Impulse Formation Research Articles

Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish

The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na+/K+-ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na+/K+-ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na+/K+-ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na+/K+-ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na+/K+-ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization.

Medaka as a model for ECG analysis and the effect of verapamil

The heart of the medaka, a small fish native to East Asia, has electrophysiological aspects similar to mammalian hearts. We found that the heart rates of medaka were more similar to humans than mice or rats. Medaka exhibited similar electrocardiogram patterns to those of humans, suggesting a similarity in cardiac impulse formation and propagation. Their hearts also exhibited similar responsiveness to verapamil, a calcium channel antagonist; atropine, a parasympathetic nerve blocker; propranolol, a sympathetic β-adrenergic blocker; and isoproterenol, a sympathetic β-adrenergic agonist. We successfully analyzed action potentials and cardiac contractile forces in vivo. Verapamil affected action potential duration and reduced heart rate, suggesting the importance of voltage-dependent calcium channels in determining the heart rhythm of medaka. We also analyzed the expression of the voltage-dependent calcium channel β2 subunit, which participates in channel formation in cardiac myocytes, and found that splice variant type-2 was the only major transcript in the heart. Our results indicate that medaka could be an appropriate animal model for studying cardiovascular pharmacology.

Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis.

Rapid electric impulse spread from the SA node to the atria, the AV node, and the ventricles is prerequisite for coordinated cardiac contraction. In cardiac arrhythmias, disturbed impulse spread can lead to ventricular or atrial tachycardia, fibrillation, and sudden cardiac death. A change in electric impulse propagation had already been proposed to underlie reentrant arrhythmias at the beginning of the 20th century.1 Slowing of propagation and the formation of unidirectional propagation block represent the 2 most important changes leading to circulating and reentrant propagation. Unidirectional propagation block is the prerequisite for the wavefront to reenter nonrefractory tissue of the original propagation path. Knowledge of the mechanisms governing abnormal impulse propagation and formation of propagation block at the level of cellular networks is important for our understanding of arrhythmogenesis and the principles underlying electric and drug therapy. This article reviews experimental and modeling studies performed to understand the basic mechanisms of cardiac impulse propagation, with specific emphasis laid on the relation between propagation and cardiac microstructure. Normally, layers and strands of electrically coupled myocytes separated by connective tissue create a mostly anisotropic compartmentation in atrial and ventricular myocardium. However, compartmentalization can assume pathological forms when fibrosis is enhanced with increasing age and during reparative fibrosis in pathological settings (myocardial infarction, volume/pressure overload, some forms of hereditary diseases). Although structural heterogeneities favor the formation of reentrant circuits, spiral waves occur in tissues with homogeneous electric and structural properties on the basis of time-dependent local changes in refractoriness, which set up the scenario for unidirectional block formation.2 The selected references cited in this short review cannot cover the large body of published literature. Moreover, this article will cover neither the topic of spiral waves nor early and delayed afterdepolarizations (disturbed Ca2+ cycling), which play a major role in the initiation …

A Case of suspected Sick Sinus Syndrome due to combined Beta-blocker and Calcium Channel Blocker Therapy: Anesthesia Management

ABSTRACT Sick sinus syndrome (SSS) is a generalized abnormality of cardiac impulse formation. Abnormalities encompassed by this syndrome may include inappropriate sinus bradycardia, sinus arrest, bradyarrhythmias, or tachyarrhythmias. We present a case of a 54-year-old hypertensive male posted for L4–L5 decompression, whom we suspected to develop SSS due to overdose of combined beta-blocker (BB) and calcium channel blocker (CCB) therapy. How to cite this article Gala AA, Dalvi NP, Gvalani SK, Mahajan S. A Case of suspected Sick Sinus Syndrome due to combined Beta-blocker and Calcium Channel Blocker Therapy: Anesthesia Management. Res Inno in Anesth 2017;2(2):68-70.

Formation of High-Frequency Impulses in a High-Power Magnetotherapeutic Apparatus

We describe here a novel method for forming magnetic field impulses for a high-power medical magnetotherapy apparatus. We present a block diagram of the apparatus for forming magnetic field impulses with specified parameters: rate of impulse rising front, impulse frequency, and magnetic field induction amplitude. The characteristics of solenoids are given, along with calculations of various device parameters.

