Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes

Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Horváth, Balázs; Ruzsnavszky, Ferenc; Váczi, Krisztina; Magyar, János; Bányász, Tamás; Varró, András; Nánási, Péter P.

doi:10.1007/s00424-014-1581-4

Cited by 40 publications

(61 citation statements)

References 29 publications

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“…The increased propensity for torsade de pointes upon dofetilide treatment could be partially accounted for by the increased beat‐to‐beat APD (and QT interval) variability, which fully complies with the TRIaD concept (see Section for discussion).…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 56%

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Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

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Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 56%

“…Repolarization variability is considerably increased in conditions associated with reduced repolarization reserve, such as I Kr blockade or an increase in late I Na , with the effect being further accentuated at slow pacing rates . These changes are more prominent in M cells compared to epicardial and endocardial myocytes.…”

Section: Triad Conceptmentioning

confidence: 99%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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“…The value of SV calculated with the formula used in this study and also in earlier publications [12,45] is not necessarily the most sensitive way to indicate if the APD of only a few beats greatly differ from the average. This is especially the case when the APD of 50 consecutive APs are used.…”

Section: Discussionmentioning

confidence: 70%

“…Short-term variability of repolarization (SV) was evaluated from a series of 50 consecutive APs evoked by 1 Hz steady-state stimulation and presented in Poincaré diagrams to visualize drug-induced changes in SV as previously [12]. The overall probability of differences between consecutive APD 90 values in each cell was averaged and plotted (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Ca2+-activated Cl− current is antiarrhythmic by reducing both spatial and temporal heterogeneity of cardiac repolarization

Hegyi

Horváth

Váczi

et al. 2017

Journal of Molecular and Cellular Cardiology

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The role of Ca2+-activated Cl− current (ICl(Ca)) in cardiac arrhythmias is still controversial. It can generate delayed afterdepolarizations in Ca2+-overloaded cells while in other studies incidence of early afterdepolarization (EAD) was reduced by ICl(Ca). Therefore our goal was to examine the role of ICl(Ca) in spatial and temporal heterogeneity of cardiac repolarization and EAD formation. Experiments were performed on isolated canine cardiomyocytes originating from various regions of the left ventricle; subepicardial, midmyocardial and subendocardial cells, as well as apical and basal cells of the midmyocardium. ICl(Ca) was blocked by 0.5 mmol/L 9-anthracene carboxylic acid (9-AC). Action potential (AP) changes were tested with sharp microelectrode recording. Whole-cell 9-AC-sensitive current was measured with either square pulse voltage-clamp or AP voltage-clamp (APVC). Protein expression of TMEM16A and Bestrophin-3, ion channel proteins mediating ICl(Ca), was detected by Western blot. 9-AC reduced phase-1 repolarization in every tested cell. 9-AC also increased AP duration in a reverse rate-dependent manner in all cell types except for subepicardial cells. Neither ICl(Ca) density recorded with square pulses nor the normalized expressions of TMEM16A and Bestrophin-3 proteins differed significantly among the examined groups of cells. The early outward component of ICl(Ca) was significantly larger in subepicardial than in subendocardial cells in APVC setting. Applying a typical subepicardial AP as a command pulse resulted in a significantly larger early outward component in both subepicardial and subendocardial cells, compared to experiments when a typical subendocardial AP was applied. Inhibiting ICl(Ca) by 9-AC generated EADs at low stimulation rates and their incidence increased upon beta-adrenergic stimulation. 9-AC increased the short-term variability of repolarization also. We suggest a protective role for ICl(Ca) against risk of arrhythmias by reducing spatial and temporal heterogeneity of cardiac repolarization and EAD formation.

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The potassium current carried by TREK-1 channels in rat cardiac ventricular muscle

Bodnár

Schlichthörl

Daut

2014

Pflugers Arch - Eur J Physiol

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We studied the potassium current flowing through TREK-1 channels in rat cardiac ventricular myocytes. We separated the TREK-1 current from other current components by blocking most other channels with a blocker cocktail. We tried to inhibit the TREK-1 current by activating protein kinase A (PKA) with a mixture of forskolin and isobutyl-methylxanthine (IBMX). Activation of PKA blocked an outwardly rectifying current component at membrane potentials positive to -40 mV. At 37 °C, application of forskolin plus IBMX reduced the steady-state outward current measured at positive voltages by about 52 %. Application of the potassium channel blockers quinidine or tetrahexylammonium also reduced the steady-state outward current by about 50 %. Taken together, our results suggest that the increase in temperature from 22 to 37 °C increased the TREK-1 current by a factor of at least 5 and that the average density of the TREK-1 current in rat cardiomyocytes at 37 °C is about 1.5 pA/pF at +30 mV. The contribution of TREK-1 to the action potential was assessed by using a dynamic patch clamp technique. After subtraction of simulated TREK-1 currents, action potential duration at 50 or 90 % repolarisation was increased by about 12 %, indicating that TREK-1 may be functionally important in rat ventricular muscle. During sympathetic stimulation, inhibition of TREK-1 channels via PKA is expected to prolong the action potential primarily in subendocardial myocytes; this may decrease the transmural dispersion of repolarisation and thus may serve to prevent the occurrence of arrhythmias.

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Contribution of ion currents to beat-to-beat variability of action potential duration in canine ventricular myocytes

Cited by 40 publications

References 29 publications

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Ca2+-activated Cl− current is antiarrhythmic by reducing both spatial and temporal heterogeneity of cardiac repolarization

The potassium current carried by TREK-1 channels in rat cardiac ventricular muscle

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