Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle.

Background: Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca(2+) current (ICaL) reactivation or sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange. In large mammals the positive action potential plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K(+) currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit ICaL reactivation.

Computational modeling of subcellular transport and signaling.

Numerous signaling processes in the cell are controlled in microdomains that are defined by cellular structures ranging from nm to μm in size. Recent improvements in microscopy enable the resolution and reconstruction of these micro domains, while new computational methods provide the means to elucidate their functional roles. Collectively these tools allow for a biophysical understanding of the cellular environment and its pathological progression in disease.

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.

A three-dimensional finite element model of human atrial anatomy: new methods for cubic Hermite meshes with extraordinary vertices.

High-order cubic Hermite finite elements have been valuable in modeling cardiac geometry, fiber orientations, biomechanics, and electrophysiology, but their use in solving three-dimensional problems has been limited to ventricular models with simple topologies. Here, we utilized a subdivision surface scheme and derived a generalization of the "local-to-global" derivative mapping scheme of cubic Hermite finite elements to construct bicubic and tricubic Hermite models of the human atria with extraordinary vertices from computed tomography images of a patient with atrial fibrillation. To an accuracy of 0.

Slow Ca²⁺ sparks de-synchronize Ca²⁺ release in failing cardiomyocytes: evidence for altered configuration of Ca²⁺ release units?

In heart failure, cardiomyocytes exhibit slowing of the rising phase of the Ca(2+) transient which contributes to the impaired contractility observed in this condition. We investigated whether alterations in ryanodine receptor function promote slowing of Ca(2+) release in a murine model of congestive heart failure (CHF). Myocardial infarction was induced by left coronary artery ligation.

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.

uPy: a ubiquitous CG Python API with biological-modeling applications.

The uPy Python extension module provides a uniform abstraction of the APIs of several 3D computer graphics programs (called hosts), including Blender, Maya, Cinema 4D, and DejaVu. A plug-in written with uPy can run in all uPy-supported hosts. Using uPy, researchers have created complex plug-ins for molecular and cellular modeling and visualization.

Slow Calcium-Depolarization-Calcium waves may initiate fast local depolarization waves in ventricular tissue.

Intercellular calcium waves in cardiac myocytes are a well-recognized, if incompletely understood, phenomenon. In a variety of preparations, investigators have reported multi-cellular calcium waves or triggered propagated contractions, but the mechanisms of propagation and pathological importance of these events remain unclear. Here, we review existing experimental data and present a computational approach to investigate the mechanisms of multi-cellular calcium wave propagation.

Modelling cardiac calcium sparks in a three-dimensional reconstruction of a calcium release unit.

Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca(2+) release unit (CRU) is the fundamental event of cardiac excitation–contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca(2+) leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the spark is determined by the local CRU geometry, as well as the localization and density of Ca(2+) handling proteins. We have created a detailed computational model of a CRU, and developed novel tools to generate the computational geometry from electron tomographic images.

Instabilities of the resting state in a mathematical model of calcium handling in cardiac myocytes.

We analyze a recently published model of calcium handling in cardiac myocytes in order to find conditions for the presence of instabilities in the resting state of the model. Such instabilities can create calcium waves which in turn may be able to initiate cardiac arrhythmias. The model was developed by Swietach, Spitzer and Vaughan-Jones in order to study the effect, on calcium waves, of varying ryanodine receptor (RyR)-permeability, sarco/endoplasmic reticulum calcium ATPase (SERCA) and calcium diffusion.

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) Ca(2+) 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.

Stochastic binding of Ca2+ ions in the dyadic cleft; continuous versus random walk description of diffusion.

Ca(2+) signaling in the dyadic cleft in ventricular myocytes is fundamentally discrete and stochastic. We study the stochastic binding of single Ca(2+) ions to receptors in the cleft using two different models of diffusion: a stochastic and discrete Random Walk (RW) model, and a deterministic continuous model. We investigate whether the latter model, together with a stochastic receptor model, can reproduce binding events registered in fully stochastic RW simulations.