Local Depolarization Research Articles

Repolarization gradient induces local depolarization abnormalities in Brugada Syndrome

Abstract Background Transmural voltage gradient in right ventricular outflow tract (RVOT) induces diagnostic ECG-phenotype in Brugada syndrome(BrS). Moreover, RVOT depolarization abnormalities have been described as contributors to BrS phenotype and arrhythmogenesis. Purpose To investigate the effect of ajmaline administration on J-elevation of RVOT unipolar signals in BrS patients. Moreover, we wanted to assess whether ajmaline-induced unipolar J-point elevation variations induced local depolarization abnormalities. Methods 21 BrS patients with spontaneous type-1 ECG pattern were enrolled. Due to the absence of BrS ECG pattern at the study, patients underwent RV endocardial mapping with the CARTO3 system, before (PRE) and after (POST) ajmaline administration. The PRE and POST data were exported from CARTO and converted into Matlab format using OpenEP. J-elevation for each point was calculated as the amplitude of the unipolar signal at J wave with respect to baseline. Activation time (AT) of each point was defined as the difference between local depolarization (minimum dV/dt of the unipolar signal) and surface ECG depolarization (time of the minimum signal on V2). With an automatic algorithm, corresponding PRE and POST points were selected. The difference between POST and PRE of each parameter was calculated to obtain the differential values delta-J and delta-AT. Differential values were then interpolated on the mesh of each subject to obtain 3D maps. The deltaJ map was divided into four intervals based on quartiles. We then selected a ROI 'IN' on a region with the greatest deltaJ variation, and a second ROI 'OUT' on the zone of lowest variation. The same ROIs were applied to the deltaAT map. The mean value of the respective differential parameters was extracted in each ROI. Results Greatest delta-J values were found in the RVOT/anterior wall. delta-J in the ROI 'IN' was greater than in the ROI 'OUT' (1.68 [1.11-2.28] vs 0.56 [0.38-0.93] mV, p<0.001). delta-AT in the ROI ‘IN’ was greater than in the ROI ‘OUT’ (27.96 [20.39-44.89] vs 7.62 [4.24-16.69] ms, p<0.001). A good correlation was found between delta-J and delta-AT, considering the data for the two ROIs together (Spearman R coefficient=0.71, p<0.001). Conclusions Our study shows that the repolarization gradient, evaluated by localized delta-J increase in RVOT, justifies BrS ECG phenotype and local depolarization abnormalities. A strong correlation was present in these RVOT areas between J-elevation variation and slow conducting zones.

REPOLARIZATION GRADIENT CAUSES LOCAL DEPOLARIZATION ABNORMALITIES IN BRUGADA SYNDROME

Abstract Background Transmural voltage gradient in RVOT induces ECG–phenotype in Brugada syndrome(BrS). Moreover,RVOT depolarization abnormalities have been described as contributors to BrS phenotype and arrhythmogenesis. Purpose To investigate the effect of ajmaline administration on J–elevation of RVOT unipolar signals in BrS patients. Moreover,we wanted to assess whether ajmaline–induced unipolar J–point elevation variations induced local depolarization abnormalities. Methods 21 BrS patients with spontaneous type–1 ECG pattern were enrolled. Due to the absence of BrS ECG pattern at the study, patients underwent RV endocardial mapping with the CARTO3 system, before (PRE) and after (POST) ajmaline administration. The data were exported from CARTO and converted into Matlab format using OpenEP. J–elevation for each point was calculated as the amplitude of the unipolar signal at J wave with respect to baseline. Activation time (AT) of each point was defined as the difference between local depolarization (minimum dV/dt of the unipolar signal) and surface ECG depolarization(time of the minimum signal on V2). With an automatic algorithm, corresponding PRE and POST points were selected. The difference between POST and PRE of each parameter was calculated to obtain the differential values delta–J and delta–AT. Differential values were then interpolated on the mesh of each subject to obtain 3D maps. The deltaJ map was divided into four intervals based on quartiles. We then selected a ROI ‘IN‘ on a region with the greatest deltaJ variation, and a second ROI ‘OUT‘ on the zone of lowest variation. The same ROIs were applied to the deltaAT map. The mean value of the respective differential parameters was extracted in each ROI. Results Greatest delta–J values were found in the RVOT/anterior wall. delta–J in the ROI ‘IN‘ was greater than in the ROI ‘OUT‘ (1.68 [1.11–2.28] vs 0.56 [0.38–0.93] mV, p<0.001). delta–AT in the ROI ‘IN’ was greater than in the ROI ‘OUT’ (27.96 [20.39–44.89] vs 7.62 [4.24–16.69] ms, p<0.001). A good correlation was found between delta–J and delta–AT, considering the data for the two ROIs together (Spearman R coefficient=0.71, p<0.001). Conclusions: Our study shows that the repolarization gradient, evaluated by localized delta–J increase in RVOT, justifies BrS ECG phenotype and local depolarization abnormalities. A strong correlation was present in these RVOT areas between J–elevation variation and slow conducting zones.

