Multisize Electrode Field-of-View: Validation by High Resolution Gadolinium-Enhanced Cardiac Magnetic Resonance.

BACKGROUND: Voltage mapping to detect ventricular scar is important for guiding catheter ablation, but the field-of-view of unipolar, bipolar, conventional, and microelectrodes as it relates to the extent of viable myocardium (VM) is not well defined. OBJECTIVES: The purpose of this study was to evaluate electroanatomic voltage-mapping (EAVM) with different-size electrodes for identifying VM, validated against high-resolution ex-vivo cardiac magnetic resonance (HR-LGE-CMR). METHODS: A total of 9 swine with early-reperfusion myocardial infarction were mapped with the QDOT microcatheter. HR-LGE-CMR (0.3-mm slices) were merged with EAVM. At each EAVM point, the underlying VM in multisize transmural cylinders and spheres was quantified from ex vivo CMR and related to unipolar and bipolar voltages recorded from conventional and microelectrodes. RESULTS: In each swine, 220 mapping points (Q1, Q3: 216, 260 mapping points) were collected. Infarcts were heterogeneous and nontransmural. Unipolar and bipolar voltage increased with VM volumes from >175 mm3 up to >525 mm3 (equivalent to a 5-mm radius cylinder with height >6.69 mm). VM volumes in subendocardial cylinders with 1- or 3-mm depth correlated poorly with all voltages. Unipolar voltages recorded with conventional and microelectrodes were similar (difference 0.17 ± 2.66 mV) and correlated best to VM within a sphere of radius 10 and 8 mm, respectively. Distance-weighting did not improve the correlation. CONCLUSIONS: Voltage increases with transmural volume of VM but correlates poorly with small amounts of VM, which limits EAVM in defining heterogeneous scar. Microelectrodes cannot distinguish thin from thick areas of subendocardial VM. The field-of-view for unipolar recordings for microelectrodes and conventional electrodes appears to be 8 to 10 mm, respectively, and unexpectedly similar.

Fast creation of data-driven low-order predictive cardiac tissue excitation models from recorded activation patterns.

Excitable systems give rise to important phenomena such as heat waves, epidemics and cardiac arrhythmias. Understanding, forecasting and controlling such systems requires reliable mathematical representations. For cardiac tissue, computational models are commonly generated in a reaction-diffusion framework based on detailed measurements of ionic currents in dedicated single-cell experiments. Here, we show that recorded movies at the tissue-level of stochastic pacing in a single variable are sufficient to generate a mathematical model. Via exponentially weighed moving averages, we create additional state variables, and use simple polynomial regression in the augmented state space to quantify excitation wave dynamics. A spatial gradient-sensing term replaces the classical diffusion as it is more robust to noise. Our pipeline for model creation is demonstrated for an in-silico model and optical voltage mapping recordings of cultured human atrial myocytes and only takes a few minutes. Our findings have the potential for widespread generation, use and on-the-fly refinement of personalised computer models for non-linear phenomena in biology and medicine, such as predictive cardiac digital twins.

Scroll Waves and Filaments in Excitable Media of Higher Spatial Dimension.

Excitable media are ubiquitous in nature, and in such systems the local excitation tends to self-organize in traveling waves, or in rotating spiral-shaped patterns in two or three spatial dimensions. Examples include waves during a pandemic or electrical scroll waves in the heart. Here we show that such phenomena can be extended to a space of four or more dimensions and propose that connections of excitable elements in a network setting can be regarded as additional spatial dimensions. Numerical simulations are performed in four dimensions using the FitzHugh-Nagumo model, showing that the vortices rotate around a two-dimensional surface which we define as the superfilament. Evolution equations are derived for general superfilaments of codimension two in an N-dimensional space, and their equilibrium configurations are proven to be minimal surfaces. We suggest that biological excitable systems, such as the heart or brain which have nonlocal connections can be regarded, at least partially, as multidimensional excitable media and discuss further possible studies in this direction.

