Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil

Takeshi Aiba, Wataru Shimizu, Masashi Inagaki, Takashi Noda, Shunichiro Miyoshi, Wei Guang Ding, Dimitar P. Zankov, Futoshi Toyoda, Hiroshi Matsuura, Minoru Horie, Kenji Sunagawa

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98 Citations (Scopus)


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). 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. 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. The I Kr block (E-4031: 1 μmol/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 μmol/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 μmol/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. 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.

Original languageEnglish
Pages (from-to)300-307
Number of pages8
JournalJournal of the American College of Cardiology
Issue number2
Publication statusPublished - 2005 Jan 18
Externally publishedYes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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