Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.

The transverse tubular system of rabbit ventricular myocytes consists of cell membrane invaginations (t-tubules) that are essential for efficient cardiac excitation-contraction coupling. In this study, we investigate how t-tubule micro-anatomy, L-type Ca(2+) channel (LCC) clustering, and allosteric activation of Na(+)/Ca(2+) exchanger by L-type Ca(2+) current affects intracellular Ca(2+) dynamics. Our model includes a realistic 3D geometry of a single t-tubule and its surrounding half-sarcomeres for rabbit ventricular myocytes. The effects of spatially distributed membrane ion-transporters (LCC, Na(+)/Ca(2+) exchanger, sarcolemmal Ca(2+) pump, and sarcolemmal Ca(2+) leak), and stationary and mobile Ca(2+) buffers (troponin C, ATP, calmodulin, and Fluo-3) are also considered. We used a coupled reaction-diffusion system to describe the spatio-temporal concentration profiles of free and buffered intracellular Ca(2+). We obtained parameters from voltage-clamp protocols of L-type Ca(2+) current and line-scan recordings of Ca(2+) concentration profiles in rabbit cells, in which the sarcoplasmic reticulum is disabled. Our model results agree with experimental measurements of global Ca(2+) transient in myocytes loaded with 50 μM Fluo-3. We found that local Ca(2+) concentrations within the cytosol and sub-sarcolemma, as well as the local trigger fluxes of Ca(2+) crossing the cell membrane, are sensitive to details of t-tubule micro-structure and membrane Ca(2+) flux distribution. The model additionally predicts that local Ca(2+) trigger fluxes are at least threefold to eightfold higher than the whole-cell Ca(2+) trigger flux. We found also that the activation of allosteric Ca(2+)-binding sites on the Na(+)/Ca(2+) exchanger could provide a mechanism for regulating global and local Ca(2+) trigger fluxes in vivo. Our studies indicate that improved structural and functional models could improve our understanding of the contributions of L-type and Na(+)/Ca(2+) exchanger fluxes to intracellular Ca(2+) dynamics

Molecular and Subcellular-Scale Modeling of Nucleotide Diffusion in the Cardiac Myofilament Lattice

AbstractContractile function of cardiac cells is driven by the sliding displacement of myofilaments powered by the cycling myosin crossbridges. Critical to this process is the availability of ATP, which myosin hydrolyzes during the cross-bridge cycle. The diffusion of adenine nucleotides through the myofilament lattice has been shown to be anisotropic, with slower radial diffusion perpendicular to the filament axis relative to parallel, and is attributed to the periodic hexagonal arrangement of the thin (actin) and thick (myosin) filaments. We investigated whether atomistic-resolution details of myofilament proteins can refine coarse-grain estimates of diffusional anisotropy for adenine nucleotides in the cardiac myofibril, using homogenization theory and atomistic thin filament models from the Protein Data Bank. Our results demonstrate considerable anisotropy in ATP and ADP diffusion constants that is consistent with experimental measurements and dependent on lattice spacing and myofilament overlap. A reaction-diffusion model of the half-sarcomere further suggests that diffusional anisotropy may lead to modest adenine nucleotide gradients in the myoplasm under physiological conditions

cbcbeat

<p>cbcbeat is a collection of Python-based solvers for cardiac electrophysiology models. cbcbeat offers basic and optimized solvers for the bidomain and monodomain equations coupled with cardiac cell models. cbcbeat is based on the FEniCS Project and dolfin-adjoint.<br>  </p

Supplementary code for "Automated adjoints of coupled PDE-ODE systems"

<p>This file contains supplementary code for the paper "Automated<br> adjoints of coupled PDE-ODE systems" by P. E. Farrell, J. E. Hake,<br> S. W. Funke and M. E. Rognes.</p> <p>This research is supported by a Center of Excellence grant awarded to<br> the Center for Biomedical Computing at Simula Research Laboratory from<br> the Research Council of Norway, by EPSRC grants EP/K030930/1 and<br> EP/M011151/1, a NOTUR grant NN9316K and the generous support of Sir<br> Michael Moritz and Harriet Heyman.</p> <p>The code relies on a working installation of the FEniCS and<br> dolfin-adjoint softwares and the cbcbeat module, all available in the<br> public domain:<br> - FEniCS: www.fenicsproject.org, version 2017.1 (or later perhaps)<br> - dolfin-adjoint: www.dolfin-adjoint.org, version compatible with the above<br> - cbcbeat: www.bitbucket.org/meg/cbcbeat, version compatible with the abov</p

Control of Ca2+ Release by Action Potential Configuration in Normal and Failing Murine Cardiomyocytes

Cardiomyocytes from failing hearts exhibit spatially nonuniform or dyssynchronous sarcoplasmic reticulum (SR) Ca2+ release. We investigated the contribution of action potential (AP) prolongation in mice with congestive heart failure (CHF) after myocardial infarction. AP recordings from CHF and control myocytes were included in a computational model of the dyad, which predicted more dyssynchronous ryanodine receptor opening during stimulation with the CHF AP. This prediction was confirmed in cardiomyocyte experiments, when cells were alternately stimulated by control and CHF AP voltage-clamp waveforms. However, when a train of like APs was used as the voltage stimulus, the control and CHF AP produced a similar Ca2+ release pattern. In this steady-state condition, greater integrated Ca2+ entry during the CHF AP lead to increased SR Ca2+ content. A resulting increase in ryanodine receptor sensitivity synchronized SR Ca2+ release in the mathematical model, thus offsetting the desynchronizing effects of reduced driving force for Ca2+ entry. A modest nondyssynchronous prolongation of Ca2+ release was nevertheless observed during the steady-state CHF AP, which contributed to increased time-to-peak measurements for Ca2+ transients in failing cells. Thus, dyssynchronous Ca2+ release in failing mouse myocytes does not result from electrical remodeling, but rather other alterations such as T-tubule reorganization

Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice.

Contractile function of cardiac cells is driven by the sliding displacement of myofilaments powered by the cycling myosin crossbridges. Critical to this process is the availability of ATP, which myosin hydrolyzes during the cross-bridge cycle. The diffusion of adenine nucleotides through the myofilament lattice has been shown to be anisotropic, with slower radial diffusion perpendicular to the filament axis relative to parallel, and is attributed to the periodic hexagonal arrangement of the thin (actin) and thick (myosin) filaments. We investigated whether atomistic-resolution details of myofilament proteins can refine coarse-grain estimates of diffusional anisotropy for adenine nucleotides in the cardiac myofibril, using homogenization theory and atomistic thin filament models from the Protein Data Bank. Our results demonstrate considerable anisotropy in ATP and ADP diffusion constants that is consistent with experimental measurements and dependent on lattice spacing and myofilament overlap. A reaction-diffusion model of the half-sarcomere further suggests that diffusional anisotropy may lead to modest adenine nucleotide gradients in the myoplasm under physiological conditions

Supporting computer code for 'The FEniCS Project Version 1.5' (release notes)

Supporting computer code for the release notes document for FEniCS 1.5

The FEniCS Project Version 1.5

The FEniCS Project is a collaborative project for the development ofinnovative concepts and tools for automated scientific computing, with a particular focus on the solution of differential equations byfinite element methods. The FEniCS Projects software consists of a collection of interoperable software components, including DOLFIN,FFC, FIAT, Instant, UFC, UFL, and mshr. This note describes the newfeatures and changes introduced in the release of FEniCSversion 1.5