Efficient termination of cardiac arrhythmias using optogenetic resonant feedback pacing.

Malignant cardiac tachyarrhythmias are associated with complex spatiotemporal excitation of the heart. The termination of these life-threatening arrhythmias requires high-energy electrical shocks that have significant side effects, including tissue damage, excruciating pain, and worsening prognosis. This significant medical need has motivated the search for alternative approaches that mitigate the side effects, based on a comprehensive understanding of the nonlinear dynamics of the heart. Cardiac optogenetics enables the manipulation of cellular function using light, enhancing our understanding of nonlinear cardiac function and control. Here, we investigate the efficacy of optically resonant feedback pacing (ORFP) to terminate ventricular tachyarrhythmias using numerical simulations and experiments in transgenic Langendorff-perfused mouse hearts. We show that ORFP outperforms the termination efficacy of the optical single-pulse (OSP) approach. When using ORFP, the total energy required for arrhythmia termination, i.e., the energy summed over all pulses in the sequence, is 1 mJ. With a success rate of 50%, the energy per pulse is 40 times lower than with OSP with a pulse duration of 10 ms. We demonstrate that even at light intensities below the excitation threshold, ORFP enables the termination of arrhythmias by spatiotemporal modulation of excitability inducing spiral wave drift.

Response function framework for the dynamics of meandering or large-core spiral waves and modulated traveling waves.

In many oscillatory or excitable systems, dynamical patterns emerge which are stationary or periodic in a moving frame of reference. Examples include traveling waves or spiral waves in chemical systems or cardiac tissue. We present a unified theoretical framework for the drift of such patterns under small external perturbations, in terms of overlap integrals between the perturbation and the adjoint critical eigenfunctions of the linearized operator (i.e., response functions). For spiral waves, the finite radius of the spiral tip trajectory and spiral wave meander are taken into account. Different coordinate systems can be chosen, depending on whether one wants to predict the motion of the spiral-wave tip, the time-averaged tip path, or the center of the meander flower. The framework is applied to analyze the drift of a meandering spiral wave in a constant external field in different regimes.

Fast-slow asymptotic for semi-analytical ignition criteria in FitzHugh-Nagumo system.

We study the problem of initiation of excitation waves in the FitzHugh-Nagumo model. Our approach follows earlier works and is based on the idea of approximating the boundary between basins of attraction of propagating waves and of the resting state as the stable manifold of a critical solution. Here, we obtain analytical expressions for the essential ingredients of the theory by singular perturbation using two small parameters, the separation of time scales of the activator and inhibitor and the threshold in the activator's kinetics. This results in a closed analytical expression for the strength-duration curve.

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.

Filament Tension and Phase Locking of Meandering Scroll Waves.

Meandering spiral waves are often observed in excitable media such as the Belousov-Zhabotinsky reaction and cardiac tissue. We derive a theory for drift dynamics of meandering rotors in general reaction-diffusion systems and apply it to two types of external disturbances: an external field and curvature-induced drift in three dimensions. We find two distinct regimes: with small filament curvature, meandering scroll waves exhibit filament tension, whose sign determines the stability and drift direction. In the regimes of strong external fields or meandering motion close to resonance, however, phase locking of the meander pattern is predicted and observed.

Quasisolitons in self-diffusive excitable systems, or Why asymmetric diffusivity obeys the Second Law.

Solitons, defined as nonlinear waves which can reflect from boundaries or transmit through each other, are found in conservative, fully integrable systems. Similar phenomena, dubbed quasi-solitons, have been observed also in dissipative, "excitable" systems, either at finely tuned parameters (near a bifurcation) or in systems with cross-diffusion. Here we demonstrate that quasi-solitons can be robustly observed in excitable systems with excitable kinetics and with self-diffusion only. This includes quasi-solitons of fixed shape (like KdV solitons) or envelope quasi-solitons (like NLS solitons). This can happen in systems with more than two components, and can be explained by effective cross-diffusion, which emerges via adiabatic elimination of a fast but diffusing component. We describe here a reduction procedure can be used for the search of complicated wave regimes in multi-component, stiff systems by studying simplified, soft systems.

Semianalytical approach to criteria for ignition of excitation waves.

We consider the problem of ignition of propagating waves in one-dimensional bistable or excitable systems by an instantaneous spatially extended stimulus. Earlier we proposed a method [I. Idris and V. N. Biktashev, Phys. Rev. Lett. 101, 244101 (2008)] for analytical description of the threshold conditions based on an approximation of the (center-)stable manifold of a certain critical solution. Here we generalize this method to address a wider class of excitable systems, such as multicomponent reaction-diffusion systems and systems with non-self-adjoint linearized operators, including systems with moving critical fronts and pulses. We also explore an extension of this method from a linear to a quadratic approximation of the (center-)stable manifold, resulting in some cases in a significant increase in accuracy. The applicability of the approach is demonstrated on five test problems ranging from archetypal examples such as the Zeldovich-Frank-Kamenetsky equation to near realistic examples such as the Beeler-Reuter model of cardiac excitation. While the method is analytical in nature, it is recognized that essential ingredients of the theory can be calculated explicitly only in exceptional cases, so we also describe methods suitable for calculating these ingredients numerically.

