Electrophysiological Substrate Research Articles

The Spatial Ventricular Gradient is Associated with Inducibility of Ventricular Arrhythmias During Electrophysiology Study

Myocardial electrical heterogeneity is critical for normal cardiac electromechanical function, but abnormal/excessive electrical heterogeneity is proarrhythmic. The spatial ventricular gradient (SVG), a vectorcardiographic measure of electrical heterogeneity, has been associated with arrhythmic events over long-term follow-up, but its relationship with short-term inducibility of ventricular arrhythmias (VAs) is unclear. Determine associations between SVG and inducible VAs during electrophysiology study (EPS). Retrospective study of adults without prior sustained VA, cardiac arrest, or implantable cardioverter-defibrillator (ICD), who underwent ventricular stimulation for evaluation of syncope, non-sustained VT, and/or risk-stratification prior to primary prevention ICD implantation. 12-lead ECGs were converted into vectorcardiograms and SVG magnitude (SVGmag) and direction (azimuth and elevation) were calculated. Odds of inducible VA were regressed using logistic models. Among 143 patients (median age 66, 80% male, median LVEF 47%, 52% myocardial infarction), 34 (23.8%) had inducible VAs. Inducible patients had lower median LVEF (38 vs 50%, p<0.0001), smaller SVGmag (29.5 vs 39.4mV*ms, p=0.0099), and smaller cosine SVG azimuth (cosSVGaz) (0.64 vs 0.89, p=0.0007). When LVEF, SVGmag, and cosSVGaz were dichotomized at their medians, there was a 39-fold increase in adjusted odds (p=0.002) between patients with all low LVEF, SVGmag, and cosSVGaz (65% inducible), compared to patients with all high LVEF, SVGmag, and cosSVGaz (4% [n=1] inducible). After multivariable adjustment, SVGmag, cosSVGaz, and sex, but not LVEF or other characteristics, remained associated with inducible VAs. Assessment of electrical heterogeneity via SVG, which reflects abnormal electrophysiological substrate, adds to LVEF and identifies patients at high and low risk of inducible VA at EPS.

Regional conduction velocities determined by noninvasive mapping are associated with arrhythmia-free survival after atrial fibrillation ablation

BackgroundAtrial arrhythmogenic substrate is a key determinant of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a noninvasive method to assess such electrophysiologic substrate is not available to date. ObjectiveThis study aimed to noninvasively assess regional conduction velocities and their association with arrhythmia-free survival after PVI. MethodsA consecutive 52 patients scheduled for AF ablation (PVI only) and 19 healthy controls were prospectively included and received electrocardiographic imaging (ECGi) to noninvasively determine regional atrial conduction velocities in sinus rhythm. A novel ECGi technology obviating the need of additional computed tomography or cardiac magnetic resonance imaging was applied and validated by invasive mapping. ResultsMean ECGi-determined atrial conduction velocities were significantly lower in AF patients than in healthy controls (1.45 ± 0.15 m/s vs 1.64 ± 0.15 m/s; P < .0001). Differences were particularly pronounced in a regional analysis considering only the segment with the lowest average conduction velocity in each patient (0.8 ± 0.22 m/s vs 1.08 ± 0.26 m/s; P < .0001). This average conduction velocity of the “slowest” segment was independently associated with arrhythmia recurrence and better discriminated between PVI responders and nonresponders than previously proposed predictors, including left atrial size and late gadolinium enhancement (magnetic resonance imaging). Patients without slow-conduction areas (mean conduction velocity <0.78 m/s) showed significantly higher 12-month arrhythmia-free survival than those with 1 or more slow-conduction areas (88.9% vs 48.0%; P = .002). ConclusionThis is the first study to investigate regional atrial conduction velocities noninvasively. The absence of ECGi-determined slow-conduction areas well discriminates PVI responders from nonresponders. Such noninvasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be a step toward personalized AF therapy.

Language prediction in monolingual and bilingual speakers: an EEG study

Prediction of upcoming words is thought to be crucial for language comprehension. Here, we are asking whether bilingualism entails changes to the electrophysiological substrates of prediction. Prior findings leave it open whether monolingual and bilingual speakers predict upcoming words to the same extent and in the same manner. We address this issue with a naturalistic approach, employing an information-theoretic metric, surprisal, to predict and contrast the N400 brain potential in monolingual and bilingual speakers. We recruited 18 Iranian Azeri-Persian bilingual speakers and 22 Persian monolingual speakers. Subjects listened to a story in Persian while their electroencephalogram (EEG) was recorded. Bayesian item-level analysis was used. While in monolingual speakers N400 was sensitive to information-theoretic properties of both the current and previous words, in bilingual speakers N400 reflected the properties of the previous word only. Our findings show evidence for a processing delay in bilingual speakers which is consistent with prior research.

Postoperative atrial fibrillation following coronary artery bypass grafting surgery: Role of IL-6 from structural to electrical remodeling

Abstract Postoperative atrial fibrillation (POAF) is a common complication of coronary artery bypass grafting surgery and contributes significantly to morbidity, mortality, and rising health care costs. Although the underlying mechanisms for POAF are not completely understood, surgery-related inflammation, often in the presence of pre-existing factors, renders the atria susceptible to the induction and persistence of POAF. Notably, interleukin-6, a primary cytokine of the inflammatory cascade, has been identified as one of the principal molecular components of POAF pathogenesis. Atrial fibrosis may also be a key mechanistic link by which inflammation contributes to POAF. Recently, it has been shown that atrial fibrosis, in combination with the presence of an electrophysiological substrate capable of maintaining atrial fibrillation, also promotes arrhythmia, suggesting that POAF shares proarrhythmic mechanisms with other types of atrial fibrillation. In this review, the impact of inflammation and the particular role of IL-6 on the structural and electrical changes that promote the development of POAF is summarized.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

Improving omnipolar electrogram reconstruction: an animal model study

Abstract Background Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide. The characterization of cardiac tissue's electrophysiological substrate is crucial for the diagnosis and treatment of these conditions. High-density (HD) electrode arrays, such as the Advisor™ HD Grid Mapping Catheter and Sensor Enabled™ (SE), are commonly used to examine cardiac tissue locally and create activation maps. However, the current method for reconstructing omnipolar EGMs, a novel technique claimed to be orientation-independent, has limitations. The enhancement of this reconstruction methodology has the potential to improve the accuracy and reliability of electrophysiological mapping. This, in turn, can have a positive impact on patients suffering from cardiac arrhythmias, ultimately leading to better clinical outcomes. Purpose We propose a novel reconstruction method to estimate omnipolar EGM that overcomes the angle dependence weakness of the current method to enhance the reconstruction of electrophysiological signals. Methodology Prior experiments were conducted on isolated rabbit hearts using a 128-electrode array with electrodes spaced 1mm apart over the ventricular epicardium. Four-electrode cliques were designed from these experiments, with different inter-electrode distances as depicted in Figure 1A, to reconstruct the current and novel omnipolar configurations. Metrics were designed to assess the quality of the electrogram signals, including the bipolar loop area and the ratio of the bipolar components of the omnipole (see fig. 2). The bipoles were calculated from unipolar electrograms, and the signal was corrected with a 45º offset in the cross. The propagation angle was then detected, and the local activation time (LAT) was estimated. Results In the bipole plots, it was observed that the morphology of the bipolar loop becomes distorted with an increase in the inter-electrode distance, becoming thinner for distances less than 2mm. There is a direct relation between the areas in the bipolar loop and the inter-electrode distance (see Figure 2A). Furthermore, the values of the area in the cross are always comparable to the best-performing triangular clique. For the ratio of bipoles, the relation is inversely related to distance (see Figure 2B). Similarly, the performance of the cross is comparable to the best-performing triangular omnipole. Conclusion This study highlights the importance of accurate reconstruction of omnipolar EGMs for the diagnosis and treatment of cardiac arrhythmias. To achieve precise reconstruction, inter-electrode distances smaller than 2mm are recommended. The proposed reconstruction method based on the cross configuration is more accurate and robust to wavefront propagation, provided that the recommended distance criterion is met. This study opens up new possibilities for the design of new devices and practices in the clinic.Figure 1Figure 2

Acute termination as an endpoint in individualised electrophysiological substrate ablation in persistent atrial fibrillation

Abstract Background Individualised electrophysiological substrate ablation in persistent atrial fibrillation (perAF) is complicated by the lack of a clearly defined procedural endpoint. The frequency of acute termination and its association with long-term outcomes is not well described. Purpose To define the frequency of acute termination with ablation in a cohort of patients with perAF undergoing catheter ablation with a non-contact charge density mapping (CDM) system and assess its correlation with long term outcomes. Methods The DISCOVER registry (NCT03893331) contains patients recruited to an ongoing multicenter, observational study of CDM guided endocardial ablation procedures. We searched the U.K. component of this registry for all patients presenting for perAF ablations to extract the necessary data for analysis. Termination was considered secondary to ablation whether occurring directly from AF, or via an organized atrial tachycardia (AT). Follow up was performed at 6 and 12 months, and included patient reported recurrence, standard 12-lead ECG, and 7-day ambulatory ECG. Results Eighty-six patients were analysed. All presented in AF at the start of their procedure. Termination was with ablation in 18 (21%). Six-month follow up data was available in 80 (93%), and 12-month in 71 (83%) patients. Freedom from AF was significantly higher in patients ablated to termination; at 6-months 82% vs 51% (p=0.02), at 12-months 69% vs 40% (p=0.04) [figure 1]. Rates of AT during follow up were similar between both groups; at 6-months 24% vs 25% (p=0.93), at 12-months 46% vs 33% (p=0.38) in ablation to termination vs no acute termination groups respectively. Conclusion Occurring in approximately 1/5th of our cohort, the value of ablation to termination as a marker of procedural endpoint may be limited; however, it is a predictor of favorable outcomes. Furthermore, there is no indication from our analysis of a hypothetical association with larger volumes of substrate modification and subsequently development of AT.Freedom from AF at 6 and 12 months

Association of Late Potentials With Fatal Arrhythmic Events in Patients With Brugada Syndrome-A Meta-analysis.

Risk stratification of patients with Brugada syndrome (BrS) remains challenging. Signal-averaged electrocardiogram (SAECG) is a noninvasive tool that can be used to identify the electrophysiologic substrate potentially underlying fatal ventricular arrhythmias. The aim of this meta-analysis is to summarize the existing evidence about the role of late potentials (LP) as a predictor for arrhythmic events in patients with BrS. A systematic search in the MedLine database through to June 2022 without any limitations was performed. Ten studies were included in the quantitative synthesis (1431 patients with BrS, mean age 47.4 years, males 86%). Of these, 1220 patients underwent SAECG evaluation (53.2% had positive LP, and 20.6% had a fatal arrhythmic event). There was a nonsignificant association between positive LPs and fatal arrhythmic events [RR: 2.06 (0.98-4.36), P = 0.06, I2 = 82%]. By including only studies with patients without a history of fatal arrhythmia, the association between LP with arrhythmic events remained nonsignificant [RR: 1.29 (0.67-2.48), P = 0.44, I2 = 54%]. In conclusion, there is a possible association between LP and fatal arrhythmic events in patients with BrS, but the literature remains inconclusive. Large cohort studies using a multiparametric approach for risk stratification purposes are needed to improve the risk stratification of BrS and to optimize the selection of BrS patients that should be referred for implantable cardioverter-defibrillator.

Genetic mechanisms underlying arrhythmogenic mitral valve prolapse: Current and future perspectives.

Mitral valve prolapse (MVP) is a heart valve disease that is often familial, affecting 2%-3% of the general population. MVP with or without mitral regurgitation can be associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Research on familial MVP has specifically focused on genetic factors, which may explain the heritable component of the disease estimated to be present in 20%-35%. Furthermore, the structural and electrophysiological substrates underlying SCD/ventricular arrhythmia risk in MVP have been studied postmortem and in the electrophysiology laboratory, respectively. Understanding how familial MVP and rhythm disorders are related may help patients with MVP by individualizing risk and working to develop effective management strategies. This contemporary, state-of-the-art, expert review focuses on genetic factors and familial components that underlie MVP and arrhythmia and encapsulates clinical, genetic, and electrophysiological issues that should be the objectives of future research.

Impact of Obesity on Atrial Electrophysiological Substrate.

(1) Background. Obesity is a well-established worldwide recognised risk factor for atrial fibrillation (AF). Prior review papers reported on the associations between obesity and AF development, but not on the relation between obesity and atrial electrophysiology. We therefore conducted a systematic review to describe the current knowledge of the characteristics of the atrial electrophysiological substrate in obese individuals and how they relate to the development of AF. (2) Methods. A search was conducted in Pubmed, Embase, and the Cochrane Library for publications evaluating the impact of obesity on atrial electrophysiology, electrical substrates, and their relation to the development of AF. (3) Results. A systematic literature search retrieved 477 potential publications based on the inclusion criteria; 76 full-text articles were selected for the present systematic review. The literature demonstrated that obesity predisposes to not only a higher AF incidence but also to more extensive atrial electrophysiological abnormalities increasing susceptibility to AF development. (4) Conclusion. Obesity may predispose to an overall increase in atrial electropathology, consisting of an increase in the slowing of the conduction, conduction block, low-voltage areas, and complex fractionated electrograms. To determine the impact of obesity-induced atrial electrical abnormalities on the long-term clinical outcome, further prospective studies are mandatory.

Unique topological classification of complex reentrant atrial tachycardias enables optimal ablation strategy

Abstract Funding Acknowledgements: Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC starting grant - SMARTHEART (Nele Vandersickel) B Reentry is a common underlying mechanism of atrial tachycardia (AT). Reentry loops form around anatomical or functional 'holes' in the electrophysiological substrate and dominate the atrial cycle. Terminating a 'full' loop may cause previously 'suppressed' loops around another hole to become dominant. Interpretation of electroanatomical maps can thus be tedious: a full loop may be easily identified, but predicting suppressed loops is complex. We propose that topological classification may aid identification of suppressed loops in complex AT and improve ablation procedures. O Given a map of reentrant clinical AT, we aim to unambiguously classify the AT and suggest an operator-independent optimal ablation strategy. M The left atrium can be described topologically as a closed surface with three ‘holes’: mitral valve, left and right pulmonary veins (similar for the right atrium). Non-conductive tissue may constitute additional topological holes in the substrate. Anatomical reentry can occur around any of the holes described above. Therefore, we uniquely categorize an AT by identifying the number of holes in combination with the presence of full and suppressed loops. Fig. 1-2 shows the finite number of possible combinations for 3 and 4 holes. An optimal ablation strategy should terminate both full and suppressed loops, by connecting their corresponding holes. Directed graph mapping (DGM) is a method and software implementation to analyze arrhythmia by constructing a directed network from local activation time maps. We extended DGM to perform topological classification of AT. We hypothesize that the full reentry loops will correspond to the cycles detected by DGM in the network, while suppressed loops are characterized by activity propagating around a hole for at least 60% of its circumference. To test our algorithms, we generated &amp;gt; 1000 simulations corresponding to 5 different scenarios of Fig. 1-2 whereby the circumference of the suppressed loop was varied between 50% and 90% by adding slow conductive tissue. We also classified 110 clinical cases of mapped AT retrospectively and compared our suggested ablation strategy with the clinical ablation lines which ended the AT. R Terminating solely the full loops by an ablation line led to the suppressed loops creating a slower AT in 95% of simulations. Further ablation to terminate the suppressed loop ended the AT. Following our suggested ablation strategy directly terminated the AT. The ablation strategy suggested by DGM was topologically equivalent to clinically successful ablations in 90% of clinical cases. In 5 cases, DGM correctly predicted that the chosen ablation lead to a suppressed loop becoming dominant, resulting in slower AT. C We presented a unique topological classification of AT. We showed that suppressed loops play a pivotal role as not ablating them leads to slower AT. Benefits include preventing redo maps, shorter and operator independent procedures, and possibly reducing AT recurrence.

Double rhythm mapping for coherent electrophysiological substrate characterization in atrial fibrillation patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) progresses with a cascade of combined structural, functional, and systemic dysfunctions. Electro-anatomical maps are employed to investigate pro-arrhythmic areas, characterized by abnormal electrical properties. However, single rhythm maps provide only a partial reconstruction: rhythm and wavefront directionality might mask some of these areas. Purpose To demonstrate that the combined quantitative analysis of different rhythm maps (i.e., parallel sinus rhythm and paced maps) could allow consistent identification of structural and functional defects sustaining AF. Methods Thirty AF clinical procedures have been performed with mapping system support. In particular, a sinus rhythm activation map and a paced map have been created with a multipolar catheter exploiting the parallel mapping feature by setting an extra beat (pacing interval = ERP + 40 ms) every three sinus beats. Areas of abnormal conduction have been identified and a comparison of electrophysiological biomarkers (EGMs voltage and fractionation) among the two rhythms has been performed. Results This comparative analysis allowed us to identify both structural and functional electrophysiological phenomena. Specifically, we distinguished: (i) abnormal conduction zones confirmed in both maps, both characterized by signal fractionation and a lower voltage (0,56 ± 0,18 mV) with respect to healthy atrial tissue (2,40 ± 0,41 mV), and (ii) abnormal conduction zones visible in only one of the two maps. In the latter, we distinguished whether the absence of the phenomena was due to wavefront orthogonality to the diseased area (revealed in paced rhythm thanks to a change in wavefront direction) or due to the presence of a functional phenomenon induced by the pacing. In the first group signal fractionation has been detected in both rhythms and a lower voltage has been found (1,79 ± 1,1 mV) with respect to normal conduction zones (3,26 ± 0,98 mV), while in functional cases EGMs fractionation has been identified only in paced maps and no significant difference has been observed in terms of voltage. Conclusion Double rhythm mapping provides a more robust characterization of atrial abnormal conduction phenomena. In fact, it allowed the distinction of true structural dysfunctions from dynamic (functional) ones thanks to the different wavefront directionality and rhythm. Moreover, the structural defects have been confirmed by EGMs analysis, which revealed both low voltage amplitude and high fractionation, characteristics that have not been reported in functional cases.

Study of the omnipolar EGM reconstruction for robustness against wavefront propagation in epicardial signals

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Research Program, Ministerio de Ciencia e Innovación, Spanish Government, Instituto de Salud Carlos III. Background Characterisation of electrophysiological substrate is commonly performed by examining cardiac tissue locally by using high-density (HD) arrays of equispaced electrodes – e.g. Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ (SE). These allow creating activation maps of local tissue and substrate exploration. Recently, a novel operation mode arouse: the omnipole, which overcomes many limitations of bipolar and unipolar electrograms, as they are claimed to be orientation independent. Nevertheless, the current technique to reconstruct omnipolar EGMs has pitfalls as the estimation of some incidence angles of the propagation wavefront. We propose a novel reconstruction method to estimate omnipolar EGMs which overcomes the angle dependence weakness of the current one, providing a more robust EGM representation. We hypothesise that this technique will improve reconstruction of electrophysiological signals. Methods Prior electrophysiological experiments on isolated rabbit hearts were used [1], including recordings with a 128-electrode array 1mm apart over ventricular epicardium at 37ºC, with bipolar electrode stimulation. Four-electrodes cliques were designed from these experiments, with different inter-electrode distances as depicted in fig. 1A, reconstructing the current, and novel omnipolar configuration. Metrics to assess the quality of the EGM signals were designed, including the bipolar loop area, and the ratio of the bipolar components of the omnipole (ox and oy) – see fig. 1B. The bipoles were calculated from unipolar EGMs, the signal was corrected with the 45º offset in the cross, the propagation angle was then detected, and the local activation time (LAT) was estimated. Results In the bipole plots, it was observed that the morphology of the bipolar loop gets distorted with an increase in the interelectrode distance – thinner for distances &amp;lt;2mm. There is a direct relation between the areas in the bipolar loop and the inter-electrode distance (see fig. 2A). Furthermore, the values of the area in the cross are always comparable to the best performing triangular clique. For the ratio of bipoles, the relation is inversely to distance (see fig. 2B), similarly, the performance of the cross is comparable to the best performing triangular omnipole. Conclusion For reconstructing omnipolar EGMs, inter-electrode distances smaller than 2mm should be employed. Furthermore, if that condition is satisfied, the novel omnipolar reconstruction method proposed based on the cross configuration is more accurate and robust to wavefront propagation, given that the omnipolar EGM performs similarly or better than the best triangular configuration – and which triangle is fixed for the whole procedure, being the current reconstruction method less robust. Thus, a new standpoint to omnipolar reconstruction in high density electrode catheters is open, towards the design of new devices, and the practice in the clinic.

Hydroxychloroquine induces long QT syndrome by blocking hERG channel

Abstract Objective In March 2022, more than 600 million cases of Corona Virus Disease 2019 (COVID-19) and about 6 million deaths have been reported worldwide. Unfortunately, while effective antiviral therapy has not yet been available, chloroquine (CQ)/hydroxychloroquine (HCQ) has been considered an option for the treatment of COVID-19. While many studies have demonstrated the potential of HCQ to decrease viral load and rescue patients’ lives, controversial results have also been reported. One concern associated with HCQ in its clinical application to COVID-19 patients is the potential of causing long QT interval (LQT), an electrophysiological substrate for the induction of lethal ventricular tachyarrhythmias. Yet, the mechanisms for this cardiotoxicity of HCQ remained incompletely understood. Materials and methods Adult New Zealand white rabbits were used for investigating the effects of HCQ on cardiac electrophysiology and expression of ion channel genes. HEK-293T cells with sustained overexpression of human-ether-a-go-go-related gene (hERG) K+ channels were used for whole-cell patch-clamp recordings of hERG K+ channel current (IhERG). Quantitative RT-PCR analysis and Western blot analysis were employed to determine the expression of various genes at mRNA and protein levels, respectively. Results electrocardiogram (ECG) recordings revealed that HCQ prolonged QT and RR intervals and slowed heart rate in rabbits. Whole-cell patch-clamp results showed that HCQ inhibited the tail current of hERG channels and slowed the reactivation process from inactivation state. HCQ suppressed the expression of hERG and hindered the formation of the heat shock protein 90 (Hsp90)/hERG complex. Moreover, the expression levels of connexin 43 (CX43) and Kir2.1, the critical molecular/ionic determinants of cardiac conduction thereby ventricular arrythmias, were decreased by HCQ, while those of Cav1.2, the main Ca2+ handling proteins, remained unchanged and SERCA2a was increased. Conclusion HCQ could induce LQT but did not induce arrhythmias, and whether it is suitable for the treatment of COVID-19 requires more rigorous investigations and validations in the future.

Effects of cognitive demand during acute exercise on inhibitory control and its electrophysiological indices: A randomized crossover study

The aim of this study was to examine the effects of cognitive demand during acute exercise on the behavioral and electrophysiological correlates of inhibitory control. In a within- participants design, 30 male participants (age range = 18–27 years) performed 20-min sessions of high cognitive-demand exercise (HE), low cognitive-demand exercise (LE), and an active control (AC) on separate days in a randomized order. A moderate-to-vigorous intensity interval step exercise was used as the exercise intervention. During the exercise periods, the participants were instructed to respond to the target among competing stimuli to impose different cognitive demands with their feet. A modified flanker task was administered to assess inhibitory control before and after the interventions, and electroencephalography was used to derive stimulus-elicited N2 and P3 components. Behavioral data showed that the participants performed significantly shorter reaction time (RT), regardless of congruency and a reduced RT flanker effect following HE and LE compared with the AC condition with large (ds = −0.934 to −1.07) and medium effect sizes (ds = −0.502 to −0.507), respectively. Electrophysiological data revealed that compared with the AC condition, acute HE and LE had facilitative effects on stimuli evaluation, as indicated by significantly shorter N2 latency for congruent trials and P3 latency regardless of congruency with medium effect sizes (ds = −0.507 to −0.777). Compared with the AC condition, only acute HE elicited more efficient neural processes in conditions requiring high inhibitory control demand, as indicated by significantly shorter N2 difference latency, with a medium effect size (d = −0.528). Overall, the findings suggest that acute HE and LE facilitate inhibitory control and the electrophysiological substrates of target evaluation. Acute exercise with higher cognitive demand may be associated with more refined neural processing for tasks demanding greater amounts of inhibitory control.

Polygenic risk scores are associated with atrial electrophysiologic substrate abnormalities and outcomes after atrial fibrillation catheter ablation

Polygenic risk scores are associated with atrial electrophysiologic substrate abnormalities and outcomes after atrial fibrillation catheter ablation

Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.

Although impaired AMPK signaling is a hallmark of metabolic diseases (MetD), which heighten arrhythmia risk, whether and how loss of AMPK activity per se promotes adverse electrophysiological (EP) remodeling independently of confounding factors in MetD remains unknown. We investigated the EP substrate of wildtype (WT) mice on high-fat diet (HFD) relative to those on normal diet (ND) and to mice expressing the muscle-specific AMPK kinase dead isoform (AMPK-KD). After 8-weeks of HFD, mice underwent hemodynamic analysis by echocardiography and ex vivo optical action potential (AP) mapping. While HFD-fed mice did not exhibit structural or hemodynamic changes by 8-weeks, they were more prone to pacing-induced VT than their ND counterparts (57% HFD vs 11% ND). Investigation of the EP substrate revealed a marked decrease in conduction velocity (CV) in HFD vs ND-fed mice (54.9±6.7 cm/s vs 71.6±10.2 cm/s, p<0.05) with no change in AP duration (APD). Importantly, we found similar CV slowing in AMPK-KD on ND as WT on HFD. Challenging AMPK-KD mice with HFD did not reduce CV further (45.4±10.6 cm/s HFD vs 49.0±11.1 cm/s ND). In contrast, APD was decreased exclusively in AMPK-KD mice on HFD, reflecting the importance of both factors (AMPK depletion and HFD) in the modulation of myocardial repolarization. Functionally, the subset of hearts that were prone to HFD-related VT exhibited decreased CV compared to those that were protected against VT. We examined the molecular correlates of myocardial conduction, and found a paradoxical increase in Nav1.5, total and Ser368-phosphorylated Cx43 in AMPK-KD, discounting overall protein expression as a factor in CV slowing. In conclusion, impaired AMPK signaling accounts for early CV defects in HFD prior to onset of structural or mechanical remodeling. Our findings highlight AMPK as a potentially powerful anti-arrhythmic target at early stages of MetD.

Opposite pattern of transcranial direct current stimulation effects in middle-aged and older adults: Behavioral and neurophysiological evidence.

Episodic memory (EM) exhibits an age-related decline, with overall increased impairment after the age of 65. The application of transcranial direct current stimulation (tDCS) to ameliorate cognitive decline in ageing has been extensively investigated, but its efficacy has been reported with mixed results. In this study, we aimed to assess whether age contributes to interindividual variability in tDCS efficacy. Thirty-eight healthy adults between 50 and 81 years old received anodal tDCS over the left prefrontal cortex during images encoding and then performed an EM recognition task while event-related potentials (ERPs) were recorded. Our results showed an opposite pattern of effect between middle-aged (50-64 years) and older (65-81 years) adults. Specifically, performance in the recognition task after tDCS was enhanced in older adults and was worsened in middle-aged adults. Moreover, ERPs acquired during the recognition task showed that two EM components related to familiarity and post-retrieval monitoring, i.e., Early Frontal and Late Frontal Old-New effects, respectively, were significantly reduced in middle-aged adults after anodal tDCS. These results support an age-dependent effect of prefrontal tDCS on EM processes and its underlying electrophysiological substrate, with opposing modulatory trajectories along the aging lifespan.

Type-2 Diabetes Alters Hippocampal Neural Oscillations and Disrupts Synchrony between the Hippocampus and Cortex.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.