Differential effect of dofetilide on ventricular repolarization during steady state and during restitution in vivo

Class III antiarrhythmic drugs alter the relation between cycle length and the QT interval. However, the relation between cycle length and the QT interval varies, whether determined for single test stimuli ("restitution") or for sustained rhythm ("steady state"). In anesthetized guinea pigs (n = 6), we assessed QT prolongation by the selective class III antiarrhythmic agent dofetilide (10 micrograms/kg intravenously) by atrial pacing during steady state and during restitution. Spontaneous sinus rhythm was abolished by electrical ablation of the sinus node area. Dofetilide prolonged QT intervals at all cycle lengths (CL), and the changes were more pronounced at long than at short CL. This reverse rate-dependent effect was significantly greater during steady state than during restitution. Thus, at a cycle length of 200 ms, the difference between QT interval during steady state and QT interval during restitution was -10.0 +/- 1.7 ms at baseline and -11.1 +/- 3.5 ms after dofetilide (p = 0.8). At a CL of 500 ms, the respective values were 11.7 +/- 1.3 and 19.1 +/- 1.9 ms (p = 0.01). Dofetilide produces substantially more reverse rate-dependent increase in QT duration during steady state than during restitution. Clinically, these findings indicate that excessive drug-induced QT prolongation by dofetilide is more likely to develop during prolonged periods of bradycardia than after single long coupled extra-beats. Such excessive QT prolongation may in turn predispose to torsade de pointes arrhythmias.