Cardiovascular Research Advance Access originally published online on March 26, 2008
Cardiovascular Research 2008 79(1):61-69; doi:10.1093/cvr/cvn075
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Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome
1 Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
2 NeuroSearch A/S and Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark
3 First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, Republic of China
4 Department of Cardiovascular Research, Institute of Environmental Medicine (RIEM), Nagoya University, Nagoya, Japan
* Corresponding author. Tel: +1 514 376 3330 (ext. 3990); fax: +1 514 376 1355. E-mail address: 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 and results: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced IKr inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with IKr suppressed by bradycardia remodelling or dofetilide exposure. 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-remodelled rabbits by approximately 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).
Conclusion: Pharmacological activation of IKr reverses acquired LQTS and TdP caused by bradycardic remodelling and IKr-blocking drugs. IKr-activating drug therapy could be a potentially interesting treatment approach for LQTS.
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.