Clofilium in the isolated perfused rabbit heart: A new model to study proarrhythmia induced by class III antiarrhythmic drugs

Abstract

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 μM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K² 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.

Conclusion: 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 millieu 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.