Reentrant Activity Research Articles

Shunt and pace: a novel experimental model of atrial fibrillation with a volume-loaded left atrium.

Atrial fibrillation (AF) is frequently seen in patients with a volume-loaded left atrium (LA) such as mitral valve regurgitation (MR). Previous animal models have incomplete relevance to human AF associated with MR. A novel experimental model with a combination of volume loading of LA by creating a shunt from the subclavian artery to pulmonary artery and electrical remodeling induced by continuous rapid LA pacing was designed and the electrophysiological effects were examined in 10 canines. Five weeks after the shunt surgery, the entire atrial epicardium was mapped during sustained AF with form-fitted electrode patches with 246 bipolar electrodes and a three-dimensional dynamic mapping system to characterize the induced AF. Three animals died of severe heart failure and pacing failure occurred in one. Remaining six animals were subjected to the analysis. The LA diameter increased progressively after the shunt surgery. Sustained AF was induced after 3 weeks of continuous rapid LA pacing in all animals. The activation maps revealed repetitive focal activations arising from the pulmonary veins, right or left atrial regions, and reentrant activations in the RA, which patterns of atrial activations are the same as those seen in human AF. The animal model with a combination of LA volume load and electrical remodeling was relevant to human AF associated with LA volume load. Studies using the present model may provide further knowledges of AF and may be useful in examining the effects of pharmacological and non-pharmacological therapies.

Homogenisation for the monodomain model in the presence of microscopic fibrotic structures

Computational models in cardiac electrophysiology are notorious for long runtimes, restricting the numbers of nodes and mesh elements in the numerical discretisations used for their solution. This makes it particularly challenging to incorporate structural heterogeneities on small spatial scales, preventing a full understanding of the critical arrhythmogenic effects of conditions such as cardiac fibrosis. In this work, we explore the technique of homogenisation by volume averaging for the inclusion of non-conductive micro-structures into larger-scale cardiac meshes with minor computational overhead. Importantly, our approach is not restricted to periodic patterns, enabling homogenised models to represent, for example, the intricate patterns of collagen deposition present in different types of fibrosis. We first highlight the importance of appropriate boundary condition choice for the closure problems that define the parameters of homogenised models. Then, we demonstrate the technique’s ability to correctly upscale the effects of fibrotic patterns with a spatial resolution of 10µm into much larger numerical mesh sizes of 100-250µm. The homogenised models using these coarser meshes correctly predict critical pro-arrhythmic effects of fibrosis, including slowed conduction, source/sink mismatch, and stabilisation of re-entrant activation patterns. As such, this approach to homogenisation represents a significant step towards whole organ simulations that unravel the effects of microscopic cardiac tissue heterogeneities.

Low cardiac frequency associated with higher number of extrasistoles in a computational model of Brugada Syndrome.

Brugada Syndrome is a form of idiopathic ventricular fibrillation, to date there is no definitive theory about how ventricular fibrillation is initiated or its substrate. Starting from the clinical observation that cardiac episodes are more frequent at rest, we developed a model in order to study the effect of cardiac frequency on reentrant activity. Our results suggest that the combination of arrhythmic substrate and cardiac frequency has a role in the insurgence of cardiac arrhythmia.

Dg-mapping as a tool to determine the spatial distribution of the focal sources and the number of reentries during torsade de pointes in the cavb dog model

