Conduction Of Electrical Impulses Research Articles

Bipolar Patient–Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here, we report the cardiac electrophysiological implications of a bipolar disorder–associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell-derived cardiomyocytes. Results indicate that the CACNA1C bipolar disorder–related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine-induced QT prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

Implications for neutrophils in cardiac arrhythmias.

Cardiac arrhythmias commonly occur as a result of aberrant electrical impulse formation or conduction in the myocardium. Frequently discussed triggers include underlying heart diseases such as myocardial ischemia, electrolyte imbalances, or genetic anomalies of ion channels involved in the tightly regulated cardiac action potential. Recently, the role of innate immune cells in the onset of arrhythmic events has been highlighted in numerous studies, correlating leukocyte expansion in the myocardium to increased arrhythmic burden. Here, we aim to call attention to the role of neutrophils in the pathogenesis of cardiac arrhythmias and their expansion during myocardial ischemia and infectious disease manifestation. In addition, we will elucidate molecular mechanisms associated with neutrophil activation and discuss their involvement as direct mediators of arrhythmogenicity.

An increase in intercellular crosstalk and electrotonic coupling between cardiomyocytes and nonmyocytes reshapes the electrical conduction in the metabolic heart characterized by short QT intervals in ECGs.

Cardiac conduction abnormalities are disorders in metabolic syndrome (MetS), however, their mechanisms are unknown. Although ventricular arrhythmia reflects the changes in QT-interval of electrocardiograms associated with the changes in cardiomyocyte action potential durations (APDs), recent studies emphasize role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)-conduction. Therefore, considering the possible increase in intercellular interactions of nonmyocytes with cardiomyocytes, we hypothesized an early-cardiac-remodeling characterized by short QT-interval via contributions and modulations of changes by nonmyocytes to the ventricular APs in an early-stage MetS hearts. Following the feeding of 8-week-old rats with a high-sucrose diet (32%; MetS rats) and validation of insulin resistance, there was a significant increase in heart rate and changes in the electrical characteristics of the hearts, especially a shortening in action potential (AP) duration of the papillary muscles. The patch-clamp analysis of ventricular cardiomyocytes showed an increase in the Na+ -channel currents while there were decreases in l-type Ca2+ -channel (LTCC) currents with unchanged K+ -channel currents. There was an increase in the phosphorylated form of connexin 43 (pCx43), mostly with lateral localization on sarcolemma, while its unphosphorylated form (Cx43) exhibited a high degree of localization within intercalated discs. A high-level positively-stained α-SMA and CD68 cells were prominently localized and distributed in interfibrillar spaces of the heart, implying the possible contributions of myofibroblasts and macrophages to both shortened APDs and abnormal electrical conduction in MetS hearts. Our data propose a previously unrecognized pathway for SQT induction in the heart. This pathway includes not only the contribution of short ventricular-APDs via ionic mechanisms but also increasing contributions of the electrotonic-cardiomyocyte depolarization, spontaneous electrical activity-associated fast heterogeneous impulse conduction in the heart via increased interactions and relocations between cardiomyocytes and nonmyocytes, which may be an explanation for the development of an SQT in early-cardiac-remodeling.

Evaluation of Cx43 Gap Junction Inhibitors Using a Quantitative Structure-Activity Relationship Model.

Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques.

CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart.

During heart maturation, gap junctions assemble into hemichannels and polarize to the intercalated disc at cell borders to mediate electrical impulse conduction. However, the molecular mechanism underpinning cardiac gap junction assembly remains elusive. Herein, we demonstrate an important role for the deubiquitinating enzyme cylindromatosis (CYLD) in this process. Depletion of CYLD in mice impairs the formation of cardiac gap junctions, accelerates cardiac fibrosis, and increases heart failure. Mechanistically, CYLD interacts with plakoglobin and removes lysine 63-linked polyubiquitin chains from plakoglobin. The deubiquitination ofplakoglobin enhances its interaction with the desmoplakin/end-binding protein 1 complex localized atthe microtubule plus end, thereby promoting microtubule-dependent transport of connexin 43 (Cx43), akey component of gap junctions, to the cell membrane. These findings establish CYLD as a critical playerin regulating gap junction assembly and have important implications in heart development and diseases.

