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Aims Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca2+ cycling remain elusive. Methods and results Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca2+ leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca2+‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca2 leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca2+ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics including SERCA activity (kSERCA) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca2+ leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end‐stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3). Conclusion This study demonstrates that neprilysin inhibitor Sac directly improves Ca2+ homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca2+ leak without acutely affecting systolic Ca2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial.

A meshless method based on the local Petrov-Galerkin approach is proposed to solve initial-boundary-value crack problems in decagonal quasicrystals. These quasicrystals belong to the class of two-dimensional (2-d) quasicrystals, where the atomic arrangement is quasiperiodic in a plane, and periodic in the perpendicular direction. The ten-fold symmetries occur in these quasicrystals. The 2-d crack problem is described by a coupling of phonon and phason displacements. Both stationary governing equations and dynamic equations represented by the Bak’s model with oscillations for phasons are analyzed here. Nodal points are spread on the analyzed domain, and each node is surrounded by a small circle for simplicity. The spatial variation of phonon and phason displacements is approximated by the moving least-squares scheme. After performing the spatial integrations, one obtains a system of ordinary differential equations for certain nodal unknowns. That system is solved numerically by the Houbolt finite-difference scheme as a time-stepping method.

In this paper, the symmetric Galerkin boundary element method (SGBEM) will be developed and applied for boundary value problems with layered and fiber reinforced piezoelectric representative volume elements (RVE) and real macroscopic structures. Mechanical and electric loadings are considered to determine the effective material properties. For this purpose, the resulting boundary value problem is formulated as boundary integral equations (BIEs). The Galerkin method is applied for the spatial discretization of the boundary to solve the BIEs numerically. The required surface derivatives of the generalized displacements are computed directly with a boundary integral equation. Numerical examples will be presented and discussed to show the efficiency of the present SGBEM and the influence of the fiber variation on the effective material properties.

Transient elastodynamic crack analysis in two-dimensional (2D), layered, anisotropic and linear elastic solids is presented in this paper. A time-domain boundary element method (BEM) in conjunction with a multi-domain technique is developed for this purpose. Time-domain elastodynamic fundamental solutions for homogenous, anisotropic and linear elastic solids are applied in the present time-domain BEM. The spatial discretization of the boundary integral equations is performed by a Galerkin-method, while a collocation method is adopted for the temporal discretization of the arising convolution integrals. An explicit time-stepping scheme is developed to compute the unknown boundary data and the crack-opening-displacements (CODs). To show the effects of the crack configuration, the material anisotropy, the layer combination and the dynamic loading on the dynamic stress intensity factors and the scattered elastic wave fields, several numerical examples are presented and discussed.

The finite element method (FEM) is developed for coupled thermoelastic crack problems if material properties are continuously varying. The weak form is utilized to derive the FEM equations. In conventional fracture theories the state of stress and strain at the crack tip vicinity is characterized by a single fracture parameter, namely the stress intensity factor or its equivalent, J-integral. In the present paper it is considered also the second fracture parameter called as the T-stress. For evaluation of both fracture parameters the quarter-point crack tip element is developed. Simple formulas for both fracture parameters are derived comparing the variation of displacements in the quarter-point element with asymptotic expression of displacement at the crack tip vicinity. The leading terms of the asymptotic expansions of fields in the crack-tip vicinity in a functionally graded material (FGM) are the same as in a homogeneous one with material coefficients taken at the crack tip.

A meshless method based on the local Petrov-Galerkin approach is proposed, to solve static and dynamic problems of two-layered magnetoelectroelastic composites with specific properties. One layer has pure piezoelectric properties and the second one is a pure piezomagnetic material. It is shown that the electric potential in the piezoelectric layer is induced by the magnetic potential in the piezomagnetic layer. The magnetoelectric effect is dependent on the ratio of the layer thicknesses. Functionally graded material properties of the piezoelectric layer and homogeneous properties of the piezomagnetic layer are considered too. The magnetoelectric composites are analyzed under a pure magnetic or combined magneto-mechanical load. Various boundary conditions and geometric parameters are considered to analyze their influence on the value of the electromagnetic parameter.

Piezoelectric materials have wide range engineering applications in smart structures and devices. They have usually anisotropic properties. Except this complication electric and mechanical fields are coupled each other and the governing equations are much more complex than that in the classical elasticity. Thus, efficient computational methods to solve the boundary or the initial-boundary value problems for piezoelectric solids are required. In this paper, the Meshless local Petrov-Galerkin (MLPG) method with a Heaviside step function as the test functions is applied to solve two-dimensional (2-D) piezoelectric problems. The mechanical fields are described by the equations of motion with an inertial term. To eliminate the time-dependence in the governing partial differential equations the Laplace-transform technique is applied to the governing equations, which are satisfied in the Laplace-transformed domain in a weak-form on small subdomains. Nodal points are spread on the analyzed domain and each node is surrounded by a small circle for simplicity. The spatial variation of the displacements and the electric potential are approximated by the Moving Least-Squares (MLS) scheme. After performing the spatial integrations, one obtains a system of linear algebraic equations for unknown nodal values. The boundary conditions on the global boundary are satisfied by the collocation of the MLS-approximation expressions for the displacements and the electric potential at the boundary nodal points. The Stehfest's inversion method is applied to obtain the final time-dependent solutions.

A contour integral method is developed for the computation of stress intensity, electric and magnetic intensity factors for cracks in continuously nonhomogeneous magnetoelectroelastic solids under a transient dynamic load. It is shown that the asymptotic fields in the crack-tip vicinity in a continuously nonhomogeneos medium are the same as in a homogeneous one. A meshless method based on the local Petrov-Galerkin approach is applied for the computation of the physical fields occurring in the contour integral expressions of intensity factors. A unit step function is used as the test functions in the local weak-form. This leads to local integral equations (LIEs) involving only contour-integrals on the surfaces of subdomains. The moving least-squares (MLS) method is adopted for approximating the physical quantities in the LIEs. The accuracy of the present method for computing the stress intensity factors (SIF), electrical displacement intensity factors (EDIF) and magnetic induction intensity factors (MIIF) are discussed by comparison with numerical solutions for homogeneous materials.

A meshless method based on the local Petrov-Galerkin approach is proposed, to solve the interface crack problem between two dissimilar anisotropic elastic solids. Both stationary and transient mechanical and thermal loads are considered for two-dimensional (2-D) problems in this paper. A Heaviside step function as the test functions is applied in the weak-form to derive local integral equations. Nodal points are spread on the analyzed domain, and each node is surrounded by a small circle for simplicity. The spatial variations of the displacements and temperature are approximated by the Moving Least-Squares (MLS) scheme. After performing the spatial integrations, one obtains a system of ordinary differential equations for certain nodal unknowns. The backward finite difference method is applied for the approximation of the diffusive term in the heat conduction equation. Then, the system of the ordinary differential equations of the second order resulting from the equations of motion is solved by the Houbolt finite-difference scheme as a time-stepping method.

In this article a hypersingular boundary element method (BEM) for bending of thin anisotropic plates is presented. A new complex variable fundamental solution is implemented in the algorithm. For spatial discretization a collocation method with discontinuous quadratic elements is adopted. The domain integrals arising from the transversely applied load are transformed analytically into boundary integrals by means of the radial integration technique. The considered numerical examples prove that the novel BEM formulation presented in this study is much more efficient than previous formulations developed for the analysis of this kind of problems.