Abstract Funding Acknowledgements Type of funding sources: None. Background Torsade de Pointes (TdP) is a ventricular tachycardia that is still incompletely understood. While the origin of the arrhythmia is generally accepted to be caused by triggered activity, the perpetuation of such an episode is still under debate. Purpose We compare the difference in reentrant activity between self- and non-terminating(ST and NT) TdP episodes. In addition, we analyzed the distribution of the triggered activity for preferred locations. Methods A total of 5 dogs with Chronic Atrioventricular Block developed 54 episodes of TdP. These episodes were examined for reentry loops and focal sources. First, to detect loops, we used Directed Graph Mapping, a novel mapping technique based on principles from network theory. Subsequently, the number of simultaneous loops and the presence of (bi-)ventricular reentry was compared between the ST and NT groups. Second, focal sources were accumulated into heatmaps. The distribution of sources was compared to a randomly distributed model for the detection of preferred locations. Results Concerning reentry, during the time at which loops are present, a typical ST episode shows an average of 1.33(±0.66) reentry loops present at one time compared to an average of 2.72(±1.48) for a typical NT episode. Looking at the (bi-)ventricular reentry, only 1 of the 4 ST episodes (25%) shows the presence of this type of reentry and only 7.12 % of the total reentry duration, while all 9 NT episodes (100%) develop (bi-)ventricular reentry to a greater degree than in the one ST episode (Between 10.10% and 69.62% of their total reentry duration). Regarding the triggered activity, we see locations in the heatmaps containing up to 23% of all detected focal sources in the entire system. Compared to a random distribution of focal sources, the chances to get as many sources in one location as shown in the data are close to 0%. Conclusion Reentry in NT TdP differentiates itself from the reentry in ST cases on the basis of the number of simultaneous loops in the system and the presence of (bi-)ventricular reentry. Triggered activity in CAVB dogs occurs at preferred locations in the ventricles. Therefore, ablating these preferred regions could be a possible strategy to prevent TdP.

Prediction of ablation success in atrial fibrillation patients based on electrocardiographic imaging

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III, and Ministerio de Ciencia, Innovación y Universidades (supported by FEDER Fondo Europeo de Desarrollo Regional PI17/01106), Agencia Estatal de Investigación (RYC2018-024346B-750 and PID2020-119364RB-100), Generalitat Valenciana Grants (ACIF/2020/265) and EIT Health (Activity code 19600), EIT Health is supported by EIT, a body of the European Union). Introduction Success rates of pulmonary vein isolation (PVI) are still suboptimal for termination of Atrial Fibrillation (AF). Electrocardiographic imaging (ECGI) could be used to determine the state of the atrial substrate non-invasively. Objective Improve the current stratification protocol for AF patients candidates to PVI using ECGI metrics prior to the referral to an ablation procedure. Methods ECGI from 35 AF patients (22 male, 10 paroxysmal, 63.3 ± 9.5 years) were recorded prior to PVI plus rotor ablation. Patients were latter classified based on their 6 months follow-up (23 sinus rhythm vs. 12 arrhythmia recurrence). ECGI dominant frequencies (DF) and rotor metrics were calculated in each patient, together with their temporal variability. Multivariate logistic regression was computed on the metrics, their variability and AF type to study the prediction power on ablation outcome. Results Dominant frequency metrics present higher values in patients with arrhythmia recurrence after the ablation. Rotor metrics showed higher variability in patients with bad PVI outcome (Table 1). ECGI metrics alone allow better outcome prediction (Fig. 1) than standard AF classification (AUC = 0.85 vs. 0.65). ECGI metrics combined with the type of AF increased outcome prediction, AUC = 0.88. Conclusion Patients with poor ablation outcome presented higher DFs and reentrant activity variability than patients with good PVI outcome. ECGI derived metrics in combination with AF classification increase PVI follow-up prediction compared to traditional patient stratification showing potential to be an alternative to the standard of care.

Detection of focal source and arrhythmogenic substrate from body surface potentials to guide atrial fibrillation ablation.

