Epicardial adipose tissue as a mediator of cardiac arrhythmias

Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Amongst fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome, and given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodelling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome, and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodelling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodelling to ameliorate arrhythmic risk.

Artificial Intelligence-Driven Algorithm for Drug Effect Prediction on Atrial Fibrillation: An in silico Population of Models Approach

Background: Antiarrhythmic drugs are the first-line treatment for atrial fibrillation (AF), but their effect is highly dependent on the characteristics of the patient. Moreover, anatomical variability, and specifically atrial size, have also a strong influence on AF recurrence.Objective: We performed a proof-of-concept study using artificial intelligence (AI) that enabled us to identify proarrhythmic profiles based on pattern identification from in silico simulations.Methods: A population of models consisting of 127 electrophysiological profiles with a variation of nine electrophysiological variables (GNa, INaK, GK1, GCaL, GKur, IKCa, [Na]ext, and [K]ext and diffusion) was simulated using the Koivumaki atrial model on square planes corresponding to a normal (16 cm2) and dilated (22.5 cm2) atrium. The simple pore channel equation was used for drug implementation including three drugs (isoproterenol, flecainide, and verapamil). We analyzed the effect of every ionic channel combination to evaluate arrhythmia induction. A Random Forest algorithm was trained using the population of models and AF inducibility as input and output, respectively. The algorithm was trained with 80% of the data (N = 832) and 20% of the data was used for testing with a k-fold cross-validation (k = 5).Results: We found two electrophysiological patterns derived from the AI algorithm that was associated with proarrhythmic behavior in most of the profiles, where GK1 was identified as the most important current for classifying the proarrhythmicity of a given profile. Additionally, we found different effects of the drugs depending on the electrophysiological profile and a higher tendency of the dilated tissue to fibrillate (Small tissue: 80 profiles vs Dilated tissue: 87 profiles).Conclusion: Artificial intelligence algorithms appear as a novel tool for electrophysiological pattern identification and analysis of the effect of antiarrhythmic drugs on a heterogeneous population of patients with AF.

Knockout of mafba Causes Inner-Ear Developmental Defects in Zebrafish via the Impairment of Proliferation and Differentiation of Ionocyte Progenitor Cells

Zebrafish is an excellent model for exploring the development of the inner ear. Its inner ear has similar functions to that of humans, specifically in the maintenance of hearing and balance. Mafba is a component of the Maf transcription factor family. It participates in multiple biological processes, but its role in inner-ear development remains poorly understood. In this study, we constructed a mafba knockout (mafba−/−) zebrafish model using CRISPR/Cas9 technology. The mafba−/− mutant inner ear displayed severe impairments, such as enlarged otocysts, smaller or absent otoliths, and insensitivity to sound stimulation. The proliferation of p63+ epidermal stem cells and dlc+ ionocyte progenitors was inhibited in mafba−/− mutants. Moreover, the results showed that mafba deletion induces the apoptosis of differentiated K+-ATPase-rich (NR) cells and H+-ATPase-rich (HR) cells. The activation of p53 apoptosis and G0/G1 cell cycle arrest resulted from DNA damage in the inner-ear region, providing a mechanism to account for the inner ear deficiencies. The loss of homeostasis resulting from disorders of ionocyte progenitors resulted in structural defects in the inner ear and, consequently, loss of hearing. In conclusion, the present study elucidated the function of ionic channel homeostasis and inner-ear development using a zebrafish Mafba model and clarified the possible physiological roles.

A Note of Caution: Gramicidin Affects Signaling Pathways Independently of Its Effects on Plasma Membrane Conductance

Gramicidin is a thoroughly studied cation ionophore widely used to experimentally manipulate the plasma membrane potential (PMP). In addition, it has been established that the drug, due to its hydrophobic nature, is capable of affecting the organization of membrane lipids. We have previously shown that modifications in the plasma membrane potential of epithelial cells in culture determine reorganizations of the cytoskeleton. To elucidate the molecular mechanisms involved, we explored the effects of PMP depolarization on some putative signaling intermediates. In the course of these studies, we came across some results that could not be interpreted in terms of the properties of gramicidin as an ionic channel. The purpose of the present work is to communicate these results and, in general, to draw attention to the fact that gramicidin effects can be misleadingly attributed to its ionic or electrical properties. In addition, this work also contributes with some novel findings of the modifications provoked on the signaling intermediates by PMP depolarization and hyperpolarization.

Effective Activation of BKCa Channels by QO-40 (5-(Chloromethyl)-3-(Naphthalen-1-yl)-2-(Trifluoromethyl)Pyrazolo [1,5-a]pyrimidin-7(4H)-one), Known to Be an Opener of KCNQ2/Q3 Channels

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one) is a novel and selective activator of KCNQ2/KCNQ3 K+ channels. However, it remains largely unknown whether this compound can modify any other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH3 lactotrophs were investigated in this study. QO-40 stimulated Ca2+-activated K+ current (IK(Ca)) with an EC50 value of 2.3 μM in these cells. QO-40-stimulated IK(Ca) was attenuated by the further addition of GAL-021 or paxilline but not by linopirdine or TRAM-34. In inside-out mode, this compound added to the intracellular leaflet of the detached patches stimulated large-conductance Ca2+-activated K+ (BKCa) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BKCa channels. The KD value required for the QO-40-mediated decrease in the slow component at the mean closure time was 1.96 μM. This compound shifted the steady-state activation curve of BKCa channels to a less positive voltage and decreased the gating charge of the channel. The application of QO-40 also increased the hysteretic strength of BKCa channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing α-hSlo, QO-40 stimulated BKCa channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BKCa channel to increase the amplitude of IK(Ca) in GH3 cells.

