Optical mapping of contracting hearts.

Optical mapping is a widely used tool to record and visualize the electrophysiological properties in a variety of myocardial preparations such as Langendorff-perfused isolated hearts, coronary-perfused wedge preparations, and cell culture monolayers. Motion artifact originating from the mechanical contraction of the myocardium creates a significant challenge to performing optical mapping of contracting hearts. Hence, to minimize the motion artifact, cardiac optical mapping studies are mostly performed on non-contracting hearts, where the mechanical contraction is removed using pharmacological excitation-contraction uncouplers. However, such experimental preparations eliminate the possibility of electromechanical interaction, and effects such as mechano-electric feedback cannot be studied. Recent developments in computer vision algorithms and ratiometric techniques have opened the possibility of performing optical mapping studies on isolated contracting hearts. In this review, we discuss the existing techniques and challenges of optical mapping of contracting hearts.

Ordinal pattern-based complexity analysis of high-dimensional chaotic time series.

The ordinal pattern-based complexity-entropy plane is a popular tool in nonlinear dynamics for distinguishing stochastic signals (noise) from deterministic chaos. Its performance, however, has mainly been demonstrated for time series from low-dimensional discrete or continuous dynamical systems. In order to evaluate the usefulness and power of the complexity-entropy (CE) plane approach for data representing high-dimensional chaotic dynamics, we applied this method to time series generated by the Lorenz-96 system, the generalized Hénon map, the Mackey-Glass equation, the Kuramoto-Sivashinsky equation, and to phase-randomized surrogates of these data. We find that both the high-dimensional deterministic time series and the stochastic surrogate data may be located in the same region of the complexity-entropy plane, and their representations show very similar behavior with varying lag and pattern lengths. Therefore, the classification of these data by means of their position in the CE plane can be challenging or even misleading, while surrogate data tests based on (entropy, complexity) yield significant results in most cases.

Estimating fractal dimensions: A comparative review and open source implementations.

The fractal dimension is a central quantity in nonlinear dynamics and can be estimated via several different numerical techniques. In this review paper, we present a self-contained and comprehensive introduction to the fractal dimension. We collect and present various numerical estimators and focus on the three most promising ones: generalized entropy, correlation sum, and extreme value theory. We then perform an extensive quantitative evaluation of these estimators, comparing their performance and precision using different datasets and comparing the impact of features like length, noise, embedding dimension, and falsify-ability, among many others. Our analysis shows that for synthetic noiseless data, the correlation sum is the best estimator with extreme value theory following closely. For real experimental data, we found the correlation sum to be more strongly affected by noise vs the entropy and extreme value theory. The recent extreme value theory estimator seems powerful as it has some of the advantages of both alternative methods. However, using four different ways for checking for significance, we found that the method yielded "significant" low-dimensional results for inappropriate data like stock market timeseries. This fact, combined with some ambiguities we found in the literature of the method applications, has implications for both previous and future real-world applications using the extreme value theory approach, as, for example, the argument for small effective dimensionality in the data cannot come from the method itself. All algorithms discussed are implemented as performant and easy to use open source code via the DynamicalSystems.jl library.

Taming cardiac arrhythmias: Terminating spiral wave chaos by adaptive deceleration pacing.

Sequences of weak electrical pulses are considered a promising alternative for terminating ventricular and atrial fibrillations while avoiding strong defibrillation shocks with adverse side effects. In this study, using numerical simulations of four different 2D excitable media, we show that pulse trains with increasing temporal intervals between successive pulses (deceleration pacing) provide high success rates at low energies. Furthermore, we propose a simple and robust approach to calculate inter-pulse spacing directly from the frequency spectrum of the dynamics (for instance, computed based on the electrocardiogram), which can be practically used in experiments and clinical applications.

Control of escapes in two-degree-of-freedom open Hamiltonian systems.

We investigate the possibility of avoiding the escape of chaotic scattering trajectories in two-degree-of-freedom Hamiltonian systems. We develop a continuous control technique based on the introduction of coupling forces between the chaotic trajectories and some periodic orbits of the system. The main results are shown through numerical simulations, which confirm that all trajectories starting near the stable manifold of the chaotic saddle can be controlled. We also show that it is possible to jump between different unstable periodic orbits until reaching a stable periodic orbit belonging to a Kolmogorov-Arnold-Moser island.

Some elements for a history of the dynamical systems theory.

Writing a history of a scientific theory is always difficult because it requires to focus on some key contributors and to "reconstruct" some supposed influences. In the 1970s, a new way of performing science under the name "chaos" emerged, combining the mathematics from the nonlinear dynamical systems theory and numerical simulations. To provide a direct testimony of how contributors can be influenced by other scientists or works, we here collected some writings about the early times of a few contributors to chaos theory. The purpose is to exhibit the diversity in the paths and to bring some elements-which were never published-illustrating the atmosphere of this period. Some peculiarities of chaos theory are also discussed.

Terminating transient chaos in spatially extended systems.