Reordering and synchronization of electrical turbulence in cardiac tissue through global and partial optogenetical illumination.

Electrical turbulence in the heart is considered the culprit of cardiac disease, including the fatal ventricular fibrillation. Optogenetics is an emerging technology that has the capability to produce action potentials of cardiomyocytes to affect the electric wave propagation in cardiac tissue, thereby possessing the potential to control the turbulence, by shining a rotating spiral pattern onto the tissue. In this paper, we present a method to reorder and synchronize electrical turbulence through optogenetics. A generic two-variable reaction-diffusion model and a simplified three-variable ionic cardiac model are used. We discuss cases involving either global or partial illumination.

Impact of electrode orientation, myocardial wall thickness, and myofiber direction on intracardiac electrograms: numerical modeling and analytical solutions.

Intracardiac electrograms (iEGMs) are time traces of the electrical potential recorded close to the heart muscle. We calculate unipolar and bipolar iEGMs analytically for a myocardial slab with parallel myofibers and validate them against numerical bidomain simulations. The analytical solution obtained via the method of mirrors is an infinite series of arctangents. It goes beyond the solid angle theory and is in good agreement with the simulations, even though bath loading effects were not accounted for in the analytical calculation. At a large distance from the myocardium, iEGMs decay as 1/R (unipolar), 1/R 2 (bipolar and parallel), and 1/R 3 (bipolar and perpendicular to the endocardium). At the endocardial surface, there is a mathematical branch cut. Here, we show how a thicker myocardium generates iEGMs with larger amplitudes and how anisotropy affects the iEGM width and amplitude. If only the leading-order term of our expansion is retained, it can be determined how the conductivities of the bath, torso, myocardium, and myofiber direction together determine the iEGM amplitude. Our results will be useful in the quantitative interpretation of iEGMs, the selection of thresholds to characterize viable tissues, and for future inferences of tissue parameters.

Numerical methods for the detection of phase defect structures in excitable media.

Electrical waves that rotate in the heart organize dangerous cardiac arrhythmias. Finding the region around which such rotation occurs is one of the most important practical questions for arrhythmia management. For many years, the main method for finding such regions was so-called phase mapping, in which a continuous phase was assigned to points in the heart based on their excitation status and defining the rotation region as a point of phase singularity. Recent analysis, however, showed that in many rotation regimes there exist phase discontinuities and the region of rotation must be defined not as a point of phase singularity, but as a phase defect line. In this paper, we use this novel methodology and perform a comparative study of three different phase definitions applied to in silico data and to experimental data obtained from optical voltage mapping experiments on monolayers of human atrial myocytes. We introduce new phase defect detection algorithms and compare them with those that appeared in literature already. We find that the phase definition is more important than the algorithm to identify sudden spatial phase variations. Sharp phase defect lines can be obtained from a phase derived from local activation times observed during one cycle of arrhythmia. Alternatively, similar quality can be obtained from a reparameterization of the classical phase obtained from observation of a single timeframe of transmembrane potential. We found that the phase defect line length was (35.9 ± 6.2)mm in the Fenton-Karma model and (4.01 ± 0.55)mm in cardiac human atrial myocyte monolayers. As local activation times are obtained during standard clinical cardiac mapping, the methods are also suitable to be applied to clinical datasets. All studied methods are publicly available and can be downloaded from an institutional web-server.

Control of the chirality of spiral waves and recreation of spatial excitation patterns through optogenetics.

Spiral waves lead to dangerous arrhythmias in the cardiac system. In 2015 Burton et al. demonstrated the reversal of the spiral wave chirality through the rotating spiral-shaped illumination on the optogenetically modified cardiac monolayers. We show that this process entails the recreation of a spiral wave. We show how this methodology can be used to control and create the desired spatial excitation pattern. We found that the control is sensitive to the area of illuminated region but independent of the phase difference of the existing spiral wave and the applied spiral-shaped light. We also discovered that our methodology can temporarily resynchronize a turbulent system. The results offer numerical evidence for the control of spatial pattern in biological excitable systems with optogenetics.

