Theory and experiments of spiral unpinning in the Belousov-Zhabotinsky reaction using a circularly polarized electric field.

We present the first experimental study of unpinning an excitation wave using a circularly polarized electric field. The experiments are conducted using the excitable chemical medium, the Belousov-Zhabotinsky (BZ) reaction, which is modeled with the Oregenator model. The excitation wave in the chemical medium is charged so that it can directly interact with the electric field. This is a unique feature of the chemical excitation wave. The mechanism of wave unpinning in the BZ reaction with a circularly polarized electric field is investigated by varying the pacing ratio, the initial phase of the wave, and field strength. The chemical wave in the BZ reaction unpins when the electric force opposite the direction of the spiral is equal to or above a threshold. We developed an analytical relation of the unpinning phase with the initial phase, the pacing ratio, and the field strength. This is then verified in experiments and simulations.

Theory of unpinning of spiral waves using circularly polarized electric fields in mathematical models of excitable media.

Spiral waves of excitation are common in many physical, chemical, and biological systems. In physiological systems like the heart, such waves can lead to cardiac arrhythmias and need to be eliminated. Spiral waves anchor to heterogeneities in the excitable medium, and to eliminate them they need to be unpinned first. Several groups focused on developing strategies to unpin such pinned waves using electric shocks, pulsed electric fields, and recently, circularly polarized electric fields (CPEF). It was shown that in many situations, CPEF is more efficient at unpinning the wave compared to other existing methods. Here, we study how the circularly polarized field acts on the pinned spiral waves and unpins it. We show that the termination always happens within the first rotation of the electric field. For a given obstacle size, there exists a threshold time period of the CPEF below which the spiral can always be terminated. Our analytical formulation accurately predicts this threshold and explains the absence of the traditional unpinning window with the CPEF. We hope our theoretical work will stimulate further experimental studies about CPEF and low energy methods to eliminate spiral waves.

Spiral wave unpinning facilitated by wave emitting sites in cardiac monolayers.

Rotating spiral waves of electrical activity in the heart can anchor to unexcitable tissue (an obstacle) and become stable pinned waves. A pinned rotating wave can be unpinned either by a local electrical stimulus applied close to the spiral core, or by an electric field pulse that excites the core of a pinned wave independently of its localization. The wave will be unpinned only when the pulse is delivered inside a narrow time interval called the unpinning window (UW) of the spiral. In experiments with cardiac monolayers, we found that other obstacles situated near the pinning centre of the spiral can facilitate unpinning. In numerical simulations, we found increasing or decreasing of the UW depending on the location, orientation and distance between the pinning centre and an obstacle. Our study indicates that multiple obstacles could contribute to unpinning in experiments with intact hearts.

Mechanisms of vortices termination in the cardiac muscle.

We propose a solution to a long-standing problem: how to terminate multiple vortices in the heart, when the locations of their cores and their critical time windows are unknown. We scan the phases of all pinned vortices in parallel with electric field pulses (E-pulses). We specify a condition on pacing parameters that guarantees termination of one vortex. For more than one vortex with significantly different frequencies, the success of scanning depends on chance, and all vortices are terminated with a success rate of less than one. We found that a similar mechanism terminates also a free (not pinned) vortex. A series of about 500 experiments with termination of ventricular fibrillation by E-pulses in pig isolated hearts is evidence that pinned vortices, hidden from direct observation, are significant in fibrillation. These results form a physical basis needed for the creation of new effective low energy defibrillation methods based on the termination of vortices underlying fibrillation.

Quantifying spatiotemporal complexity of cardiac dynamics using ordinal patterns.

Analyzing the dynamics of complex excitation wave patterns in cardiac tissue plays a key role for understanding the origin of life-threatening arrhythmias and for devising novel approaches to control them. The quantification of spatiotemporal complexity, however, remains a challenging task. This holds in particular for the analysis of data from fluorescence imaging (optical mapping), which allows for the measurement of membrane potential and intracellular calcium at high spatial and temporal resolution. Hitherto methods, like dominant frequency maps and the analysis of phase singularities, address important aspects of cardiac dynamics, but they consider very specific properties of excitable media, only. This article focuses on the benchmark of spatial complexity measures over time in the context of cardiac cell cultures. Standard Shannon Entropy and Spatial Permutation Entropy, an adaption of [1], have been implemented and applied to optical mapping data from embryonic chicken cell culture experiments. We introduce spatial separation of samples when generating ordinal patterns and show its importance for Spatial Permutation Entropy. Results suggest that Spatial Permutation Entropies provide a robust and interpretable measure for detecting qualitative changes in the dynamics of this excitable medium.

Spiral-wave dynamics in a mathematical model of human ventricular tissue with myocytes and fibroblasts.