In many real-life systems, transient chaotic dynamics plays a major role. For instance, the chaotic spiral or scroll wave dynamics of electrical excitation waves during life-threatening cardiac arrhythmias can terminate by itself. Epileptic seizures have recently been related to the collapse of transient chimera states. Controlling chaotic transients, either by maintaining the chaotic dynamics or by terminating it as quickly as possible, is often desired and sometimes even vital (as in the case of cardiac arrhythmias). We discuss in this study that the difference of the underlying structures in state space between a chaotic attractor (persistent chaos) and a chaotic saddle (transient chaos) may have significant implications for efficient control strategies in real life systems. In particular, we demonstrate that in the latter case, chaotic dynamics in spatially extended systems can be terminated via a relatively low number of (spatially and temporally) localized perturbations. We demonstrate as a proof of principle that control and targeting of high-dimensional systems exhibiting transient chaos can be achieved with exceptionally small interactions with the system. This insight may impact future control strategies in real-life systems like cardiac arrhythmias.

Multiscale Modeling of Dyadic Structure-Function Relation in Ventricular Cardiac Myocytes.

Cardiovascular disease is often related to defects of subcellular components in cardiac myocytes, specifically in the dyadic cleft, which include changes in cleft geometry and channel placement. Modeling of these pathological changes requires both spatially resolved cleft as well as whole cell level descriptions. We use a multiscale model to create dyadic structure-function relationships to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling. This multiscale model incorporates stochastic simulation of individual L-type calcium channels and ryanodine receptor channels, spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca2+ and Ca2+-binding molecules in the bulk of the cell. We found action potential duration, systolic, and diastolic [Ca2+] to respond most sensitively to changes in L-type calcium channel current. The ryanodine receptor channel cluster structure inside dyadic clefts was found to affect all biomarkers investigated. The shape of clusters observed in experiments by Jayasinghe et al. and channel density within the cluster (characterized by mean occupancy) showed the strongest correlation to the effects on biomarkers.

Terminal Transient Phase of Chaotic Transients.

Transient chaos in spatially extended systems can be characterized by the length of the transient phase, which typically grows quickly with the system size (supertransients). For a large class of these systems, the chaotic phase terminates abruptly, without any obvious precursors in commonly used observables. Here we investigate transient spatiotemporal chaos in two different models of this class. By probing the state space using perturbed trajectories we show the existence of a "terminal transient phase," which occurs prior to the abrupt collapse of chaotic dynamics. During this phase the impact of perturbations is significantly different from the earlier transient and particular patterns of (non)susceptible regions in state space occur close to the chaotic trajectories. We therefore hypothesize that even without perturbations proper precursors for the collapse of chaotic transients exist, which might be highly relevant for coping with spatiotemporal chaos in cardiac arrhythmias or brain functionality, for example.

Observing spatio-temporal dynamics of excitable media using reservoir computing.

We present a dynamical observer for two dimensional partial differential equation models describing excitable media, where the required cross prediction from observed time series to not measured state variables is provided by Echo State Networks receiving input from local regions in space, only. The efficacy of this approach is demonstrated for (noisy) data from a (cubic) Barkley model and the Bueno-Orovio-Cherry-Fenton model describing chaotic electrical wave propagation in cardiac tissue.

Features of Chaotic Transients in Excitable Media Governed by Spiral and Scroll Waves.

In excitable media, chaotic dynamics governed by spiral or scroll waves is often not persistent but transient. Using extensive simulations employing different mathematical models we identify a specific type-II supertransient by an exponential increase of transient lifetimes with the system size in 2D and an investigation of the dynamics (number and lifetime of spiral waves, Kaplan-Yorke dimension). In 3D, simulations exhibit an increase of transient lifetimes and filament lengths only above a critical thickness. Finally, potential implications for understanding cardiac arrhythmias are discussed.

Emergent dynamics of spatio-temporal chaos in a heterogeneous excitable medium.

Self-organized activation patterns in excitable media such as spiral waves and spatio-temporal chaos underlie dangerous cardiac arrhythmias. While the interaction of single spiral waves with different types of heterogeneity has been studied extensively, the effect of heterogeneity on fully developed spatio-temporal chaos remains poorly understood. We investigate how the complexity and stability properties of spatio-temporal chaos in the Bär-Eiswirth model of excitable media depend on the heterogeneity of the underlying medium. We employ different measures characterizing the chaoticity of the system and find that the spatial arrangement of multiple discrete lower excitability regions has a strong impact on the complexity of the dynamics. Varying the number, shape, and spatial arrangement of the heterogeneities, we observe strong emergent effects ranging from increases in chaoticity to the complete cessation of chaos, contrasting the expectation from the homogeneous behavior. The implications of our findings for the development and treatment of arrhythmias in the heterogeneous cardiac muscle are discussed.

Basin structure of optimization based state and parameter estimation.