A Phase Defect Framework for the Analysis of Cardiac Arrhythmia Patterns.

During cardiac arrhythmias, dynamical patterns of electrical activation form and evolve, which are of interest to understand and cure heart rhythm disorders. The analysis of these patterns is commonly performed by calculating the local activation phase and searching for phase singularities (PSs), i.e., points around which all phases are present. Here we propose an alternative framework, which focuses on phase defect lines (PDLs) and surfaces (PDSs) as more general mechanisms, which include PSs as a specific case. The proposed framework enables two conceptual unifications: between the local activation time and phase description, and between conduction block lines and the central regions of linear-core rotors. A simple PDL detection method is proposed and applied to data from simulations and optical mapping experiments. Our analysis of ventricular tachycardia in rabbit hearts (n = 6) shows that nearly all detected PSs were found on PDLs, but the PDLs had a significantly longer lifespan than the detected PSs. Since the proposed framework revisits basic building blocks of cardiac activation patterns, it can become a useful tool for further theory development and experimental analysis.

Scroll wave with negative filament tension in a model of the left ventricle of the human heart and its overdrive pacing.

Nonlinear waves of electrical excitation initiate cardiac contraction. Abnormal wave propagation in the heart, e.g., spiral waves, can lead to sudden cardiac arrest. This study analyzed the dynamics of spiral waves under the influence of an instability called negative filament tension, and examined how the spiral waves can be eliminated through high-frequency pacing. A generic anatomical model of the left ventricle of the human heart and the Aliev-Panfilov model for cardiac tissue were used. The study showed that the source of such arrhythmia is elongated filaments with lengths that can be 10-20 times greater than the characteristic thickness of the heart wall. In anisotropic tissue, the filament elongated before it was annihilated at the base of the heart. The spiral waves were eliminated through overdrive pacing with stimulation periods from 0.8 to 0.95 relative to the spiral wave period. The minimum time for the expulsion was about 10 s.

High-frequency pacing of scroll waves in a three-dimensional slab model of cardiac tissue.

Vortices in excitable media underlie dangerous cardiac arrhythmias. One way to eliminate them is by stimulating the excitable medium with a period smaller than the period of the vortex. So far, this phenomenon has been studied mostly for two-dimensional vortices known as spiral waves. Here we present a first study of this phenomenon for three-dimensional vortices, or scroll waves, in a slab. We consider two main types of scroll waves dynamics: with positive filament tension and with negative filament tension and show that such elimination is possible for some values of the period in all cases. However, in the case of negative filament tension for relatively long stimulation periods, three-dimensional instabilities occur and make elimination impossible. We derive equations of motion for the drift of paced filaments and identify a bifurcation parameter that determines whether the filaments orient themselves perpendicular to the impeding wave train or not.

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.

GEMS: A Fully Integrated PETSc-Based Solver for Coupled Cardiac Electromechanics and Bidomain Simulations.

Cardiac contraction is coordinated by a wave of electrical excitation which propagates through the heart. Combined modeling of electrical and mechanical function of the heart provides the most comprehensive description of cardiac function and is one of the latest trends in cardiac research. The effective numerical modeling of cardiac electromechanics remains a challenge, due to the stiffness of the electrical equations and the global coupling in the mechanical problem. Here we present a short review of the inherent assumptions made when deriving the electromechanical equations, including a general representation for deformation-dependent conduction tensors obeying orthotropic symmetry, and then present an implicit-explicit time-stepping approach that is tailored to solving the cardiac mono- or bidomain equations coupled to electromechanics of the cardiac wall. Our approach allows to find numerical solutions of the electromechanics equations using stable and higher order time integration. Our methods are implemented in a monolithic finite element code GEMS (Ghent Electromechanics Solver) using the PETSc library that is inherently parallelized for use on high-performance computing infrastructure. We tested GEMS on standard benchmark computations and discuss further development of our software.

