Purkinje-myocardial Junctions Research Articles

Digital twinning of the human ventricular activation sequence to Clinical 12-lead ECGs and magnetic resonance imaging using realistic Purkinje networks for in silico clinical trials

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions.

The Purkinje-myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmia syndrome caused by gene mutations that render RYR2 Ca release channels hyperactive, provoking spontaneous Ca release and delayed afterdepolarizations (DADs). What remains unknown is the cellular source of ventricular arrhythmia triggered by DADs: Purkinje cells in the conduction system or ventricular cardiomyocytes in the working myocardium. To answer this question, we used a genetic approach in mice to knock out cardiac calsequestrin either in Purkinje cells or in ventricular cardiomyocytes. Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. We found that loss of calsequestrin only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of calsequestrin only in Purkinje cells were comparable to WT mice. Subendocardial chemical ablation or restoration of calsequestrin expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias. In silico modeling demonstrated that DADs in ventricular myocardium can trigger full action potentials in the Purkinje fiber, but not vice versa. Hence, ectopic beats in CPVT are likely generated at the Purkinje–myocardial junction via a heretofore unrecognized tissue mechanism, whereby DADs in the ventricular myocardium trigger full action potentials in adjacent Purkinje cells.

Estimation of Personalized Minimal Purkinje Systems From Human Electro-Anatomical Maps.

The Purkinje system is a heart structure responsible for transmitting electrical impulses through the ventricles in a fast and coordinated way to trigger mechanical contraction. Estimating a patient-specific compatible Purkinje Network from an electro-anatomical map is a challenging task, that could help to improve models for electrophysiology simulations or provide aid in therapy planning, such as radiofrequency ablation. In this study, we present a methodology to inversely estimate a Purkinje network from a patient's electro-anatomical map. First, we carry out a simulation study to assess the accuracy of the method for different synthetic Purkinje network morphologies and myocardial junction densities. Second, we estimate the Purkinje network from a set of 28 electro-anatomical maps from patients, obtaining an optimal conduction velocity in the Purkinje network of 1.95 ± 0.25 m/s, together with the location of their Purkinje-myocardial junctions, and Purkinje network structure. Our results showed an average local activation time error of 6.8±2.2 ms in the endocardium. Finally, using the personalized Purkinje network, we obtained correlations higher than 0.85 between simulated and clinical 12-lead ECGs.

Automatic estimation of Purkinje-Myocardial junction hot-spots from noisy endocardial samples: A simulation study.

The reconstruction of the ventricular cardiac conduction system (CCS) from patient-specific data is a challenging problem. High-resolution imaging techniques have allowed only the segmentation of proximal sections of the CCS from images acquired ex vivo. In this paper, we present an algorithm to estimate the location of a set of Purkinje-myocardial junctions (PMJs) from electro-anatomical maps, as those acquired during radio-frequency ablation procedures. The method requires a mesh representing the myocardium with local activation time measurements on a subset of nodes. We calculate the backwards propagation of the electrical signal from the measurement points to all the points in the mesh to define a set of candidate PMJs that is iteratively refined. The algorithm has been tested on several Purkinje network configurations, with simulated activation maps, subject to different error amplitudes. The results show that the method is able to build a set of PMJs that explain the observed activation map for different synthetic CCS configurations. In the tests, the average error in the predicted activation time is below the amplitude of the error applied to the data.

Efficient Computational Modeling of Human Ventricular Activation and Its Electrocardiographic Representation: A Sensitivity Study

Patient-specific models of the ventricular myocardium, combined with the computational power to run rapid simulations, are approaching the level where they could be used for personalized cardiovascular medicine. A major remaining challenge is determining model parameters from available patient data, especially for models of the Purkinje-myocardial junctions (PMJs): the sites of initial ventricular electrical activation. There are no non-invasive methods for localizing PMJs in patients, and the relationship between the standard clinical ECG and PMJ model parameters is underexplored. Thus, this study aimed to determine the sensitivity of the QRS complex of the ECG to the anatomical location and regional number of PMJs. The QRS complex was simulated using an image-based human torso and biventricular model, and cardiac electrophysiology was simulated using Cardioid. The PMJs were modeled as discrete current injection stimuli, and the location and number of stimuli were varied within initial activation regions based on published experiments. Results indicate that the QRS complex features were most sensitive to the presence or absence of four “seed” stimuli, and adjusting locations of nearby “regional” stimuli provided finer tuning. Decreasing number of regional stimuli by an order of magnitude resulted in virtually no change in the QRS complex. Thus, a minimal 12-stimuli configuration was identified that resulted in physiological excitation, defined by QRS complex feature metrics and ventricular excitation pattern. Overall, the sensitivity results suggest that parameterizing PMJ location, rather than number, be given significantly higher priority in future studies creating personalized ventricular models from patient-derived ECGs.