Most data based state and parameter estimation methods require suitable initial values or guesses to achieve convergence to the desired solution, which typically is a global minimum of some cost function. Unfortunately, however, other stable solutions (e.g., local minima) may exist and provide suboptimal or even wrong estimates. Here, we demonstrate for a 9-dimensional Lorenz-96 model how to characterize the basin size of the global minimum when applying some particular optimization based estimation algorithm. We compare three different strategies for generating suitable initial guesses, and we investigate the dependence of the solution on the given trajectory segment (underlying the measured time series). To address the question of how many state variables have to be measured for optimal performance, different types of multivariate time series are considered consisting of 1, 2, or 3 variables. Based on these time series, the local observability of state variables and parameters of the Lorenz-96 model is investigated and confirmed using delay coordinates. This result is in good agreement with the observation that correct state and parameter estimation results are obtained if the optimization algorithm is initialized with initial guesses close to the true solution. In contrast, initialization with other exact solutions of the model equations (different from the true solution used to generate the time series) typically fails, i.e., the optimization procedure ends up in local minima different from the true solution. Initialization using random values in a box around the attractor exhibits success rates depending on the number of observables and the available time series (trajectory segment).

Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction.

RATIONALE: Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca(2+) release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). OBJECTIVES: Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. METHODS AND RESULTS: Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT-associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca(2+) release and action potential prolongation. CONCLUSIONS: This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca(2+) release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing.

Local observability of state variables and parameters in nonlinear modeling quantified by delay reconstruction.

Features of the Jacobian matrix of the delay coordinates map are exploited for quantifying the robustness and reliability of state and parameter estimations for a given dynamical model using a measured time series. Relevant concepts of this approach are introduced and illustrated for discrete and continuous time systems employing a filtered Hénon map and a Rössler system.

Optimising low-energy defibrillation in 2D cardiac tissue with a genetic algorithm.

Sequences of low-energy electrical pulses can effectively terminate ventricular fibrillation (VF) and avoid the side effects of conventional high-energy electrical defibrillation shocks, including tissue damage, traumatic pain, and worsening of prognosis. However, the systematic optimisation of sequences of low-energy pulses remains a major challenge. Using 2D simulations of homogeneous cardiac tissue and a genetic algorithm, we demonstrate the optimisation of sequences with non-uniform pulse energies and time intervals between consecutive pulses for efficient VF termination. We further identify model-dependent reductions of total pacing energy ranging from ∼4% to ∼80% compared to reference adaptive-deceleration pacing (ADP) protocols of equal success rate (100%).

Non-monotonous dose response function of the termination of spiral wave chaos.

The conventional termination technique of life threatening cardiac arrhythmia like ventricular fibrillation is the application of a high-energy electrical defibrillation shock, coming along with severe side-effects. In order to improve the current treatment reducing these side-effects, the application of pulse sequences of lower energy instead of a single high-energy pulse are promising candidates. In this study, we show that in numerical simulations the dose-response function of pulse sequences applied to two-dimensional spiral wave chaos is not necessarily monotonously increasing, but exhibits a non-trivial frequency dependence. This insight into crucial phenomena appearing during termination attempts provides a deeper understanding of the governing termination mechanisms in general, and therefore may open up the path towards an efficient termination of cardiac arrhythmia in the future.

The role of pulse timing in cardiac defibrillation.

Life-threatening cardiac arrhythmias require immediate defibrillation. For state-of-the-art shock treatments, a high field strength is required to achieve a sufficient success rate for terminating the complex spiral wave (rotor) dynamics underlying cardiac fibrillation. However, such high energy shocks have many adverse side effects due to the large electric currents applied. In this study, we show, using 2D simulations based on the Fenton-Karma model, that also pulses of relatively low energy may terminate the chaotic activity if applied at the right moment in time. In our simplified model for defibrillation, complex spiral waves are terminated by local perturbations corresponding to conductance heterogeneities acting as virtual electrodes in the presence of an external electric field. We demonstrate that time series of the success rate for low energy shocks exhibit pronounced peaks which correspond to short intervals in time during which perturbations aiming at terminating the chaotic fibrillation state are (much) more successful. Thus, the low energy shock regime, although yielding very low temporal average success rates, exhibits moments in time for which success rates are significantly higher than the average value shown in dose-response curves. This feature might be exploited in future defibrillation protocols for achieving high termination success rates with low or medium pulse energies.

Drift and termination of spiral waves in optogenetically modified cardiac tissue at sub-threshold illumination.

The development of new approaches to control cardiac arrhythmias requires a deep understanding of spiral wave dynamics. Optogenetics offers new possibilities for this. Preliminary experiments show that sub-threshold illumination affects electrical wave propagation in the mouse heart. However, a systematic exploration of these effects is technically challenging. Here, we use state-of-the-art computer models to study the dynamic control of spiral waves in a two-dimensional model of the adult mouse ventricle, using stationary and non-stationary patterns of sub-threshold illumination. Our results indicate a light-intensity-dependent increase in cellular resting membrane potentials, which together with diffusive cell-cell coupling leads to the development of spatial voltage gradients over differently illuminated areas. A spiral wave drifts along the positive gradient. These gradients can be strategically applied to ensure drift-induced termination of a spiral wave, both in optogenetics and in conventional methods of electrical defibrillation.