Drift of scroll waves in thin layers caused by thickness features: asymptotic theory and numerical simulations.

A scroll wave in a very thin layer of excitable medium is similar to a spiral wave, but its behavior is affected by the layer geometry. We identify the effect of sharp variations of the layer thickness, which is separate from filament tension and curvature-induced drifts described earlier. We outline a two-step asymptotic theory describing this effect, including asymptotics in the layer thickness and calculation of the drift of so-perturbed spiral waves using response functions. As specific examples, we consider drift of scrolls along thickness steps, ridges, ditches, and disk-shaped thickness variations. Asymptotic predictions agree with numerical simulations.

Classification of wave regimes in excitable systems with linear cross diffusion.

We consider principal properties of various wave regimes in two selected excitable systems with linear cross diffusion in one spatial dimension observed at different parameter values. This includes fixed-shape propagating waves, envelope waves, multienvelope waves, and intermediate regimes appearing as waves propagating at a fixed shape most of the time but undergoing restructuring from time to time. Depending on parameters, most of these regimes can be with and without the "quasisoliton" property of reflection of boundaries and penetration through each other. We also present some examples of the behavior of envelope quasisolitons in two spatial dimensions.

Envelope quasisolitons in dissipative systems with cross-diffusion.

We consider two-component nonlinear dissipative spatially extended systems of reaction-cross-diffusion type. Previously, such systems were shown to support "quasisoliton" pulses, which have a fixed stable structure but can reflect from boundaries and penetrate each other. Herein we demonstrate a different type of quasisolitons, with a phenomenology resembling that of the envelope solitons in the nonlinear Schrödinger equation: spatiotemporal oscillations with a smooth envelope, with the velocity of the oscillations different from the velocity of the envelope.

Asymptotics of conduction velocity restitution in models of electrical excitation in the heart.

We extend a non-Tikhonov asymptotic embedding, proposed earlier, for calculation of conduction velocity restitution curves in ionic models of cardiac excitability. Conduction velocity restitution is the simplest non-trivial spatially extended problem in excitable media, and in the case of cardiac tissue it is an important tool for prediction of cardiac arrhythmias and fibrillation. An idealized conduction velocity restitution curve requires solving a non-linear eigenvalue problem with periodic boundary conditions, which in the cardiac case is very stiff and calls for the use of asymptotic methods. We compare asymptotics of restitution curves in four examples, two generic excitable media models, and two ionic cardiac models. The generic models include the classical FitzHugh-Nagumo model and its variation by Barkley. They are treated with standard singular perturbation techniques. The ionic models include a simplified "caricature" of Noble (J. Physiol. Lond. 160:317-352, 1962) model and Beeler and Reuter (J. Physiol. Lond. 268:177-210, 1977) model, which lead to non-Tikhonov problems where known asymptotic results do not apply. The Caricature Noble model is considered with particular care to demonstrate the well-posedness of the corresponding boundary-value problem. The developed method for calculation of conduction velocity restitution is then applied to the Beeler-Reuter model. We discuss new mathematical features appearing in cardiac ionic models and possible applications of the developed method.

Computation of the drift velocity of spiral waves using response functions.

Rotating spiral waves are a form of self-organization observed in spatially extended systems of physical, chemical, and biological nature. In the presence of a small perturbation, the spiral wave's center of rotation and fiducial phase may change over time, i.e., the spiral wave drifts. In linear approximation, the velocity of the drift is proportional to the convolution of the perturbation with the spiral's response functions, which are the eigenfunctions of the adjoint linearized operator corresponding to the critical eigenvalues λ=0,±iω . Here, we demonstrate that the response functions give quantitatively accurate prediction of the drift velocities due to a variety of perturbations: a time dependent, periodic perturbation (inducing resonant drift); a rotational symmetry-breaking perturbation (inducing electrophoretic drift); and a translational symmetry-breaking perturbation (inhomogeneity induced drift) including drift due to a gradient, stepwise, and localized inhomogeneity. We predict the drift velocities using the response functions in FitzHugh-Nagumo and Barkley models, and compare them with the velocities obtained in direct numerical simulations. In all cases good quantitative agreement is demonstrated.

Riding a spiral wave: numerical simulation of spiral waves in a comoving frame of reference.

We describe an approach to numerical simulation of spiral waves dynamics of large spatial extent, using small computational grids.

Orbital motion of spiral waves in excitable media.

