Why Is Only Type 1 Electrocardiogram Diagnostic of Brugada Syndrome? Mechanistic Insights From Computer Modeling

2021 ◽  
Author(s):  
Zhaoyang Zhang ◽  
Peng-Sheng Chen ◽  
James N. Weiss ◽  
Zhilin Qu
Keyword(s):  
Brugada Syndrome ◽  
Potassium Current ◽  
Sodium Current ◽  
Single Cells ◽  
Spiral Wave ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Late Sodium Current

Background: Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered. Methods: Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (I to ), sodium current, and L-type calcium current (I Ca,L ) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R). Results: Although a sufficiently large peak I to was required to result in the type 1 ECG pattern and P2R, increasing the late component of I to converted type 1 ECG to type 2 ECG and suppressed P2R. Increasing the peak I to promoted spiral wave breakup, potentiating the transition from tachycardia to fibrillation, but increasing the late I to prevented spiral wave breakup by flattening the action potential duration restitution and preventing P2R. A sufficiently large I Ca,L conductance was needed for P2R to occur, but once above the critical conductance, blocking I Ca,L promoted P2R. However, selectively blocking the window and late components of I Ca,L suppressed P2R, countering the effect of the late I to . Blocking either the peak or late components of sodium current promoted P2R, with the late sodium current blockade having the larger effect. As expected, increasing other potassium currents potentiated P2R, with ATP-sensitive potassium current exhibiting a larger effect than rapid and slow component of the delayed rectifier potassium current. Conclusions: The peak I to promotes type 1 ECG and P2R, whereas the late I to converts type 1 ECG to type 2 ECG and suppresses P2R. Blocking the peak I Ca,L and either the peak or the late sodium current promotes P2R, whereas blocking the window and late I Ca,L suppresses P2R. These results provide important insights into the mechanisms of arrhythmogenesis and potential therapeutic targets for treatment of Brugada syndrome.

scholarly journals Electrophysiological Properties of Inferior Olive Neurons: A Compartmental Model

1999 ◽  
Vol 82 (2) ◽  
pp. 804-817 ◽  
Author(s):  
Nicolas Schweighofer ◽  
Kenji Doya ◽  
Mitsuo Kawato
Keyword(s):  
Calcium Current ◽  
Potassium Current ◽  
Inferior Olive ◽  
Sodium Current ◽  
Electrical Coupling ◽  
Biophysical Model ◽  
Delayed Rectifier ◽  
High Threshold ◽  
Electrophysiological Properties

As a step in exploring the functions of the inferior olive, we constructed a biophysical model of the olivary neurons to examine their unique electrophysiological properties. The model consists of two compartments to represent the known distribution of ionic currents across the cell membrane, as well as the dendritic location of the gap junctions and synaptic inputs. The somatic compartment includes a low-threshold calcium current ( I Ca_l), an anomalous inward rectifier current ( I h), a sodium current ( I Na), and a delayed rectifier potassium current ( I K_dr). The dendritic compartment contains a high-threshold calcium current ( I Ca_h), a calcium-dependent potassium current ( I K_Ca), and a current flowing into other cells through electrical coupling ( I c). First, kinetic parameters for these currents were set according to previously reported experimental data. Next, the remaining free parameters were determined to account for both static and spiking properties of single olivary neurons in vitro. We then performed a series of simulated pharmacological experiments using bifurcation analysis and extensive two-parameter searches. Consistent with previous studies, we quantitatively demonstrated the major role of I Ca_l in spiking excitability. In addition, I h had an important modulatory role in the spike generation and period of oscillations, as previously suggested by Bal and McCormick. Finally, we investigated the role of electrical coupling in two coupled spiking cells. Depending on the coupling strength, the hyperpolarization level, and the I Ca_l and I hmodulation, the coupled cells had four different synchronization modes: the cells could be in-phase, phase-shifted, or anti-phase or could exhibit a complex desynchronized spiking mode. Hence these simulation results support the counterintuitive hypothesis that electrical coupling can desynchronize coupled inferior olive cells.

Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenile rat preparation

2007 ◽  
Vol 103 (1) ◽  
pp. 220-227 ◽  
Author(s):  
Veronica A. L. Toppin ◽  
Michael B. Harris ◽  
Anna M. Kober ◽  
J. C. Leiter ◽  
Walter M. St.-John
Keyword(s):  
Sodium Current ◽  
Critical Role ◽  
Serotonergic Receptors ◽  
Neural Activities ◽  
Vagal Nerves ◽  
Powerful Mechanism

