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(Circulation Research. 2006;99:1225.)
© 2006 American Heart Association, Inc.

Cellular Biology

Altered Na⁺ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes

Sandra Fredj, Nicolas Lindegger, Kevin J. Sampson, Peter Carmeliet, Robert S. Kass

From the Department of Pharmacology (S.F., N.L., K.J.S., R.S.K.), Columbia University Medical Center, New York; and Center for Transgene Technology and Gene Therapy (P.C.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.

Correspondence to Robert S. Kass, PhD, Department of Pharmacology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032. E-mail rsk20{at}columbia.edu

Long QT syndrome (LQTS) type 3 (LQT3), typified by the KPQ mutation (LQT3 mutation in which amino acid residues 1505 to 1507 [KPQ] are deleted), is caused by increased sodium entry during the action potential plateau resulting from mutation-altered inactivation of the Na_v1.5 channel. Although rare, LQT3 is the most lethal of common LQTS variants. Here we tested the hypothesis that cellular electrical dysfunction, caused not only by action potential prolongation but also by mutation-altered Na⁺ entry, distinguishes LQT3 from other LQTS variants and may contribute to its distinct lethality. We compared cellular electrical activity in myocytes isolated from mice heterozygous for the KPQ mutation (KPQ) and myocytes from wild-type littermates. Current-clamp pause protocols induced rate-dependent spontaneous diastolic activity (delayed after depolarizations) in 6 of 7 KPQ, but no wild-type, myocytes (n=11) tested. Voltage-clamp pause protocols that independently control depolarization duration and interpulse interval identified a distinct contribution of both depolarization duration and mutant Na⁺ channel activity to the generation of Ca_i²⁺-dependent diastolic transient inward current. This was found at rates and depolarization durations relevant both to the mouse model and to LQT3 patients. Flecainide, which preferentially inhibits mutation-altered late Na⁺ current and is used to treat LQT3 patients, suppresses transient inward current formation in voltage-clamped KPQ myocytes. Our results demonstrate a marked contribution of mutation-altered Na⁺ entry to the incidence of pause-dependent spontaneous diastolic activity in KPQ myocytes and suggest that altered Na⁺ entry may contribute to the elevated lethality of LQT3 versus other LQTS variants.

Key Words: ion channels • persistent current • long QT syndrome

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