Electrochemical and Electroconductive Behavior of Silk Fibroin Electrospun Membrane Coated with Gold or Silver Nanoparticles.

The surface modification of materials obtained from natural polymers, such as silk fibroin with metal nanoparticles that exhibit intrinsic electrical characteristics, allows the obtaining of biocomposite materials capable of favoring the propagation and conduction of electrical impulses, acting as communicating structures in electrically isolated areas. On that basis, this investigation determined the electrochemical and electroconductive behavior through electrochemical impedance spectroscopy of a silk fibroin electrospun membrane from silk fibrous waste functionalized with gold or silver nanoparticles synthetized by green chemical reduction methodologies. Based on the results obtained, we found that silk fibroin from silk fibrous waste (SFw) favored the formation of gold (AuNPs-SFw) and silver (AgNPs-SFw) nanoparticles, acting as a reducing agent and surfactant, forming a micellar structure around the individual nanoparticle. Moreover, different electrospinning conditions influenced the morphological properties of the fibers, in the presence or absence of beads and the amount of sample collected. Furthermore, treated SFw electrospun membranes, functionalized with AuNPs-SFw or AgNPS-SFw, allowed the conduction of electrical stimuli, acting as stimulators and modulators of electric current.

Prolonged Codeine Administration Causes Degeneration of Myelinated Axons and Motor Dysfunction in Wistar Rats.

Over-the-counter (OTC) anti-cough medications which contain codeine (an opioid) are extensively available in Nigeria, and hence prone to overuse or abuse. The study aimed to understand the effects of oral codeine administration on the integrity of neurons of the cerebral cortex and cerebellum and its behavioral implications in male Wistar rats. Thirty adult male Wistar rats of comparable weights were obtained and randomly allocated into 5 groups: A, B, C, D, and E (n = 6). Drugs used for the study were ArchilinTM with codeine and dihydrocodeine 30mg. Group A served as control and was administered 0.5mL/kg of normal saline. Groups B and C were treated with 1mg/kg and 2mg/kg of dihydrocodeine, respectively; Group D and E received 2mL/kg and 4mL/kg of ArchilinTM codeine syrup, respectively. The ArchilinTM codeine syrup and dihydrocodeine solutions were administered to the animals based on their body weight, orally and daily with the aid of oropharyngeal tubes for 21 days. The experimental animals were subjected to neurobehavioral studies using beam walk and open field. At the end of the treatment period, the animals were anesthetized with ketamine-hydrochloride intraperitoneally. The brains were quickly dissected out, rinsed with normal saline, and tissue processed for myelin studies. The beam walking and open field result revealed that prolonged codeine administration interfered with motor function in the experimental animals. Sections of the prefrontal cortex and cerebellum of rats given normal saline showed normal myelin sheaths, whereas animals in the treatment group showed degenerating myelin compared to the control. Prolonged consumption of prescription codeine causes degeneration of the myelin sheaths and this may affect the conduction of electrical impulses in myelinated axons thus resulting in motor function insufficiency.

Effects of Antiarrhythmic Drugs on Antiepileptic Drug Action-A Critical Review of Experimental Findings.

Severe cardiac arrhythmias developing in the course of seizures increase the risk of SUDEP (sudden unexpected death in epilepsy). Hence, epilepsy patients with pre-existing arrhythmias should receive appropriate pharmacotherapy. Concomitant treatment with antiarrhythmic and antiseizure medications creates, however, the possibility of drug–drug interactions. This is due, among other reasons, to a similar mechanism of action. Both groups of drugs inhibit the conduction of electrical impulses in excitable tissues. The aim of this review was the analysis of such interactions in animal seizure models, including the maximal electroshock (MES) test in mice, a widely accepted screening test for antiepileptic drugs.

Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics.

