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Altered response to ibutilide in a heart failure model
S S Chugh1, S B Johnson, D L Packer
1Division of Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA. chughs@ohsu.edu
Insights
Congestive heart failure (CHF) alters how anti-arrhythmic drugs like ibutilide work, increasing action potential duration and dispersion. These findings highlight potential risks of using such drugs in CHF patients due to electrical remodeling.
Area of Science:
- Cardiology
- Electrophysiology
- Pharmacology
Background:
- Anti-arrhythmic drugs are widely used, but their effects in congestive heart failure (CHF) are not well understood.
- Left ventricular dysfunction in CHF may alter drug responses.
Purpose of the Study:
- To investigate the electrophysiologic effects of type III anti-arrhythmic drugs in a canine model of pacing-induced dilated cardiomyopathy.
- To examine how left ventricular dysfunction impacts the action of ibutilide.
Main Methods:
- Evaluated ibutilide's effects on action potential duration at 90% (APD(90)) in canine models with and without pacing-induced dilated cardiomyopathy.
- Recorded monophasic action potentials from ventricular endocardium/epicardium after administering three doses of ibutilide.
Main Results:
- Ibutilide caused significantly greater APD(90) prolongation in CHF animals compared to controls at a low dose (0.01 mg/kg).
- Increased dispersion of ventricular APD(90) was observed in CHF animals but not in controls.
- A trend towards increased non-sustained polymorphic ventricular tachycardia was noted in CHF.
Conclusions:
- The electrophysiologic actions of ibutilide are significantly altered in the presence of congestive heart failure.
- These alterations may be attributed to myocardial electrical remodeling in CHF, affecting drug efficacy and safety.
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.