title: Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil.
abstract: OBJECTIVE
  We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I(Ks) gene) defect linked to acquired long QT syndrome (LQTS).
  
  
  BACKGROUND
  Agents with an I(Kr)-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP.
  
  
  METHODS
  Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations.
  
  
  RESULTS
  The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I(Kr) blocker under conditions with I(Ks) suppression by chromanol 293B 10 micromol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I(Ks) and I(Kr) suppression. Verapamil (0.1 to 5.0 micromol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP.
  
  
  CONCLUSIONS
  Subclinical I(Ks) dysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.
authors.affiliation: Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Masashi
authors.initials: M
authors.lastname: Inagaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Noda
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002415:Cats; D002839:Chromans / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D046509:Tissue Culture Techniques; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002839:Chromans; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D014700:Verapamil