The development of neuronal circuitry required for cognition, complex motor behaviors, and sensory integration requires myelination. The role of glial cells such as astrocytes and microglia in shaping synapses and circuits have been covered in other reviews in this journal and elsewhere. This review summarizes the role of another glial cell type, oligodendrocytes, in shaping synapse formation, neuronal circuit development, and myelination in both normal development and in demyelinating disease. Oligodendrocytes ensheath and insulate neuronal axons with myelin, and this facilitates fast conduction of electrical nerve impulses via saltatory conduction. Oligodendrocytes also proliferate during postnatal development, and defects in their maturation have been linked to abnormal myelination. Myelination also regulates the timing of activity in neural circuits and is important for maintaining the health of axons and providing nutritional support. Recent studies have shown that dysfunction in oligodendrocyte development and in myelination can contribute to defects in neuronal synapse formation and circuit development. We discuss glutamatergic and GABAergic receptors and voltage gated ion channel expression and function in oligodendrocyte development and myelination. We explain the role of excitatory and inhibitory neurotransmission on oligodendrocyte proliferation, migration, differentiation, and myelination. We then focus on how our understanding of the synaptic connectivity between neurons and OPCs can inform future therapeutics in demyelinating disease, and discuss gaps in the literature that would inform new therapies for remyelination.

Sodium channels and the intercalated disk - it is all about location, location, location.

Cardiac arrhythmias are often driven by defects in electrical impulse conduction and are common to multiple pathologies, including heart failure and cardiomyopathy. However, the structural substrate of arrhythmias has proven difficult to study or influence in an experimental setting, and even more so in the clinic. Emerging evidence suggests that structural substrates for arrhythmias can exist at subcellular spatial scales extending down to the nanometre level. Such evidence derives mainly from experimental and modelling studies of the intercalated disk (ID), sites of cell–cell contact. The ID is home to gap junctions (GJ) and cardiac voltage-gated Na+ channels (NaV1.5), which are considered to be critical determinants of electrical conduction in cardiac tissue. The GJ and Na+ channel proteins are known to cluster and form nanodomains within regions of narrow intermembrane separation called the perinexi. Disruption of perinexi and the ID is associated with increased risk for arrhythmias: experimental perturbation of ID nanodomains induces proarrhythmic conduction defects, and disruption of perinexal nanodomains has been identified in human arrhythmia patients (Raisch et al. 2018). However, limitations of current technology preclude direct functional investigation of cardiac impulse propagation at the nanoscale. Thus, for the foreseeable future, computational models will be uniquely capable of tackling such questions. While conventional cardiac tissue modelling approaches typically neglect ID structure and Na+ channel clustering, and therefore cannot represent these ID perturbations, earlier studies have modelled simplified representations of the ID. Kucera and colleagues identified a critical mechanism in which Na+ channels localized at the ID impact conduction: ID-localized Na+ currents hyperpolarized the intercellular cleft (the narrow extracellular space between coupled myocytes), which depolarized the post-junctional ID membrane and activated downstream Na+ current (Kucera et al. 2002). These interactions occurring in the extracellular space are collectively termed ephaptic coupling. This and other studies showed that ephaptic coupling can impact conduction in a complex manner, dependent on structural and tissue properties including GJ coupling, cleft width, and ID Na+ channel localization (Weinberg, 2017). Yet these early works still considered the ID as a homogeneous structure, neglecting the significant heterogeneity that arises due to ion channel clustering around GJs. Hichri and colleagues illustrated a pivotal advance: 2D finite-element modelling of the ID membrane and cleft space demonstrated that the size and location of Na+ channel clusters within the ID could also significantly impact ephaptic coupling (Hichri et al. 2018). In this issue of The Journal of Physiology, Ivanovic and Kucera further extend this work to consider important structural details, specifically the effects of Na+ channel clustering around the GJ plaque and location within the narrow perinexus region (Ivanovic & Kucera, 2021). The authors developed a 3D high-resolution finite-element model of two apposing cells and a GJ plaque-adjacent Na+ channel cluster, in which they rigorously investigated the relationship between intermembrane separation and the relative location of Na+ channels, the perinexus, and the GJ plaque, along with the resulting propagation delay between cells. The authors demonstrated that the location of the Na+ channel clusters both near GJs and within a narrow perinexus were critical factors in facilitating impulse transmission. Transmission between cells was successful for a wide range of conditions when Na+ channels were located near GJs within a narrow perinexus. In contrast, transmission failed for nearly all conditions when Na+ channels were outside of the narrow perinexus. These important structural details have important implications for pathological conditions, in which ID structural remodelling results in Na+ channels translocating away from GJ plaques and widening of the perinexi. This study required the development of sophisticated numerical methods and model reduction techniques, which facilitated a more detailed investigation of mechanisms underlying ephaptic coupling that would not have been possible with a simpler model. The authors considered a novel hypothesized two-step interaction occurring in ephaptic coupling, specifically, that (1) inward Na+ current on the pre-junctional ID membrane can, upon cell entry, flow via GJs into the post-junctional cell, and (2) subsequently activate Na+ channels on the post-junctional ID membrane. Interestingly, simulations identified conditions in which the first step occurred, but in general the second step did not occur. Additionally, Ivanovic and Kucera identified a new mechanism involved in ephaptic coupling, termed ‘Na+ transfer’. During impulse transmission, Na+ current in the pre-junctional ID membrane is briefly outward, which acts as a current source for Na+ current flowing into the post-junctional cell. This study represents an important advance in understanding the functional role of the ID and the clinical significance of ID disruption and ion channel organization. The authors acknowledge limitations of their approach, in particular the simplified representation of the overall ID geometry. The authors assumed a flat ID, while noting the known highly tortuous morphology identified in microscopy studies, and also simulated a single Na+ channel cluster and GJ plaque. Our group recently developed a finite-element-based approach to study the effects of heterogeneous ID geometry (e.g. distinct plicate and interplicate regions) and region-specific GJ plaque sizes, and found that these properties also impacted conduction by modulating ephaptic coupling (Moise et al. 2021). Thus, there is a critical need to develop new approaches that can interrogate the role of structural detail across a wide range of spatial scales: computational models integrating high-resolution Na+ channel clusters, heterogeneous ID structure, and tissue-scale propagation; and experimental tools that can identify, quantify, and perturb ID structure and ion channel organization. These tools and techniques will ultimately provide a deeper understanding of the link between cardiac ID structure and conduction. This concept, once established, will be the gateway to new diagnostic tools which directly investigate ID structure and new therapies that can modulate or repair it and thus improve cardiac conduction. No competing interests declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This perspective was supported by funding from National Institutes of Health grant numbers R01HL138003 (to S.H.W.) and R01HL148736 (to R.V.).