A voltage-based Event-Timing-Dependent Plasticity rule accounts for LTP subthreshold and suprathreshold for dendritic spikes in CA1 pyramidal neurons.

Long-term potentiation (LTP) is a synaptic mechanism involved in learning and memory. Experiments have shown that dendritic sodium spikes (Na-dSpikes) are required for LTP in the distal apical dendrites of CA1 pyramidal cells. On the other hand, LTP in perisomatic dendrites can be induced by synaptic input patterns that can be both subthreshold and suprathreshold for Na-dSpikes. It is unclear whether these results can be explained by one unifying plasticity mechanism. Here, we show in biophysically and morphologically realistic compartmental models of the CA1 pyramidal cell that these forms of LTP can be fully accounted for by a simple plasticity rule. We call it the voltage-based Event-Timing-Dependent Plasticity (ETDP) rule. The presynaptic event is the presynaptic spike or release of glutamate. The postsynaptic event is the local depolarization that exceeds a certain plasticity threshold. Our model reproduced the experimentally observed LTP in a variety of protocols, including local pharmacological inhibition of dendritic spikes by tetrodotoxin (TTX). In summary, we have provided a validation of the voltage-based ETDP, suggesting that this simple plasticity rule can be used to model even complex spatiotemporal patterns of long-term synaptic plasticity in neuronal dendrites.

Spreading depolarization suppression from inter-astrocytic gap junction blockade assessed with multimodal imaging and a novel wavefront detection scheme

Spreading depolarizations (SDs) are an enigmatic and ubiquitous co-morbidity of neural dysfunction. SDs are propagating waves of local field depolarization and increased extracellular potassium. They increase the metabolic demand on brain tissue, resulting in changes in tissue blood flow, and are associated with adverse neurological consequences including stroke, epilepsy, neurotrauma, and migraine. Their occurrence is associated with poor patient prognosis through mechanisms which are only partially understood. Here we show in vivo that two (structurally dissimilar) drugs, which suppress astroglial gap junctional communication, can acutely suppress SDs. We found that mefloquine hydrochloride (MQH), administered IP, slowed the propagation of the SD potassium waveform and intermittently led to its suppression. The hemodynamic response was similarly delayed and intermittently suppressed. Furthermore, in instances where SD led to transient tissue swelling, MQH reduced observable tissue displacement. Administration of meclofenamic acid (MFA) IP was found to reduce blood flow, both proximal and distal, to the site of SD induction, preceding a large reduction in the amplitude of the SD-associated potassium wave. We introduce a novel image processing scheme for SD wavefront localization under low-contrast imaging conditions permitting full-field wavefront velocity mapping and wavefront parametrization. We found that MQH administration delayed SD wavefront's optical correlates. These two clinically used drugs, both gap junctional blockers found to distinctly suppress SDs, may be of therapeutic benefit in the various brain disorders associated with recurrent SDs.

