Computer based method for identification of fibrotic scars from electrograms and local activation times on the epi- and endocardial surfaces of the ventricles.

Cardiac fibrosis stands as one of the most critical conditions leading to lethal cardiac arrhythmias. Identifying the precise location of cardiac fibrosis is crucial for planning clinical interventions in patients with various forms of ventricular and atrial arrhythmias. As fibrosis impedes and alters the path of electrical waves, detecting fibrosis in the heart can be achieved through analyzing electrical signals recorded from its surface. In current clinical practices, it has become feasible to record electrical activity from both the endocardial and epicardial surfaces of the heart. This paper presents a computational method for reconstructing 3D fibrosis using unipolar electrograms obtained from both surfaces of the ventricles. The proposed method calculates the percentage of fibrosis in various ventricular segments by analyzing the local activation times and peak-to-peak amplitudes of the electrograms. Initially, the method was tested using simulated data representing idealized fibrosis in a heart segment; subsequently, it was validated in the left ventricle with fibrosis obtained from a patient with nonischemic cardiomyopathy. The method successfully determined the location and extent of fibrosis in 204 segments of the left ventricle model with an average error of 0.0±4.3% (N = 204). Moreover, the method effectively detected fibrotic scars in the mid-myocardial region, a region known to present challenges in accurate detection using electrogram amplitude as the primary criterion.

Directed Graph Mapping exceeds Phase Mapping for the detection of simulated 2D meandering rotors in fibrotic tissue with added noise.

Cardiac arrhythmias such as atrial fibrillation (AF) are recognised to be associated with re-entry or rotors. A rotor is a wave of excitation in the cardiac tissue that wraps around its refractory tail, causing faster-than-normal periodic excitation. The detection of rotor centres is of crucial importance in guiding ablation strategies for the treatment of arrhythmia. The most popular technique for detecting rotor centres is Phase Mapping (PM), which detects phase singularities derived from the phase of a signal. This method has been proven to be prone to errors, especially in regimes of fibrotic tissue and temporal noise. Recently, a novel technique called Directed Graph Mapping (DGM) was developed to detect rotational activity such as rotors by creating a network of excitation. This research aims to compare the performance of advanced PM techniques versus DGM for the detection of rotors using 64 simulated 2D meandering rotors in the presence of various levels of fibrotic tissue and temporal noise. Four strategies were employed to compare the performances of PM and DGM. These included a visual analysis, a comparison of F2-scores and distance distributions, and calculating p-values using the mid-p McNemar test. Results indicate that in the case of low meandering, fibrosis and noise, PM and DGM yield excellent results and are comparable. However, in the case of high meandering, fibrosis and noise, PM is undeniably prone to errors, mainly in the form of an excess of false positives, resulting in low precision. In contrast, DGM is more robust against these factors as F2-scores remain high, yielding F2≥0.931 as opposed to the best PM F2≥0.635 across all 64 simulations.

Directed graph mapping shows rotors maintain non-terminating and focal sources maintain self-terminating Torsade de Pointes in canine model.

Torsade de Pointes is a polymorphic ventricular tachycardia which is as yet incompletely understood. While the onset of a TdP episode is generally accepted to be caused by triggered activity, the mechanisms for the perpetuation is still under debate. In this study, we analysed data from 54 TdP episodes divided over 5 dogs (4 female, 1 male) with chronic atrioventricular block. Previous research on this dataset showed both reentry and triggered activity to perpetuate the arrhythmia. 13 of those TdP episodes showed reentry as part of the driving mechanism of perpetuating the episode. The remaining 41 episodes were purely ectopic. Reentry was the main mechanism in long-lasting episodes (>14 beats), while focal sources were responsible for maintaining shorter episodes. Building on these results, we re-analysed the data using directed graph mapping This program uses principles from network theory and a combination of positional data and local activation times to identify reentry loops and focal sources within the data. The results of this study are twofold. First, concerning reentry loops, we found that on average non-terminating (NT) episodes (≥10 s) show significantly more simultaneous reentry loops than self-terminating (ST) TdP (<10 s). Non-terminating episodes have on average 2.72 ± 1.48 simultaneous loops, compared to an average of 1.33 ± 0.66 for self-terminating episodes. In addition, each NT episode showed a presence of (bi-)ventricular loops between 10.10% and 69.62% of their total reentry duration. Compared to the ST episodes, only 1 in 4 episodes (25%) showed (bi-)ventricular reentry, lasting only 7.12% of its total reentry duration. This suggests that while focal beats trigger TdP, macro-reentry and multiple simultaneous localized reentries are the major drivers of long-lasting episodes. Second, using heatmaps, we found focal sources to occur in preferred locations, instead of being distributed randomly. This may have implications on treatment if such focal origins can be disabled reliably.

