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Cardiovascular Research 2002 54(3):624-629; doi:10.1016/S0008-6363(02)00265-1
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Rate-dependent QT shortening mechanism for the LQT3 {Delta}KPQ mutant

Toshihisa Nagatomoa,b, Craig T. Januarya, Bin Yea, Haruhiko Abeb, Yasuhide Nakashimab and Jonathan C. Makielskia,*

aDepartment of Medicine, Cardiology Section, University of Wisconsin, Madison, WI, USA
bThe 2nd Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

jcm{at}medicine.wisc.edu

* Corresponding author. University of Wisconsin Clinics and Hospitals, 600 Highland Avenue H6/349, Madison, WI 53792, USA. Tel.: +1-608-2639-648; fax: +1-608-2630-405

Objective: For the congenital long QT (LQT) syndrome involving mutations of the cardiac sodium channel gene SCN5A, LQT3, the initiation of sudden cardiac death tends to be bradycardia- or pause-dependent, contrary to other LQT syndromes that tend to be adrenergic dependent. Enhanced shortening of the prolonged QT interval with increased heart rate has been reported in LQT3 patients. We hypothesized that the rate-dependent shortening of the QT interval may be attributed to the kinetic properties of inactivation the late sodium current (INa) in LQT3. Methods: The {Delta}KPQ mutant of the human heart voltage-gated sodium channel {alpha}-subunit was stably transfected into a mammalian cell line (HEK293). INa was recorded using a whole-cell patch-clamp technique. Results: A train of 50 depolarizing pulses or a train of 50 ventricular action potential waveforms was applied with different interpulse durations. Peak INa for the 50th pulse compared with that of INa in the first pulse was decreased <2% for interpulse durations as short as 20 ms, but late INa amplitude measured at the end of the pulse was decreased 95, 78, 68, 56 and 47% with 1000, 500, 200, 100, 20 ms interpulse intervals, respectively. Using the action potential waveform a similar rate-dependent reduction of late INa was found with minimal reduction of peak INa. Conclusions: Late INa amplitude in the {Delta}KPQ mutation is strongly rate dependent. Rate-dependent reductions of late INa may cause shortening the QT interval at higher rates. This provides a mechanism correlating the genotype with the clinical phenotype, and provides a rationale for the effectiveness of pacemaker therapy in LQT3 patients.

KEYWORDS Arrhythmia (mechanisms); Long QT syndrome; Membrane currents; Na-channel; Sudden death


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