scholarly journals Why Pacing Frequency Affects the Production of Early Afterdepolarizations in Cardiomyocytes: An Explanation Revealed by Slow/Fast Analysis of a Minimal Model

2019 ◽  
Author(s):  
Theodore Vo ◽  
Richard Bertram
Keyword(s):  
Action Potential ◽  
Intermediate Frequency ◽  
Tissue Level ◽  
Phase 2 ◽  
Fast Analysis ◽  
Early Afterdepolarizations ◽  
Low Frequencies ◽  
Pharmacological Agents ◽  
Intracellular Ca ◽  
Biophysical Mechanism

AbstractEarly afterdepolarizations (EADs) are pathological voltage oscillations in cardiomyocytes that have been observed in response to a number of pharmacological agents and disease conditions. Phase-2 EADs consist of small voltage fluctuations that occur during the plateau of an action potential, typically under conditions in which the action potential is elongated. Although a single-cell behavior, EADs can lead to tissue-level arrhythmias, including ventricular tachycardia. Much is currently known about the biophysical mechanisms (i.e., the roles of ion channels and intracellular Ca2+ stores) for the various forms of EADs, due partially to the development and analysis of mathematical models. This includes the application of slow/fast analysis, which takes advantage of timescale separation inherent in the system to simplify its analysis. We take this further, using a minimal 3D model to demonstrate that the phase-2 EADs are canards that are formed in the neighborhood of a folded node singularity. This knowledge allows us to determine the number of EADs that can be produced for a given parameter set without performing computer simulations, and provides guidance on parameter changes that can facilitate or inhibit EAD production. With this approach, we demonstrate why periodic stimulation, as would occur in an intact heart, preferentially facilitates EAD production when applied at low frequencies,. We also explain the origin of complex alternan dynamics that can occur with intermediate-frequency stimulation, in which varying numbers of EADs are produced with each stimulation. These revelations fall out naturally from an understanding of folded node singularities, but are hard or impossible to glean from a knowledge of the biophysical mechanism for EADs alone. Therefore, an understanding of the canard mechanism is a useful complement to an understanding of the biophysical mechanism that has been developed over years of experimental and computational investigations.

scholarly journals Arrhythmogenic Mechanisms in Hypokalaemia: Insights From Pre-clinical Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Gary Tse ◽  
Ka Hou Christien Li ◽  
Chloe Kwong Yee Cheung ◽  
Konstantinos P. Letsas ◽  
Aishwarya Bhardwaj ◽  
...  
Keyword(s):  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Clinical Findings ◽  
Excitation Wavelength ◽  
Early Afterdepolarizations ◽  
Intracellular Ca ◽  
Life Threatening ◽  
Clinical Models ◽  
Delayed Afterdepolarizations

Potassium is the predominant intracellular cation, with its extracellular concentrations maintained between 3. 5 and 5 mM. Among the different potassium disorders, hypokalaemia is a common clinical condition that increases the risk of life-threatening ventricular arrhythmias. This review aims to consolidate pre-clinical findings on the electrophysiological mechanisms underlying hypokalaemia-induced arrhythmogenicity. Both triggers and substrates are required for the induction and maintenance of ventricular arrhythmias. Triggered activity can arise from either early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). Action potential duration (APD) prolongation can predispose to EADs, whereas intracellular Ca2+ overload can cause both EADs and DADs. Substrates on the other hand can either be static or dynamic. Static substrates include action potential triangulation, non-uniform APD prolongation, abnormal transmural repolarization gradients, reduced conduction velocity (CV), shortened effective refractory period (ERP), reduced excitation wavelength (CV × ERP) and increased critical intervals for re-excitation (APD–ERP). In contrast, dynamic substrates comprise increased amplitude of APD alternans, steeper APD restitution gradients, transient reversal of transmural repolarization gradients and impaired depolarization-repolarization coupling. The following review article will summarize the molecular mechanisms that generate these electrophysiological abnormalities and subsequent arrhythmogenesis.

I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium

1996 ◽  
Vol 271 (2) ◽  
pp. H548-H561 ◽  
Author(s):  
J. M. Di Diego ◽  
Z. Q. Sun ◽  
C. Antzelevitch
Keyword(s):  
Action Potential ◽  
Phase 1 ◽  
Outward Current ◽  
Disulfonic Acid ◽  
Transient Outward Current ◽  
Pharmacological Agents ◽  
Whole Cell Patch Clamp ◽  
Chloride Channel Blocker ◽  
The Right ◽  
Basic Cycle Length

Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.

