Opposing effects of bepridil on ventricular repolarization in humans. Inhomogeneous prolongation of the action potential duration vs flattening of its restitution kinetics.
BACKGROUND
Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action.


RESULTS
Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172 +/-26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD(90S) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD(90) was greater in RVOT (approximately 13%) than RVA (approximately 8%). Bepridil flattened the MAPD(90) restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65 +/-0.22 vs 0.95 +/-0.38) and RVA (0.65 +/-0.14 vs 0.94 +/-0.29). The T(peak-end) interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response.


CONCLUSIONS
Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization.
Osaka
Toshiyuki
T
Division of Arrhythmia and Electrophysiology, Shizuoka Saiseikai General Hospital, Suruga-ku, Shizuoka, Japan. t130915@siz.saiseikai.or.jp
Yokoyama
Eriko
E
Kushiyama
Yasunori
Y
Hasebe
Hideyuki
H
Kuroda
Yusuke
Y
Suzuki
Tomoyuki
T
Kodama
Itsuo
I
D000200:Action Potentials; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D015764:Bepridil / Q000009:adverse effects / Q000627:therapeutic use*; D016022:Case-Control Studies; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D016896:Treatment Outcome; D016278:Ventricular Function, Right / Q000187:drug effects*
D000889:Anti-Arrhythmia Agents; D015764:Bepridil