Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil
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*
* Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Suita, Osaka, Japan
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan
|| Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
Manuscript received August 24, 2004;
accepted September 28, 2004.
* 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 (Email: wshimizu{at}hsp.ncvc.go.jp).
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 (IKs gene) 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 IKr 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 IKr blocker under conditions with IKs 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 IKs and IKr 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.
CONCLUSIONS: Subclinical IKs 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.
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Abbreviations and Acronyms
| | APD90 = action potential duration measured at 90% repolarization | | BCL = basic cycle length | | EAD = early afterdepolarization | | IK = delayed rectifier potassium current | | IKr = rapidly activating delayed rectifier potassium current | | IKs = slowly activating delayed rectifier potassium current | | LQTS = long QT syndrome | | TdP = Torsade de Pointes | | TDR = transmural dispersion of repolarization |
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