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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 26, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn075
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Antiarrhythmic Properties of a Rapid Delayed-Rectifier Current Activator in Rabbit Models of Acquired Long QT Syndrome

Thomas G. Diness, MSc1,2,{dagger}, Yung-Hsin Yeh, MD1,3,{dagger}, XiaoYan Qi, PhD1, Denis Chartier, BSc1, Yukiomi Tsuji, MD, PhD4, Rie S. Hansen, PhD2, Soren-Peter Olesen, PhD2, Morten Grunnet, PhD2 and Stanley Nattel, MD1

1 From the Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
2 NeuroSearch A/S and Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Denmark
3 First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
4 Department of Cardiovascular Research, Institute of Environmental Medicine (RIEM), Nagoya University, Nagoya, Japan

Correspondence to Stanley Nattel, 5000 Belanger St. E., Montreal, Quebec H1T 1C8, Canada. Fax: 514-376-1355; Tel: 514-376-3330; E-mail: stanley.nattel{at}icm-mhi.org

Aims: Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to torsades de pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, IKr, in two rabbit models of acquired LQTS.

Methods: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: 1) 3-week atrioventricular block with ventricular bradypacing; 2) dofetilide-induced IKr inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with IKr suppressed by bradycardia remodeling or dofetilide exposure.

Results: Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased IKr in cardiomyocytes isolated from normal and bradycardia-remodeled rabbits by ~75 and 50%, respectively (p<0.001 for each). Similarly, NS1643 restored IKr suppressed by 5 nmol/L dofetilide (tail current 0.28±0.03 pA/pF pre-dofetilide, 0.20±0.01 pA/pF in the presence of dofetilide, 0.27±0.02 pA/pF after adding NS1643 to dofetilide-containing solution, p<0.01).

Conclusions: Pharmacological activation of IKr reverses acquired LQTS and TdP caused by bradycardic remodeling and IKr-blocking drugs. IKr -activating drug therapy could be a potentially interesting treatment approach for the long QT syndrome.

KEYWORDS ion channels; antiarrhythmic agents; arrhythmia (mechanisms); long QT syndrome; ventricular arrhythmias

Time for primary review: 27 days

* These authors contributed equally and should be considered to share first authorship.


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