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 β-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

Ventricular Conduction System Modeling for Electrophysiological Simulation of the Porcine Heart

Depolarization sequences triggering mechanical contraction of the heart are largely determined by the cardiac conduction system (CS). Many biophysical models of cardiac electrophysiology still have poor representations of the CS. This work proposes a semiautomatic method for the generation of an anatomically-realistic porcine CS that reproduces ventricular activation properties in swine computational models. Personalized swine biventricular models were built from magnetic resonance images. Electrical propagation was described by the monodomain model. The CS was defined from manually-determined anatomic landmarks using geodesic paths and a fractal tree algorithm. Two CS distributions were defined, one restricted to the subendocardium and another one by performing a subendo-to-intramyocardium projection based on histological porcine data. Depolarization patterns as well as left ventricular transmural and inter-ventricular delays were assessed to describe ventricular activation by the two CS distributions. The electrical excitations calculated using the two CS distributions were in good agreement with reported activation patterns. The pig-specific subendo-intramyocardial CS led to improved reproduction of experimental activation delays in ventricular endocardium and epicardium

An explicit total Lagrangian Fragile Points Method for finite deformation of hyperelastic materials

This research explored a novel explicit total Lagrangian Fragile Points Method (FPM) for finite deformation of hyperelastic materials. In contrast to mesh-based methods, where mesh distortion may pose numerical challenges, meshless methods are more suitable for large deformation modelling since they use enriched shape functions for the approximation of displacements. However, this comes at the expense of extra computational overhead and higher-order quadrature is required to obtain accurate results. In this work, the novel meshless method FPM was used to derive an explicit total Lagrangian algorithm for finite deformation. FPM uses simple one-point integration for exact integration of the Galerkin weak form since it employs simple discontinuous polynomials as trial and test functions, leading to accurate results even with single-point quadrature. The proposed method was evaluated by comparing it with FEM in several case studies considering both the extension and compression of a hyperelastic material. It was demonstrated that FPM maintained good accuracy even for large deformations where FEM failed to converge

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

Simple Summary:& nbsp;This study used GATE and GGEMS simulation toolkits, to estimate dose distribution on Brachytherapy procedures. Specific guidelines were followed as defined by the American Association of Physicists in Medicine (AAPM) as well as by the European SocieTy for Radiotherapy and Oncology (ESTRO). Several types of brachytherapy seeds were modelled and simulated, namely Low-Dose-Rate (LDR), High-Dose-Rate (HDR), and Pulsed-Dose-Rate (PDR). The basic difference between GATE and GGEMS is that GGEMS incorporates GPU capabilities, which makes the use of Monte Carlo (MC) simulations more accessible in clinical routine, by minimizing the computational time to obtain a dose map. During the validation procedure of both codes with protocol data, differences as well as uncertainties were measured within the margins defined by the guidelines. The study concluded that MC simulations may be utilized in clinical practice, to optimize dose distribution in real time, as well as to evaluate therapeutic plans.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

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