Mid-infrared thermal radiation resonating with longitudinal-optical like phonon from n++-doped GaN–semi-insulating GaN grating structure

The mid-infrared emission mechanism of line-and-space structures of metallic plates on dielectric materials is substantiated using high conductive n-doped (n++-) GaN–semi-insulating (SI-) GaN microstripe structures on an SI-GaN epitaxial layer, which was veiled when using line-and-space structures of Au plates. The present structure exhibits a few thermal emission lines originating from electric dipoles resonating with the coherent longitudinal optical (LO) phonon-like lattice vibration, which are formed by the local depolarization electric field in the surface n++-GaN/SI-GaN/n++-GaN regions. The energies of the LO-phonon-like modes shift from the original LO-phonon energy of GaN to the lower energy region, which contrasts with the LO-phonon resonant emission from the microstructures on GaAs. These emission lines have another notable feature, i.e. the observed peak energies are independent of the polar emission angle for both s- and p-polarizations, unlike the emissions by surface phonon polaritons showing a significant directive nature of peak energies. The results show that each peak energy of the present emission lines is positioned at the zero-point of the real part of the electric permittivity comprising the components of the transverse optical phonon and other electric dipoles induced by the LO-like modes, excluding the target mode. The significant peak-energy shift of the LO-like phonons is applicable to materials with wide Reststrahlen bands, which contrasts with that of the nearly LO-phonon resonating feature of materials with narrow Reststrahlen bands, such as GaAs. The peak energy shift depending on the emission direction is observed for Au–GaN stripe structures. This property is ascribed to the imperfect Au/GaN interface with surface states through the theoretical analysis of the modified electric permittivity in the surface region, numerical simulation of the local electric field via finite-difference time-domain calculation, and experimental studies on a Ti–GaN structure and emission peaks originating from an LO-like phonon of the α-Al2O3 substrate.

Інтелектуальна система оцінювання ступеня локальної деполяризації полів лазерної автофлуоресценції двопроменезаломлюючих мереж протеїнових кристалів

The theoretical foundations of the description of scattered coherent radiation fields using a new correlation parameter - the degree of local depolarization (DLD) - are presented. The data of measuring the coordinate distributions of the DLD of laser images of healthy and pathologically altered rat skin are presented. The values and ranges of change of statistical (moments of the 1st - 4th orders), correlation (correlation area) and fractal (slopes and variance of extremes of logarithmic dependences of power spectra) parameters of the coordinate distributions of the DLD are investigated. The objective criteria for diagnosing oncological changes in the structure of the rat skin are determined.

Wide-field fluorescence lifetime imaging of neuron spiking and subthreshold activity in vivo.

The development of voltage-sensitive fluorescent probes suggests fluorescence lifetime as a promising readout for electrical activity in biological systems. Existing approaches fail to achieve the speed and sensitivity required for voltage imaging in neuroscience applications. We demonstrated that wide-field electro-optic fluorescence lifetime imaging microscopy (EO-FLIM) allows lifetime imaging at kilohertz frame-acquisition rates, spatially resolving action potential propagation and subthreshold neural activity in live adult Drosophila. Lifetime resolutions of <5 picoseconds at 1 kilohertz were achieved for single-cell voltage recordings. Lifetime readout is limited by photon shot noise, and the method provides strong rejection of motion artifacts and technical noise sources. Recordings revealed local transmembrane depolarizations, two types of spikes with distinct fluorescence lifetimes, and phase locking of spikes to an external mechanical stimulus.

Left bundle branch area pacing results in more physiological ventricular activation than biventricular pacing in patients with left bundle branch block heart failure.

