Clofilium in the isolated perfused rabbit heart: a new model to study proarrhythmia induced by class III antiarrhythmic drugs.
OBJECTIVE
The clinical usefulness of class III antiarrhythmic drugs for the treatment of tachyarrhythmias is limited by their potential proarrhythmic effects, mainly torsades-depointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhibiting typical characteristics of class III drug-induced ventricular arrhythmias.


METHODS
Isolated rabbit hearts were perfused with a Krebs-Henseleit buffer containing 10 microM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K+ and 0.5 mM Mg2+. Hearts subjected to either clofilium alone or modified buffer alone were used as controls.


RESULTS
Under clofilium the QT interval increased from 187 +/- 16 to 282 +/- 33 ms. Within 8 to 25 s after the change of the perfusate, ventricular arrhythmias developed in all hearts associated with a further QT prolongation to 380 +/- 73 ms when the first ventricular extrasystole occurred. Simultaneously, the monophasic action potential durations increased relatively more during late repolarization; from 99 +/- 21 to 110 +/- 25 ms (+11%) at 50% repolarization, from 143 +/- 24 to 178 +/- 40 ms (+24%) at 70%, and from 200 +/- 30 to 275 +/- 53 ms (+38%) at 90%. The predominant rhythm was polymorphic with either two alternating or multiple QRS morphologies exhibiting the characteristic features of torsades-depointes. All control hearts stayed in normal sinus rhythm.


CONCLUSIONS
Under the conditions selected, the isolated perfused rabbit heart represents a useful experimental approach to study the proarrhythmic effects of class III agents. This model provides a convenient way to manipulate the ionic and pharmacologic milieu in a preparation conserving the functional anatomy of the whole organ without interference by cardiovascular reflexes. It might be useful for analyzing the conditions favoring and preventing drug-induced torsades-depointes.
Johna
R
R
Westfälische Wilhelms-Universität, Innere Medizin C, Münster, Germany. johna@uni-muenster.de
Mertens
H
H
Haverkamp
W
W
Eckardt
L
L
Niederbröker
T
T
Borggrefe
M
M
Breithardt
G
G
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques / Q000379:methods*; D011188:Potassium / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D000644:Quaternary Ammonium Compounds; C022799:clofilium; D008274:Magnesium; D011188:Potassium