Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early afterdepolarizations in an intact heart model of LQT3.
BACKGROUND
In long QT syndrome (LQTS), prolongation of the QT-interval is associated with sudden cardiac death resulting from potentially life-threatening polymorphic tachycardia of the torsade de pointes (TdP) type. Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS. We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3.


RESULTS
In 8 Langendorff-perfused rabbit hearts, veratridine (0.1 microM), an inhibitor of sodium channel inactivation, led to a marked increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p < 0.05) thereby mimicking LQT3. In bradycardic (AV-blocked) hearts, simultaneous recording of up to eight epi- and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p < 0.05) and reverse frequency-dependence. After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts. Additional infusion of verapamil (0.75 microM) suppressed EADs and consecutively TdP in all hearts. Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization.


CONCLUSIONS
Verapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3. These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.
Milberg
P
P
Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, Albert-Schweitzer Str. 33 , 48149, Münster, Germany. milbergp@uni-muenster.de
Reinsch
N
N
Osada
N
N
Wasmer
K
K
Mönnig
G
G
Stypmann
J
J
Breithardt
G
G
Haverkamp
W
W
Eckardt
L
L
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011817:Rabbits; D016171:Torsades de Pointes / Q000517:prevention & control*; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
D014700:Verapamil; D002118:Calcium