title: Prevention of acute inducible atrial flutter in dogs by using an ibutilide-polymer-coated pacing electrode.
abstract: Atrial arrhythmias (atrial fibrillation or atrial flutter) after coronary artery bypass graft surgery are difficult to prevent or treat and often result in significant morbidity. Prior experimental studies by our group showed improved therapeutic efficacy for antiarrhythmic drugs delivered via controlled-release polymeric matrices implanted on the epicardial surface. These experiments were conducted to test the hypothesis that direct atrial epicardial administration of ibutilide from a controlled-release system (compared with intravenous administration) can reduce the inducibility of atrial flutter in the acute postoperative atrial myocardium. Polymeric sustained-release preparations were formulated by solvent casting of an ibutilide and polyurethane (Pellathane) solution in tetrahydrofurane. Multilayer solvent-casted coatings on pacing electrode wires were carried out to fabricate a sustained-release electrode system. In animal model studies, each dog underwent a thoracotomy, followed by a right atriotomy that was repaired. Induction of atrial flutter was attempted by burst pacing with the bipolar pacing catheter. Sinus rhythm was restored with overdrive pacing. After determining the induction rate (percentage) of atrial flutter in the baseline state, a stainless-steel wire coated with the drug-delivery system, 10% ibutilide/90% polyurethane (n = 7), or without drug (polyurethane coating without ibutilide, n = 5; control) was sewn onto the right atrium. Systemic intravenous administration of ibutilide (1.2 microg/kg/h) also was carried out in a separate group of animals after atriotomy (n = 5). For ibutilide (at an estimated dose of 1.2 microg/kg/h), the atrial-flutter results were 41.85 +/- 2.21% induction for baseline compared with 12.42 +/- 5.26% (p = 0.02) after the ibutilide wire implant. In the control dogs, atrial flutter was induced 29.4 +/- 4.7% at baseline and 25.2 +/- 5.1% after implantation of the control wire (p = 0.4). Ibutilide coronary venous serum concentrations at the end of the ibutilide-polyurethane electrode experiments were 2.25 +/- 0.2 ng/ml (mean +/- SEM) versus systemic levels that were below the limits of detection. Systemic intravenous ibutilide infusions had no effect on the inducibility of atrial flutter. In conclusion, an epicardial implantable electrode coating with an ibutilide controlled drug-release system significantly reduced the inducibility of atrial flutter in an experimental atriotomy model. These results suggest that atrial arrhythmias occurring after coronary bypass surgery may be prevented by local atrial administration of ibutilide from a controlled-release pacing electrode.
authors.affiliation: University of Michigan Medical School, Ann Arbor, USA.
authors.forename: V
authors.initials: V
authors.lastname: Labhasetwar
authors.forename: S A
authors.initials: SA
authors.lastname: Strickberger
authors.forename: T
authors.initials: T
authors.lastname: Underwood
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.forename: R J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000517:prevention & control*; D004285:Dogs; D016503:Drug Delivery Systems; D004566:Electrodes; D008855:Microscopy, Electron, Scanning; D010138:Pacemaker, Artificial; D011108:Polymers; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D011108:Polymers; D013449:Sulfonamides; C067192:ibutilide