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 for the ventricular fiber arrangements and lower than 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

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

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

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 β-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 β-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 β-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 β-adrenergic stimulation. During stress test recovery, constant and time-varying β-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 β-adrenergic stimulation in contributing to QT interval adaptation to gradually increasing HR changes as those seen during the exercise phase of a stress test

Changes in QRS and T-wave Loops Subsequent to an Increase in Left Ventricle Globularity as in Intrauterine Growth Restriction: a Simulation Study

[EN] Cardiovascular remodeling induced by intrauterine growth restriction manifests in adulthood by more globular ventricles, as evidenced by in vivo measurements. The angle between the dominant vectors of the QRS and T-wave loops has been reported to be significantly altered as a result of the induced remodeling. To investigate whether the more globular ventricular shape was a major factor contributing to such alteration, we performed electrophysiological simulations in a human biventricular model for control and in a model obtained by deforming the control one to represent a more spherical left ventricle (SLV). Transmural ventricular heterogeneities and a Purkinje network were included. 12-lead ECGs were calculated, from which spatial QRS and T-wave angles were computed. The angle between the T-wave and the XZ-plane was found to increase in the SLV model, showing a variation similar to that reported in in vivo studies. However, the angle between the dominant vectors of the QRS and T-wave loops projected onto the XY-plane was lower for control, contrary to clinical observations in IUGR adults. Other clinical results could not be reproduced in our simulations either. Our findings suggest that a more globular left ventricular shape leads to changes in the angles of QRS and T-wave loops, but further research is needed to fully understand these changes and the underlying mechanismsI would like to acknowledge support by Fundaci ' on Carolina, Universidad de Zaragoza and Universidad Polit ' ecnica Salesiana through its doctoral scholar-ship. This work was supported by projects ERC-StG 638284 (ERC), PID2019-105674RB-I00 and PID2019104881RB-I00 (MICINN) and LMP124-18 and reference group T39-20R (Arag ' on Government cofunded by FEDER 2014-2020 "Building Europe from Aragon"). Computations were performed using ICTS NANBIOSIS (HPC unit at U. Zaragoza). N. Ortigosa acknowledges support from Generalitat Valenciana under grant Prometeo/2017/102 and Spanish MINECO under grant MTM2016-76647-PBueno-Palomeque, FL.; Mountris, KA.; Mincholé, A.; Ortigosa, N.; Bailón, R.; Pueyo, E.; Laguna, P. (2020). Changes in QRS and T-wave Loops Subsequent to an Increase in Left Ventricle Globularity as in Intrauterine Growth Restriction: a Simulation Study. IEEE. 1-4. https://doi.org/10.22489/CinC.2020.438S1

Cell-based maximum entropy approximants for three-dimensional domains: Application in large strain elastodynamics using the meshless total Lagrangian explicit dynamics method

We present the cell-based maximum entropy (CME) approximants in E3 space by constructing the smooth approximation distance function to polyhedral surfaces. CME is a meshfree approximation method combining the properties of the maximum entropy approximants and the compact support of element-based interpolants. The method is evaluated in problems of large strain elastodynamics for three-dimensional (3D) continua using the well-established meshless total Lagrangian explicit dynamics method. The accuracy and efficiency of the method is assessed in several numerical examples in terms of computational time, accuracy in boundary conditions imposition, and strain energy density error. Due to the smoothness of CME basis functions, the numerical stability in explicit time integration is preserved for large time step. The challenging task of essential boundary condition (EBC) imposition in noninterpolating meshless methods (eg, moving least squares) is eliminated in CME due to the weak Kronecker-delta property. The EBCs are imposed directly, similar to the finite element method. CME is proven a valuable alternative to other meshless and element-based methods for large-scale elastodynamics in 3D. A naive implementation of the CME approximants in E3 is available to download at https://www.mountris.org/software/mlab/cme.Fil: Mountris, Konstantinos A.. Universidad de Zaragoza; EspañaFil: Bourantas, George C.. University of Western Australia; AustraliaFil: Millán, Raúl Daniel. Universidad Nacional de Cuyo. Facultad de Ciencias Aplicadas a la Industria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; ArgentinaFil: Joldes, Grand R.. University of Western Australia; AustraliaFil: Miller, Karol. Cardiff University; Reino Unido. University of Western Australia; AustraliaFil: Pueyo, Esther. Centro de Investigacion Biomedica En Red.; España. Universidad de Zaragoza; EspañaFil: Wittek, Adam. University of Western Australia; Australi

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 vibratomesliced. By histological analysis of the transmural biopsies, we showed that tissue architecture and cellular organization were preserved. Enzymatic and vital staining methods verifed viability. Optically mapped transmembrane potentials confrmed 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 β-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.Fil: Oliván Viguera, Aida. Universidad de Zaragoza; EspañaFil: Pérez Zabalza, María. Universidad de Zaragoza; EspañaFil: García Mendívil, Laura. Universidad de Zaragoza; EspañaFil: Mountris, Konstantinos A.. Universidad de Zaragoza; EspañaFil: Orós Rodrigo, Sofía. Universidad de Zaragoza; EspañaFil: Ramos Marquès, Estel. Universidad de Zaragoza; EspañaFil: Vallejo Gil, José María. University Hospital Miguel Servet; EspañaFil: Fresneda Roldán, Pedro Carlos. University Hospital Miguel Servet; EspañaFil: Fañanás Mastral, Javier. University Hospital Miguel Servet; EspañaFil: Vázquez Sancho, Manuel. University Hospital Miguel Servet; EspañaFil: Matamala Adell, Marta. University Hospital Miguel Servet; EspañaFil: Sorribas Berjón, Fernando. University Hospital Miguel Servet; EspañaFil: Bellido Morales, Javier André. University Hospital Miguel Servet; EspañaFil: Mancebón Sierra, Francisco Javier. University Hospital Miguel Servet; EspañaFil: Vaca Núñez, Alexánder Sebastián. University Hospital Miguel Servet; EspañaFil: Ballester Cuenca, Carlos. University Hospital Miguel Servet; EspañaFil: Marigil, Miguel Ángel. Hospital San Jorge; EspañaFil: Pastor, Cristina. Aragón Institute of Health Sciences; EspañaFil: Ordovás, Laura. Aragón Agency for Research and Development; España. Universidad de Zaragoza; EspañaFil: Köhler, Ralf. Aragón Institute of Health Sciences; España. Aragón Agency for Research and Development; EspañaFil: Diez, Emiliano Raúl. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Humana Normal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Pueyo, Esther. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina; España. Universidad de Zaragoza; Españ

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