A quantitative structural and morphometric analysis of the Purkinje network and the Purkinje-myocardial junctions in pig hearts.

The morpho-functional properties of the distal section of the cardiac Purkinje network (PN) and the Purkinje-myocardial junctions (PMJs) are fundamental to understanding the sequence of electrical activation in the heart. The overall structure of the system has already been described, and several computational models have been developed to gain insight into its involvement in cardiac arrhythmias or its interaction with implantable devices, such as pacemakers. However, anatomical descriptions of the PN in the literature have not enabled enough improvements in the accuracy of anatomical-based electrophysiological simulations of the PN in 3D hearts models. In this work, we study the global distribution and morphological properties of the PN, with special emphasis on the cellular and architectural characterization of its intramural branching structure, mesh-like sub-endocardial network, and the PMJs in adult pig hearts by both histopathological and morphometric evaluation. We have defined three main patterns of PMJ: contact through cell bodies, contact through cell prolongations either thick or piliform, and contact through transitional cells. Moreover, from hundreds of micrographs, we quantified the density of PMJs and provided data for the basal/medial/apical regions, anterior/posterior/septal/lateral regions and myocardial/sub-endocardial distribution. Morphometric variables, such as Purkinje cell density and thickness of the bundles, were also analyzed. After combining the results of these parameters, a different septoanterior distribution in the Purkinje cell density was observed towards the cardiac apex, which is associated with a progressive thinning of the conduction bundles and the posterolateral ascension of intramyocardial terminal scattered fibers. The study of the PMJs revealed a decreasing trend towards the base that may anatomically explain the early apical activation. The anterolateral region contains the greatest number of contacts, followed by the anterior and septal regions. This supports the hypothesis that thin distal Purkinje bundles create a junction-rich network that may be responsible for the quick apical depolarization. The PN then ascends laterally and spreads through the anterior and medial walls up to the base. We have established the first morphometric study of the Purkinje system, and provided quantitative and objective data that facilitate its incorporation into the development of models beyond gross and variable pathological descriptions, and which, after further studies, could be useful in the characterization of pathological processes or therapeutic procedures.

Analysis of Microstructure of the Cardiac Conduction System Based on Three-Dimensional Confocal Microscopy.

The specialised conducting tissues present in the ventricles are responsible for the fast distribution of the electrical impulse from the atrio-ventricular node to regions in the subendocardial myocardium. Characterisation of anatomical features of the specialised conducting tissues in the ventricles is highly challenging, in particular its most distal section, which is connected to the working myocardium via Purkinje-myocardial junctions. The goal of this work is to characterise the architecture of the distal section of the Purkinje network by differentiating Purkinje cells from surrounding tissue, performing a segmentation of Purkinje fibres at cellular scale, and mathematically describing its morphology and interconnections. Purkinje cells from rabbit hearts were visualised by confocal microscopy using wheat germ agglutinin labelling. A total of 16 3D stacks including labeled Purkinje cells were collected, and semi-automatically segmented. State-of-the-art graph metrics were applied to estimate regional and global features of the Purkinje network complexity. Two types of cell types, tubular and star-like, were characterised from 3D segmentations. The analysis of 3D imaging data confirms the previously suggested presence of two types of Purkinje-myocardium connections, a 2D interconnection sheet and a funnel one, in which the narrow side of a Purkinje fibre connect progressively to muscle fibres. The complex network analysis of interconnected Purkinje cells showed no small-world connectivity or assortativity properties. These results might help building more realistic computational PK systems at high resolution levels including different cell configurations and shapes. Better knowledge on the organisation of the network might help in understanding the effects that several treatments such as radio-frequency ablation might have when the PK system is disrupted locally.