Design of a Wireless Single Arm Electrocardiograph System

Electrocardiograms (ECGs) are a method of assessment of cardiac electrical activity. It is the heart’s electrophysiological activity which occurs by the conduction of electrical impulses from the Sinoatrial (SA) node and the Atrioventricular (AV) node across the cardiac muscles and is displayed as a voltage-time graph. Conventionally, they have been acquired using a system of ten surface electrodes placed in different locations throughout the body in a 12-lead system. Single Arm ECG systems, where the ECG rhythm is obtained from only a single part of the body, replace the need for ten different electrodes to detect the heart's activity. Three pre-gelled electrodes are applied in different locations of the left arm to derive the sinus rhythm signal of a subject. An op-amp based hardware instrument has been developed for this purpose with active filters and amplifiers to perform signal conditioning. This paper demonstrates the implementation of a single arm hardware system of small size to improve portability, used as an ECG detection method and the results from various subjects taken at different gain values to improve the view of the signal, while also presenting a method to transmit the data of the signals wirelessly through an Internet-of-things (IoT) platform.

An improved cardiac arrhythmia classification using an RR interval-based approach

Accurate and early detection of cardiac arrhythmia present in an electrocardiogram (ECG) can prevent many premature deaths. Cardiac arrhythmia arises due to the improper conduction of electrical impulses throughout the heart. In this paper, we propose an improved RR interval-based cardiac arrhythmia classification approach. The Discrete Wavelet Transform (DWT) and median filters were used to remove high-frequency noise and baseline wander from the raw ECG. Next, the processed ECG was segmented after the determination of the QRS region. We extracted the primary feature RR interval and other statistical features from the beats to classify the Normal, Premature Ventricular Contraction (PVC), and Premature Atrial Contraction (PAC). The K-Nearest Neighbour (k-NN), Support Vector Machine (SVM), Decision Tree (DT), Naïve Bayes (NB), and Random Forest (RF) classifier were utilised for classification. Overall performance of SVM with Gaussian kernel achieved Se % = 99.28, Sp % = 99.63, +P % = 99.28, and Acc % = 99.51, which is better than the other classifiers used in this method. The obtained results of the proposed method are significantly better and more accurate.

Gap Junctional Communication via Connexin43 between Purkinje Fibers and Working Myocytes Explains the Epicardial Activation Pattern in the Postnatal Mouse Left Ventricle.

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium.

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury.

Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

The Pathophysiology, Diagnosis, and Management of Wolff-Parkinson-White Syndrome in the Neonate.

Wolff-Parkinson-White (WPW) is a congenital defect of the cardiac conduction system (CCS), with proliferation of extra embryologic conduction pathways and rapid conduction of electrical impulses. The estimated neonatal incidence of 0.1% to 0.2% may be misrepresented secondary to missed or misdiagnosis. Undiagnosed WPW can result in sudden cardiac death. To discuss the pathogenesis, manifestations, diagnosis, management, and lifespan implications of WPW in the prenatal and postnatal periods. A literature review was conducted using PubMed, CINAHL, and Google Scholar (2013-2019). Search terms included (newborn OR infant), wolff parkinson white, pathogenesis, management, and ventricular preexcitation. After removal of duplicates, 267 references were identified, abstracts reviewed, and 30 publications fully evaluated. Separation of the heart chambers begins around 7 weeks' gestation with formation of the annulus fibrosis complete after term. The unknown external environmental influence on the development of the preterm infant's CCS places neonates at risk for persistent atrioventricular reentrant tachycardia with WPW development. Ensuring an appropriate diagnosis is crucial, as an incorrect diagnosis could mean death. Due to the rarity of WPW, any fetal or neonatal supraventricular tachycardia requires further evaluation with an electrocardiogram and involvement of an experienced cardiologist for diagnosis. One episode of supraventricular tachycardia warrants evaluation for WPW, as recurring episodes may result in irreversible damage. The recommendations for treatment of WPW in the prenatal and immediate postnatal periods are based heavily on standards of care for the adult population. A paucity of evidenced-based literature exists and future research is crucial to understand the true incidence, physiologic effects, and lifespan implications of WPW on neonates.

Adaptações cardíacas fisiológicas induzidas pelo exercício físico em atletas amadores: revisão narrativa

Objetivo: Compilar evidências científicas recentes sobre as adaptações fisiológicas que ocorrem no coração de atletas amadores. Revisão bibliográfica: A prática de exercícios físicos proporciona um aumento do trabalho cardíaco para suprir a demanda metabólica, o que pode provocar adaptações fisiológicas a depender de vários fatores, como o tipo de exercício realizado, sendo esse predominantemente de força, resistência ou misto. Com a popularização da prática de atividades físicas por pessoas que não dependem do esporte como fonte de renda, os atletas amadores, tornou-se significativo a análise de registros de adaptações cardíacas fisiológicas induzidas pelo exercício que podem ocorrer nesses indivíduos. Com isso, foi possível observar as principais adaptações em praticantes de exercícios de resistência, que incluem as adaptações morfológicas do coração, no sistema de condução do impulso elétrico, além de adaptações bioquímicas e funcionais do sistema cardiovascular. Já as induzidas pelos exercícios de força, incluem predominantemente as adaptações morfológicas e funcionais, enquanto as desenvolvidas pela prática de exercícios mistos incluem alterações funcionais, morfológicas e elétricas. Considerações finais: Percebe-se a necessidade de um maior monitoramento cardiológico em atletas amadores, tendo em vista o risco aumentado de complicações cardiovasculares nesses atletas.

The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice

The heart contains an abundant fibroblast population that may play a role in homeostasis, by maintaining the extracellular matrix (ECM) network, by regulating electrical impulse conduction, and by supporting survival and function of cardiomyocytes and vascular cells. Despite an explosion in our understanding of the role of fibroblasts in cardiac injury, the homeostatic functions of resident fibroblasts in adult hearts remain understudied. TGF-β-mediated signaling through the receptor-activated Smads, Smad2 and Smad3 critically regulates fibroblast function. We hypothesized that baseline expression of Smad2/3 in fibroblasts may play an important role in cardiac homeostasis. Smad2 and Smad3 were constitutively expressed in normal mouse hearts and in cardiac fibroblasts. In cultured cardiac fibroblasts, Smad2 and Smad3 played distinct roles in regulation of baseline ECM gene synthesis. Smad3 knockdown attenuated collagen I, collagen IV and fibronectin mRNA synthesis and reduced expression of the matricellular protein thrombospondin-1. Smad2 knockdown on the other hand attenuated expression of collagen V mRNA and reduced synthesis of fibronectin, periostin and versican. In vivo, inducible fibroblast-specific Smad2 knockout mice and fibroblast-specific Smad3 knockout mice had normal heart rate, preserved cardiac geometry, ventricular systolic and diastolic function, and normal myocardial structure. Fibroblast-specific Smad3, but not Smad2 loss modestly but significantly reduced collagen content. Our findings suggest that fibroblast-specific Smad3, but not Smad2, may play a role in regulation of baseline collagen synthesis in adult hearts. However, at least short term, these changes do not have any impact on homeostatic cardiac function.

