Networks provide a powerful methodology with applications in a variety of biological, technological and social systems such as analysis of brain data, social networks, internet search engine algorithms, etc. To date, directed networks have not yet been applied to characterize the excitation of the human heart. In clinical practice, cardiac excitation is recorded by multiple discrete electrodes. During (normal) sinus rhythm or during cardiac arrhythmias, successive excitation connects neighboring electrodes, resulting in their own unique directed network. This in theory makes it a perfect fit for directed network analysis. In this study, we applied directed networks to the heart in order to describe and characterize cardiac arrhythmias. Proof-of-principle was established using in-silico and clinical data. We demonstrated that tools used in network theory analysis allow determination of the mechanism and location of certain cardiac arrhythmias. We show that the robustness of this approach can potentially exceed the existing state-of-the art methodology used in clinics. Furthermore, implementation of these techniques in daily practice can improve the accuracy and speed of cardiac arrhythmia analysis. It may also provide novel insights in arrhythmias that are still incompletely understood.

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Networks provide a powerful methodology with applications in a variety of biological, technological and social systems such as analysis of brain data, social networks, internet search engine algorithms, etc. To date, directed networks have not yet been applied to characterize the excitation of the human heart. In clinical practice, cardiac excitation is recorded by multiple discrete electrodes. During (normal) sinus rhythm or during cardiac arrhythmias, successive excitation connects neighboring electrodes, resulting in their own unique directed network. This in theory makes it a perfect fit for directed network analysis. In this study, we applied directed networks to the heart in order to describe and characterize cardiac arrhythmias. Proofof-principle was established using in-silico and clinical data. We demonstrated that tools used in network theory analysis allow to determine the mechanism and location of certain cardiac arrhythmias. We show that the robustness of this approach can potentially exceed the existing state-of-the art methodology used in clinics. Furthermore, implementation of these techniques in daily practice can improve accuracy and speed of cardiac arrhythmia analysis. It may also provide novel insights in arrhythmias that are still incompletely understood. network theory| cardiac arrhythmia Correspondence: nele.vandersickel@ugent.be

Early Afterdepolarizations, EADs, are defined as the reversal of the action potential before completion of the repolarization phase, which can result in ectopic beats. However, the series of mechanisms of EADs leading to these ectopic beats and related cardiac arrhythmias are not well understood. Therefore, we aimed to investigate the influence of this single cell behavior on the whole heart level. For this study we used a modified version of the Ten Tusscher-Panfilov model of human ventricular cells (TP06) which we implemented in a 3D ventricle model including realistic fiber orientations. To increase the likelihood of EAD formation at the single cell level, we reduced the repolarization reserve (RR) by reducing the rapid delayed rectifier Potassium current and raising the L-type Calcium current. Varying these parameters defined a 2D parametric space where different excitation patterns could be classified. Depending on the initial conditions, by either exciting the ventricles with a spiral formation or burst pacing protocol, we found multiple different spatio-temporal excitation patterns. The spiral formation protocol resulted in the categorization of a stable spiral (S), a meandering spiral (MS), a spiral break-up regime (SB), spiral fibrillation type B (B), spiral fibrillation type A (A) and an oscillatory excitation type (O). The last three patterns are a 3D generalization of previously found patterns in 2D. First, the spiral fibrillation type B showed waves determined by a chaotic bi-excitable regime, i.e. mediated by both Sodium and Calcium waves at the same time and in same tissue settings. In the parameter region governed by the B pattern, single cells were able to repolarize completely and different (spiral) waves chaotically burst into each other without finishing a 360 degree rotation. Second, spiral fibrillation type A patterns consisted of multiple small rotating spirals. Single cells failed to repolarize to the resting membrane potential hence prohibiting the Sodium channel gates to recover. Accordingly, we found that Calcium waves mediated these patterns. Third, a further reduction of the RR resulted in a more exotic parameter regime whereby the individual cells behaved independently as oscillators. The patterns arose due to a phase-shift of different oscillators as disconnection of the cells resulted in continuation of the patterns. For all patterns, we computed realistic 9 lead ECGs by including a torso model. The B and A type pattern exposed the behavior of Ventricular Tachycardia (VT). We conclude that EADs at the single cell level can result in different types of cardiac fibrillation at the tissue and 3D ventricle level.