Moderated Posters 251Gap junction uncoupling during ischaemia activates normally quiescent purkinje-myocardial junctions resulting in accelerated and more complex activation patterns52The role of gαi2 signalling in cardiac electrophysiology53Midline atrial tachycardia: mapping and differentiation54A multicentre experience of percutaneous left atrial appendage occlusion using different technologies in the united kingdom55Opportunistic screening for atrial fibrillation during flu clinics56Primary care achievement of anticoagulation in atrial

Moderated Posters 251Gap junction uncoupling during ischaemia activates normally quiescent purkinje-myocardial junctions resulting in accelerated and more complex activation patterns52The role of gαi2 signalling in cardiac electrophysiology53Midline atrial tachycardia: mapping and differentiation54A multicentre experience of percutaneous left atrial appendage occlusion using different technologies in the united kingdom55Opportunistic screening for atrial fibrillation during flu clinics56Primary care achievement of anticoagulation in atrial

Estimation of Purkinje trees from electro-anatomical mapping of the left ventricle using minimal cost geodesics.

The electrical activation of the heart is a complex physiological process that is essential for the understanding of several cardiac dysfunctions, such as ventricular tachycardia (VT). Nowadays, patient-specific activation times on ventricular chambers can be estimated from electro-anatomical maps, providing crucial information to clinicians for guiding cardiac radio-frequency ablation treatment. However, some relevant electrical pathways such as those of the Purkinje system are very difficult to interpret from these maps due to sparsity of data and the limited spatial resolution of the system. We present here a novel method to estimate these fast electrical pathways from the local activations maps (LATs) obtained from electro-anatomical maps. The location of Purkinje-myocardial junctions (PMJs) is estimated considering them as critical points of a distance map defined by the activation maps, and then minimal cost geodesic paths are computed on the ventricular surface between the detected junctions. Experiments to validate the proposed method have been carried out in simplified and realistic simulated data, showing good performance on recovering the main characteristics of simulated Purkinje networks (e.g. PMJs). A feasibility study with real cases of fascicular VT was also performed, showing promising results.

Demonstration of posterior fascicle to myocardial conduction block during ablation of idiopathic left ventricular tachycardia: An electrophysiological predictor of long-term success

Idiopathic left ventricular tachycardia (ILVT) is a common form of ventricular tachycardia (VT) in structurally normal heart. Different methods have been proposed for radiofrequency ablation (RFA) of ILVT that have good short-term results but recurrence is higher. Termination of tachycardia during RFA and/or noninduciblity has been the procedural end point. To describe electrophysiological markers that add to long-term freedom from recurrences. Fifteen patients with ILVT underwent RFA guided by 3-dimensional electroanatomical mapping. After creating a 3-dimensional geometry of the left ventricle (LV), the conduction system of the LV was mapped by tracing from His recording from the left ventricular outflow tract and distally till the fascicles and perifascicular myocardium. VT was induced by using programmed electrical stimulation. Ablation was done targeting the distal posterior fascicle and extended linearly to the surrounding myocardium till conduction block was achieved between the fascicle-Purkinje network and the left ventricular myocardium. All patients (13 men; mean age 32 ± 9 years) had inducible VTs. The mean tachycardia cycle length was 320 ± 28 ms. Radiofrequency energy was given to the distal posterior fascicle and the myocardium, with an aim to achieve a myocardial-fascicular conduction block in addition to the termination of VT and noninducibility. Ablation was successful in all. No recurrence of tachycardia was seen in any patient on follow-up (20.8 ± 8.5 months). Distal posterior fascicle and Purkinje-myocardial junction is an effective target site for ILVT ablation. The demonstration of myocardial to fascicle conduction block serves as an important electrophysiological marker of successful ablation and improved long-term success.

Purkinje-mediated Effects in the Response of Quiescent Ventricles to Defibrillation Shocks

In normal cardiac function, orderly activation of the heart is facilitated by the Purkinje system (PS), a specialized network of fast-conducting fibers that lines the ventricles. Its role during ventricular defibrillation remains unelucidated. Physical characteristics of the PS make it a poor candidate for direct electrical observation using contemporary experimental techniques. This study uses a computer modeling approach to assess contributions by the PS to the response to electrical stimulation. Normal sinus rhythm was simulated and epicardial breakthrough sites were distributed in a manner consistent with experimental results. Defibrillation shocks of several strengths and orientations were applied to quiescent ventricles, with and without PS, and electrical activation was analyzed. All shocks induced local polarizations in PS branches parallel to the field, which led to the rapid spread of excitation through the network. This produced early activations at myocardial sites where tissue was unexcited by the shock and coupled to the PS. Shocks along the apico-basal axis of the heart resulted in a significant abbreviation of activation time when the PS was present; these shocks are of particular interest because the fields generated by internal cardioverter defibrillators tend to have a strong component in the same direction. The extent of PS-induced changes, both temporal and spatial, was constrained by the amount of shock-activated myocardium. Increasing field strength decreased the transmission delay between PS and ventricular tissue at Purkinje-myocardial junctions (PMJs), but this did not have a major effect on the organ-level response. Weaker shocks directly affect a smaller volume of myocardial tissue but easily excite the PS, which makes the PS contribution to far field excitation more substantial than for stronger shocks.