Analysis of Ionic Domains on a Proton Exchange Membrane Using a Numerical Approximation Model Based on Electrostatic Force Microscopy

Understanding the ionic channel network of proton exchange membranes that dictate fuel cell performance is crucial when developing proton exchange membrane fuel cells. However, it is difficult to characterize this network because of the complicated nanostructure and structure changes that depend on water uptake. Electrostatic force microscopy (EFM) can map surface charge distribution with nano-spatial resolution by measuring the electrostatic force between a vibrating conductive tip and a charged surface under an applied voltage. Herein, the ionic channel network of a proton exchange membrane is analyzed using EFM. A mathematical approximation model of the ionic channel network is derived from the principle of EFM. This model focusses on free charge movement on the membrane based on the force gradient variation between the tip and the membrane surface. To verify the numerical approximation model, the phase lag of dry and wet Nafion is measured with stepwise changes to the bias voltage. Based on the model, the variations in the ionic channel network of Nafion with different amounts of water uptake are analyzed numerically. The mean surface charge density of both membranes, which is related to the ionic channel network, is calculated using the model. The difference between the mean surface charge of the dry and wet membranes is consistent with the variation in their proton conductivity.

Highly Proton Conductive Sulfonyl Imide Based Polymer Blended from Poly(arylene ether sulfone) and Parmax-1200 for Fuel Cells

Thermally and chemically stable, sulfonyl imide-based polymer blends have been prepared from sulfonimide poly(arylene ether sulfone) (SI-PAES) and sulfonimide Parmax-1200 (SI-Parmax-1200) using the solvent casting method. Initially, sulfonimide poly(arylene ether sulfone) (SI-PAES) polymers have typically been synthesized via direct polymerization of bis(4-chlorophenyl) sulfonyl imide (SI-DCDPS) and bis(4-fluorophenyl) sulfone (DFDPS) with bisphenol A (BPA). Subsequently, SI-Parmax-1200 has been synthesized via post-modification of the existing Parmax-1200 polymer followed by sulfonation and imidization. The SI-PAES/SI-Parmax-1200 blend membranes show high ion exchange capacity ranging from 1.65 to 1.97 meq/g, water uptake ranging from 22.8 to 65.4% and proton conductivity from 25.9 to 78.5 mS/cm. Markedly, the SI-PAES-40/SI-Parmax-1200 membrane (blended-40) exhibits the highest proton conductivity (78.5 mS/cm), which is almost similar to Nafion 117® (84.73 mS/cm). The thermogravimetric analysis (TGA) and Fenton's test confirm the excellent thermal and chemical stability of the synthetic polymer blends. Furthermore, the scanning electron microscopy (SEM) study shows a distinct phase separation at the hydrophobic/hydrophilic segments, which facilitate proton conduction throughout the ionic channel of the blend polymers. Therefore, the synthetic polymer blends represent an alternative to Nafion 117® as proton exchangers for fuel cells.

Analysis of Ionic Domains on a Proton Exchange Membrane using a Numerical Approximation Model based on Electrostatic Force Microscopy

Understanding the ionic channel network of proton exchange membranes, which dictate fuel cell performance, is crucial when developing proton exchange membrane fuel cells. However, itis difficult to characterize due to complicated nano structure and differing changes to their structure with different amounts of water uptake. Electrostatic force microscopy (EFM) can map surface charge distribution as nano special resolution by measuring the electrostatic force between a vibrating conductive tip and a charged surface under an applied voltage, . In this study, the ionic channel network of a proton exchange membrane is analyzed using EFM. A mathematical approximation model of the ionic channel network is first derived, to explain changes in force gradient on the surface using EFM. The phase lag of dry and wet Nafion under stepwise changes to bias voltage is then measured. Based on the model, variations in the ionic channel network of Nafion with different amounts of water uptake are analyzed numerically. The mean surface charge density of both membranes, which is connected with the ionic channel network, is calculated using the model. The results show that the difference between the mean surface charge of the dry and wet membranes is consistent with the variation in their proton conductivity.

Investigating two kinds of cellular alternans and corresponding TWA induced by impaired calcium cycling in myocardial ischemia

<abstract> <sec><title>Background</title><p>The utility of T wave alternans (TWA) in identifying arrhythmia risk has been demonstrated. During myocardial ischemia (MI), TWA could be induced by cellular alternans. However, the relationship between cellular alternans patterns and TWA patterns in MI has not been investigated thoroughly.</p> </sec> <sec><title>Methods</title><p>We set MI conditions to simulate alternans. Either prolonging Ca²⁺ release or increasing spark-induced sparks (secondary sparks) can give rise to different patterns of APD alternans and TWA. In addition, different ischemic zones and reduced conduction velocity are also considered in one dimensional simulation.</p> </sec> <sec><title>Results</title><p>Delay of Ca²⁺ release can produce discordant Ca²⁺-driven alternans in single cell simulation. Increasing secondary sparks leads to concordant alternans. Correspondingly, morphology and magnitude of TWA vary in two different cellular alternans. Epi ischemia results in alternans concentrating in the first half of T wave. Endo and transmural ischemia lead to fluctuations in the second half of T wave. In addition, slowing conduction velocity has no effect on TWA magnitude.</p> </sec> <sec><title>Conclusion</title><p>Specific ionic channel dysfunction and ischemic zones affect TWA patterns.</p> </sec> </abstract>