title: Rate-dependent QT shortening mechanism for the LQT3 deltaKPQ mutant.
abstract: 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 (I(Na)) in LQT3.
  
  
  METHODS
  The deltaKPQ mutant of the human heart voltage-gated sodium channel alpha-subunit was stably transfected into a mammalian cell line (HEK293). I(Na) 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 I(Na) for the 50th pulse compared with that of I(Na) in the first pulse was decreased <2% for interpulse durations as short as 20 ms, but late I(Na) 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 I(Na) was found with minimal reduction of peak I(Na).
  
  
  CONCLUSIONS
  Late I(Na) amplitude in the deltaKPQ mutation is strongly rate dependent. Rate-dependent reductions of late I(Na) 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.
authors.affiliation: Department of Medicine, Cardiology Section, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Nagatomo
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Abe
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000200:Action Potentials; D002461:Cell Line, Transformed; D002999:Clone Cells; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection
chemical_list: D015222:Sodium Channels