Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations

Mitsunori Maruyama, Jianmin Xiao, Qiang Zhou, Kannan Vembaiyan, Su Kiat Chua, Michael Rubart-von der Lohe, Shien-Fong Lin, Thomas G. Back, Sr Wayne Chen, Peng-Sheng Chen

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2). Objective: To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs). Methods: Intracellular Ca2+ and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects. Results: Spontaneous intracellular Ca2+ elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496+/- mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied. Conclusions: A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.

Original languageEnglish
Pages (from-to)101-107
Number of pages7
JournalHeart Rhythm
Volume10
Issue number1
DOIs
StatePublished - Jan 2013

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Rabbits
Ryanodine Receptor Calcium Release Channel
Long QT Syndrome
Intracellular Membranes
Diastole
Atrioventricular Block
Isoproterenol
Tachycardia
Cardiac Arrhythmias
carvedilol

Keywords

  • Afterdepolarization
  • Intracellular calcium
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. / Maruyama, Mitsunori; Xiao, Jianmin; Zhou, Qiang; Vembaiyan, Kannan; Chua, Su Kiat; Rubart-von der Lohe, Michael; Lin, Shien-Fong; Back, Thomas G.; Wayne Chen, Sr; Chen, Peng-Sheng.

In: Heart Rhythm, Vol. 10, No. 1, 01.2013, p. 101-107.

Research output: Contribution to journalArticle

Maruyama, Mitsunori ; Xiao, Jianmin ; Zhou, Qiang ; Vembaiyan, Kannan ; Chua, Su Kiat ; Rubart-von der Lohe, Michael ; Lin, Shien-Fong ; Back, Thomas G. ; Wayne Chen, Sr ; Chen, Peng-Sheng. / Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. In: Heart Rhythm. 2013 ; Vol. 10, No. 1. pp. 101-107.
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T1 - Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations

AU - Maruyama, Mitsunori

AU - Xiao, Jianmin

AU - Zhou, Qiang

AU - Vembaiyan, Kannan

AU - Chua, Su Kiat

AU - Rubart-von der Lohe, Michael

AU - Lin, Shien-Fong

AU - Back, Thomas G.

AU - Wayne Chen, Sr

AU - Chen, Peng-Sheng

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N2 - Background: Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2). Objective: To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs). Methods: Intracellular Ca2+ and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects. Results: Spontaneous intracellular Ca2+ elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496+/- mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied. Conclusions: A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.

AB - Background: Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2). Objective: To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs). Methods: Intracellular Ca2+ and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects. Results: Spontaneous intracellular Ca2+ elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496+/- mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied. Conclusions: A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.

KW - Afterdepolarization

KW - Intracellular calcium

KW - Long QT syndrome

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