Biventricular pacing (Biv) and left bundle branch area pacing (LBBAP) are methods of cardiac resynchronization therapy (CRT). Currently, little is known about how they differ in terms of ventricular activation. This study compared ventricular activation patterns in left bundle branch block (LBBB) heart failure patients using an ultra-high-frequency electrocardiography (UHF-ECG). This was a retrospective analysis including 80 CRT patients from two centres. UHF-ECG data were obtained during LBBB, LBBAP, and Biv. Left bundle branch area pacing patients were divided into non-selective left bundle branch pacing (NSLBBP) or left ventricular septal pacing (LVSP) and into groups with V6 R-wave peak times (V6RWPT) < 90 ms and ≥ 90 ms. Calculated parameters were: e-DYS (time difference between the first and last activation in V1-V8 leads) and Vdmean (average of V1-V8 local depolarization durations). In LBBB patients (n = 80) indicated for CRT, spontaneous rhythms were compared with Biv (39) and LBBAP rhythms (64). Although both Biv and LBBAP significantly reduced QRS duration (QRSd) compared with LBBB (from 172 to 148 and 152 ms, respectively, both P < 0.001), the difference between them was not significant (P = 0.2). Left bundle branch area pacing led to shorter e-DYS (24 ms) than Biv (33 ms; P = 0.008) and shorter Vdmean (53 vs. 59 ms; P = 0.003). No differences in QRSd, e-DYS, or Vdmean were found between NSLBBP, LVSP, and LBBAP with paced V6RWPTs < 90 and ≥ 90 ms. Both Biv CRT and LBBAP significantly reduce ventricular dyssynchrony in CRT patients with LBBB. Left bundle branch area pacing is associated with more physiological ventricular activation.

Left bundle branch area pacing produces more physiological ventricular activation than biventricular pacing in patients with heart failure and LBBB

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Institute for Research of Metabolic and Cardiovascular Diseases, Programme EXCELES, Ministry of Health of the Czech Republic, grant number NU21-02-00584. Introduction Biventricular pacing (BiV) is an established treatment for patients with heart failure and dyssynchronous ventricular activation. Left bundle branch area pacing (LBBAP) appears to be a promising alternative to BiV-CRT. To date, there is insufficient data regarding their effect on the reduction of ventricular dyssynchrony. Purpose To compare ventricular synchrony during spontaneous rhythm, BiV and LBBAP in patients with heart failure, reduced left ventricular ejection fraction (LVEF), and LBBB using ultra-high-frequency ECG (UHF-ECG). Methods This was a retrospective analysis of consecutive patients with indication to CRT from two centers. It included patients with heart failure, QRS of LBBB morphology, and LVEF ≤ 40%, treated by BiV and/or LBBAP-CRT. UHF-ECG data were obtained during spontaneous and paced rhythms. These parameters were calculated: eDYS (time difference between the first and last activation), Vdmean (average of V1-V8 local depolarization durations) and QRSd (measured from pacing artifact). Results Analyzes were performed on 80 spontaneous rhythms, 39 biventricular captures and 64 LBBAP, obtained from 80 patients. Their mean age was 74±10 years, 61% were men, mean LV ejection fraction was 31±9 %, and 32% had ischemic cardiomyopathy. Both BiV and LBBAP-CRT significantly reduced QRSd compared to the spontaneous rhythm (from 172 ms, 95% CI [168;176] to 146 ms [141;152] during BiV and 143 ms [139;149] during LBBAP). Also, the eDYS and Vdmean were significantly reduced by both BiV and LBBAP-CRT, i.e., the eDYS from 82 ms [76;86] during LBBB to 33 ms [28;37], p&amp;lt;0.001 during biventricular pacing and to 24 ms [20;28], p&amp;lt;0.001, during LBBAP and Vdmean from 71 ms [68;73] to 59 ms [56;61], p&amp;lt;0.001 during BiV and to 53 ms [51;55], p&amp;lt;0.001 during LBBAP. Although the QRSd did not differ between LBBAP and biventricular pacing (143ms [139;148] vs 146ms [141;152], p=NS), LBBAP compared to BiV led to significantly shorter eDYS (24ms [20;28] vs 33ms [28;38]; p&amp;lt;0.008 and Vdmean (53ms [51;55] vs 59ms [56;61], respectively; p&amp;lt;0.003}. Conclusions In patients with heart failure, LBBB and reduced LVEF, both BiV and LBBAP CRT significantly reduce ventricular dyssynchrony compared to the spontaneous rhythm. Our results indicate that LBBAP is associated with more physiological ventricular activation than BiV-CRT.

