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 Scopus citations

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 (US)
Pages (from-to)101-107
Number of pages7
JournalHeart Rhythm
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2013

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Keywords

  • Afterdepolarization
  • Intracellular calcium
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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