Experimentally-guided in silico design of engineered heart tissues to improve cardiac electrical function after myocardial infarction.

Engineered heart tissues (EHTs) built from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) showed promising results for cardiac function restoration following myocardial infarction. Nevertheless, human iPSC-CMs have longer action potential and lower cell-to-cell coupling than adult-like CMs. These immature electrophysiological properties favor arrhythmias due to the generation of electrophysiological gradients when hiPSC-CMs are injected in the cardiac tissue. Culturing hiPSC-CMs on three-dimensional (3D) scaffolds can promote their maturation and influence their alignment. However, it is still uncertain how on-scaffold culturing influences the overall electrophysiology of the in vitro and implanted EHTs, as it requires expensive and time consuming experimentation. Here, we computationally investigated the impact of the scaffold design on the EHT electrical depolarization and repolarization before and after engraftment on infarcted tissue. We first acquired and processed electrical recordings from in vitro EHTs, which we used to calibrate the modeling and simulation of in silico EHTs to replicate experimental outcomes. Next, we built in silico EHT models for a range of scaffold pore sizes, shapes (square, rectangular, auxetic, hexagonal) and thicknesses. In this setup, we found that scaffolds made of small (0.2 mm2), elongated (30° half-angle) hexagons led to faster EHT activation and better mimicked the cardiac anisotropy. The scaffold thickness had a marginal role on the not engrafted EHT electrophysiology. Moreover, EHT engraftment on infarcted tissue showed that the EHT conductivity should be at least 5% of that in healthy tissue for bidirectional EHT-myocardium electrical propagation. For conductivities above such threshold, the scaffold made of small elongated hexagons led to the lowest activation time (AT) in the coupled EHT-myocardium. If the EHT conductivity was further increased and the hiPSC-CMs were uniformly oriented parallel to the epicardial cells, the total AT and the repolarization time gradient decreased substantially, thus minimizing the likelihood for arrhythmias after EHT transplantation.

Meshless Simulation of Multi-site Radio Frequency Catheter Ablation through the Fragile Points Method.

Computational models for radio frequency catheter ablation (RFCA) of cardiac arrhythmia have been developed and tested in conditions where a single ablation site is considered. However, in reality arrhythmic events are generated at multiple sites which are ablated during treatment. Under such conditions, heat accumulation from several ablations is expected and models should take this effect into account. Moreover, such models are solved using the Finite Element Method which requires a good quality mesh to ensure numerical accuracy. Therefore, clinical application is limited since heat accumulation effects are neglected and numerical accuracy depends on mesh quality. In this work, we propose a novel meshless computational model where tissue heat accumulation from previously ablated sites is taken into account. In this way, we aim to overcome the mesh quality restriction of the Finite Element Method and enable realistic multi-site ablation simulation. We consider a two ablation sites protocol where tissue temperature at the end of the first ablation is used as initial condition for the second ablation. The effect of the time interval between the ablation of the two sites is evaluated. The proposed method demonstrates that previous models that do not account for heat accumulation between ablations may underestimate the tissue heat distribution.Clinical relevance- The proposed computational model may be used to build and update a heat map for ablation guidance taking into account the contribution from previously ablated sites. Being a meshless model, it does not require significant input from the user during preprocessing. Therefore, it is suitable for application in a clinical setting.

QRS-T Angles as Markers for Heart Sphericity in Subjects With Intrauterine Growth Restriction: A Simulation Study.

