Anisotropic shortening in the wavelength of electrical waves promotes onset of electrical turbulence in cardiac tissue: An in silico study.

Several pathological conditions introduce spatial variations in the electrical properties of cardiac tissue. These variations occur as localized or distributed gradients in ion-channel functionality over extended tissue media. Electrical waves, propagating through such affected tissue, demonstrate distortions, depending on the nature of the ionic gradient in the diseased substrate. If the degree of distortion is large, reentrant activity may develop, in the form of rotating spiral (2d) and scroll (3d) waves of electrical activity. These reentrant waves are associated with the occurrence of lethal cardiac rhythm disorders, known as arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), which are believed to be common precursors of sudden cardiac arrest. By using state-of-the-art mathematical models for generic, and ionically-realistic (human) cardiac tissue, we study the detrimental effects of these ionic gradients on electrical wave propagation. We propose a possible mechanism for the development of instabilities in reentrant wave patterns, in the presence of ionic gradients in cardiac tissue, which may explain how one type of arrhythmia (VT) can degenerate into another (VF). Our proposed mechanism entails anisotropic reduction in the wavelength of the excitation waves because of anisotropic variation in its electrical properties, in particular the action potential duration (APD). We find that the variation in the APD, which we induce by varying ion-channel conductances, imposes a spatial variation in the spiral- or scroll-wave frequency ω. Such gradients in ω induce anisotropic shortening of wavelength of the spiral or scroll arms and eventually leads to instabilitites.

Reentry via high-frequency pacing in a mathematical model for human-ventricular cardiac tissue with a localized fibrotic region.

Localized heterogeneities, caused by the regional proliferation of fibroblasts, occur in mammalian hearts because of diseases like myocardial infarction. Such fibroblast clumps can become sources of pathological reentrant activities, e.g., spiral or scroll waves of electrical activation in cardiac tissue. The occurrence of reentry in cardiac tissue with heterogeneities, such as fibroblast clumps, can depend on the frequency at which the medium is paced. Therefore, it is important to study the reentry-initiating potential of such fibroblast clumps at different frequencies of pacing. We investigate the arrhythmogenic effects of fibroblast clumps at high- and low-frequency pacing. We find that reentrant waves are induced in the medium more prominently at high-frequency pacing than with low-frequency pacing. We also study the other factors that affect the potential of fibroblast clumps to induce reentry in cardiac tissue. In particular, we show that the ability of a fibroblast clump to induce reentry depends on the size of the clump, the distribution and percentage of fibroblasts in the clump, and the excitability of the medium. We study the process of reentry in two-dimensional and a three-dimensional mathematical models for cardiac tissue.

A Computational Study of the Factors Influencing the PVC-Triggering Ability of a Cluster of Early Afterdepolarization-Capable Myocytes.

Premature ventricular complexes (PVCs), which are abnormal impulse propagations in cardiac tissue, can develop because of various reasons including early afterdepolarizations (EADs). We show how a cluster of EAD-generating cells (EAD clump) can lead to PVCs in a model of cardiac tissue, and also investigate the factors that assist such clumps in triggering PVCs. In particular, we study, through computer simulations, the effects of the following factors on the PVC-triggering ability of an EAD clump: (1) the repolarization reserve (RR) of the EAD cells; (2) the size of the EAD clump; (3) the coupling strength between the EAD cells in the clump; and (4) the presence of fibroblasts in the EAD clump. We find that, although a low value of RR is necessary to generate EADs and hence PVCs, a very low value of RR leads to low-amplitude EAD oscillations that decay with time and do not lead to PVCs. We demonstrate that a certain threshold size of the EAD clump, or a reduction in the coupling strength between the EAD cells, in the clump, is required to trigger PVCs. We illustrate how randomly distributed inexcitable obstacles, which we use to model collagen deposits, affect PVC-triggering by an EAD clump. We show that the gap-junctional coupling of fibroblasts with myocytes can either assist or impede the PVC-triggering ability of an EAD clump, depending on the resting membrane potential of the fibroblasts and the coupling strength between the myocyte and fibroblasts. We also find that the triggering of PVCs by an EAD clump depends sensitively on factors like the pacing cycle length and the distribution pattern of the fibroblasts.

A Comparative Study of Early Afterdepolarization-Mediated Fibrillation in Two Mathematical Models for Human Ventricular Cells.

Early afterdepolarizations (EADs), which are abnormal oscillations of the membrane potential at the plateau phase of an action potential, are implicated in the development of cardiac arrhythmias like Torsade de Pointes. We carry out extensive numerical simulations of the TP06 and ORd mathematical models for human ventricular cells with EADs. We investigate the different regimes in both these models, namely, the parameter regimes where they exhibit (1) a normal action potential (AP) with no EADs, (2) an AP with EADs, and (3) an AP with EADs that does not go back to the resting potential. We also study the dependence of EADs on the rate of at which we pace a cell, with the specific goal of elucidating EADs that are induced by slow or fast rate pacing. In our simulations in two- and three-dimensional domains, in the presence of EADs, we find the following wave types: (A) waves driven by the fast sodium current and the L-type calcium current (Na-Ca-mediated waves); (B) waves driven only by the L-type calcium current (Ca-mediated waves); (C) phase waves, which are pseudo-travelling waves. Furthermore, we compare the wave patterns of the various wave-types (Na-Ca-mediated, Ca-mediated, and phase waves) in both these models. We find that the two models produce qualitatively similar results in terms of exhibiting Na-Ca-mediated wave patterns that are more chaotic than those for the Ca-mediated and phase waves. However, there are quantitative differences in the wave patterns of each wave type. The Na-Ca-mediated waves in the ORd model show short-lived spirals but the TP06 model does not. The TP06 model supports more Ca-mediated spirals than those in the ORd model, and the TP06 model exhibits more phase-wave patterns than does the ORd model.