Phase-locked rhythms in periodically stimulated heart cell aggregates

1988 ◽  
Vol 254 (1) ◽  
pp. H1-H10 ◽  
Author(s):  
M. R. Guevara ◽  
A. Shrier ◽  
L. Glass
Keyword(s):  
Action Potential ◽  
Classification Scheme ◽  
Stimulation Frequency ◽  
Heart Cell ◽  
Heart Cells ◽  
Complete Suppression ◽  
Intrinsic Frequency ◽  
Low Frequencies ◽  
High Frequencies ◽  
Biological Oscillators

We have studied the effect of injecting a periodic train of current pulses into spontaneously beating aggregates of embryonic chick ventricular heart cells. Over a range of stimulation frequencies around the intrinsic frequency of an aggregate we find one action potential for each stimulus with a fixed latency from each stimulus to the subsequent action potential. For a stimulation frequency higher (lower) than the intrinsic frequency, this corresponds to overdrive (underdrive). At high frequencies of stimulation dropped beats occur leading to complex rhythms analogous to various Wenckebach rhythms observed clinically. At higher stimulation frequencies one can obtain a complete suppression of action potential generation. At low frequencies of stimulation, there are rhythms containing escape beats. Almost every rhythm seen bears a striking resemblance to some cardiac arrhythmia. We present a simple classification scheme that predicts the order of appearance of all the classes of rhythms experimentally observed as one changes the stimulation frequency. We propose that this scheme can be used generally to describe the behavior of other biological oscillators.

scholarly journals Intramural optical mapping of Vm and Cai2+ during long-duration ventricular fibrillation in canine hearts

2012 ◽  
Vol 302 (6) ◽  
pp. H1294-H1305 ◽  
Author(s):  
Wei Kong ◽  
Raymond E. Ideker ◽  
Vladimir G. Fast
Keyword(s):  
Ventricular Fibrillation ◽  
Action Potential ◽  
Short Duration ◽  
Action Potential Duration ◽  
Cycle Length ◽  
The Other ◽  
Membrane Voltage ◽  
Long Duration ◽  
Intracellular Ca ◽  
Rapid Pacing

Intramural gradients of intracellular Ca2+ (Cai2+) Cai2+ handling, Cai2+ oscillations, and Cai2+ transient (CaT) alternans may be important in long-duration ventricular fibrillation (LDVF). However, previous studies of Cai2+ handling have been limited to recordings from the heart surface during short-duration ventricular fibrillation. To examine whether abnormalities of intramural Cai2+ handling contribute to LDVF, we measured membrane voltage ( Vm) and Cai2+ during pacing and LDVF in six perfused canine hearts using five eight-fiber optrodes. Measurements were grouped into epicardial, midwall, and endocardial layers. We found that during pacing at 350-ms cycle length, CaT duration was slightly longer (by ≃10%) in endocardial layers than in epicardial layers, whereas action potential duration (APD) exhibited no difference. Rapid pacing at 150-ms cycle length caused alternans in both APD (APD-ALT) and CaT amplitude (CaA-ALT) without significant transmural differences. For 93% of optrode recordings, CaA-ALT was transmurally concordant, whereas APD-ALT was either concordant (36%) or discordant (54%), suggesting that APD-ALT was not caused by CaA-ALT. During LDVF, Vm and Cai2+ progressively desynchronized when not every action potential was followed by a CaT. Such desynchronization developed faster in the epicardium than in the other layers. In addition, CaT duration strongly increased (by ∼240% at 5 min of LDVF), whereas APD shortened (by ∼17%). CaT rises always followed Vm upstrokes during pacing and LDVF. In conclusion, the fact that Vm upstrokes always preceded CaTs indicates that spontaneous Cai2+ oscillations in the working myocardium were not likely the reason for LDVF maintenance. Strong Vm-Cai2+ desynchronization and the occurrence of long CaTs during LDVF indicate severely impaired Cai2+ handling and may potentially contribute to LDVF maintenance.

The Action Potential in Chara corallina: Effect of Temperature

1976 ◽  
Vol 3 (3) ◽  
pp. 275 ◽  
Author(s):  
MJ Beilby ◽  
HGJ Coster
Keyword(s):  
Action Potential ◽  
Voltage Clamp ◽  
Chara Corallina ◽  
Transient Current ◽  
Effect Of Temperature ◽  
Progressive Change ◽  
Low Frequencies ◽  
Voltage Clamps ◽  
Conductance Changes ◽  
Increasing Temperature