Spread of excitation in a myocardial volume: simulation studies in a model of anisotropic ventricular muscle activated by point stimulation.

The purpose of this study was to present simulations of excitation wavefronts spreading through a parallelepipedal slab of ventricular tissue measuring 6.5 x 6.5 x 1.0 cm. The slab incorporates the anisotropic properties of the myocardium including the transmural counterclockwise fiber rotation from epicardium to endocardium. Simulations were based on an eikonal model that determines excitation times throughout the ventricular wall, which is represented as an anisotropic bidomain. Excitation was initiated by delivering ectopic stimuli at various intramural depths. We also investigated the effect of a simplified Purkinje network on excitation patterns. Excitation wavefronts in the plane of pacing, parallel to epicardial-endocardial surfaces, were oblong with the major axis approximately oriented along the local fiber direction, with bulges and deformations due to attraction from rotating fibers in adjacent planes. The oblong intersections of the wavefront with planes at increasing distance from pacing plane rotated clockwise or counterclockwise, depending on pacing depth, but wavefront rotation was always less than fiber rotation in the same plane. For all pacing depths, excitation returned toward the plane of pacing. Return occurred in multiple, varying sectors of the slab depending on pacing depth, and was observed as close as 6 mm to the pacing site. Curvature of wavefronts and collision with boundaries of slab markedly affected local velocities. Shape and separation of epicardial isochrones and spatial distribution of epicardial velocities varied as a function of site and depth of pacing. When the Purkinje network was added to the model, epicardial velocities revealed the subendocardial location of the Purkinje-myocardial junctions. Considerable insight into intramural events could be obtained from epicardial isochrones. If validated experimentally, results may be applicable to epicardial isochrones recorded at surgery.

QRS waveform of ventricular extrasystoles and their differentiation from aberrant conduction.

Horizontal and frontal plane QRS loops of patients in sinus rhythm with uniform ventricular extrasystoles were constructed from digitised Frank orthogonal electrocardiogram. In 4 patients ventricular extrasystoles were indistinguishable from right bundle-branch complexes, and in another 4 from left bundle-branch complexes. In 25 patients ventricular extrasystoles showed an initial delay (greater than or equal to 20 msec) of the QRS, followed by an R loop, which in 13 patients resembled LBBB complexes, and 12 patients resembled RBBB complexes with an anterior clockwise loop in the horizontal plane. However, the frontal plane loop was often atypical of either RBBB or LBBB. In 51 patients ventricular extraplane loop was often atypical of either RBBB or LBBB. In 51 patients ventricular extrasystoles and an initial delay which was prolonged into the efferent limb of the QRS loop with acceleration of the afferent limb and/or the QRS loop was directed anteriorly, inferiorly and to the left. Conventional recordings of these extrasystoles usually showed an initial slow upstroke (or downstroke) of the QRS resembling a delta wave. It is suggested that extrasystoles resembling bundle-branch complexes arise close to the main bundle branches but that the other extrasystoles arise at the Purkinje-myocardial junction. Identification and differentiation of ventricular extrasystoles from aberrant conduction is aided by vectorcardiography.

EFFECTS OF AMODIAQUIN AND QUINIDINE ON CARDIAC CONDUCTION

The effects of the antiarrhythmia agents amodiaquin and quinidine on conduction times through the atrium and the specialized conducting tissue to the ventricular myocardium have been determined from records obtained with needle electrodes suitably placed in isolated blood perfused dog hearts. Quinidine slowed conduction through each portion of the total pathway when very low concentrations were infused but had a preferential depressant effect on atrial conduction at slightly higher concentrations. Amodiaquin slowed conduction in the atrioventricular node to a greater extent than in the other parts of the common pathway at all concentrations tested. The major effect of each drug on extra-atrial conduction occurred at the atrioventricular node and at the Purkinje–myocardial junction. Amodiaquin did not induce bigeminal rhythm in the isolated heart.