Focal sources (FS) are believed to be important triggers and a perpetuation mechanism for paroxysmal atrial fibrillation (AF). Detecting FS and determining AF sustainability in atrial tissue can help guide ablation targeting. We hypothesized that sustained rotors during FS-driven episodes indicate an arrhythmogenic substrate for sustained AF, and that non-invasive electrical recordings, like electrocardiograms (ECGs) or body surface potential maps (BSPMs), could be used to detect FS and AF sustainability. Computer simulations were performed on five bi-atrial geometries. FS were induced by pacing at cycle lengths of 120–270 ms from 32 atrial sites and four pulmonary veins. Self-sustained reentrant activities were also initiated around the same 32 atrial sites with inexcitable cores of radii of 0, 0.5 and 1 cm. FS fired for two seconds and then AF inducibility was tested by whether activation was sustained for another second. ECGs and BSPMs were simulated. Equivalent atrial sources were extracted using second-order blind source separation, and their cycle length, periodicity and contribution, were used as features for random forest classifiers. Longer rotor duration during FS-driven episodes indicates higher AF inducibility (area under ROC curve = 0.83). Our method had accuracy of 90.6±1.0% and 90.6±0.6% in detecting FS presence, and 93.1±0.6% and 94.2±1.2% in identifying AF sustainability, and 80.0±6.6% and 61.0±5.2% in determining the atrium of the focal site, from BSPMs and ECGs of five atria. The detection of FS presence and AF sustainability were insensitive to vest placement (±9.6%). On pre-operative BSPMs of 52 paroxysmal AF patients, patients classified with initiator-type FS on a single atrium resulted in improved two-to-three-year AF-free likelihoods (p-value < 0.01, logrank tests). Detection of FS and arrhythmogenic substrate can be performed from ECGs and BSPMs, enabling non-invasive mapping towards mechanism-targeted AF treatment, and malignant ectopic beat detection with likely AF progression.

Purkinje network and myocardial substrate at the onset of human ventricular fibrillation: implications for catheter ablation.

AimsMapping data of human ventricular fibrillation (VF) are limited. We performed detailed mapping of the activities underlying the onset of VF and targeted ablation in patients with structural cardiac abnormalities.Methods and resultsWe evaluated 54 patients (50 ± 16 years) with VF in the setting of ischaemic (n = 15), hypertrophic (n = 8) or dilated cardiomyopathy (n = 12), or Brugada syndrome (n = 19). Ventricular fibrillation was mapped using body-surface mapping to identify driver (reentrant and focal) areas and invasive Purkinje mapping. Purkinje drivers were defined as Purkinje activities faster than the local ventricular rate. Structural substrate was delineated by electrogram criteria and by imaging. Catheter ablation was performed in 41 patients with recurrent VF. Sixty-one episodes of spontaneous (n = 10) or induced (n = 51) VF were mapped. Ventricular fibrillation was organized for the initial 5.0 ± 3.4 s, exhibiting large wavefronts with similar cycle lengths (CLs) across both ventricles (197 ± 23 vs. 196 ± 22 ms, P = 0.9). Most drivers (81%) originated from areas associated with the structural substrate. The Purkinje system was implicated as a trigger or driver in 43% of patients with cardiomyopathy. The transition to disorganized VF was associated with the acceleration of initial reentrant activities (CL shortening from 187 ± 17 to 175 ± 20 ms, P < 0.001), then spatial dissemination of drivers. Purkinje and substrate ablation resulted in the reduction of VF recurrences from a pre-procedural median of seven episodes [interquartile range (IQR) 4–16] to 0 episode (IQR 0–2) (P < 0.001) at 56 ± 30 months.ConclusionsThe onset of human VF is sustained by activities originating from Purkinje and structural substrate, before spreading throughout the ventricles to establish disorganized VF. Targeted ablation results in effective reduction of VF burden.Key questionThe initial phase of human ventricular fibrillation (VF) is critical as it involves the primary activities leading to sustained VF and arrhythmic sudden death. The origin of such activities is unknown.Key findingBody-surface mapping shows that most drivers (≈80%) during the initial VF phase originate from electrophysiologically defined structural substrates. Repetitive Purkinje activities can be elicited by programmed stimulation and are implicated as drivers in 37% of cardiomyopathy patients.Take-home messageThe onset of human VF is mostly associated with activities from the Purkinje network and structural substrate, before spreading throughout the ventricles to establish sustained VF. Targeted ablation reduces or eliminates VF recurrence.

Optogenetic Control of Human Induced Pluripotent Stem Cell-Derived Cardiac Tissue Models.