Cardiac fibroblasts, when coupled functionally with myocytes, can modulate the electrophysiological properties of cardiac tissue. We present systematic numerical studies of such modulation of electrophysiological properties in mathematical models for (a) single myocyte-fibroblast (MF) units and (b) two-dimensional (2D) arrays of such units; our models build on earlier ones and allow for zero-, one-, and two-sided MF couplings. Our studies of MF units elucidate the dependence of the action-potential (AP) morphology on parameters such as [Formula: see text], the fibroblast resting-membrane potential, the fibroblast conductance [Formula: see text], and the MF gap-junctional coupling [Formula: see text]. Furthermore, we find that our MF composite can show autorhythmic and oscillatory behaviors in addition to an excitable response. Our 2D studies use (a) both homogeneous and inhomogeneous distributions of fibroblasts, (b) various ranges for parameters such as [Formula: see text], and [Formula: see text], and (c) intercellular couplings that can be zero-sided, one-sided, and two-sided connections of fibroblasts with myocytes. We show, in particular, that the plane-wave conduction velocity [Formula: see text] decreases as a function of [Formula: see text], for zero-sided and one-sided couplings; however, for two-sided coupling, [Formula: see text] decreases initially and then increases as a function of [Formula: see text], and, eventually, we observe that conduction failure occurs for low values of [Formula: see text]. In our homogeneous studies, we find that the rotation speed and stability of a spiral wave can be controlled either by controlling [Formula: see text] or [Formula: see text]. Our studies with fibroblast inhomogeneities show that a spiral wave can get anchored to a local fibroblast inhomogeneity. We also study the efficacy of a low-amplitude control scheme, which has been suggested for the control of spiral-wave turbulence in mathematical models for cardiac tissue, in our MF model both with and without heterogeneities.

Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture.

Pacemaker interactions can lead to complex wave dynamics seen in certain types of cardiac arrhythmias. We use experimental and mathematical models of pacemakers in heterogeneous excitable media to investigate how pacemaker interactions can be a mechanism for wave break and reentrant wave dynamics. Embryonic chick ventricular cells are cultured in vitro so as to create a dominant central pacemaker site that entrains other pacemakers in the medium. Exposure of those cultures to a potassium channel blocker, E-4031, leads to emergence of peripheral pacemakers that compete with each other and with the central pacemaker. Waves emitted by faster pacemakers break up over the slower pacemaker to form reentrant waves. Similar dynamics are observed in a modified FitzHugh-Nagumo model of heterogeneous excitable media with two distinct sites of pacemaking. These findings elucidate a mechanism of pacemaker-induced reentry in excitable media.

Scaling properties of conduction velocity in heterogeneous excitable media.

Waves of excitation through excitable media, such as cardiac tissue, can propagate as plane waves or break up to form reentrant spiral waves. In diseased hearts reentrant waves can be associated with fatal cardiac arrhythmias. In this paper we investigate the conditions that lead to wave break, reentry, and propagation failure in mathematical models of heterogeneous excitable media. Two types of heterogeneities are considered: sinks are regions in space in which the voltage is fixed at its rest value, and breaks are nonconducting regions with no-flux boundary conditions. We find that randomly distributed heterogeneities in the medium have a decremental effect on the velocity, and above a critical density of such heterogeneities the conduction fails. Using numerical and analytical methods we derive the general relationship among the conduction velocity, density of heterogeneities, diffusion coefficient, and the rise time of the excitation in both two and three dimensions. This work helps us understand the factors leading to reduced propagation velocity and the formation of spiral waves in heterogeneous excitable media.

Spiral-wave turbulence and its control in the presence of inhomogeneities in four mathematical models of cardiac tissue.

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control schemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation.

Spiral-wave dynamics depend sensitively on inhomogeneities in mathematical models of ventricular tissue.

Every sixth death in industrialized countries occurs because of cardiac arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF). There is growing consensus that VT is associated with an unbroken spiral wave of electrical activation on cardiac tissue but VF with broken waves, spiral turbulence, spatiotemporal chaos and rapid, irregular activation. Thus spiral-wave activity in cardiac tissue has been studied extensively. Nevertheless, many aspects of such spiral dynamics remain elusive because of the intrinsically high-dimensional nature of the cardiac-dynamical system. In particular, the role of tissue heterogeneities in the stability of cardiac spiral waves is still being investigated. Experiments with conduction inhomogeneities in cardiac tissue yield a variety of results: some suggest that conduction inhomogeneities can eliminate VF partially or completely, leading to VT or quiescence, but others show that VF is unaffected by obstacles. We propose theoretically that this variety of results is a natural manifestation of a complex, fractal-like boundary that must separate the basins of the attractors associated, respectively, with spiral breakup and single spiral wave. We substantiate this with extensive numerical studies of Panfilov and Luo-Rudy I models, where we show that the suppression of spiral breakup depends sensitively on the position, size, and nature of the inhomogeneity.