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 f or the treatment of tachyarrhythmias is limited by their potential pro arrhythmic effects, mainly torsades-de-pointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhib iting typical characteristics of class III drug-induced ventricular ar rhythmias. Methods: Isolated rabbit hearts were perfused with a Krebs- Henseleit buffer containing 10 mu M clofilium and then exposed to a mo dified Krebs-Henseleit buffer with 2.0 mM K+ and 0.5 mM Mg2+. Hearts s ubjected to either clofilium alone or modified buffer alone were used as controls. Results: Under clofilium the QT interval increased from 1 87 +/- 16 to 282 +/- 33 ms. Within 8 to 25 s after the change of the p erfusate, ventricular arrhythmias developed in all hearts associated w ith a further QT prolongation to 380 +/- 73 ms when the first ventricu lar extrasystole occurred. Simultaneously, the monophasic action poten tial durations increased relatively more during late repolarization; f rom 99 +/- 21 to 110 +/- 25 ms (+11 %) at 50 % repolarization, from 14 3 +/- 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 ch aracteristic features of torsades-de-pointes. All control hearts staye d in normal sinus rhythm. Conclusion: Under the conditions selected, t he isolated perfused rabbit heart represents a useful experimental app roach to study the proarrhythmic effects of class III agents. This mod el provides a convenient way to manipulate the ionic and pharmacologic milieu in a preparation conserving the functional anatomy of the whol e organ without interference by cardiovascular reflexes. It might be u seful for analyzing the conditions favoring and preventing drug-induce d torsades-de-pointes.