Stochastic theory of ferroelectric domain structure formation dominated by quenched disorder

A self-consistent stochastic model of domain structure formation in a uniaxial ferroelectric, quenched from a high-temperature paraelectric phase to a low-temperature ferroelectric phase, is developed with an account of the applied electric field and the feedback effect via local depolarization fields. Both polarization and field components are considered as Gauss random variables. A system of integro-differential equations for correlation functions of all involved variables is derived and solved analytically and numerically. Phase diagram in terms of the average value and dispersion of polarization reveals different possible equilibrium states and available final single-domain and multi-domain states. The time-dependent evolution of the average polarization and dispersion discloses a bifurcation behavior and the temperature-dependent value of the electric field, deciding between the single-domain and multi-domain final states, which can be interpreted as the coercive field. Analytical and numerical results for the time-dependent correlation length and correlation functions exhibit plausible agreement with available experimental data.

Two subcompartments of the smooth endoplasmic reticulum in perisynaptic astrocytic processes: ultrastructure and distribution in hippocampal and neocortical synapses

Perisynaptic astrocytic processes involved in the tripartite synapse functioning respond to its activation by local depolarization with calcium release from the intracellular stores inside nodes of astrocytic processes and develop local and generalized calcium events. However, based on the first electron microscopy studies a point of view was formed that terminal astrocytic lamellae are devoid of any organelles, including the main astrocytic calcium store - the cisternae of the smooth endoplasmic reticulum. Indeed, analysis of smooth endoplasmic reticulum cisternae could be limited by their weak electron contrast, the studying of astrocytic processes on single sections, and insufficient optical resolution of the equipment used. Here, by using serial section transmission electron microscopy and 3D reconstructions, we analyzed astrocytic processes in murine hippocampal and cortical synapses. As a result of unit membranes contrast enhancement, it was shown for the first time that perisynaptic processes of astrocytes with a morphology of thin branchlets contain two types of smooth endoplasmic reticulum cisternae and microvesicles. Unlike branchlets, membrane organelles inside terminal lamellae were comprised by only short fragments of thin smooth endoplasmic reticulum cister-nae and microvesicles, whose groups tend to be located in close proximity to active zones of the most active synapses. We speculate both on reliability of the alternative methods in electron microscopy while studying astrocytic microenvironment of synapses and structure-function aspects of smooth endoplasmic reticulum cisternae compartmentalization inside the perisynaptic processes of astrocytes.

Potent dual MAGL/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain

BackgroundEngaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues.MethodsBoth MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC–MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non-migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested.ResultsThe basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking.ConclusionsIn the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment.Graphical

Bipolar anodal septal pacing with direct LBB capture preserves physiological ventricular activation better than unipolar left bundle branch pacing.

Left bundle branch pacing (LBBP) produces delayed, unphysiological activation of the right ventricle. Using ultra-high-frequency electrocardiography (UHF-ECG), we explored how bipolar anodal septal pacing with direct LBB capture (aLBBP) affects the resultant ventricular depolarization pattern. In patients with bradycardia, His bundle pacing (HBP), unipolar nonselective LBBP (nsLBBP), aLBBP, and right ventricular septal pacing (RVSP) were performed. Timing of local ventricular activation, in leads V1-V8, was displayed using UHF-ECG, and electrical dyssynchrony (e-DYS) was calculated as the difference between the first and last activation. Durations of local depolarizations were determined as the width of the UHF-QRS complex at 50% of its amplitude. aLBBP was feasible in 63 of 75 consecutive patients with successful nsLBBP. aLBBP significantly improved ventricular dyssynchrony (mean -9 ms; 95% CI (-12;-6) vs. -24 ms (-27;-21), ), p < 0.001) and shortened local depolarization durations in V1-V4 (mean differences -7 ms to -5 ms (-11;-1), p < 0.05) compared to nsLBBP. aLBBP resulted in e-DYS -9 ms (-12; -6) vs. e-DYS 10 ms (7;14), p < 0.001 during HBP. Local depolarization durations in V1-V2 during aLBBP were longer than HBP (differences 5-9 ms (1;14), p < 0.05, with local depolarization duration in V1 during aLBBP being the same as during RVSP (difference 2 ms (-2;6), p = 0.52). Although aLBBP improved ventricular synchrony and depolarization duration of the septum and RV compared to unipolar nsLBBP, the resultant ventricular depolarization was still less physiological than during HBP.