Changes induced by intrauterine growth restriction (IUGR) in cardiovascular anatomy and function that persist throughout life have been associated with a higher predisposition to heart disease in adulthood. Together with cardiac morphological remodelling, evaluated through the ventricular sphericity index, alterations in cardiac electrical function have been reported by characterization of the depolarization and repolarization loops, and their angular relationship, measured from the vectorcardiogram. The underlying relationship between the morphological remodelling and the angular variation of QRS and T-wave dominant vectors, if any, has not been explored. The aim of this study was to evaluate this relationship using computational models based on realistic heart and torso in which IUGR-induced morphological changes were incorporated by reducing the ventricular sphericity index. Specifically, we departed from a control model and we built eight different globular heart models by reducing the base-to-apex length and enlarging the basal ventricular diameter. We computed QRS and T-wave dominant vectors and angles from simulated pseudo-electrocardiograms and we compared them with clinical measurements. Results for the QRS to T angles follow a change trend congruent with that reported in clinical data, supporting the hypothesis that the IUGR-induced morphological remodelling could contribute to explain the observed angle changes in IUGR patients. By additionally varying the position of the ventricles with respect to the torso and the electrodes, we found that electrode displacement can impact the quantified angles and should be considered when interpreting the results.

Steady-state and transient effects of SK channel block and adrenergic stimulation to counteract acetylcholine-induced arrhythmogenic effects in the human atria: A computational study.

Hyperactivity of the parasympathetic nervous system has been linked to the development of paroxysmal atrial fibrillation (AF). The parasympathetic neurotransmitter acetylcholine (ACh) causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry. Research suggests that small-conductance calcium activated potassium (SK) channels may be an effective target for treating AF. Therapies targeting the autonomic nervous system, either alone or in combination with other drugs, have been explored and have been shown to decrease the incidence of atrial arrhythmias. This study uses computational modeling and simulation to examine the impact of SK channel block (SKb) and ß-adrenergic stimulation through Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration. The results showed that SKb alone prolonged APD90 and was able to stop sustained rotors in the presence of ACh concentrations up to 0.01 µM. Iso terminated rotors under all tested ACh concentrations, but resulted in highly-variable steady-state outcomes depending on baseline AP morphology. Importantly, the combination of SKb and Iso resulted in greater APD90 prolongation and showed promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility.

The role of ß-adrenergic stimulation in QT interval adaptation to heart rate during stress test.

The adaptation lag of the QT interval after heart rate (HR) has been proposed as an arrhythmic risk marker. Most studies have quantified the QT adaptation lag in response to abrupt, step-like changes in HR induced by atrial pacing, in response to tilt test or during ambulatory recordings. Recent studies have introduced novel methods to quantify the QT adaptation lag to gradual, ramp-like HR changes in stress tests by evaluating the differences between the measured QT series and an estimated, memoryless QT series obtained from the instantaneous HR. These studies have observed the QT adaptation lag to progressively reduce when approaching the stress peak, with the underlying mechanisms being still unclear. This study analyzes the contribution of ß-adrenergic stimulation to QT interval rate adaptation in response to gradual, ramp-like HR changes. We first quantify the QT adaptation lag in Coronary Artery Disease (CAD) patients undergoing stress test. To uncover the involved mechanisms, we use biophysically detailed computational models coupling descriptions of human ventricular electrophysiology and ß-adrenergic signaling, from which we simulate ventricular action potentials and ECG signals. We characterize the adaptation of the simulated QT interval in response to the HR time series measured from each of the analyzed CAD patients. We show that, when the simulated ventricular tissue is subjected to a time-varying ß-adrenergic stimulation pattern, with higher stimulation levels close to the stress peak, the simulated QT interval presents adaptation lags during exercise that are more similar to those measured from the patients than when subjected to constant ß-adrenergic stimulation. During stress test recovery, constant and time-varying ß-adrenergic stimulation patterns render similar adaptation lags, which are generally shorter than during exercise, in agreement with results from the patients. In conclusion, our findings support the role of time-varying ß-adrenergic stimulation in contributing to QT interval adaptation to gradually increasing HR changes as those seen during the exercise phase of a stress test.

A meshless fragile points method for rule-based definition of myocardial fiber orientation.