Late Na+ Current Contributes to Arrhythmogenic Diastolic Ca2+ release in catecholaminergic polymorphic ventricular tachycardia (CPVT)

Arrhythmias caused by abnormal impulse formation including CPVT are associated with aberrant diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum. Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and the arrhythmogenic disturbances in Ca2+ handling (aberrant Na+/Ca2+ signaling) in CPVT remains elusive. To address this issue we used a murine model of cardiac calsequestrin‐associated CPVT. We performed confocal microscopy in isolated ventricular myocytes to assess Ca2+ handling during various pharmacological interventions. Immunocytochemistry experiments were performed to determine the structural underpinnings of Na+/Ca2+ signaling. Late Na+ current (INa) was assessed in whole cell patch‐clamp mode. To monitor arrhythmic activity in vivo surface electrocardiograms were performed before and after intraperitoneal injection of epinephrine (1.5mg/kg) and caffeine (120mg/kg). Immunocytochemistry experiments revealed that neuronal Na+ channels (nNav) colocalize with the ryanodine receptors (RyR2) Ca2+ release channels on the sarcoplasmic reticulum. Isoproterenol (Iso; 100nM) induced late INa in isolated CPVT myocytes which was sensitive to 100nM tetrodotoxin (TTX). Furthermore, nNav blockade with either TTX, riluzole (10μM) or flecainide (2.5 μM) reduced DCR frequency. This antiarrhythmic effect on cellular level translated in decreased ventricular tachycardia (VT) incidence in vivo. On the other hand, nNav augmentation with β‐Pompilidotoxin (β‐PMTX, 40μM) increased both the late INa as well as DCR frequency and VT all of which were reversed by nNav blockade with riluzole or flecainide. These data suggest that Iso‐promoted, nNav‐mediated late INa contributes to the generation of arrhythmogenic DCR in CPVT and can therefore serve as an antiarrhythmic target.Support or Funding InformationThis work was supported by NIH Grants R01‐HL074045, R01‐HL063043 (to S.G.) and K99‐HL127299 (to P.B.R).

Mechanism of Proarrhythmic Effects of Potassium Channel Blockers.

Any disturbance of electrical impulse formation in the heart and of impulse conduction or action potential (AP) repolarization can lead to rhythm disorders. Potassium (K(+)) channels play a prominent role in the AP repolarization process. In this review we describe the causes and mechanisms of proarrhythmic effects that arise as a response to blockers of cardiac K(+) channels. The largest and chemically most diverse groups of compound targets are Kv11.1 (hERG) and Kv7.1 (KvLQT1) channels. Finally, the proarrhythmic propensity of atrial-selective K(+) blockers inhibiting Kv1.5, Kir3.1/3.4, SK, and K2P channels is discussed.

A regular narrow QRS tachycardia in a young man

1547-5271/$-see front matter B 2016 Published by Elsevier Inc. on behalf of Hea patient takes a deep breath, the 1:1 relationship between P wave and QRS changes. One P wave is not conducted to the ventricle, which rules out a tachycardia using a circuit incorporating the AV node and an accessory AV pathway. Could it be a tachycardia of the uncommon variety (the location of the P wave) originating in the AV node with 1 episode of block to the ventricle? Atrial activation during AV nodal impulse formation typically shows similar narrow and negative P waves in leads II and III. This is not the case in our patient. Therefore, we come to the diagnosis of an atrial tachycardia. Next, we need to address the site of origin of the tachycardia. That information comes from a close look at

The electrical heart: 25 years of discovery in cardiac electrophysiology, arrhythmias and sudden death.

This review summarizes progress in the fields of cardiac electrophysiology, arrhythmias and sudden death made in the 25-year interval between 1992 and 2016 during which time Cardiovascular Pathology has been published. Organized along clinical lines, it considers the major heart rhythm disorders underlying atrial, atrioventricular and ventricular arrhythmias, and sudden cardiac death. There is a strong focus on the remarkable advances in understanding the genetic basis for cardiac rhythm disturbances and elucidating fundamental mechanisms of abnormal conduction and impulse formation. During this 25-year period, our understanding of how altered tissue structure (classical pathology) contributes to arrhythmias and sudden death has undergone continuous refinement as new insights have been gained about arrhythmia mechanisms and the dynamic interplay between anatomic substrates and triggers of the major heart rhythm disorders.

MicroRNA expression changes after atrial fibrillation catheter ablation.

Atrial fibrillation (AF) is most common arrhythmia in general population, with increasing trend in mortality and morbidity. Electrophysiological and structural abnormalities, promoting abnormal impulse formation and propagation, lead to this disease. AF catheter ablation is related to a not small percentage of nonresponder patients. microRNAs (miRs) have been used as AF fibrotic and electrical alterations biomarkers. miRs may differentiate responders patients to ablative approach. Selective miR target therapy, as upregulation by adenovirus transfection and/or miR downregulation by antagomiR, may be used to treat AF patients. Catheter ablation of triggering electrical pulmonary veins activity or fibrotic areas defragmentation may be upgraded by miR therapy to prevent cardiac electrical and fibrotic remodeling after AF ablation.