Entanglement dynamics of noisy random circuits

The process by which open quantum systems thermalize with an environment is both of fundamental interest and relevant to noisy quantum devices. As a minimal model of this process, we consider a qudit chain evolving under local random unitaries and local depolarization channels. After mapping to a statistical mechanics model, the depolarization (noise) acts like a symmetry-breaking field, and we argue that it causes the system to thermalize within a timescale independent of system size. We show that various bipartite entanglement measures---mutual information, operator entanglement, and entanglement negativity---grow at a speed proportional to the size of the bipartition boundary. As a result, these entanglement measures obey an area law: Their maximal value during the dynamics is bounded by the boundary instead of the volume. In contrast, if the depolarization only acts at the system boundary, then the maximum value of the entanglement measures obeys a volume law. We complement our analysis with scalable simulations involving Clifford gates, for both one- and two-dimensional systems.

The Cup Whisperer

The Cup Whisperer

Learning entanglement breakdown as a phase transition by confusion

Quantum technologies require methods for preparing and manipulating entangled multiparticle states. However, the problem of determining whether a given quantum state is entangled or separable is known to be an NP-hard problem in general, and even the task of detecting entanglement breakdown for a given class of quantum states is difficult. In this work, we develop an approach for revealing entanglement breakdown using a machine learning technique, which is known as ‘learning by confusion’. We consider a family of quantum states, which is parameterized such that there is a single critical value dividing states within this family into separate and entangled. We demonstrate the ‘learning by confusion’ scheme allows us to determine the critical value. Specifically, we study the performance of the method for the two-qubit, two-qutrit, and two-ququart entangled state. In addition, we investigate the properties of the local depolarization and the generalized amplitude damping channel in the framework of the confusion scheme. Within our approach and setting the parameterization of special trajectories, we obtain an entanglement-breakdown ‘phase diagram’ of a quantum channel, which indicates regions of entangled (separable) states and the entanglement-breakdown region. Then we extend the way of using the ‘learning by confusion’ scheme for recognizing whether an arbitrary given state is entangled or separable. We show that the developed method provides correct answers for a variety of states, including entangled states with positive partial transpose. We also present a more practical version of the method, which is suitable for studying entanglement breakdown in noisy intermediate-scale quantum devices. We demonstrate its performance using an available cloud-based IBM quantum processor.

Body Surface Mapping system - a potential diagnostic tool for unmasking delayed right ventricular epicardial activation in ARVC patients and phenotype-negative gene-carriers