BACKGROUND AND OBJECTIVE: Rule-based methods are commonly used to estimate the arrangement of myocardial fibers by solving the Laplace problem with appropriate Dirichlet boundary conditions. Existing algorithms are using the Finite Element Method (FEM) to solve the Laplace-Dirichlet problem. However, meshless methods are under development for cardiac electrophysiology simulation. The objective of this work is to propose a meshless rule based method for the determination of myocardial fiber arrangement without requiring a mesh discretization as it is required by FEM. METHODS: The proposed method employs the Fragile Points Method (FPM) for the solution of the Laplace-Dirichlet problem. FPM uses simple discontinuous trial functions and single-point exact integration for linear trial functions that set it as a promising alternative to the Finite Element Method. We derive the FPM formulation of the Laplace-Dirichlet and we estimate ventricular and atrial fiber arrangements according to rules based on histology findings for four different geometries. The obtained fiber arrangements from FPM are compared with the ones obtained from FEM by calculating the angle between the fiber vector fields of the two methods for three different directions (i.e., longitudinal, sheet, transverse). RESULTS: The fiber arrangements that were generated with FPM were in close agreement with the generated arrangements from FEM for all three directions. The mean angle difference between the FPM and FEM vector fields were lower than 0.030∘ for the ventricular fiber arrangements and lower than 0.036∘ for the atrial fiber arrangements. DISCUSSION: The proposed meshless rule-based method was proven to generate myocardial fiber arrangements with very close agreement with FEM while alleviates the requirement for a mesh of the latter. This is of great value for cardiac electrophysiology solvers that are based on meshless methods since they require a well defined myocardial fiber arrangement to simulate accurately the propagation of electrical signals in the heart. Combining a meshless solution for both the determination of the fibers and the electrical signal propagation can allow for solution that do not require the definition of a mesh. To our knowledge, this work is the first one to propose a meshless rule-based method for myocardial fiber arrangement determination.

Image-based Cardiac Electrophysiology Simulation through the Meshfree Mixed Collocation Method.

State-of-the-art solvers for in silico cardiac electro-physiology employ the Finite Element Method to solve complex anatomical models. While this is a robust and accurate tech-nique, it requires a high-quality mesh to prevent its accuracy from being severely deteriorated. The generation of a good quality mesh for realistic anatomical models can be very time-consuming, making the translation to the clinics challenging, especially if we try to use patient-specific geometries.Aiming to tackle this challenge, we propose an image-based model generation approach based on the meshfree Mixed Col-location Method. The flexibility provided by this method during model generation allows building meshfree models directly from the image data in an automatic procedure. Furthermore, this approach allows interpreting the simulation results directly in the voxel coordinates system of the image.We simulate electrical propagation in a porcine biventricular model with the proposed method and we compare the results with those obtained using the Finite Element Method. We conclude that the proposed method can generate results that are in good agreement with the Finite Element Method solution, alleviating the requirement of a mesh and user-input during modeling with only minimum efficiency overhead.

Standardization and Validation of Brachytherapy Seeds' Modelling Using GATE and GGEMS Monte Carlo Toolkits.

This study aims to validate GATE and GGEMS simulation toolkits for brachytherapy applications and to provide accurate models for six commercial brachytherapy seeds, which will be freely available for research purposes. The AAPM TG-43 guidelines were used for the validation of two Low Dose Rate (LDR), three High Dose Rate (HDR), and one Pulsed Dose Rate (PDR) brachytherapy seeds. Each seed was represented as a 3D model and then simulated in GATE to produce one single Phase-Space (PHSP) per seed. To test the validity of the simulations' outcome, referenced data (provided by the TG-43) was compared with GATE results. Next, validation of the GGEMS toolkit was achieved by comparing its outcome with the GATE MC simulations, incorporating clinical data. The simulation outcomes on the radial dose function (RDF), anisotropy function (AF), and dose rate constant (DRC) for the six commercial seeds were compared with TG-43 values. The statistical uncertainty was limited to 1% for RDF, to 6% (maximum) for AF, and to 2.7% (maximum) for the DRC. GGEMS provided a good agreement with GATE when compared in different situations: (a) Homogeneous water sphere, (b) heterogeneous CT phantom, and (c) a realistic clinical case. In addition, GGEMS has the advantage of very fast simulations. For the clinical case, where TG-186 guidelines were considered, GATE required 1 h for the simulation while GGEMS needed 162 s to reach the same statistical uncertainty. This study produced accurate models and simulations of their emitted spectrum of commonly used commercial brachytherapy seeds which are freely available to the scientific community. Furthermore, GGEMS was validated as an MC GPU based tool for brachytherapy. More research is deemed necessary for the expansion of brachytherapy seed modeling.