In severe hypoxia or ischemia, normal eupneic breathing is replaced by gasping, which can serve as a powerful mechanism for “autoresuscitation.” We have proposed that gasping is generated by medullary neurons having intrinsic pacemaker bursting properties dependent on a persistent sodium current. A number of neuromodulators, including serotonin, influence persistent sodium currents. Thus we hypothesized that endogenous serotonin is essential for gasping to be generated. To assess such a critical role for serotonin, a preparation of the perfused, juvenile in situ rat was used. Activities of the phrenic, hypoglossal, and vagal nerves were recorded. We added blockers of type 1 and/or type 2 classes of serotonergic receptors to the perfusate delivered to the preparation. Eupnea continued following additions of any of the blockers. Changes were limited to an increase in the frequency of phrenic bursts and a decline in peak heights of all neural activities. In ischemia, gasping was induced following any of the blockers. Few statistically significant changes in parameters of gasping were found. We thus did not find a differential suppression of gasping, compared with eupnea, following blockers of serotonin receptors. Such a differential suppression had been proposed based on findings using an in vitro preparation. We hypothesize that multiple neurotransmitters/neuromodulators influence medullary mechanisms underlying the neurogenesis of gasping. In greatly reduced in vitro preparations, the importance of any individual neuromodulator, such as serotonin, may be exaggerated compared with its role in more intact preparations.

scholarly journals Cytosolic calcium changes affect the incidence of early afterdepolarizations in canine ventricular myocytes

2015 ◽  
Vol 93 (7) ◽  
pp. 527-534 ◽  
Author(s):  
Balázs Horváth ◽  
Bence Hegyi ◽  
Kornél Kistamás ◽  
Krisztina Váczi ◽  
Tamás Bányász ◽  
...  
Keyword(s):  
Action Potentials ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Cytosolic Calcium ◽  
Delayed Rectifier ◽  
Isolated Cells ◽  
Experimental Conditions ◽  
Early Afterdepolarizations ◽  
Late Sodium Current ◽  
Underlying Mechanisms

This study was designed to investigate the influence of cytosolic Ca2+ levels ([Ca2+]i) on action potential duration (APD) and on the incidence of early afterdepolarizations (EADs) in canine ventricular cardiomyocytes. Action potentials (AP) of isolated cells were recorded using conventional sharp microelectrodes, and the concomitant [Ca2+]i was monitored with the fluorescent dye Fura-2. EADs were evoked at a 0.2 Hz pacing rate by inhibiting the rapid delayed rectifier K+ current with dofetilide, by activating the late sodium current with veratridine, or by activating the L-type calcium current with BAY K8644. These interventions progressively prolonged the AP and resulted in initiation of EADs. Reducing [Ca2+]i by application of the cell-permeant Ca2+ chelator BAPTA-AM lengthened the AP at 1.0 Hz if it was applied alone, in the presence of veratridine, or in the presence of BAY K8644. However, BAPTA-AM shortened the AP if the cells were pretreated with dofetilide. The incidence of the evoked EADs was strongly reduced by BAPTA-AM in dofetilide, moderately reduced in veratridine, whereas EAD incidence was increased by BAPTA-AM in the presence of BAY K8644. Based on these experimental data, changes in [Ca2+]i have marked effects on APD as well as on the incidence of EADs; however, the underlying mechanisms may be different, depending on the mechanism of EAD generation. As a consequence, reduction of [Ca2+]i may eliminate EADs under some, but not all, experimental conditions.

Sustained and transient potassium currents of cultured horizontal cells isolated from white bass retina

1990 ◽  
Vol 64 (6) ◽  
pp. 1758-1766 ◽  
Author(s):  
J. M. Sullivan ◽  
E. M. Lasater
Keyword(s):  
Potassium Current ◽  
Potassium Currents ◽  
Calcium Currents ◽  
Horizontal Cells ◽  
Delayed Rectifier ◽  
White Bass ◽  
A Value ◽  
Outward Potassium Current ◽  
A Current

1. Horizontal cells (HCs) are second-order neurons in the retina that receive direct photoreceptor input. They rest at around -20 mV in the dark, because of the continuous release of neurotransmitter from photoreceptors. HCs respond to light with graded hyperpolarizations, which can reach -70 to -80 mV in the presence of very bright stimuli. 2. HCs from the retinas of white bass were isolated and maintained in culture. Potassium currents in three morphological types of HCs--H1, H2, and H4--were studied in culture with whole-cell, patch-clamp techniques, when sodium and calcium currents were blocked. 3. A transient outward potassium current (IA), with many characteristics of the A-current, was found in all H2s and H4s but only occasionally in H1s. The threshold for activation of this current was around -40 mV, a value more depolarized than usual for the A-current. The peak IA was typically smaller than 300 pA when the membrane was stepped from a holding potential of -70 mV to a command potential of -10 mV, the upper limit of the in vivo range of HC membrane potentials. Steady-state inactivation is expected to reduce the magnitude of IA in vivo. 4. A sustained outward potassium current (IK) was found in all types of HCs. This sustained potassium current did not activate until the membrane was stepped to potentials above -10 mV, a value much more depolarized than those reported for the delayed rectifier current in other neurons. As a result, IK is absent over the in vivo operating range of these cells. 5. No calcium-dependent potassium current was found in any cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Voltage-dependent ionic currents in solitary horizontal cells isolated from cat retina