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Selanders stiftelsen Background Life-threatening ventricular arrhythmias can occur at any stages of ARVC – the detection of early manifestations of the disease may have prognostic implications. Purpose The purpose was to explore the usefulness of a 252-leads noninvasive Body Surface Mapping (BSM) system for the detection of delayed epicardial activation in ARVC patients and phenotype-negative gene-carriers (GC). Methods Twelve patients with ARVC, 20 GC and 8 genotype and phenotype negative family members served as controls (C) were included. 12-lead ECG, signal-averaged-electrocardiogram, echocardiography, 252-lead BSM recordings and thoracic CT scan were performed in all subjects. The noninvasively reconstructed epicardial signals of the right ventricle (RV) were analysed using the Activation Time Editing tool of the BSM system. Local depolarisation was defined as the steepest negative dV/dt of the local epicardial signal. The time from the start of RV epicardial signals to the earliest local depolarisation (ELD) and to the latest local depolarisation (LLD), were measured for the whole RV and separately for the anterior free wall (AW) and inferior wall (IW). The duration of the activation, defined as LLD-ELD, was calculated for AW, IW and the whole RV. Results The ELDs was similar in all study groups whereas the LLD in the IW and whole RV was significantly longer among ARVC patients compared to C. Although the activation durations in the AW and IW did not differ between the groups, the activation duration of the whole RV was significantly longer in ARVC patients. A LLD cut off of 81ms in RV and an activation duration cut off of 49msec in RV discriminated ARVC patients from C with highest sensitivity and specificity. Based on these cut-offs, 35% of GC group had longer LLD times and 70 % had longer activation duration (figure 1). Conclusions ARVC patients as well as the majority of GC demonstrated prolonged LLD and/or activation duration times in RV compared to C, suggesting that the 252-leads noninvasive BSM system may be a useful tool for early detection of delayed RV epicardial activations. Larger studies are required to confirm our results.

Subthreshold delayed afterdepolarizations mediated by reduced tissue conductivity form a substrate for unidirectional block and reentry within the infarcted heart

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation, Wellcome Trust Background Delayed afterdepolarizations (DADs) due to spontaneous calcium release (SCR) events at the subcellular scale have been associated with arrhythmia formation in the border zone (BZ) of infarcted hearts. DADs may not only summate to form ectopic focal sources but may also inactivate sodium channels forming a substrate for unidirectional conduction block and reentry. The role played by infarct anatomy and altered intracellular coupling in facilitating this phenomenon is not fully understood. Purpose To use computational modelling to investigate the role of anatomical properties of the infarct BZ in creating a substrate for DAD-mediated conduction block and reentry. Methods MRI data from a porcine post-infarction heart was used to build the computational model. A phenomenological model was used to simulate SCRs in the BZ. Arrhythmia susceptibility was quantified by pacing the model followed by a pause, to see whether DADs would occur, and an extra S2 beat with different coupling intervals (CIs). Tissue conductivity in the BZ was decreased to investigate the effect of uncoupling on DAD-mediated conduction block. Results Subthreshold DADs occurring within the infarct BZ inactivated the fast sodium channels which resulted in block of S2 beats. This occurred most readily in narrow isthmuses where electrotonic load was attenuated by the non-conducting scar. DADs rendered the entire isthmus area refractory establishing a substrate for unidirectional block and reentry (see Fig. A). Reduced tissue conductivity in the BZ reduced electrotonic load on cells undergoing DADs. This led to more local tissue depolarization (Vm) as uncoupling prevented current from flowing to neighboring cells at rest (Fig. B-C). Reduced tissue conductivity also enhanced DAD-mediated block by increasing the vulnerable window for reentry initiation (700ms &amp;lt; S2 CI &amp;lt; 900ms as shown in Fig. D). Conclusion Subthreshold DADs provide a substrate for arrhythmogenesis in the infarct BZ. Tissue uncoupling enhanced the arrhythmogenic risk by increasing the time window of unidirectional block.

Left ventricular septal pacing: how deep is enough?