Location of Parasympathetic Innervation Regions From Electrograms to Guide Atrial Fibrillation Ablation Therapy: An in silico Modeling Study.

The autonomic nervous system (ANS) plays an essential role in the generation and maintenance of cardiac arrhythmias. The cardiac ANS can be divided into its extrinsic and intrinsic components, with the latter being organized in an epicardial neural network of interconnecting axons and clusters of autonomic ganglia called ganglionated plexi (GPs). GP ablation has been associated with a decreased risk of atrial fibrillation (AF) recurrence, but the accurate location of GPs is required for ablation to be effective. Although GP stimulation triggers both sympathetic and parasympathetic ANS branches, a predominance of parasympathetic activity has been shown. This study aims was to develop a method to locate atrial parasympathetic innervation sites based on measurements from a grid of electrograms (EGMs). Electrophysiological models representative of non-AF, paroxysmal AF (PxAF), and persistent AF (PsAF) tissues were developed. Parasympathetic effects were modeled by increasing the concentration of the neurotransmitter acetylcholine (ACh) in randomly distributed circles across the tissue. Different circle sizes of ACh and fibrosis geometries were considered, accounting for both uniform diffuse and non-uniform diffuse fibrosis. Computational simulations were performed, from which unipolar EGMs were computed in a 16 × 1 6 electrode mesh. Different distances of the electrodes to the tissue (0.5, 1, and 2 mm) and noise levels with signal-to-noise ratio (SNR) values of 0, 5, 10, 15, and 20 dB were tested. The amplitude of the atrial EGM repolarization wave was found to be representative of the presence or absence of ACh release sites, with larger positive amplitudes indicating that the electrode was placed over an ACh region. Statistical analysis was performed to identify the optimal thresholds for the identification of ACh sites. In all non-AF, PxAF, and PsAF tissues, the repolarization amplitude rendered successful identification. The algorithm performed better in the absence of fibrosis or when fibrosis was uniformly diffuse, with a mean accuracy of 0.94 in contrast with a mean accuracy of 0.89 for non-uniform diffuse fibrotic cases. The algorithm was robust against noise and worked for the tested ranges of electrode-to-tissue distance. In conclusion, the results from this study support the feasibility to locate atrial parasympathetic innervation sites from the amplitude of repolarization wave.

Clinical Evaluation of a Three-Dimensional Internal Dosimetry Technique for Liver Radioembolization with 90Y Microspheres Using Dose Voxel Kernels.

