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.
Chugh
S S
SS
Division of Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA. chughs@ohsu.edu
Johnson
S B
SB
Packer
D L
DL
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000502:physiology; D008297:Male; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D017180:Tachycardia, Ventricular / Q000139:chemically induced; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide