Electrophysiological Heterogeneity Research Articles

Atrial Fibrillation and Underlying Structural and Electrophysiological Heterogeneity.

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF.

In silico evaluation of cell therapy in acute versus chronic infarction: role of automaticity, heterogeneity and Purkinje in human

Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. Here, after demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI and the role of cell heterogeneity, scar size and the Purkinje system. Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars and acute infarction. We conclude that homogeneity in injected ventricular-like cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.

Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Stem cell-derived cardiomyocyte heterogeneity confounds electrophysiological insights.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model for studying drug cardiotoxicity and patient-specific cardiovascular disease. The inherent electrophysiological heterogeneity of these cells limits the depth of insights that can be drawn from well-designed experiments. In this review, we provide our perspective on some sources and the consequences of iPSC-CM heterogeneity. We demonstrate the extent of heterogeneity in the literature and explain how such heterogeneity is exacerbated by patch-clamp experimental artifacts in the manual and automated set-up. Finally, we discuss how this heterogeneity, caused by both intrinsic and extrinsic factors, limits our ability to build digital twins of patient-derived cardiomyocytes.

Electrical Instability of the Myocardium in Children and Adolescents

Currently, there is no doubt that the problem of electrical instability of the myocardium in pediatric cardiology is relevant. The determination of various indicators of electrical instability of the myocardium, which are predictors of life-threatening rhythm disorders and sudden cardiac death, presents an underdeveloped task not only for functional diagnostics specialists, but also for pediatricians, neonatologists, pediatric cardiologists and doctors of other specialties. Non-invasive research methods such as electrocardiography (ECG), Holter ECG monitoring (HM ECG), available in almost all pediatric treatment and prevention institutions, are quite informative in terms of detecting electrophysiological heterogeneity of the myocardium as a predictor of sudden cardiac death, which is especially important in children at risk, as well as young athletes. Thus, the determination of indicators of electrical instability of the myocardium is of great interest, it is a promising direction in modern clinical practice, allowing to predict the risk of developing fatal arrhythmias in children and adolescents.

Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re-entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+ release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three-dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1 ) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed-afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+ load. This feature was accentuated in 3D tissue compared to single cells (Δ half-maximal [Ca2+ ]SR =58μM vs. 22μM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re-entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF-like patterns than the PVs. Thus, a reduced IK1 , less negative resting membrane potential, and fibrosis-induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers. KEY POINTS: Focal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated. We applied a multi-scale computational modelling approach to elucidate the mechanisms underlying such localisations. Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time-independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues. The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re-entrant-like excitation patterns to emerge without traditional conduction block.

In situ monolayer patch clamp of acutely stimulated human iPSC-derived cardiomyocytes promotes consistent electrophysiological responses to SK channel inhibition

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) represent an in vitro model of cardiac function. Isolated iPSC-CMs, however, exhibit electrophysiological heterogeneity which hinders their utility in the study of certain cardiac currents. In the healthy adult heart, the current mediated by small conductance, calcium-activated potassium (SK) channels (ISK) is atrial-selective. Functional expression of ISK within atrial-like iPSC-CMs has not been explored thoroughly. The present study therefore aimed to investigate atrial-like iPSC-CMs as a model system for the study of ISK. iPSCs were differentiated using retinoic acid (RA) to produce iPSC-CMs which exhibited an atrial-like phenotype (RA-iPSC-CMs). Only 18% of isolated RA-iPSC-CMs responded to SK channel inhibition by UCL1684 and isolated iPSC-CMs exhibited substantial cell-to-cell electrophysiological heterogeneity. This variability was significantly reduced by patch clamp of RA-iPSC-CMs in situ as a monolayer (iPSC-ML). A novel method of electrical stimulation was developed to facilitate recording from iPSC-MLs via In situ Monolayer Patch clamp of Acutely Stimulated iPSC-CMs (IMPASC). Using IMPASC, > 95% of iPSC-MLs could be paced at a 1 Hz. In contrast to isolated RA-iPSC-CMs, 100% of RA-iPSC-MLs responded to UCL1684, with APD50 being prolonged by 16.0 ± 2.0 ms (p < 0.0001; n = 12). These data demonstrate that in conjunction with IMPASC, RA-iPSC-MLs represent an improved model for the study of ISK. IMPASC may be of wider value in the study of other ion channels that are inconsistently expressed in isolated iPSC-CMs and in pharmacological studies.

Diagnosis of coronary microvascular dysfunction using magnetocardiography

Abstract Background In patients with ischemia and non-obstructive coronary artery disease (INOCA), diagnosing coronary microvascular dysfunction (CMD) is limited to invasive, expensive, and/or difficult to access methods. Magnetocardiography (MCG) is a rest-based scan that measures weak magnetic fields generated by cardiac ionic currents and has been validated for diagnosing ischemia secondary to obstructive coronary artery disease (CAD). Objectives The goal of this study was to validate MCG for diagnosing CMD in patients with INOCA as compared to invasive coronary functional angiography (CFA), the gold-standard for evaluation of CMD by coronary flow reserve (CFR). Methods Forty-eight patients with INOCA (58 ± 10.5 years of age) underwent both CFA and a noninvasive 36-channel MCG scan. CFA diagnosed 21 patients with CMD (CFR &amp;lt;2 by Doppler wire method or CFR &amp;lt;2.5 by thermodilution method) and 27 patients were confirmed as negative for CMD. Using MCG, patients were classified as either CMD positive or CMD negative using an adaptive rules-based system, originally developed for evaluating ischemia secondary to obstructive coronary artery disease. These rules based on 5 features involve the analysis of depolarization and repolarization to observe regions where electrophysiological heterogeneity exists and action potentials in affected tissue are altered in amplitude and/or rate. Results Of the 21 patients confirmed positive for CMD by CFA, 15 had at least one abnormal finding on the MCG. Of the 27 patients confirmed negative for CMD by CFA, 19 had no abnormal findings in the MCG. Using gold standard invasive CFR as reference, MCG had a mean accuracy of 71%, sensitivity of 71% and specificity of 70% for the detection of CMD. Figure 1 shows an example of CMD negative and CMD positive patient. In patients that exhibited more than one abnormal finding on the MCG rules (n =5), accuracy was 80%, with 4 patients correctly characterized as CMD positive, and one patient being characterized as falsely positive. Conclusions In INOCA patients, MCG demonstrates ability to noninvasively assess for CMD. An MCG-based diagnostic pathway for CMD merits further clinical evaluation. Abbreviations and Acronyms: CMD, coronary microvascular dysfunction; MCG, magnetocardiography; CFR, coronary flow reserve; INOCA, ischemia and non-obstructive coronary artery disease; CFA, coronary functional angiographyFigure 1

T-Wave Analysis on the 24 h Holter ECG Monitoring as a Predictive Assessment of Major Adverse Cardiovascular Events in Patients with Myocardial Infarction: A Literature Review and Future Perspectives.

Myocardial ischemia is a pathophysiological state characterized by inadequate perfusion of the myocardium, resulting in an imbalance between myocardial oxygen demand and supply. It is most commonly caused by coronary artery disease, in which atherosclerotic plaques lead to luminal narrowing and reduced blood flow to the heart. Myocardial ischemia can manifest as angina pectoris or silent myocardial ischemia and can progress to myocardial infarction or heart failure if left untreated. Diagnosis of myocardial ischemia typically involves a combination of clinical evaluation, electrocardiography and imaging studies. Electrocardiographic parameters, as assessed by 24 h Holter ECG monitoring, can predict the occurrence of major adverse cardiovascular events in patients with myocardial ischemia, independent of other risk factors. The T-waves in patients with myocardial ischemia have prognostic value for predicting major adverse cardiovascular events, and their electrophysiological heterogeneity can be visualized using various techniques. Combining the electrocardiographic findings with the assessment of myocardial substrate may offer a better picture of the factors that can contribute to cardiovascular death.

Droplet-based transcriptome profiling of individual synapses.

Synapses are crucial structures that mediate signal transmission between neurons in complex neural circuits and display considerable morphological and electrophysiological heterogeneity. So far we still lack a high-throughput method to profile the molecular heterogeneity among individual synapses. In the present study, we develop a droplet-based single-cell (sc) total-RNA-sequencing platform, called Multiple-Annealing-and-Tailing-based Quantitative scRNA-seq in Droplets, for transcriptome profiling of individual neurites, primarily composed of synaptosomes. In the synaptosome transcriptome, or 'synaptome', profiling of both mouse and human brain samples, we detect subclusters among synaptosomes that are associated with neuronal subtypes and characterize the landscape of transcript splicing that occurs within synapses. We extend synaptome profiling to synaptopathy in an Alzheimer's disease (AD) mouse model and discover AD-associated synaptic gene expression changes that cannot be detected by single-nucleus transcriptome profiling. Overall, our results show that this platform provides a high-throughput, single-synaptosome transcriptome profiling tool that will facilitate future discoveries in neuroscience.

Parameters Of Myocardial Electrical Instability In Patients After Myocardial Infarction Comorbid With A Novel Coronavirus Infection (COVID-19)

Objective — This article aims to assess parameters of myocardial electrical instability and arrhythmic events in patients after myocardial infarction (MI), with and without ST-segment elevation, comorbid/noncomorbid with a novel coronavirus infection (COVID-19) using a long-term electrocardiographic (ECG) monitoring. Methods — The study included 64 subjects: 25 (39%) patients with MI comorbid with COVID-19 (MI+C group) and 39 (61%) patients with MI noncomorbid with a novel coronavirus infection (MI group). The mean age of patients was 54.3±6.8 years. A long-term ECG monitoring for 97.4 (95% CI 77.9-115.2) hours was performed with Astrocard®-Telemetry system (Meditek JSC, Russia), starting from the 4th day of MI. Rhythm and conduction disorders, along with ischemic episodes were recorded; an analysis of ventricular late potentials, heart rate turbulence, and QT dispersion was carried out. Results — There were no differences in the frequency of delayed afterdepolarizations in MI and MI+C groups: 15-28% and 18-33% of patients, respectively. An analysis of turbulence parameters did not reveal statistically significant differences between the groups. Such arrhythmic events as frequent supraventricular extrasystole and life-threatening arrhythmias (ventricular extrasystole of grade 4A and higher sensu B. Lown and M. Wolf) were recorded significantly more often in the MI+C group than in the MI group: 48% vs. 20.5% (p=0.021) and 24% vs. 5.1% (p=0.026), respectively. Conclusion — The novel coronavirus infection (COVID-19) exacerbates myocardial electrophysiological heterogeneity in the acute cardiovascular event and is associated with an increase in clinically significant arrhythmic events.

Acute afterload leads to increased electrophysiological heterogeneity after myocardial infarction

Abstract Background Myocardial infarction (MI) results in altered mechanical loading and changes in the cardiac electrical properties. The infarct border zone is pro-arrhythmic but the exact role of mechano-electrical coupling remains unclear. Objective We studied spatial electrical heterogeneity in MI animals during acute afterload increase using a novel E-field methodology for high resolution mapping of local activation-repolarization intervals (ARI) in vivo. Methods Anterior-septal MI was induced in five domestic pigs by 120-minute occlusion of the left anterior descending artery followed by reperfusion. This led to an infarct size of 17.7±2.1% of the left ventricle. After 1 month, electro-anatomical mapping was performed before and during an acute afterload challenge induced by partially inflating a balloon in the descending aorta. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the left ventricle. The non-contact electrograms were processed to determine the ARIs using a custom-made algorithm, previously validated against monophasic action potential recordings. Based on the contact map we defined border zone (BZ, voltage 0.5 to 1.5 mV) and remote (&amp;gt;1.5mV) regions. Heterogeneity was defined as the interquartile range (IQR) of ARIs in fixed neighborhoods of 1cm radius (figure 1A) and analyzed in 10 segments (5 BZ and 5 remote) of a modified version of the AHA model (49 segments by dividing the 16 non-apical segments). Other segments were discarded due to artefacts mainly caused by the array touching the septal and apical wall. Results Acute afterload challenge resulted in an increase of the systolic left ventricular pressure of 41.7±5.4% and increased left ventricular repolarization heterogeneity (IQR 4.03±1.23ms baseline to 4.85±1.38ms during inflation, p=0.004). There was a significant increase in heterogeneity in both BZ (4.78±1.60ms to 5.64±1.66ms, p=0.020) and remote (2.24±0.17ms to 3.00±0.86ms, p=0.034) regions (figure 1B). The IQR in the infarct BZ was higher compared to the remote zone at rest (4.78±1.60ms vs 2.24±0.17ms, p=0.010) as well as during inflation (5.64±1.66ms vs 3.00±0.86ms, p=0.008) (figure 1B). Both BZ and remote regions responded equally to acute afterload (p for interaction = 0.803). Conclusion Increased afterload leads to increased repolarization heterogeneity. This heterogeneity is higher in the infarct BZ. These alterations could provide a functional substrate for reentry. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): KU Leuven - C1 funding

Amplification of input differences by dynamic heterogeneity in the spiral ganglion.

A defining feature of type I primary auditory afferents that compose ∼95% of the spiral ganglion is their intrinsic electrophysiological heterogeneity. This diversity is evident both between and within unitary, rapid, and slow adaptation (UA, RA, and SA) classes indicative of specializations designed to shape sensory receptor input. But to what end? Our initial impulse is to expect the opposite: that auditory afferents fire uniformly to represent acoustic stimuli with accuracy and high fidelity. Yet this is clearly not the case. One explanation for this neural signaling strategy is to coordinate a system in which differences between input stimuli are amplified. If this is correct, then stimulus disparity enhancements within the primary afferents should be transmitted seamlessly into auditory processing pathways that utilize population coding for difference detection. Using sound localization as an example, one would expect to observe separately regulated differences in intensity level compared with timing or spectral cues within a graded tonotopic distribution. This possibility was evaluated by examining the neuromodulatory effects of cAMP on immature neurons with high excitability and slow membrane kinetics. We found that electrophysiological correlates of intensity and timing were indeed independently regulated and tonotopically distributed, depending on intracellular cAMP signaling level. These observations, therefore, are indicative of a system in which differences between signaling elements of individual stimulus attributes are systematically amplified according to auditory processing constraints. Thus, dynamic heterogeneity mediated by cAMP in the spiral ganglion has the potential to enhance the representations of stimulus input disparities transmitted into higher level difference detection circuitry.NEW & NOTEWORTHY Can changes in intracellular second messenger signaling within primary auditory afferents shift our perception of sound? Results presented herein lead to this conclusion. We found that intracellular cAMP signaling level systematically altered the kinetics and excitability of primary auditory afferents, exemplifying how dynamic heterogeneity can enhance differences between electrophysiological correlates of timing and intensity.

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation. Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI). In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n=17), and a basket catheter was positioned in the left ventricle (n=6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS. During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from-18.3% ± 6.3% to-2.1% ± 14.7%) and ARI dispersion (from 104ms2 [1 to 1,108ms2] to -108ms2 [IQR: -588 to 30ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P< 0.05). After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes.

Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells. APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK. Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.

Поздние потенциалы желудочков у детей школьного возраста с сахарным диабетом I типа

Purpose — to study the indicators characterizing the ventricular late potentials (VLP) in schoolchildren with type I diabetes mellitus (TIDM). Materials and methods. 120 children aged 6–17 years were examined (56 — primary school age (6–11 years old), 64 children — senior school age (12–17 years old)). Of which at the age of 6–11 years old: 36 — with TIDM main group I, 20 healthy children (control group I). Of children 12–17 years old, 44 children were with TIDM — main group II, 20 healthy children were included in the control group II. In each age main group рatients with TIDM were divided into 2 subgroups depending on the duration of the disease: subgroup A — 39 patients (22 — primary school age, 17 — senior school age) with diabetes duration 1–3 years and subgroup B — 41 patients (14 и 27 retrospectively) with diabetes duration 4 years or more. All children underwent registration of VLP by high$resolution ECG. The following parameters were calculated: duration of the filtered QRS complex (TotORS, ms), the duration of the low$amplitude (up to 40 μV) part of the signal at the end of the QRS complex (LAS40, ms), the rms amplitude of oscillations in the last 40 ms of the ORS complex (RMS40, μV), as well as the ratio TotQRS / RMS40. The obtained results were processed on the basis of Microsoft Office Excel 2007 spreadsheets using the Statistica 7.0 package for Windows. Results. When analyzing the indicators, it was found that children with diabetes in comparison with healthy children had differences that could be interpreted as signs of lifespan (increase in TotORS, LAS40 and TotQRS / RMS40 ratio, decrease in RMS40 values). Such changes with varying degrees of reliability were recorded in all age groups, and were more pronounced in subgroups B, both in children 6–11 years old, and in patients 12–17 years old. This speaks in favor of the aggravation of the disturbance in the electrical stability of the myocardium as the duration of the disease increases. Conclusions. Thus, the data obtained indicate that children with type I diabetes have foci of delayed fragmented activity due to the electrophysiological heterogeneity of the myocardium. The presence of such foci is recognized as an independent prognostic factor for the risk of fatal arrhythmias, which poses the task of the specialists involved in the management of these patients with the early detection of VLP in order to prevent life$threatening conditions. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local ethics committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: type I diabetes mellitus, children, ventricular late potentials, cardiac autonomic neuropathy.

Dynamic Heterogeneity Shapes Patterns of Spiral Ganglion Activity.

Neural response properties that typify primary sensory afferents are critical to fully appreciate because they establish and, ultimately represent, the fundamental coding design used for higher-level processing. Studies illuminating the center-surround receptive fields of retinal ganglion cells, for example, were ground-breaking because they determined the foundation of visual form detection. For the auditory system, a basic organizing principle of the spiral ganglion afferents is their extensive electrophysiological heterogeneity establishing diverse intrinsic firing properties in neurons throughout the spiral ganglion. Moreover, these neurons display an impressively large array of neurotransmitter receptor types that are responsive to efferent feedback. Thus, electrophysiological diversity and its neuromodulation are a fundamental encoding mechanism contributed by the primary afferents in the auditory system. To place these features into context, we evaluated the effects of hyperpolarization and cAMP on threshold level as indicators of overall afferent responsiveness in CBA/CaJ mice of either sex. Hyperpolarization modified threshold gradients such that distinct voltage protocols could shift the relationship between sensitivity and stimulus input to reshape resolution. This resulted in an "accordion effect" that appeared to stretch, compress, or maintain responsivity across the gradient of afferent thresholds. cAMP targeted threshold and kinetic shifts to rapidly adapting neurons, thus revealing multiple cochleotopic properties that could potentially be independently regulated. These examples of dynamic heterogeneity in primary auditory afferents not only have the capacity to shift the range, sensitivity, and resolution, but to do so in a coordinated manner that appears to orchestrate changes with a seemingly unlimited repertoire.SIGNIFICANCE STATEMENT How do we discriminate the more nuanced qualities of the sound around us? Beyond the basics of pitch and loudness, aspects, such as pattern, distance, velocity, and location, are all attributes that must be used to encode acoustic sensations effectively. While higher-level processing is required for perception, it would not be unexpected if the primary auditory afferents optimized receptor input to expedite neural encoding. The findings reported herein are consistent with this design. Neuromodulation compressed, expanded, shifted, or realigned intrinsic electrophysiological heterogeneity to alter neuronal responses selectively and dynamically. This suggests that diverse spiral ganglion phenotypes provide a rich substrate to support an almost limitless array of coding strategies within the first neural element of the auditory pathway.

Ion Channels and Electrophysiological Properties of Astrocytes: Implications for Emergent Stimulation Technologies.

Astrocytes comprise a heterogeneous cell population characterized by distinct morphologies, protein expression and function. Unlike neurons, astrocytes do not generate action potentials, however, they are electrically dynamic cells with extensive electrophysiological heterogeneity and diversity. Astrocytes are hyperpolarized cells with low membrane resistance. They are heavily involved in the modulation of K+ and express an array of different voltage-dependent and voltage-independent channels to help with this ion regulation. In addition to these K+ channels, astrocytes also express several different types of Na+ channels; intracellular Na+ signaling in astrocytes has been linked to some of their functional properties. The physiological hallmark of astrocytes is their extensive intracellular Ca2+ signaling cascades, which vary at the regional, subregional, and cellular levels. In this review article, we highlight the physiological properties of astrocytes and the implications for their function and influence of network and synaptic activity. Furthermore, we discuss the implications of these differences in the context of optogenetic and DREADD experiments and consider whether these tools represent physiologically relevant techniques for the interrogation of astrocyte function.

Atrial fibrillation rhythm is associated with marked changes in metabolic and myofibrillar protein expression in left atrial appendage

Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up and downregulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.

Optimal pacing sites in cardiac resynchronization by left ventricular activation front analysis

Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, about one-third of patients who are implanted, derive no measurable benefit from CRT. Non-response may partly be due to suboptimal activation of the left ventricle (LV) caused by electrophysiological heterogeneities. The goal of this study is to investigate the performance of a newly developed method used to analyze electrical wavefront propagation in a heart model including myocardial scar and compare this to clinical benchmark studies. We used computational models to measure the maximum activation front (MAF) in the LV during different pacing scenarios. Different heart geometries and scars were created based on cardiac MR images of three patients. The right ventricle (RV) was paced from the apex and the LV was paced from 12 different sites, single site, dual-site and triple site. Our results showed that for single LV site pacing, the pacing site with the largest MAF corresponded with the latest activated regions of the LV demonstrated during RV pacing, which also agrees with previous markers used for predicting optimal single-site pacing location. We then demonstrated the utility of MAF in predicting optimal electrode placements in more complex scenarios including scar and multi-site LV pacing. This study demonstrates the potential value of computational simulations in understanding and planning CRT.