Paradoxical Onset of Arrhythmic Waves from Depolarized Areas in Cardiac Tissue Due to Curvature-Dependent Instability.

The generation of abnormal excitations in pathological regions of the heart is a main trigger for lethal cardiac arrhythmias. Such abnormal excitations, also called ectopic activity, often arise from areas with local tissue heterogeneity or damage accompanied by localized depolarization. Finding the conditions that lead to ectopy is important to understand the basic biophysical principles underlying arrhythmia initiation and might further refine clinical procedures. In this study, we are the first to address the question of how geometry of the abnormal region affects the onset of ectopy using a combination of experimental, in silico, and theoretical approaches. We paradoxically find that, for any studied geometry of the depolarized region in optogenetically modified monolayers of cardiac cells, primary ectopic excitation originates at areas of maximal curvature of the boundary, where the stimulating electrotonic currents are minimal. It contradicts the standard critical nucleation theory applied to nonlinear waves in reaction-diffusion systems, where a higher stimulus is expected to produce excitation more easily. Our in silico studies reveal that the nonconventional ectopic activity is caused by an oscillatory instability at the boundary of the damaged region, the occurrence of which depends on the curvature of that boundary. The onset of this instability is confirmed using the Schrödinger equation methodology proposed by Rinzel and Keener [SIAM J. Appl. Math. 43, 907 (1983)]. Overall, we show distinctively novel insight into how the geometry of a heterogeneous cardiac region determines ectopic activity, which can be used in the future to predict the conditions that can trigger cardiac arrhythmias.

Measurement and structure of spiral wave response functions.

The rotating spiral waves that emerge in diverse natural and man-made systems typically exhibit a particle-like behaviour since their adjoint critical eigenmodes (response functions) are often seen to be localised around the spiral core. We present a simple method to numerically compute response functions for circular-core and meandering spirals by recording their drift response to many elementary perturbations. Although our method is computationally more expensive than solving the adjoint system, our technique is fully parallellisable, does not suffer from memory limitations and can be applied to experiments. For a cardiac tissue model with the linear spiral core, we find that the response functions are localised near the turning points of the trajectory.

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.

Spiral wave chimeras in locally coupled oscillator systems.

The recently discovered chimera state involves the coexistence of synchronized and desynchronized states for a group of identical oscillators. In this work, we show the existence of (inwardly) rotating spiral wave chimeras in the three-component reaction-diffusion systems where each element is locally coupled by diffusion. A transition from spiral waves with the smooth core to spiral wave chimeras is found as we change the local dynamics of the system or as we gradually increase the diffusion coefficient of the activator. Our findings on the spiral wave chimera in the reaction-diffusion systems suggest that spiral chimera states may be found in chemical and biological systems that can be modeled by a large population of oscillators indirectly coupled via a diffusive environment.

Variational principle for nonlinear wave propagation in dissipative systems.

The dynamics of many natural systems is dominated by nonlinear waves propagating through the medium. We show that in any extended system that supports nonlinear wave fronts with positive surface tension, the asymptotic wave-front dynamics can be formulated as a gradient system, even when the underlying evolution equations for the field variables cannot be written as a gradient system. The variational potential is simply given by a linear combination of the occupied volume and surface area of the wave front and changes monotonically over time.

Phase-locked scroll waves defy turbulence induced by negative filament tension.

Scroll waves in a three-dimensional media may develop into turbulence due to negative tension of the filament. Such negative tension-induced instability of scroll waves has been observed in the Belousov-Zhabotinsky reaction systems. Here we propose a method to restabilize scroll wave turbulence caused by negative tension in three-dimensional chemical excitable media using a circularly polarized (rotating) external field. The stabilization mechanism is analyzed in terms of phase-locking caused by the external field, which makes the effective filament tension positive. The phase-locked scroll waves that have positive tension and higher frequency defy the turbulence and finally restore order. A linear theory for the change of filament tension caused by a generic rotating external field is presented and its predictions closely agree with numerical simulations.