Author + information
- Received August 24, 2004
- Accepted September 28, 2004
- Published online January 18, 2005.
- Takeshi Aiba, MD, PhD*,
- Wataru Shimizu, MD, PhD†,* (, )
- Masashi Inagaki, MD*,
- Takashi Noda, MD, PhD*,
- Shunichiro Miyoshi, MD, PhD‡,
- Wei-Guang Ding, MD, PhD§,
- Dimitar P. Zankov, MD§∥,
- Futoshi Toyoda, PhD§,
- Hiroshi Matsuura, MD, PhD§,
- Minoru Horie, MD, PhD∥ and
- Kenji Sunagawa, MD, PhD*
- ↵*Reprint requests and correspondence:
Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565 Japan
Objectives 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(IKsgene) defect linked to acquired long QT syndrome (LQTS).
Background Agents with an IKr-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 IKrblock (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 IKrblocker under conditions with IKssuppression by chromanol 293B 10 μmol/l mimicking the KCNQ1defect (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 IKsand IKrsuppression. 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.
Conclusions Subclinical IKsdysfunction 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.
This study was supported by the Program for Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (of Japan) (to Dr. Sunagawa), a grant from the Japan Cardiovascular Research Foundation (to Dr. Aiba), Fukuda Foundation for Medical Technology (to Dr. Inagaki), Vehicle Racing Commemorative Foundation (to Dr. Shimizu), Health Sciences Research Grants from the Ministry of Health, Labour and Welfare (to Dr. Shimizu), and the Research grant for Cardiovascular Disease (15C-6) from the Ministry of Health, Labour and Welfare (to Dr. Shimizu).
- Received August 24, 2004.
- Accepted September 28, 2004.
- American College of Cardiology Foundation