Directed Graph Mapping for Ventricular Tachycardia: A Comparison to Established Mapping Techniques.

BACKGROUND: Understanding underlying mechanism(s) and identifying critical circuit components are fundamental to successful ventricular tachycardia (VT) ablation. Directed graph mapping (DGM) offers a novel technique to identify the mechanism and critical components of a VT circuit. OBJECTIVES: This study sought to evaluate the accuracy of DGM in VT ablation compared with traditional mapping techniques and a commercially available automated conduction velocity mapping (ACVM) tool. METHODS: Patients with structural heart disease who had undergone a VT ablation with entrainment-proven critical isthmus and a high-density electroanatomical activation map were included. Traditional mapping (TM) consisted of a combination of local activation time and entrainment mapping and was considered the gold standard for determining the VT mechanism, circuit, and isthmus location. The same local activation time values were then processed using DGM and a commercially available ACVM (Coherent Mapping, Biosense Webster) tool. The aim of this study was to compare TM vs DGM and ACVM in their ability to identify the VT mechanism, characterize the VT circuit, and locate the critical isthmus. RESULTS: Thirty-five cases were identified. TM classified the VT mechanism as focal in 7 patients and re-entrant in 28 patients. TM classified 11 VTs as single-loop re-entry, 15 as dual-loop re-entry, 1 as complex, and 1 case was indeterminant. The overall agreement between DGM and TM for determining VT mechanism and circuit type was strong (kappa value = 0.79; P < 0.01), as was the agreement between ACVM and TM (kappa value = 0.66; P < 0.01). Both DGM and ACVM identified the putative VT isthmus in 25 (89%) of the re-entrant cases. Focal activation was correctly identified by both techniques in all cases. CONCLUSIONS: DGM is a rapid automated algorithm that has a strong level of agreement with TM for manually re-annotated VT maps.

DG-Mapping: a novel software package for the analysis of any type of reentry and focal activation of simulated, experimental or clinical data of cardiac arrhythmia.

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 . Graphical Abstract Direct-Graph-Mapping is a method to automatically analyze a given arrhythmia by converting measured data of the electrodes in a directed network. DGM requires the local activation times (LAT) and the spatial coordinates of the measured electrodes. There is no requirement for any spatial organization of the electrodes, allowing to analyze clinical, experimental or computational data (see left). An example could be the LATs and coordinates from a CARTO file. DGM creates a directed network of the activation by (1) determining the neighbors of each node, 2 (2) allowing a directed arrow between two neighbors if propagation of the electrical wave is possible, (3) repeating this process for all nodes, (4) if necessary, redistributing the nodes more uniformly and repeating step (1)-(3). Two possible steps are (5) to visualize the wavefront by creating an average graph or (6) find the cycles in the network which represent the reentry loops. Focal sources are nodes with only outgoing arrows.

Directed graph mapping exceeds phase mapping in discriminating true and false rotors detected with a basket catheter in a complex in-silico excitation pattern.

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 CVmin=0.01cmms, 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 CVmin to 0.02cmms had a stronger effect on the false rotors than on the true rotor. This led to a detection rate of 56.6% 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 CVmin=0.01cmms (14.7%). For CVmin=0.02cmms 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 (CVmin). The true rotor is less dependent on this parameter than the false rotors, which disappear at a CVmin=0.02cmms. In order to increase to detection rate of the true rotor, one can decrease CVmin and discard the new rotors which also appear at lower values of CVmin.

Evaluation of Directed Graph-Mapping in Complex Atrial Tachycardias.