Spiral waves in active media react to small perturbations as particlelike objects. Here we apply asymptotic theory to the interaction of spiral waves with a localized inhomogeneity, which leads to a novel prediction: drift of the spiral rotation center along circular orbits around the inhomogeneity. The stationary orbits have fixed radii and alternating stability, determined by the properties of the bulk medium and the type of inhomogeneity, while the drift speed along an orbit depends on the strength of the inhomogeneity. Direct numerical simulations confirm the validity and robustness of the theoretical predictions and show that these unexpected effects should be observable in experiment.

Alternative stable scroll waves and conversion of autowave turbulence.

Rotating spiral and scroll waves (vortices) are investigated in the FitzHugh-Nagumo model of excitable media. The focus is on a parameter region in which there exists bistability between alternative stable vortices with distinct periods. Response functions are used to predict the filament tension of the alternative scrolls and it is shown that the slow-period scroll has negative filament tension, while the filament tension of the fast-period scroll changes sign within a hysteresis loop. The predictions are confirmed by direct simulations. Further investigations show that the slow-period scrolls display features similar to delayed after-depolarization and tend to develop into turbulence similar to ventricular fibrillation (VF). Scrolls with positive filament tension collapse or stabilize, similar to monomorphic ventricular tachycardia (VT). Perturbations, such as boundary interaction or shock stimulus, can convert the vortex with negative filament tension into the vortex with positive filament tension. This may correspond to transition from VF to VT unrelated to pinning.

[Negative refractoriness in excitable systems with cross-diffusion].

The results of numerical experiments with mathematical models of excitable systems with cross-diffusion are presented. It was shown that the refractoriness in such systems may be negative. The effects of negative refractoriness on the propagation and interaction of waves are demonstrated.

Computation of the response functions of spiral waves in active media.

Rotating spiral waves are a form of self-organization observed in spatially extended systems of physical, chemical, and biological natures. A small perturbation causes gradual change in spatial location of spiral's rotation center and frequency, i.e., drift. The response functions (RFs) of a spiral wave are the eigenfunctions of the adjoint linearized operator corresponding to the critical eigenvalues lambda=0,+/-iomega. The RFs describe the spiral's sensitivity to small perturbations in the way that a spiral is insensitive to small perturbations where its RFs are close to zero. The velocity of a spiral's drift is proportional to the convolution of RFs with the perturbation. Here we develop a regular and generic method of computing the RFs of stationary rotating spirals in reaction-diffusion equations. We demonstrate the method on the FitzHugh-Nagumo system and also show convergence of the method with respect to the computational parameters, i.e., discretization steps and size of the medium. The obtained RFs are localized at the spiral's core.

Spontaneous traveling waves in oscillatory systems with cross diffusion.

We identify a type of pattern formation in spatially distributed active systems. We simulate one-dimensional two-component systems with predator-prey local interaction and pursuit-evasion taxis between the components. In a sufficiently large domain, spatially uniform oscillations in such systems are unstable with respect to small perturbations. This instability, through a transient regime appearing as spontaneous focal sources, leads to establishment of periodic traveling waves. The traveling wave regime is established even if boundary conditions do not favor such solutions. The stable wavelength is within a range bounded both from above and from below, and this range does not coincide with instability bands of the spatially uniform oscillations.

Analytical approach to initiation of propagating fronts.

We consider the problem of initiation of a propagating wave in a one-dimensional bistable or excitable fiber. In the Zeldovich-Frank-Kamenetskii equation, also known as the Nagumo equation and Schlögl model, the key role is played by the "critical nucleus" solution whose stable manifold is the threshold surface separating initial conditions leading to the initiation of propagation and decay. An approximation of this manifold by its tangent linear space yields an analytical criterion of initiation which is in good agreement with direct numerical simulations.

Control of scroll-wave turbulence using resonant perturbations.

Turbulence of scroll waves is a sort of spatiotemporal chaos that exists in three-dimensional excitable media. Cardiac tissue and the Belousov-Zhabotinsky reaction are examples of such media. In cardiac tissue, chaotic behavior is believed to underlie fibrillation which, without intervention, precedes cardiac death. In this study we investigate suppression of the turbulence using stimulation of two different types, "modulation of excitability" and "extra transmembrane current." With cardiac defibrillation in mind, we used a single pulse as well as repetitive extra current with both constant and feedback controlled frequency. We show that turbulence can be terminated using either a resonant modulation of excitability or a resonant extra current. The turbulence is terminated with much higher probability using a resonant frequency perturbation than a nonresonant one. Suppression of the turbulence using a resonant frequency is up to fifty times faster than using a nonresonant frequency, in both the modulation of excitability and the extra current modes. We also demonstrate that resonant perturbation requires strength one order of magnitude lower than that of a single pulse, which is currently used in clinical practice to terminate cardiac fibrillation. Our results provide a robust method of controlling complex chaotic spatiotemporal processes. Resonant drift of spiral waves has been studied extensively in two dimensions, however, these results show for the first time that it also works in three dimensions, despite the complex nature of the scroll wave turbulence.