Altered response to ibutilide in a heart failure model

OBJECTIVE: Despite the frequent use of anti-arrhythmic drugs in the general population, the electrophysiologic effects of these agents have not been elucidated in congestive heart failure (CHF). METHODS: To examine the impact of left ventricular dysfunction on actions of type III anti-arrhythmic drugs, we evaluated the actions of ibutilide in a canine model of pacing-induced dilated cardiomyopathy. Following ablation of the atrioventricular node, effects on action potential duration at 90% (APD(90)) were compared in vivo, between eight CHF animals and seven controls. Monophasic action potential recordings were obtained from right and left ventricular endocardium/epicardium during and after three doses of ibutilide (0. 01, 0.02 and 0.05 mg/kg), at pacing cycle lengths of 300-1000 ms. RESULTS: APD(90) prolongation with ibutilide (0.01 mg/kg) was significantly greater in CHF vs. controls (P=0.0026, ANOVA). However, plasma ibutilide levels at this dose, were not significantly different between the two groups. In CHF, maximal effects were observed at the lowest dose, whereas effects were gradual and dose-dependent in controls. With ibutilide administration (0.01 mg/kg), an increased dispersion of left-right ventricular APD(90) was observed in CHF, but not in controls (P=0.03). A trend was observed, for increased incidence of non-sustained polymorphic ventricular tachycardia in CHF. CONCLUSIONS: In the presence of CHF, the actions of ibutilide are altered significantly. These findings may reflect altered tissue effects, as a consequence of myocardial electrical remodeling in CHF.