BackgroundOptogenetics, using light‐sensitive proteins, emerged as a unique experimental paradigm to modulate cardiac excitability. We aimed to develop high‐resolution optogenetic approaches to modulate electrical activity in 2‐ and 3‐dimensional cardiac tissue models derived from human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes.Methods and ResultsTo establish light‐controllable cardiac tissue models, opsin‐carrying HEK293 cells, expressing the light‐sensitive cationic‐channel CoChR, were mixed with hiPSC‐cardiomyocytes to generate 2‐dimensional hiPSC‐derived cardiac cell‐sheets or 3‐dimensional engineered heart tissues. Complex illumination patterns were designed with a high‐resolution digital micro‐mirror device. Optical mapping and force measurements were used to evaluate the tissues' electromechanical properties. The ability to optogenetically pace and shape the tissue's conduction properties was demonstrated by using single or multiple illumination stimulation sites, complex illumination patterns, or diffuse illumination. This allowed to establish in vitro models for optogenetic‐based cardiac resynchronization therapy, where the electrical activation could be synchronized (hiPSC‐derived cardiac cell‐sheets and engineered heart tissue models) and contractile properties improved (engineered heart tissues). Next, reentrant activity (rotors) was induced in the hiPSC‐derived cardiac cell‐sheets and engineered heart tissue models through optogenetics programmed‐ or cross‐field stimulations. Diffuse illumination protocols were then used to terminate arrhythmias, demonstrating the potential to study optogenetics cardioversion mechanisms and to identify optimal illumination parameters for arrhythmia termination.ConclusionsBy combining optogenetics and hiPSC technologies, light‐controllable human cardiac tissue models could be established, in which tissue excitability can be modulated in a functional, reversible, and localized manner. This approach may bring a unique value for physiological/pathophysiological studies, for disease modeling, and for developing optogenetic‐based cardiac pacing, resynchronization, and defibrillation approaches.

Real-Time Phase Mapping-Based Adjunctive Substrate Ablation of Reentrant Activities Improves Outcome in Persistent Atrial Fibrillation

Real-Time Phase Mapping-Based Adjunctive Substrate Ablation of Reentrant Activities Improves Outcome in Persistent Atrial Fibrillation

The Purkinje network plays a major role in low-energy ventricular defibrillation

BackgroundDuring ventricular fibrillation (VF), targeting the excitable gap (EG) of reentry throughout the myocardium with low-energy surface stimulation shows promise for painless defibrillation. However, the Purkinje network may provide alternative pathways for reentry to evade termination. This study investigates the role of the Purkinje network in painless defibrillation. MethodsIn a computational human biventricular model featuring a Purkinje network, VF was initiated with 4 Hz epicardial pacing. Defibrillation was attempted by stimulating myocardial surface EG with a low-energy 2 ms duration pulse at 2x stimulus capture, which was administered at coupling intervals incremented by 0.25 s between 0.25 and 5 s after VF initiation. Defibrillation was accomplished if reentry ceased ≤ 1 s after the defibrillation pulse. The protocol was repeated with the Purkinje network and myocardial surface EG stimulated simultaneously, and again after uncoupling the Purkinje network from the myocardium. ResultsVF with the Purkinje network coupled and uncoupled had comparable dominant frequency in the left (3.81 ± 0.44 versus 3.77 ± 0.53 Hz) and right (3.80 ± 0.37 versus 3.76 ± 0.48 Hz) ventricles. When uncoupling the Purkinje network, myocardial surface EG stimulation terminated VF for all defibrillation pulses. When coupled, myocardial EG surface stimulation terminated VF for only 55% of the defibrillation pulses, but improved to 100% when stimulated simultaneously with Purkinje network EG. Defibrillation failures were attributed to EG evading stimulation in the Purkinje network. ConclusionsDefibrillation that exclusively targets myocardium can fail due to accessory pathways in the Purkinje network that allow for reentrant activity to evade termination and maintain VF. Painless defibrillation strategies should be adapted to include the Purkinje network.