OBJECTIVES: Directed graph-mapping (DGM) is a novel operator-independent automatic tool that can be applied to the identification of the atrial tachycardia (AT) mechanism. In the present study, for the first time, DGM was applied in complex AT cases, and diagnostic accuracy was evaluated. BACKGROUND: Catheter ablation of ATs still represents a challenge, as the identification of the correct mechanism can be difficult. New algorithms for high-density activation mapping (HDAM) render an easier acquisition of more detailed maps; however, understanding of the mechanism and, thus, identification of the ablation targets, especially in complex cases, remains strongly operator-dependent. METHODS: HDAMs acquired with the latest algorithm (COHERENT version 7, Biosense Webster, Irvine, California) were interpreted offline by 4 expert electrophysiologists, and the acquired electrode recordings with corresponding local activation times (LATs) were analyzed by DGM (also offline). Entrainment maneuvers (EM) were performed to understand the correct mechanism, which was then confirmed by successful ablation (13 cases were centrifugal, 10 cases were localized re-entry, 22 cases were macro-re-entry, and 6 were double-loops). In total, 51 ATs were retrospectively analyzed. We compared the diagnoses made by DGM were compared with those of the experts and with additional EM results. RESULTS: In total, 51 ATs were retrospectively analyzed. Experts diagnosed the correct AT mechanism and location in 33 cases versus DGM in 38 cases. Diagnostic accuracy varied according to different AT mechanisms. The 13 centrifugal activation patterns were always correctly identified by both methods; 2 of 10 localized reentries were identified by the experts, whereas DGM diagnosed 7 of 10. For the macro-re-entries, 12 of 22 were correctly identified using HDAM versus 13 of 22 for DGM. Finally, 6 of 6 double-loops were correctly identified by the experts, versus 5 of 6 for DGM. CONCLUSIONS: Even in complex cases, DGM provides an automatic, fast, and operator-independent tool to identify the AT mechanism and location and could be a valuable addition to current mapping technologies.

Finding type and location of the source of cardiac arrhythmias from the averaged flow velocity field using the determinant-trace method.

Life threatening cardiac arrhythmias result from abnormal propagation of nonlinear electrical excitation waves in the heart. Finding the locations of the sources of these waves remains a challenging problem. This is mainly due to the low spatial resolution of electrode recordings of these waves. Also, these recordings are subjected to noise. In this paper, we develop a different approach: the AFV-DT method based on an averaged flow velocity (AFV) technique adopted from the analysis of optical flows and the determinant-trace (DT) method used for vector field analysis of dynamical systems. This method can find the location and determine all important types of sources found in excitable media such as focal activity, spiral waves, and waves rotating around obstacles. We test this method on in silico data of various wave excitation patterns obtained using the Luo-Rudy model for cardiac tissue. We show that the method works well for data with low spatial resolutions (up to 8×8) and is stable against noise. Finally, we apply it to two clinical cases and show that it can correctly identify the arrhythmia type and location. We discuss further steps on the development and improvement of this approach.

Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating.

Cx43 hemichannels (HCs) are electrically and chemically gated transmembrane pores with low open probability and multiple conductance states, which makes kinetic studies of channel gating in large datasets challenging. Here, we developed open access software, named HemiGUI, to analyze HC gating transitions and investigated voltage-induced HC opening based on up to ≈4000 events recorded in HeLa-Cx43-overexpressing cells. We performed a detailed characterization of Cx43 HC gating profiles and specifically focused on the role of the C-terminal tail (CT) domain by recording the impact of adding an EGFP tag to the Cx43 CT end (Cx43-EGFP) or by supplying the Cx43 HC-inhibiting peptide Gap19 that interferes with CT interaction with the cytoplasmic loop (CL). We found that Gap19 not only decreased HC opening activity to the open state (≈217 pS) but also increased the propensity of subconductance (≈80 pS) transitions that additionally became slower as compared to the control. The work demonstrates that large sample transition analysis allows detailed investigations on Cx43 HC gating and shows that Gap19 acts as a HC gating modifier by interacting with the CT that forms a crucial gating element.

Prospective evaluation of entrainment mapping as an adjunct to new-generation high-density activation mapping systems of left atrial tachycardias.