EP News: Basic and Translational

Arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum. Surprisingly, these patients often respond to treatment with Na+ channel blockers. The relationship between Na+ influx and disturbances in Ca2+ handling preceding CPVT arrhythmias remains poorly understood. Radwański et al (Cardiovasc Res 2014; PMID 25538156) performed optical Ca2+ and membrane potential imaging in myocytes and intact cardiac muscle as well as electrocardiograms on a CPVT mouse model with a mutation in calsequestrin. They demonstrated that a subpopulation of Na+ channels (neuronal Nav [nNav]) colocalize with ryanodine receptor channels. Disruption of the cross-talk between nNav and ryanodine receptor channels by nNav blockade with riluzole reduced and desynchronized DCR in both myocytes and intact muscle. Such desynchronization of DCR on cellular and tissue levels translated into decreased arrhythmias in CPVT mice. The authors conclude that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy.

Neuronal Na+ Channels as a Novel Cardiac Antiarrhythmic Target

BackgroundCertain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum. Surprisingly, CPVT patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains elusive.MethodsConfocal microscopy and patch‐clamp recordings ofventricular myocytes isolated from CPVT mouse model with genetic ablation of cardiac calsequestrinwere used to assess Ca2+ handling and Na+ current density during various pharmacological interventions, while surface electrocardiograms were performed during catecholamine challenge.ResultsA subpopulation of Na+ channels (neuronal‐ and not cardiac‐type Na+ channels) colocalize with RyR2. Disruption of the cross‐talk between these by neuronal Na+ channel blockade abolished persistent Na+ current and reduced DCR in cells (Fig a).imageSuch reduction of DCR on cellular level translated in decreased arrhythmias in vivo (Fig b). On the other hand, augmentation of the neuronal Na+ channel activity with β‐Pompilidotoxin (β‐PMTX) increased DCR and caused frequent arrhythmias.ConclusionThese data suggest that neuronal Na+ channels can potentially serve as an antiarrhythmic target. As current antiarrhythmic drugs are all cardiac‐type Na+ channel blockers, this is a major conceptual shift in cellular arrhythmogenesis.

Axonal morphological changes following impulse activity in mouse peripheral nerve in vivo: the return pathway for sodium ions.

Conduction in myelinated axons involves substantial ion movements that must be reversed to restore homeostasis. The pathway taken by sodium ions returning to their original location and the potential osmotic consequences are currently unknown. We report striking morphological changes in axons following sustained impulse conduction that appear to result from osmosis and to indicate accumulation of ions in the periaxonal space followed by their release at the paranode. We conclude that the morphological changes illustrate a hitherto unrecognized part of normal axonal physiology that may also indicate the return pathway for the sodium ions involved in impulse formation. Myelinated axons can conduct sustained trains of impulses at high frequency, but this involves substantial ion movements that must be reversed to restore homeostasis. Little attention has been paid to the potential osmotic consequences of the ion movements or to the pathway taken by sodium ions returning to their original endoneurial location, given that the axolemmal Na(+)-K(+)-ATPase extrudes these ions into the periaxonal space beneath the myelin rather than into the endoneurium. Serial confocal imaging of fluorescent axons conducting at sustained physiological frequencies in vivo has revealed surprising morphological changes that may illuminate these problems. Saphenous nerves and spinal roots of anaesthetized transgenic mice expressing axoplasmic yellow fluorescent protein were stimulated electrically or pharmacologically (veratridine). Within 2 h, the axon herniated on one or both sides of the nodal membrane, displacing the paranodal myelin and widening the nodal gap. The herniated axoplasm became directed back towards the internode, forming a 'cap' up to 30 μm long. Concurrently, the fluid in the expanded periaxonal space accumulated into droplets that appeared to travel to the paranode, where they escaped. No such alterations occurred in axons treated with sodium channel or Na(+)-K(+)-ATPase inhibitors. Remarkably, impulse conduction continued throughout, and all these changes reversed spontaneously over hours or days. The morphological changes were verified ultrastructurally, and occurred in virtually all myelinated axons. The findings appear to reveal an overlooked part of the physiological repertoire of nerve fibres, and here they are interpreted in terms of osmotic changes that may illuminate the pathway by which sodium ions return to the endoneurial space after they have entered the axon during impulse conduction.

Generation of Mechanical Waves in Metals under the High Power Ion Beam Irradiation

The system model «high power ion beam – metal» is suggested. Regularities of impulse formation of mechanical load in the volume of metal target subjected to the action of ion beams of different component composition in the range of power density 107...1010 W/cm2 have been considered. The influence of generation mechanisms on the profile and amplitude-to-time parameters of shock-wave excitation is studied.

