Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen-Tawil syndrome

Hiroshi Morita, Douglas P. Zipes, Shiho T. Morita, Jiashin Wu

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Objective: Andersen-Tawil syndrome (ATS) is a channelopathy affecting inward rectifier potassium IK1 with QT prolongation, large U waves, and frequent ventricular tachycardia (VT). Although ATS is clinically defined and genetically identified, its electrophysiological mechanism is still unclear, and thus, was the subject of the current study. Methods and results: We replicated the major electrophysiological features of ATS with cesium chloride (CsCl, at IK1 blockade concentration of 5-10 mmol/l) in 23 isolated canine left ventricular tissues perfused arterially with Tyrode's solution having normal or low potassium concentrations, [K+]o. We mapped action potentials (APs) on the cut-exposed transmural surface of the wedges in control, after CsCl, and CsCl with 0.15 μmol/l isoproterenol (CsCl + ISP). CsCl delayed late phase 3 repolarization and prolonged the duration of the AP, more so during low [K+]o perfusion. Rapid pacing induced delayed afterdepolarizations (DADs) in all low [K+]o and in 71% of normal [K+]o preparations after CsCl treatment. Addition of ISP induced DADs in all preparations. DADs originated in mid-to-endocardium, and initiated VT after CsCl + ISP. Migration of DAD-VT foci resulted in multifocal VT. Alternating DADs at 2 foci resulted in bidirectional VT. There were more foci and longer durations of VT at low [K+]o than at normal [K+]o. Delayed late phase 3 repolarization of APs and DADs generated U waves. Verapamil abolished all DADs and VT. Conclusions: CsCl blockade of IK1 produced a ventricular wedge model of ATS. Suppressing IK1 generated U waves by delaying late repolarization of APs and creating DADs, and promoted polymorphic VT by triggering DADs at multiple shifting sites.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalCardiovascular Research
Volume75
Issue number3
DOIs
Publication statusPublished - Aug 1 2007
Externally publishedYes

Keywords

  • Arrhythmia (mechanisms)
  • ECG
  • Mapping
  • Membrane potential
  • Repolarization

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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