Abstract 14293: Automated Arrhythmia Detection in HiPSC-Derived Cardiac Cell Sheet Models for Drug Testing and Disease Modeling

Introduction: The use of human-induced pluripotent stem cells (hiPSC) derived cardiomyocytes may bring a unique value for drug testing and disease modeling applications. In this project, we developed an automatic and robust arrhythmia detection tool that enables recognition of early-after-depolarizations (EADs) and reentrant activity (spiral waves) in hiPSC-derived cardiac tissue models. Methods and Results: hiPSCs were differentiated into cardiomyocytes, seeded as large-scale hiPSC-derived cardiac cell-sheets (hiPSC-CCSs), loaded with a voltage-sensitive dye, and optically mapped. Arrhythmias were induced either spontaneously, using pacing interventions, or following drug applications. We examined two algorithms to detect spiral wave arrhythmias: optical flow (OF) and dominant frequency (DF). OF enables flow detection through spatial analysis of local velocity vectors (Fig.1 a-d). DF maps depict the frequency with the highest energy in each pixel (Fig.1 e-f). Spiral waves were readily detected by both approaches by the presence of significant diversity in both the frequencies maps (DF) and in the velocity angles (OF). Moreover, in DF maps, the core of the spiral wave (singularity point) could be identified as pixels displaying high dominant frequency as compared to values in other parts of the specimen. (Figure 1). Finally, EADs could be detected using a curve-fitting approach (Fig.1g). Figure 1: (a-d) Consecutive optical map frames (a, c) and velocity vector maps (b, d) of normal (a, b) and a spiral wave (c-d) propagations. (e-f ) DF maps of normal (e) and spiral wave (f) propagations. (g) EAD detection in red. Conclusion: Automatic algorithms were developed to enable robust detection of arrhythmic activity (EADs and spiral waves) in a hiPSC-based cardiac tissue model. This novel approach may bring a unique value to arrhythmia mechanistic studies, high throughput drug screening, and disease modeling.

Abstract 10530: Stretch-Induced Arrhythmias Are Increased by Microtubule Detyrosination in a TRPA1 Dependent Manner in the Rabbit Heart

Introduction: Clinical evidence indicates that in hypertension, acute fluctuations in blood pressure can trigger ventricular arrhythmias. Single cell rabbit studies suggest that these stretch-induced arrhythmias (SIA) are related to increased microtubule (MT) density or detyrosination and depend on transient receptor potential ankyrin 1 channels (TRPA1). However, whether these mechanisms of SIA apply to the whole heart is unknown. Hypothesis: An increase in MT density or detyrosination will reduce the threshold for SIA in the whole heart and be dependent on TRPA1. Methods: Isolated rabbit hearts were instrumented with surface electrodes to monitor electrical activity and an intraventricular balloon to alter LV load. Transient changes in LV volume were applied to induce SIA (50-500μL, 10mL/s, 20 repetitions of each volume separated by 30s). SIA incidence vs volume was used to calculate the volume that resulted in a 50% SIA incidence (V 50 ). Paclitaxel (5μM) was applied alone to increase MT density and detyrosination or in combination with parthenolide (10μM) to prevent the increase in detyrosination or HC-030031 (10μM) to block TRPA1. Voltage optical mapping was used to determine the nature of SIA. MT density was assessed by immunofluorescence in isolated LV myocytes. Results: Paclitaxel reduced the threshold for SIA (decreased V 50 versus control: 133±16 vs 173±11μL; n =8 , p =0.02 by paired t-test) and resulted in the conversion of some stretch-induced ectopy to sustained activity. These effects were prevented by reduced detyrosination with parthenolide (262±27 vs 256±26μL; n =8 , p =0.75). Paclitaxel also increased MT density versus control, however this was not prevented by parthenolide (63±3 and 60±3 vs 50±4%; n =15, p =0.04 by one-way ANOVA). The decreased V 50 and occurrence of sustained arrhythmias with paclitaxel was also prevented by TRPA1 block with HC-030031 (249±26 vs 237±27μL; n =8, p =0.60). Optical mapping revealed stretch-induced ectopic excitation originating from the LV freewall, which resulted in re-entrant activity with paclitaxel. Conclusions: An increase in MT detyrosination leads to a reduced threshold for SIA and the triggering of sustained arrhythmias in the whole heart in a TRPA1 dependent manner.