Background: The purpose of this study was to develop a rapid, reliable, and efficient tool for three-dimensional (3D) dosimetry treatment planning and post-treatment evaluation of liver radioembolization with 90Y microspheres, using tissue-specific dose voxel kernels (DVKs) that can be used in everyday clinical practice. Materials and Methods: Two tissue-specific DVKs for 90Y were calculated through Monte Carlo (MC) simulations. DVKs for the liver and lungs were generated, and the dose distribution was compared with direct MC simulations. A method was developed to produce a 3D dose map by convolving the calculated DVKs with the activity biodistribution derived from clinical single-photon emission computed tomography (SPECT) or positron emission tomography (PET) images. Image registration for the SPECT or PET images with the corresponding computed tomography scans was performed before dosimetry calculation. The authors first compared the DVK convolution dosimetry with a direct full MC simulation on an XCAT anthropomorphic phantom. They then tested it in 25 individual clinical cases of patients who underwent 90Y therapy. All MC simulations were carried out using the GATE MC toolkit. Results: Comparison of the measured absorbed dose using tissue-specific DVKs and direct MC simulation on 25 patients revealed a mean difference of 1.07% ± 1.43% for the liver and 1.03% ± 1.21% for the tumor tissue, respectively. The largest difference between DVK convolution and full MC dosimetry was observed for the lung tissue (10.16% ± 1.20%). The DVK statistical uncertainty was <0.75% for both media. Conclusions: This semiautomatic algorithm is capable of performing rapid, accurate, and efficient 3D dosimetry. The proposed method considers tissue and activity heterogeneity using tissue-specific DVKs. Furthermore, this method provides results in <1 min, making it suitable for everyday clinical practice.

A dual adaptive explicit time integration algorithm for efficiently solving the cardiac monodomain equation.

The monodomain model is widely used in in-silico cardiology to describe excitation propagation in the myocardium. Frequently, operator splitting is used to decouple the stiff reaction term and the diffusion term in the monodomain model so that they can be solved separately. Commonly, the diffusion term is solved implicitly with a large time step while the reaction term is solved by using an explicit method with adaptive time stepping. In this work, we propose a fully explicit method for the solution of the decoupled monodomain model. In contrast to semi-implicit methods, fully explicit methods present lower memory footprint and higher scalability. However, such methods are only conditionally stable. We overcome the conditional stability limitation by proposing a dual adaptive explicit method in which adaptive time integration is applied for the solution of both the reaction and diffusion terms. We perform a set of numerical examples where cardiac propagation is simulated under physiological and pathophysiological conditions. Results show that the proposed method presents preserved accuracy and improved computational efficiency as compared to standard operator splitting-based methods.

Minimally invasive system to reliably characterize ventricular electrophysiology from living donors.

Cardiac tissue slices preserve the heterogeneous structure and multicellularity of the myocardium and allow its functional characterization. However, access to human ventricular samples is scarce. We aim to demonstrate that slices from small transmural core biopsies collected from living donors during routine cardiac surgery preserve structural and functional properties of larger myocardial specimens, allowing accurate electrophysiological characterization. In pigs, we compared left ventricular transmural core biopsies with transmural tissue blocks from the same ventricular region. In humans, we analyzed transmural biopsies and papillary muscles from living donors. All tissues were vibratome-sliced. By histological analysis of the transmural biopsies, we showed that tissue architecture and cellular organization were preserved. Enzymatic and vital staining methods verified viability. Optically mapped transmembrane potentials confirmed that action potential duration and morphology were similar in pig biopsies and tissue blocks. Action potential morphology and duration in human biopsies and papillary muscles agreed with published ranges. In both pigs and humans, responses to increasing pacing frequencies and ß-adrenergic stimulation were similar in transmural biopsies and larger tissues. We show that it is possible to successfully collect and characterize tissue slices from human myocardial biopsies routinely extracted from living donors, whose behavior mimics that of larger myocardial preparations both structurally and electrophysiologically.

SK Channel Block and Adrenergic Stimulation Counteract Acetylcholine-Induced Arrhythmogenic Effects in Human Atria.

