Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia.
BACKGROUND
In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I(Kr) is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals.


RESULTS
Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10(-5)M and 2 x 10(-5)M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 +/- 1 to 48 +/- 2 ms at 100 ms basic cycle length (BCL), from 38 +/- 2 to 54 +/- 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 +/- 1 vs. 4 +/- 1 ms, APD90max-min: 12 +/- 1 vs. 5 +/- 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K(+) =3.0 mM and in 10 of 12 hearts at K(+) = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 +/- 3 ms; APD90max-min: 25 +/- 3 ms; p < 0.05).


CONCLUSIONS
This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.
Fabritz
Larissa
L
Medizinische Klinik und Poliklinik C - Kardiologie und Angiologie, Universitätsklinikum Münster, Germany. fabritzl@uni-muenster.de
Kirchhof
Paulus
P
Franz
Michael R
MR
Eckardt
Lars
L
Mönnig
Gerold
G
Milberg
Peter
P
Breithardt
Günter
G
Haverkamp
Wilhelm
W
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D006327:Heart Block / Q000503:physiopathology; D007008:Hypokalemia / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D013015:Sotalol / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D016171:Torsades de Pointes / Q000503:physiopathology
D013015:Sotalol