Anesthetic Management of a Patient with Sick Sinus Syndrome during General Anesthesia for Maxillofacial Surgery

Sick sinus syndrome (SSS) is a generalized abnormality of cardiac impulse formation. Patients with SSS occasionally need temporary pacing during general anesthesia. The most common issue arising in the perioperative period is electromagnetic interference with device function. We report a case of a 66-year-old man who required temporary cardiac pacing during maxillary cyst extirpation using electrocautery.

Protective effects of kaempferol against cardiac sinus node dysfunction via CaMKII deoxidization.

Kaempferol exerts cardioprotective actions through incompletely understood mechanisms. This study investigated the molecular mechanisms underlying the cardioprotective effects of kaempferol in sinus node dysfunction (SND) heart. Here, we demonstrate that angiotensin II (Ang II) infusion causes SND through oxidized calmodulin kinase II (CaMKII). In contrast to this, kaempferol protects sinus node against Ang II-induced SND. Ang II evoked apoptosis with caspase-3 activation in sinus nodal cells. However, kaempferol lowered the CaMKII oxidization and the sinus nodal cell death. To block the CaMKII oxidization, gene of p47phox, a cytosolic subunit of NADPH oxidase, was deleted using Cas9 KO plasmid. In the absence of p47phox, sinus nodal cells were highly resistance to Ang II-induced apoptosis, suggesting that oxidized-CaMKII contributed to sinus nodal cell death. In Langendorff heart from Ang II infused mice, kaempferol preserved normal impulse formation at right atrium. These data suggested that kaempferol protects sinus node via inhibition of CaMKII oxidization and may be useful for preventing SND in high risk patients.

Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release

Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice. Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy.

Analisis Penerapan Akuntansi Lingkungan Di Rumah Sakit Mardi Waluyo Metro

Environmental pollution in Indonesia has reached the stage of worrying . Environment is increasingly polluted by waste from industrial activities of factories, hospitals , and hotels . This has subsequently become impulse formation Pollution Control Association (Appli) dated December 10, 2008 . Hospitals that an organization must be able to provide health insurance to the public, it is appropriate to control the waste that would have an impact on the spread of disease . Create a healthy environment should be one of the missions of organizations engaged in the field of health . So that the application of accounting and environmental management becomes an important requirement that must be done.

Vagomimetic effects of fingolimod: physiology and clinical implications.

SummaryFingolimod is a sphingosine 1‐phosphate (S1P) receptor modulator approved to treat relapsing‐remitting multiple sclerosis (MS). Initiation of treatment with fingolimod has been found to produce transient bradycardia and/or slowing of atrioventricular impulse conduction in a small proportion of patients. This effect is thought to be due to the interaction of fingolimod with S1P receptors on the surface membrane of atrial myocytes causing a vagomimetic effect, similar to the action of acetylcholine on muscarinic receptors. As a precaution, patients are under electrocardiogram (ECG) monitoring for 6 h after receiving their first dose. Fingolimod is contraindicated in patients with overt or concealed cardiac diseases. However, the Fingolimod Initiation and caRdiac Safety Trial (FIRST), which was designed specifically to investigate the cardiac profile of fingolimod, did not show an increased risk of clinically relevant cardiac events with fingolimod. This review examines the electrophysiology and pathophysiology of cardiac impulse formation in the context of fingolimod. It concludes that these vagomimetic effects should be considered benign and should not prevent the effective use of fingolimod in the treatment of patients with MS.

English

We here present our experience with ventricular tachycardia (VT) leading to cardiac arrest in a patient with American Society of Anesthesiologists grade-I (ASA-I) 11 hours after cholecystectomy. Excessive fluid overload and hypoxemia due to lung congestion may lead to cardiac arrest in this case. Immediate diagnosis and appropriate intervention saved the life of the patient. INTRODUCTION: Cardiac dysrhythmia that occur during the perioperative period can usually be explained on the basis of abnormalities of cardiac pulse conduction, re-entry or impulse formation, specific rhythm disturbances, arterial hypoxemia, electrolyte disturbances (Potassium, magnesium), Acid base disturbances, altered activity of autonomic nervous system, hypertension, intubation, myocardial ischemia, catecholamine's, volatile anesthetics, co-existing cardiac diseases can be associated with initiation of cardiac dysrhythmias.1 Better understanding of pathophysiology of the specific arrhythmia is essential for the Surgical team, because evoking event of arrhythmia occurrence correction should be tried before starting anti arrhythmic drugs. Here we are presenting a case of cholecystectomy who developed ventricular tachycardia after 11hours of uneventful cholecystectomy, and ventricular tachycardia (VT) turned into cardiac arrest. Excessive fluid overload and hypoxemia due to lung congestion may lead to VT which caused cardiac arrest in this case.