Higher reproducibility of phase derived metrics from electrocardiographic imaging during atrial fibrillation in patients remaining in sinus rhythm after pulmonary vein isolation

BackgroundElectrocardiographic imaging (ECGI) allows evaluating the complexity of the reentrant activity of atrial fibrillation (AF) patients. In this study, we evaluated the ability of ECGI metrics to predict the success of pulmonary vein isolation (PVI) to treat AF. MethodsECGI of 24 AF patients (6 males, 13 paroxysmal, 61.8 ± 14 years) was recorded prior to PVI. Patients were distributed into two groups based on their PVI outcome 6 months after ablation (sinus vs. arrhythmia recurrence). Metrics derived from phase analysis of ECGI signals were computed for two different temporal segments before ablation. Correlation analysis and variability over time were studied between the two recorded segments and were compared between patient groups. ResultsTemporal variability of both rotor duration and spatial entropy of the rotor histogram presented statistical differences between groups with different PVI outcome (p < 0.05). The reproducibility of reentrant metrics was higher (R2 > 0.8) in patients with good outcome rather than arrhythmia recurrence patients (R2 < 0.62). Prediction of PVI success based on ECGI temporal variability metrics allows for an increased specificity over the classification into paroxysmal or persistent (0.85 vs. 0.64). ConclusionsPatients with favorable PVI outcome present ECGI metrics more reproducible over time than patients with AF recurrence. These results suggest that ECGI derived metrics may allow selecting which patients would benefit from ablation therapies.

Atrial proarrhythmic effect of lead as one of the PM10 metal components of air pollution. An in-silico study.

Particulate matter (PM) is considered the most severe environmental pollution problem due to its serious effects on human health associated with an increased risk of cardiovascular morbidity and mortality. In this work, a physicochemical characterization of PM10 from the city of Medellin was developed. The results evince that lead (Pb) is one of the most abundant elements since it is present in all analyzed samples. Therefore, Pb was chosen to perform an in-silico study to assess its effects on atrial arrhythmias generation. For this purpose, we developed a model representing the Pb2+ blocking effect on the L-type calcium channel. This formulation was incorporated in a human atrial cell mathematical model and in 2D and 3D models of human atria. The simulations showed a proarrhythmic effect at high Pb2+ concentrations, through shortening of action potential duration inducing the generation of reentrant activity and atrial flutter. The results contribute to the knowledge about the cardiac physiopathological processes, triggered by lead as one of the main PM10 metal components of air pollution, that yields the generation of arrhythmias.

Isolated superfused rats atrial model for the investigation of atrial fibrillation mechanisms and treatment