BACKGROUND: Identification of atrial tachycardia (AT) mechanism remains challenging. OBJECTIVE: We sought to investigate the added value of entrainment maneuvers (EM) when using new high-density activation mapping (HDAM) technologies for the identification of complex left ATs. METHODS: Thirty-six consecutive complex ATs occurring after ablation of persistent atrial fibrillation were prospectively analyzed. The AT mechanism was diagnosed in 2 steps by 2 experts: (1) based on HDAM only (Coherent module, CARTO, Biosense Webster Inc., Irvine, CA) and (2) with additional analysis from EM. RESULTS: EM resulted in atrial fibrillation in 1 patient, who was excluded from the analysis. Ten of 11 single loop macroreentries identified by HDAM were confirmed by EM. Only 4 of 14 double loop macroreentries identified by HDAM wereconfirmed by EM (in 10 patients, EM unmasked passive activation of one of the visual circuits). One sole microreentry circuit identified by HDAM was confirmed by EM. A combination of macro- and microreentry circuits was visualized in 3 ATs using HDAM. However, EM revealed passive activation of the visual macroreentrant loop in 2 of these 3 cases. By using HDAM in 6 of 35 ATs (17%), no univocal mechanism could be identified, whereas EM finally enabled the diagnosis of 5 microreentry circuits and 1 macroreentrant AT. All the diagnoses made from EM in addition to HDAM were confirmed by ablation. CONCLUSION: Entrainment maneuvers are still useful during mapping of complex left ATs, mostly to differentiate active from passive macroreentrant loops and to demonstrate microreentry circuits.

R-From-T as a Common Mechanism of Arrhythmia Initiation in Long QT Syndromes.

BACKGROUND: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. METHODS: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. RESULTS: Spontaneous initiation of PVT was elicited by gradually ramping up ICa,L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As ICa,L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced ICa,L lead to PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. CONCLUSIONS: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting ICa,L properties, such as suppressing window ICa,L or preventing excessive ICa,L increase, could be an effective unified therapy for arrhythmia prevention in LQTS.

Directed Networks as a Novel Way to Describe and Analyze Cardiac Excitation: Directed Graph Mapping.

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.

Dynamical anchoring of distant arrhythmia sources by fibrotic regions via restructuring of the activation pattern.

Rotors are functional reentry sources identified in clinically relevant cardiac arrhythmias, such as ventricular and atrial fibrillation. Ablation targeting rotor sites has resulted in arrhythmia termination. Recent clinical, experimental and modelling studies demonstrate that rotors are often anchored around fibrotic scars or regions with increased fibrosis. However, the mechanisms leading to abundance of rotors at these locations are not clear. The current study explores the hypothesis whether fibrotic scars just serve as anchoring sites for the rotors or whether there are other active processes which drive the rotors to these fibrotic regions. Rotors were induced at different distances from fibrotic scars of various sizes and degree of fibrosis. Simulations were performed in a 2D model of human ventricular tissue and in a patient-specific model of the left ventricle of a patient with remote myocardial infarction. In both the 2D and the patient-specific model we found that without fibrotic scars, the rotors were stable at the site of their initiation. However, in the presence of a scar, rotors were eventually dynamically anchored from large distances by the fibrotic scar via a process of dynamical reorganization of the excitation pattern. This process coalesces with a change from polymorphic to monomorphic ventricular tachycardia.

Effects of early afterdepolarizations on excitation patterns in an accurate model of the human ventricles.

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.

Spatial Patterns of Excitation at Tissue and Whole Organ Level Due to Early Afterdepolarizations.

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.

Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue.