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Charles University Research Program Background When pacing in the left septal area, it is not clear where the pacing lead needs to be implanted to obtain the most physiological ventricular activation during pure myocardial pacing. Objective To use UHF-ECG to compare ventricular activation between myocardial pacing of the left septum with and without the possibility to capture the left bundle branch by high output pacing. Methods This was a retrospective study of patients with bradycardia and deep septal myocardial pacing close to LBB (paraLBBP) or deep septal pacing more distant from LBB (DSTP), which both produced a pseudo-right bundle branch morphology in V1. During paraLBBP, left bundle branch capture was feasible during increasing pacing output up to 5V at 0.5 ms, but during DSTP, LBB capture was not possible during high output pacing. Only patients with both paraLBBP and DSTP were analyzed. Paced QRS morphology, presence of LBBpotential, QRSduration, R wave peak time (RWPT) in V5, lead depth in the septum and UHF-ECG parameters of dyssynchrony, i.e., e-DYS as the difference between the first and last ventricular activation and local depolarization durations in precordial leads (V1-V8d) were compared between them. Results From 119 consecutive bradycardia patients enrolled, we identified 23 with both paraLBBP and DSTP during an implant procedure. On X-ray, a lead tip was placed shallower during DSTP than paraLBBP (12 ± 3 vs. 15 ± 3 mm, p &amp;lt; 0.001). A pseudo right bundle branch block morphology was present in all cases, but LBB potential was more frequently present in paraLBBP (17 of 23) than in DSTP (4 of 36; p &amp;lt; 0.0001). QRSd was not significantly different (146 ± 14 vs. 142 ± 14 ms, p = 0.08), but DSTP had longer V5RWPT (86 ± 11 vs. 83 ± 9 ms; p = 0.03). paraLBBP resulted in larger interventricular dyssynchrony, e-DYS (-20 ± 15 vs. -12 ± 18 ms; p = 0.046), the same V1-6d, but its local depolarization durations in V7 and V8 (V7 and V8d) were shorter compared to DSTP (-5 and -7 ms; p &amp;lt; 0.05). Conclusion Interventricular dyssynchrony and LV lateral wall depolarization during myocardial pacing of the left septum are dependent on the relation of the leads´ tip to the LBB. Pacing positions closer to the LBB are responsible for bigger interventricular dyssynchrony and more physiological LV lateral wall depolarization.

Left bundle branch pacing with normal paced QRS axis produce more physiological left ventricular lateral wall depolarization than its pacing resulting in heart axis deviation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic Background Left bundle branch pacing is defined as the pacing of the trunk or its proximal fascicles, usually with septal myocardial pacing at low output. It preserves physiological left ventricular activation; however, it is unknown if there is a difference between captures with normal or deviated axes and pacing in proximal vs. distal locations. Objective To study ventricular activation during nonselective LBB pacing (nsLBBp) resulting in different paced QRS axes and proximal vs. distal pacing positions using ultra-high-frequency ECG (UHF-ECG). Methods This was a retrospective analysis of patients with bradycardia in which nsLBBp was archived during an implant procedure, and UHF-ECG analysis of ventricular activation was performed. nsLBBp captures were classified according to paced QRS axis as with superior (-30°;-90°), normal (-29°;60°), or inferior (61°;120°) axis deviation and proximal (LBbpo to ventricular EGM signal distance ≥ 26 ms) vs. distal (LBBpo to ventricular EGM signal distance &amp;lt; 26 ms). UHF-ECG electrical dyssynchrony parameters – e-DYS (difference between the first and last ventricular activation), local depolarization durations in precordial leads (V1-V8d), and their mean value (Vdmean) were calculated. Results We have studied 79 nsLBBp, of which 35 had superior, 28 normal, and 16 had inferior paced QRS axes. There was no difference in LBBpo to V distance, QRSduration, V5 RWPT, or e-DYS (-27 ms vs. – 22 ms vs. -25 ms for superior vs. normal vs. inferior axes; p = NS) between them. However, nsLBBp with normal paced QRS axis had shorter Vdmean (43 ±6 ms) compared to captures with superior (48 ± 7 ms) and inferior axis deviation (48 ± 6 ms); p &amp;lt; 0.05. It was mainly due to shorter V7-8d during nsLBBp with normal axis (mean difference of - 10 ms; p &amp;lt; 0.05) than in captures with superior or inferior axes. No difference in any of the studied parameters was noted when comparing proximal vs. distal pacing locations. Conclusion Nonselective capture of the left bundle branch resulting in normal paced QRS axis produces more physiological LV activation compared to captures with superior or inferior axes deviations.