included dependency on the small local volumes used for analysis and often indirect measurement of compressibility. Our novel findings suggest that proper accounting for the myocardial effective compressibility at the ∼1 cc volume scale can improve the accuracy of existing kinematic indices, such as wall thickening and axial shortening, and simulations of LV remodeling following MI.

Insights into the passive mechanical behavior of left ventricular myocardium using a robust constitutive model based on full 3D kinematics.

Myocardium possesses a hierarchical structure that results in complex three-dimensional (3D) mechanical behavior, forming a critical component of ventricular function in health and disease. A wide range of constitutive model forms have been proposed for myocardium since the first planar biaxial studies were performed by Demer and Yin (J. Physiol. 339 (1), 1983). While there have been extensive studies since, none have been based on full 3D kinematic data, nor have they utilized optimal experimental design to estimate constitutive parameters, which may limit their predictive capability. Herein we have applied our novel 3D numerical-experimental methodology (Avazmohammadi et al., Biomechanics Model. Mechanobiol. 2018) to explore the applicability of an orthotropic constitutive model for passive ventricular myocardium (Holzapfel and Ogden, Philos. Trans. R. Soc. Lond.: Math. Phys. Eng. Sci. 367, 2009) by integrating 3D optimal loading paths, spatially varying material structure, and inverse modeling techniques. Our findings indicated that the initial model form was not successful in reproducing all optimal loading paths, due to previously unreported coupling behaviors via shearing of myofibers and extracellular collagen fibers in the myocardium. This observation necessitated extension of the constitutive model by adding two additional terms based on the I8(C) pseudo-invariant in the fiber-normal and sheet-normal directions. The modified model accurately reproduced all optimal loading paths and exhibited improved predictive capabilities. These unique results suggest that more complete constitutive models are required to fully capture the full 3D biomechanical response of left ventricular myocardium. The present approach is thus crucial for improved understanding and performance in cardiac modeling in healthy, diseased, and treatment scenarios.

Kinetic Analysis of Ultrasound-Induced Oil Exchange in Oil-in-Water Emulsions through Contrast Variation Time-Resolved Small-Angle Neutron Scattering.

Ultrasound is one of the most commonly used methods for synthesizing and processing emulsion systems. In this study, the kinetics of acoustically induced emulsion oil exchange was examined using contrast variation time-resolved small-angle neutron scattering (CV-SANS). A custom-built sample environment was used to deliver acoustic forces while simultaneously performing CV-SANS experiments. It was observed that the oil exchange rate was significantly accelerated when sonicating at high acoustic pressures, where violent cavitation events can induce droplet coalescence and breakup. No significant oil exchange occurred at acoustic pressures below the cavitation threshold within the short time scales of the experiments. It was also observed that the oil exchange kinetics was deterred when emulsions were stabilized by surfactants. In addition, oil exchange rates varied nonlinearly with the concentration of surfactant, and exchange was slowest when the emulsions were stabilized by an intermediate concentration. It is hypothesized that emulsion size, electrostatic repulsion, and Gibbs elasticity of the oil-water interface play significant roles in the observed trends. The observed trends in oil exchange rates versus surfactant concentration coincide well with theoretical models for the fluctuation of the elasticity of the interface. Acoustically induced oil exchange was most inefficient when the interfacial elasticity was at its maximum value.

Interactions Between Structural Remodeling and Hypertrophy in the Right Ventricle in Response to Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) exerts substantial pressure overload on the right ventricle (RV), inducing RV remodeling and myocardial tissue adaptation often leading to right heart failure. The associated RV free wall (RVFW) adaptation involves myocardial hypertrophy, augmented intrinsic contractility, collagen fibrosis, and structural remodeling in an attempt to cope with pressure overload. If RVFW adaptation cannot maintain the RV stroke volume (SV), RV dilation will prevail as an exit mechanism, which usually decompensates RV function, leading to RV failure. Our knowledge of the factors determining the transition from the upper limit of RVFW adaptation to RV decompensation and the role of fiber remodeling events such as extracellular fibrosis and fiber reorientation in this transition remains very limited. Computational heart models that connect the growth and remodeling (G&R) events at the fiber and tissue levels with alterations in the organ-level function are essential to predict the temporal order and the compensatory level of the underlying mechanisms. In this work, building upon our recently developed rodent heart models (RHM) of PAH, we integrated mathematical models that describe volumetric growth of the RV and structural remodeling of the RVFW. The time-evolution of RV remodeling from control and post-PAH time points was simulated. The results suggest that the augmentation of the intrinsic contractility of myofibers, accompanied by an increase in passive stiffness of RVFW, is among the first remodeling events through which the RV strives to maintain the cardiac output. Interestingly, we found that the observed reorientation of the myofibers toward the longitudinal (apex-to-base) direction was a maladaptive mechanism that impaired the RVFW contractile pattern and advanced along with RV dilation at later stages of PAH. In fact, although individual fibers were more contractile post-PAH, the disruption in the optimal transmural fiber architecture compromised the effective contractile function of the RVFW, contributing to the depressed ejection fraction (EF) of the RV. Our findings clearly demonstrate the critical need for developing multiscale approaches that can model and delineate relationships between pathological alterations in cardiac function and underlying remodeling events across fiber, cellular, and molecular levels.