Managing lethal cardiac arrhythmias is one of the biggest challenges in modern cardiology, and hence it is very important to understand the factors underlying such arrhythmias. While early afterdepolarizations (EAD) of cardiac cells is known to be one such arrhythmogenic factor, the mechanisms underlying the emergence of tissue level arrhythmias from cellular level EADs is not fully understood. Another known arrhythmogenic condition is fibrosis of cardiac tissue that occurs both due to aging and in many types of heart diseases. In this paper we describe the results of a systematic in-silico study, using the TNNP model of human cardiac cells and MacCannell model for (myo)fibroblasts, on the possible effects of diffuse fibrosis on arrhythmias occurring via EADs. We find that depending on the resting potential of fibroblasts (VFR), M-F coupling can either increase or decrease the region of parameters showing EADs. Fibrosis increases the probability of occurrence of arrhythmias after a single focal stimulation and this effect increases with the strength of the M-F coupling. While in our simulations, arrhythmias occur due to fibrosis induced ectopic activity, we do not observe any specific fibrotic pattern that promotes the occurrence of these ectopic sources.

Short-Lasting Episodes of Torsade de Pointes in the Chronic Atrioventricular Block Dog Model Have a Focal Mechanism, While Longer-Lasting Episodes Are Maintained by Re-Entry.

OBJECTIVES: This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. BACKGROUND: The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the initiation and the perpetuation of TdP. METHODS: In 5 TdP-sensitive chronic atrioventricular block dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10 s. Software was developed to automatically detect activation times and to create 3-dimensional visualizations of the arrhythmia. For each episode of ectopic activity (ranging from 2 beats to NT episodes), a novel methodology was created to construct directed graphs of the wave propagation and detect re-entry loops by using an iterative depth-first-search algorithm. RESULTS: Depending on the TdP definition (number of consecutive ectopic beats), we analyzed 29 to 54 TdP: 29 were longer than 5 beats. In the total group, 9 were NT and 45 were self-terminating. Initiation and termination were always based on focal activity. Re-entry becomes more important in the longer-lasting episodes (>14 beats), whereas in all NT TdP, re-entry was the last active mechanism. During re-entry, excitation fronts were constantly present in the heart, while during focal TdP, there was always a silent interval between 2 consecutive waves (142 ms) during which excitation fronts were absent. Interbeat intervals were significantly smaller for re-entry episodes-220 versus 310 ms in focal. Electrograms recorded in particular areas during NT TdP episodes had significantly smaller amplitude (0.38) than during focal episodes (0.59). CONCLUSIONS: TdP can be driven by focal activity as well as by re-entry depending on the duration of the episode. NT episodes are always maintained by re-entry, which can be identified in local unipolar electrograms by shorter interbeat intervals and smaller deflection amplitude.

Physiology-based regularization of the electrocardiographic inverse problem.

The inverse problem of electrocardiography aims at noninvasively reconstructing electrical activity of the heart from recorded body-surface electrocardiograms. A crucial step is regularization, which deals with ill-posedness of the problem by imposing constraints on the possible solutions. We developed a regularization method that includes electrophysiological input. Body-surface potentials are recorded and a computed tomography scan is performed to obtain the torso-heart geometry. Propagating waveforms originating from several positions at the heart are simulated and used to generate a set of basis vectors representing spatial distributions of potentials on the heart surface. The real heart-surface potentials are then reconstructed from the recorded body-surface potentials by finding a sparse representation in terms of this basis. This method, which we named 'physiology-based regularization' (PBR), was compared to traditional Tikhonov regularization and validated using in vivo recordings in dogs. PBR recovered details of heart-surface electrograms that were lost with traditional regularization, attained higher correlation coefficients and led to improved estimation of recovery times. The best results were obtained by including approximate knowledge about the beat origin in the PBR basis.

Global alternans instability and its effect on non-linear wave propagation: dynamical Wenckebach block and self terminating spiral waves.

The main mechanism of formation of reentrant cardiac arrhythmias is via formation of waveblocks at heterogeneities of cardiac tissue. We report that heterogeneity and the area of waveblock can extend itself in space and can result formation of new additional sources, or termination of existing sources of arrhythmias. This effect is based on a new form of instability, which we coin as global alternans instability (GAI). GAI is closely related to the so-called (discordant) alternans instability, however its onset is determined by the global properties of the APD-restitution curve and not by its slope. The APD-restitution curve relates the duration of the cardiac pulse (APD) to the time interval between the pulses, and can easily be measured in an experimental or even clinical setting. We formulate the conditions for the onset of GAI, study its manifestation in various 1D and 2D situations and discuss its importance for the onset of cardiac arrhythmias.