Abstract Background One of the major barriers to an improved mechanistic understanding of atrial fibrillation (AF), and thus in the pipeline of drug development, has been a lack of appropriate tissue models, especially in small animals. Aim We propose an advanced anatomical ex-vivo model based on rat atria for acute assessment of AF susceptibility. This novel model could yield a better understanding of arrhythmia mechanisms as well as the development of potential therapeutic strategies for the prevention or termination of atrial arrhythmias. Methods Wistar rats atria (N=25) were isolated, flattened and pinned to a custom-made silicon plate. Atria were superfused with an oxygenized Tyrode's solution. Tissues were then loaded with a voltage-sensitive dye and mapped using a high-resolution optical mapping system. AF was induced with 1uM carbamylcholine (N=23) coupled with pacing maneuvers and treated with 30uM Vernakalant (N=10) or 10uM Flecainide (N=10). Finally, the feasibility of a new ablation technique (electroporation) was evaluated. Results Optical mapping results suggested that the superfusion procedure led to a fast atrial recovery. Sinus activity was conserved for all atria for a long period. All the anatomical landmarks were clearly visualized. The acquired optical signals were analyzed during sinus rhythm and pacing, which allowed the creation of detailed activation maps and measurements of action potential duration (APD) and conduction velocity (CV) at different pacing rates. The resulting APD restitution curves revealed electrical excitation at high pacing rates (cycle length between 50ms and 300ms) with a relatively flattened curve. AF was successfully induced and optically mapping confirmed the presence of reentrant activity. AF was successfully treated using Vernacalant and Flecainide. Finally, we demonstrated the feasibility of a new ablation approach (electroporation) for creation of a continuous linear lesion serving as a functional block. Conclusion The isolated superfused atria model, coupled with voltage-sensitive dyes, can be utilized for long-term high-resolution functional imaging of the atria during sinus rhythm, pacing and arrhythmogenic activity. This allows the study of the atrial electrophysiological properties, the mechanisms involved in AF initiation, perpetuation, and termination as well as the study of drug and new ablation modalities. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) Spontaneous activation of isolated atria

Machine Learning Identification of Pro-arrhythmic Structures in Cardiac Fibrosis.

Cardiac fibrosis and other scarring of the heart, arising from conditions ranging from myocardial infarction to ageing, promotes dangerous arrhythmias by blocking the healthy propagation of cardiac excitation. Owing to the complexity of the dynamics of electrical signalling in the heart, however, the connection between different arrangements of blockage and various arrhythmic consequences remains poorly understood. Where a mechanism defies traditional understanding, machine learning can be invaluable for enabling accurate prediction of quantities of interest (measures of arrhythmic risk) in terms of predictor variables (such as the arrangement or pattern of obstructive scarring). In this study, we simulate the propagation of the action potential (AP) in tissue affected by fibrotic changes and hence detect sites that initiate re-entrant activation patterns. By separately considering multiple different stimulus regimes, we directly observe and quantify the sensitivity of re-entry formation to activation sequence in the fibrotic region. Then, by extracting the fibrotic structures around locations that both do and do not initiate re-entries, we use neural networks to determine to what extent re-entry initiation is predictable, and over what spatial scale conduction heterogeneities appear to act to produce this effect. We find that structural information within about 0.5 mm of a given point is sufficient to predict structures that initiate re-entry with more than 90% accuracy.

The change of cardiac axis deviation in catheter ablation of verapamil-sensitive idiopathic left ventricular tachycardia.

The underlying mechanism of verapamil-sensitive idiopathic left ventricular tachycardia (ILVT) has been postulated to be reentrant activation in the Purkinje fiber network of the left posterior fascicle or the left anterior fascicle (LAF). However, changing of cardiac axis deviation in sinus rhythm (SR) or during ILVT after radiofrequency catheter ablation (RFCA) has been rarely analyzed. Of the 232 patients with sustained ILVT induced and surface electrocardiogram (ECG) in SR recorded before and after RFCA, the changes of ECG morphology in SR and during ILVT were analyzed. The surface ECG in SR changed in 114 (49.1%) patients after RFCA. ILVT could still be induced in 27 (23.7%) patients. In comparison with the original ILVT, three forms of ECG morphology were observed. In eight patients, the ILVT morphology was unchanged. In the 13 patients with ILVT axis deviation conversion after ablation, the successful target was more proximal. In the six patients with ILVT morphology change but without axis deviation conversion after ablation, the successful ablation site was more distal. Among 15 patients with recurrent ILVT during follow-up, seven patients had previous axis deviation changes in SR after RFCA, the changes maintained in four patients and recovered in three patients. The morphology changes on surface ECG in SR after RFCA would not be a necessary prerequisite or a good endpoint for ILVT ablation. To analyze ILVT morphology changes after ablation would help to further clarify an appropriate approach for catheter ablation of ILVT.

Arrhythmogenic effects of ultra-long and bistable cardiac action potentials.