An investigation has been made of the effect of temperature on excitation in cells of C. corallina. It was found that the duration both of the action potential and of the transient current during excitation under voltage clamp increased with decreasing temperature, from ~1 s at 40°C to ~30 s at 3.5°C. The form of the transient response, however, was independent of temperature. While the peak potential during an action potential was largely independent of temperature, the peak transient current during a voltage clamp increased with increasing temperature up to ~30°C. Beyond this temperature, the peak current decreased again with increasing temperature. The activation enthalphy (ΔH*) calculated from Arrhenius plots of the duration of the action potential or of the transient current under voltage clamp varied continuously with temperature, having the values of ~7 kJ/mol for T > 20°C and ~350 kJ/mol for T < 7°C. The peak of the transient conductance changes (during voltage clamp at -45 mV) increased progressively with increasing temperatures; for T < 7°C there was almost no transient change in conductance. °H* for peak transient conductance change was ~7 kJ/mol for T > 20°C and ~145 kJ/mol for T < 7°C. At low temperatures (<7°C), ΔH* for the excitation channels was similar to that for the dehydration of K+, Na+ or Cl- ions. At high temperatures (>35°C), ΔH* for both the passive and excitation channels was about the same as that for diffusion in a free solution. This suggests a progressive change in the degree of dehydration required for ion permeation in the channels. In the light of the known frequency dependence of the membrane capacitance of this species (at low frequencies), considerations are also given to the implications of the similarity in their temperature dependence, of the duration of the action potential and the duration of the transient currents during voltage clamps.

Hypoxic release of calcium from the sarcoplasmic reticulum of pulmonary artery smooth muscle

2001 ◽  
Vol 281 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Michelle Dipp ◽  
Piers C. G. Nye ◽  
A. Mark Evans
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Phase 1 ◽  
Transient Phase ◽  
Phase 2 ◽  
Hypoxic Response ◽  
Pulmonary Vessels ◽  
Intracellular Ca ◽  
Pulmonary Artery Smooth Muscle ◽  
Phase Phase

The hypoxic constriction of isolated pulmonary vessels is composed of an initial transient phase ( phase 1) followed by a slowly developing increase in tone ( phase 2). We investigated the roles of the endothelium and of intracellular Ca2+ stores in both preconstricted and unpreconstricted intrapulmonary rabbit arteries when challenged with hypoxia (Po 2 16–21 Torr). Removing the endothelium did not affect phase 1, but phase 2 appeared as a steady plateau. Removing extracellular Ca2+ had essentially the same effect as removing the endothelium. Depletion of sarcoplasmic reticulum Ca2+stores with caffeine and ryanodine abolished the hypoxic response. Omitting preconstriction reduced the amplitude of the hypoxic response but did not qualitatively affect any of the above responses. We conclude that hypoxia releases intracellular Ca2+ from ryanodine-sensitive stores by a mechanism intrinsic to pulmonary vascular smooth muscle without the need for Ca2+ influx across the plasmalemma or an endothelial factor. Our results also suggest that extracellular Ca2+ is required for the release of an endothelium-derived vasoconstrictor.

A Novel Ca2+ Influx Pathway in Mammalian Primary Sensory Neurons Is Activated by Caffeine

2001 ◽  
Vol 86 (1) ◽  
pp. 190-196 ◽  
Author(s):  
Robert E. Hoesch ◽  
Daniel Weinreich ◽  
Joseph P. Y. Kao
Keyword(s):  
Sensory Neurons ◽  
Ryanodine Receptors ◽  
Reversal Potential ◽  
Significant Rise ◽  
Adult Rabbit ◽  
Pharmacological Agents ◽  
Inward Current ◽  
Whole Cell Patch Clamp ◽  
Intracellular Ca ◽  
Ganglion Neurons

Single-cell microfluorimetry and electrophysiology techniques were used to identify and characterize a novel Ca2+ influx pathway in adult rabbit vagal sensory neurons. Acutely dissociated nodose ganglion neurons (NGNs) exhibit robust Ca2+-induced Ca2+ release (CICR) that can be triggered by 10 mM caffeine, the classic agonist of CICR. A caffeine-induced increase in cytosolic-free Ca2+ concentration ([Ca2+]i) is considered diagnostic evidence of the existence of CICR. However, when CICR was disabled through depletion of intracellular Ca2+stores or pharmacological blockade of intracellular Ca2+ release channels (ryanodine receptors), caffeine still elicited a significant rise in [Ca2+]i in ∼50% of NGNs. The same response was not elicited by pharmacological agents that elevate cyclic nucleotide concentrations. Moreover, extracellular Ca2+ was obligatory for such caffeine-induced [Ca2+]i rises in this population of NGNs, suggesting that Ca2+ influx is responsible for this rise. Simultaneous microfluorimetry with whole cell patch-clamp studies showed that caffeine activates an inward current that temporally parallels the rise in [Ca2+]i. The inward current had a reversal potential of +8.1 ± 6.1 (SE) mV ( n = 4), a mean peak amplitude of −126 ± 24 pA ( n = 4) at E m = −50 mV, and a slope conductance of 1.43 ± 0.79 nS ( n= 4). Estimated EC50 values for caffeine-induced CICR and for caffeine-activated current were 1.5 and ∼0.6 mM, respectively. These results indicate that caffeine-induced rises in [Ca2+]i, in the presence of extracellular Ca2+, can no longer be interpreted as unequivocal diagnostic evidence for CICR in neurons. These results also indicate that sensory neurons possess a novel Ca2+ influx pathway.

Sign in / Sign up

Export Citation Format

Share Document