There is increasing evidence on the role of the autonomic nervous system in the pathogenesis of atrial fibrillation. Interventions targeting autonomic modulation of atrial electrical activity have been shown to reduce the incidence of atrial arrhythmias. Additionally, recent investigations have proved that pharmacological therapies inhibiting small-conductance calcium-activated potassium (SK) channels are able to lessen cholinergic effects in the atria.In this study we use computational modeling and simulation to test individual and combined effects of SK channel block and adrenergic stimulation in counteracting detrimental effects induced by the parasympathetic neurotransmitter acetylcholine (ACh) on human atrial electrophysiology. Cell and tissue models are built that incorporate descriptions of SK channels as well as of isoproterenol (Iso)- and ACh-mediated regulation of the atrial action potential (AP). Three different cellular AP models, representing a range of physiological AP shapes, are considered and both homogeneous and heterogeneous ACh distributions in atrial tissue are simulated.At the cellular level, SK channel block is demonstrated to partially revert shortening of AP duration (APD) mediated by ACh at various doses, whereas 1 µM Iso has a variable response depending on the AP shape. The combination of SK block and Iso is in all cases able to take APD back to baseline levels, recovering between 82% and 120% of the APD shortening induced by 0.1 µM ACh. At the tissue level, SK block and Iso alone or in combination do not exert remarkable effects on conduction velocity, but the combination of the two is able to notably prolong the ACh-mediated APD shortening, thus increasing the wavelength for reentry.In conclusion, the results from this study support the combination of SK channel block and adrenergic stimulation as a potential option to counteract parasympathetically-mediated proarrhythmic effects in the human atria.

Prostate Volume Segmentation in TRUS Using Hybrid Edge-Bhattacharyya Active Surfaces.

OBJECTIVE: We present a new hybrid edge and region-based parametric deformable model, or active surface, for prostate volume segmentation in transrectal ultrasound (TRUS) images. METHODS: Our contribution is threefold. First, we develop a new edge detector derived from the radial bas-relief approach, allowing for better scalar prostate edge detection in low contrast configurations. Second, we combine an edge-based force derived from the proposed edge detector with a new region-based force driven by the Bhattacharyya gradient flow and adapted to the case of parametric active surfaces. Finally, we develop a quasi-automatic initialization technique for deformable models by analyzing the profiles of the proposed edge detector response radially to obtain initial landmark points toward which an initial surface model is warped. RESULTS: We validate our method on a set of 36 TRUS images for which manual delineations were performed by two expert radiation oncologists, using a wide variety of quantitative metrics. The proposed hybrid model achieved state-of-the-art segmentation accuracy. CONCLUSION: Results demonstrate the interest of the proposed hybrid framework for accurate prostate volume segmentation. SIGNIFICANCE: This paper presents a modular framework for accurate prostate volume segmentation in TRUS, broadening the range of available strategies to tackle this open problem.

DVH-Based Inverse Planning Using Monte Carlo Dosimetry for LDR Prostate Brachytherapy.

PURPOSE: Inverse planning is an integral part of modern low-dose-rate brachytherapy. Current clinical planning systems do not exploit the total dose information and largely use the American Association of Physicists in Medicine TG-43 dosimetry formalism to ensure clinically acceptable planning times. Thus, suboptimal plans may be derived as a result of TG-43-related dose overestimation and nonconformity with dose distribution requirements. The purpose of this study was to propose an inverse planning approach that can improve planning quality by combining dose-volume information and precision without compromising the overall execution times. METHODS AND MATERIALS: The dose map was generated by accumulating precomputed Monte Carlo (MC) dose kernels for each candidate source implantation site. The MC computational burden was reduced by using graphics processing unit acceleration, allowing accurate dosimetry calculations to be performed in the intraoperative environment. The proposed dose-volume histogram (DVH) fast simulated annealing optimization algorithm was evaluated using clinical plans that were delivered to 18 patients who underwent low-dose-rate prostate brachytherapy. RESULTS: Our method generated plans in 37.5 ± 3.2 seconds with similar prostate dose coverage, improved prostate dose homogeneity of up to 6.1%, and lower dose to the urethra of up to 4.0%. CONCLUSIONS: A DVH-based optimization algorithm using MC dosimetry was developed. The inclusion of the DVH requirements allowed for increased control over the optimization outcome. The optimal plan's quality was further improved by considering tissue heterogeneity.