Contemporary accounts of the initiation of cardiac arrhythmias typically rely on after-depolarizations as the trigger for reentrant activity. The after-depolarizations are usually triggered by calcium entry or spontaneous release within the cells of the myocardium or the conduction system. Here we propose an alternative mechanism whereby arrhythmias are triggered autonomously by cardiac cells that fail to repolarize after a normal heartbeat. We investigated the proposal by representing the heart as an excitable medium of FitzHugh-Nagumo cells where a proportion of cells were capable of remaining depolarized indefinitely. As such, those cells exhibit bistable membrane dynamics. We found that heterogeneous media can tolerate a surprisingly large number of bistable cells and still support normal rhythmic activity. Yet there is a critical limit beyond which the medium is persistently arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Moreover, arrhythmogenesis was found to emerge preferentially at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from tissue boundaries such as the cuff of the pulmonary vein.

Using machine learning to identify local cellular properties that support re-entrant activation in patient-specific models of atrial fibrillation.

AimsAtrial fibrillation (AF) is sustained by re-entrant activation patterns. Ablation strategies have been proposed that target regions of tissue that may support re-entrant activation patterns. We aimed to characterize the tissue properties associated with regions that tether re-entrant activation patterns in a validated virtual patient cohort.Methods and resultsAtrial fibrillation patient-specific models (seven paroxysmal and three persistent) were generated and validated against local activation time (LAT) measurements during an S1–S2 pacing protocol from the coronary sinus and high right atrium, respectively. Atrial models were stimulated with burst pacing from three locations in the proximity of each pulmonary vein to initiate re-entrant activation patterns. Five atria exhibited sustained activation patterns for at least 80 s. Models with short maximum action potential durations (APDs) were associated with sustained activation. Phase singularities were mapped across the atria sustained activation patterns. Regions with a low maximum conduction velocity (CV) were associated with tethering of phase singularities. A support vector machine (SVM) was trained on maximum local conduction velocity and action potential duration to identify regions that tether phase singularities. The SVM identified regions of tissue that could support tethering with 91% accuracy. This accuracy increased to 95% when the SVM was also trained on surface area.ConclusionIn a virtual patient cohort, local tissue properties, that can be measured (CV) or estimated (APD; using effective refractory period as a surrogate) clinically, identified regions of tissue that tether phase singularities. Combing CV and APD with atrial surface area further improved the accuracy in identifying regions that tether phase singularities.

Inverse mechano-electrical reconstruction of cardiac excitation wave patterns from mechanical deformation using deep learning.

The inverse mechano-electrical problem in cardiac electrophysiology is the attempt to reconstruct electrical excitation or action potential wave patterns from the heart's mechanical deformation that occurs in response to electrical excitation. Because heart muscle cells contract upon electrical excitation due to the excitation-contraction coupling mechanism, the resulting deformation of the heart should reflect macroscopic action potential wave phenomena. However, whether the relationship between macroscopic electrical and mechanical phenomena is well-defined and unique enough to be utilized for an inverse imaging technique in which mechanical activation mapping is used as a surrogate for electrical mapping has yet to be determined. Here, we provide a numerical proof-of-principle that deep learning can be used to solve the inverse mechano-electrical problem in phenomenological two- and three-dimensional computer simulations of the contracting heart wall, or in elastic excitable media, with muscle fiber anisotropy. We trained a convolutional autoencoder neural network to learn the complex relationship between electrical excitation, active stress, and tissue deformation during both focal or reentrant chaotic wave activity and, consequently, used the network to successfully estimate or reconstruct electrical excitation wave patterns from mechanical deformation in sheets and bulk-shaped tissues, even in the presence of noise and at low spatial resolutions. We demonstrate that even complicated three-dimensional electrical excitation wave phenomena, such as scroll waves and their vortex filaments, can be computed with very high reconstruction accuracies of about 95% from mechanical deformation using autoencoder neural networks, and we provide a comparison with results that were obtained previously with a physics- or knowledge-based approach.