Cytosolic calcium accumulation and delayed repolarization associated with ventricular arrhythmias in a guinea pig model of Andersen-Tawil syndrome.

Abstract

BACKGROUND:

Andersen-Tawil syndrome (ATS1)-associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity. Previous ex vivo studies in drug-induced Andersen-Tawil syndrome (DI-ATS1) models have proposed that arrhythmia propensity in DI-ATS1 derives from cytosolic Ca(2+) ([Ca(2+)](i)) accumulation leading to increased triggered activity.

OBJECTIVE:

The purpose of this study was to test the hypothesis that elevated [Ca(2+)](i) with concomitant APD prolongation, rather than APD dispersion, underlies arrhythmia propensity during DI-ATS1.

METHODS:

DI-ATS1 was induced in isolated guinea pig ventricles by perfusion of 2 mM KCl Tyrode solution containing 10 μM BaCl(2). APD and [Ca(2+)](i) from the anterior epicardium were quantified by ratiometric optical voltage (di-4-ANEPPS) or Ca(2+) (Indo-1) mapping during right ventricular pacing with or without the ATP-sensitive potassium channel opener pinacidil (15 μM).

RESULTS:

APD gradients under all conditions were insufficient for arrhythmia induction by programmed stimulation. However, 38% of DI-ATS1 preparations experienced ventricular tachycardias (VTs), and all preparations experienced a high incidence of premature ventricular complexes (PVCs). Pinacidil decreased APD and APD dispersion and reduced VTs (to 6%), and PVC frequency (by 79.5%). However, PVC frequency remained significantly greater relative to control (0.5% ± 0.3% of DI-ATS1). Importantly, increased arrhythmia propensity during DI-ATS1 was associated with diastolic [Ca(2+)](i) accumulation and increased [Ca(2+)](i) transient amplitudes. Pinacidil partially attenuated the former but did not alter the latter.

CONCLUSION:

The study data suggest that arrhythmias during DI-ATS1 may be a result of triggered activity secondary to prolonged APD and altered [Ca(2+)](i) cycling and less likely dependent on large epicardial APD gradients forming the substrate for reentry. Therefore, therapies aimed at reducing [Ca(2+)](i) rather than APD gradients may prove effective in treatment of ATS1.

• Authors: Przemysław B Radwański, Rengasayee Veeraraghavan, Steven Poelzing
• Journal: Heart rhythm (Heart Rhythm) Vol. 7 Issue 10 Pg. 1428-1435.e1 (Oct 2010) ISSN: 1556-3871 [Electronic] United States
• PMID: 20380896 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Transport Modulators
• Pinacidil
• Calcium

Topics

• Action Potentials
• Andersen Syndrome (chemically induced, metabolism, physiopathology)
• Animals
• Arrhythmias, Cardiac (etiology, metabolism, physiopathology)
• Calcium (metabolism)
• Cardiac Pacing, Artificial
• Cytosol (metabolism)
• Electrocardiography
• Electrophysiologic Techniques, Cardiac
• Guinea Pigs
• In Vitro Techniques
• Male
• Membrane Transport Modulators (pharmacology)
• Pericardium (cytology, metabolism)
• Pinacidil (pharmacology)
• Voltage-Sensitive Dye Imaging