Emerging Function of Cardiac Macrophages Ushers in a New Era for the Electrophysiology of the Heart

Maintaining a coordinated heart rhythm is essential for maintaining the heart’s pumping function and blood circulation. Every heartbeat is generated by electrical impulse propagation that is passing through gap junctions, which are composed of connexin proteins. In mammalian hearts, Cx43, Cx40, Cx45, and Cx30.2 are expressed and regulated by post-translational modification. Cardiac macrophages account for only a small number of total heart cells, but they reside all around the heart. They are primarily established prenatally, and they arise from embryonic yolk sac progenitors. Recently, increasing attention has been directed toward novel roles for cardiac resident macrophages, especially in the heart’s electrical impulse conduction. Here, we provide an overview of the recent findings on connexins, with a focus on the emerging function of cardiac macrophages, and we discuss the future directions of treatment for heart disease.

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function.

Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of βIV-spectrin deficiency. Loss of βIV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in βIV-spectrin-deficient fibroblasts by expressing a βIV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global βIV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of βIV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the βIV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).

A study to compare the haemodynamic stability and side effects when using 0.5 percent levobupivacaine vs combination of 0.5 percent levobupivacaine and hyaluronidase, in ultrasound guided axillary brachial plexus block for forearm and hand surgeries

Background: One key component of enhanced recovery protocols is standardized analgesic and anesthetic regimens. Peripheral nerve blocks in particular help in enhanced recovery of the patient by the possibility of early mobilization of the patient. Local Anesthetics are drugs that prevent conduction of electrical impulses on the membranes of nerve and muscle. Adjutants are pharmacological drugs that when co- administered with local anaesthetic agents may improve speed of onset as well as the quality and duration of analgesia. Hyaluronidase drug works as a spreading factor by increasing tissue membrane permeability and reducing the viscosity. Objective: To find if there are any hemodynamic problems or any side effects when Levobupivacaine is used alone compared to Levobupivacaine when used with Hyaluronidase. Materials and Methods: After institutional ethical committee clearance 60 ASA PS class 1 and 2 adult patients in age group of 18 to 60 years who underwent elective upper limb surgeries in Sridevi Institute of Medical Sciences, Tumkur from October 2017 to October 2019 were included. Any patient with history of bleeding disorders, documented neuromuscular disorders, known allergy to Local anesthetics drugs, Psychiatric patients and if on anticoagulants were excluded from the study. Patients were alternately assigned to two groups Group A and Group B each containing 30 patients. Patients undergoing Ultrasound guided Axillary Brachial plexus block with. Group A: 20 ml of 0.5% Levobupivacaine and Hyaluronidase 300 Units (15U/ml of local anesthetic). Group B: 20 ml of 0.5% Levobupivacaine. The patients were given Ultrasound guided Axillary brachial plexus block. Hemodynamic parameters like pulse rate, non-invasive blood pressure, oxygen saturation was monitored. Mean arterial blood pressure (MAP) and pulse rate (PR), oxygen saturation was recorded before application of the block as well as immediately after block & 3 min intervals until the end of the operation. Any drop-in blood pressure more than 20% from the baseline signifies hypotension and was managed with Inj ephedrine 6 mg. Any decrease in pulse rate of less than 60 beats /min was managed with Inj. atropine 0.6mg. Any other complication other than this was noted. Results: Mean pulse rate was similar in both groups with Group A 81.87 and Group B 81.43. Mean arterial pressure between 2 groups was also similar MAP of Group A 105.3 and Group B 105.07. Conclusion: No significant hemodynamic changes were noted between both the groups. Hyaluronidase used as adjuvants along with local anaesthetics to improve the quality of block has no adverse effect on the hemodynamics, unlike other agents (adrenaline, dexmeditomidine, clonidine). It has a good safety profile.