title: Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes.
abstract: Various drugs are reported to prolong the QT-interval on the surface ECG, thereby increasing the risk of developing a potentially fatal arrhythmia known as Torsades de Pointes (TdP). TdP case reports for these drugs have often been associated with risk factors such as overdosing, concomitant drugs and/or existing pathophysiological conditions. A few cases appear to be devoid of these factors. To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP. An uncommon missense change, R1047L, was identified in two of seven patients who experienced TdP as compared with five of 98 individuals who were free of TdP. Included in the affected individuals was the only subject homozygous for this SNP. Cellular electrophysiological studies revealed a 10-mV positive shift in the steady-state activation curve of the 1047L hERG channel stably expressed in HEK-293 cells as compared with the wild-type (WT) channel. The activation and inactivation kinetics of the 1047L current were significantly slower than the WT (P < 0.05) at given membrane potentials. A computer simulation using a rabbit ventricular myocyte model indicated that same extent of changes in the I(Kr) channel may result in an approximately 15% prolongation in the action potential duration. Our study suggests that 1047L leads to a functional impairment of the hERG channel, which may contribute to the higher incidence of TdP in 1047L carriers when challenged with a channel blocker.
authors.affiliation: Department of Safety Pharmacology, World-Wide Safety Sciences, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Zhuoqian
authors.initials: Z
authors.lastname: Sun
authors.forename: Patrice M
authors.initials: PM
authors.lastname: Milos
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: David B
authors.initials: DB
authors.lastname: Lloyd
authors.forename: Amy
authors.initials: A
authors.lastname: Mank-Seymour
authors.forename: Jodi
authors.initials: J
authors.lastname: Richmond
authors.forename: Jason S
authors.initials: JS
authors.lastname: Cordes
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D003198:Computer Simulation; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels; D006720:Homozygote; D006801:Humans; D007930:Leucine / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D011817:Rabbits; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D001120:Arginine; D007930:Leucine; C063533:dofetilide