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Early after depolarizations (EAD) occur in many pathological conditions, such as congenital or acquired channelopathies, drug induced arrhythmias, and several other situations that are associated with increased arrhythmogenicity. In this paper we present an overview of the relevant computational studies on spatial EAD dynamics in 1D, 2D, and in 3D anatomical models and discuss the relation of EADs to cardiac arrhythmias. We also discuss unsolved problems and highlight new lines of research in this area.

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practise. One of the major problems in the management of AF is the difficulty in identifying the arrhythmia sources from clinical recordings. That difficulty occurs because it is currently impossible to verify algorithms which determine these sources in clinical data, as high resolution true excitation patterns cannot be recorded in patients. Therefore, alternative approaches, like computer modelling are of great interest. In a recent published study such an approach was applied for the verification of one of the most commonly used algorithms, phase mapping (PM). A meandering rotor was simulated in the right atrium and a basket catheter was placed at 3 different locations: at the Superior Vena Cava (SVC), the Crista Terminalis (CT) and at the Coronary Sinus (CS). It was shown that although PM can identify the true source, it also finds several false sources due to the far-field effects and interpolation errors in all three positions. In addition, the detection efficiency strongly depended on the basket location. Recently, a novel tool was developed to analyse any arrhythmia called Directed Graph Mapping (DGM). DGM is based on network theory and creates a directed graph of the excitation pattern, from which the location and the source of the arrhythmia can be detected. Therefore, the objective of the current study was to compare the efficiency of DGM with PM on the basket dataset of this meandering rotor. The DGM-tool was applied for a wide variety of conduction velocities (minimal and maximal), which are input parameters of DGM. Overall we found that DGM was able to distinguish between the true rotor and false rotors for both the SVC and CT basket positions. For example, for the SVC position with a , DGM detected the true core with a prevalence of 82% versus 94% for PM. Three false rotors where detected for 39.16% (DGM) versus 100% (PM); 22.64% (DGM) versus 100% (PM); and 0% (DGM) versus 57% (PM). Increasing to had a stronger effect on the false rotors than on the true rotor. This led to a detection rate of for the true rotor, while all the other false rotors disappeared. A similar trend was observed for the CT position. For the CS position, DGM already had a low performance for the true rotor for (14.7%). For the false and the true rotors could therefore not be distinguished. We can conclude that DGM can overcome some of the limitations of PM by varying one of its input parameters ( ). The true rotor is less dependent on this parameter than the false rotors, which disappear at a . In order to increase to detection rate of the true rotor, one can decrease and discard the new rotors which also appear at lower values of .

In this work we present the release of a novel easy-to-use software package called DGM or Directed-Graph-Mapping. DGM can automatically analyze any type of arrhythmia to find reentry or focal sources if the measurements are synchronized in time. Currently, DGM requires the local activation times (LAT) and the spatial coordinates of the measured electrodes. However, there is no requirement for any spatial organization of the electrodes, allowing to analyze clinical, experimental or computational data. DGM creates directed networks of the activation, which are analyzed with fast algorithms to search for reentry (cycles in the network) and focal sources (nodes with outgoing arrows). DGM has been mainly optimized to analyze atrial tachycardia, but we also discuss other applications of DGM demonstrating its wide applicability. The goal is to release a free software package which can allow researchers to save time in the analysis of cardiac data. An academic license is attached to the software, allowing only non-commercial use of the software. All updates of the software, user and installation guide will be published on a dedicated website www.dgmapping.com.