1992 ◽  
Vol 68 (4) ◽  
pp. 1143-1150 ◽  
Author(s):  
Y. Ueda ◽  
A. Kaneko ◽  
M. Kaneda
Keyword(s):  
Potassium Current ◽  
Horizontal Cell ◽  
Potassium Currents ◽  
Ionic Currents ◽  
Horizontal Cells ◽  
Membrane Properties ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Cat Retina ◽  
Voltage Dependent

1. Horizontal cells of the cat retina were isolated by enzymatic dissociation. Two types of horizontal cells were identified: the axonless (A-type) horizontal cell having four to six thick, long (approximately 100 microns) dendrites, and the short-axon (B-type) horizontal cell having many (> 5) fine, short (approximately 30 microns) dendrites. 2. Membrane properties of isolated horizontal cells were analyzed under current-clamp and voltage-clamp conditions. In the A-type cell, the average resting potential was -55 mV and the mean membrane capacitance was 110 pF, whereas values in the B-type cell were -58 mV and 40 pF, respectively. The A-type cell showed long-lasting Ca spikes, but B-type cells had no Ca spikes. 3. Five types of voltage-dependent ionic currents were recorded: a sodium current (INa), a calcium current (ICa), and three types of potassium currents. Potassium currents consisted of potassium current through the inward rectifier (Ianomal), transient outward potassium current (IA), and potassium current through the delayed rectifier (IK(v)). INa was recorded only from A-type cells. Other currents were recorded from both types of cells. 4. INa activated when cells were depolarized from a holding potential (Vh) of -95 mV, and it was maximal at -25 mV. This current was blocked by tetrodotoxin. Approximately half of the A-type cells had INa, but no B-type cell had this current. 5. L-type ICa, an inward-going sustained current, was activated with depolarization more positive than -25 mV. Current amplitude reached a maximal value near 15 mV and became smaller with further depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

2010 ◽  
Vol 299 (3) ◽  
pp. H643-H655 ◽  
Author(s):  
Katja E. Odening ◽  
Malcolm Kirk ◽  
Michael Brunner ◽  
Ohad Ziv ◽  
Peem Lorvidhaya ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Optical Mapping ◽  
Delayed Rectifier ◽  
Syndrome Type ◽  
Long Qt ◽  
Av Conduction ◽  
Electrophysiological Studies ◽  
Qt Syndrome

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [ IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [ IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block . The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 ( P < 0.05) or LMC ( P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

Ionic currents during action potentials in mammalian skeletal muscle fibers analyzed with loose patch clamp

1994 ◽  
Vol 267 (6) ◽  
pp. C1699-C1706 ◽  
Author(s):  
H. Wolters ◽  
W. Wallinga ◽  
D. L. Ypey ◽  
H. B. Boom
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Action Potentials ◽  
Potassium Current ◽  
Sodium Current ◽  
Delayed Rectifier ◽  
Mammalian Skeletal Muscle ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Patch Clamp Technique

The loose patch-clamp technique was applied to analyze transmembrane currents during propagating action potentials in superficial fibers of musculi extensor digitorum longus of the mouse in vitro. Experimentally three components were identified in the transmembrane current: 1) a capacitive, 2) an inward sodium, and 3) an outward potassium current. Other components were negligible. The capacitive current was similar in shape to the first derivative of the intracellularly measured action potential. Tetrodotoxin, tetraethylammonium, and 4-aminopyridine, applied in the pipette, were used to identify the contribution in the current by sodium and potassium ions. With extracellularly applied depolarization steps only a sodium current was observed, not a potassium current. Occasionally found outward currents were artifactual. The behaviour of delayed rectifier potassium channels in muscle fiber membranes is discussed in the light of these unexpected findings. We conclude that potassium channel activity contributing to and measured during action potential generation is in some way inaccessible to loose patch extracellular voltage-clamp stimulation and that loose patch action current recording is a useful noninvasive method to analyze membrane conductances involved in action potential generation.

scholarly journals Terminating spiral wave and spatiotemporal chaos in cardiac tissues by using late sodium current

2017 ◽  
Vol 66 (13) ◽  
pp. 138201
Author(s):  
Wang Xiao-Yan ◽  
Wang Peng ◽  
Li Qian-Yun ◽  
Tang Guo-Ning
Keyword(s):  
Sodium Current ◽  
Spiral Wave ◽  
Spatiotemporal Chaos ◽  
Late Sodium Current ◽  
Cardiac Tissues
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