Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias

In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dro n, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de poi ntes (TdP) provides an ideal substrate to evaluate ventricular repolarizati on abnormalities. Six ECG leads and two endocardial monophasic action poten tial (MAP) recordings in the left and right ventricle (LV and RV) were simu ltaneously recorded to measure QT time, action-potential duration (APD), in terventricular dispersion (Delta APD = LVAPD - RVAPD) early afterdepolariza tions (EADs), ectopic beats (EBs), and TdP. Measurements were made at the s pontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. T o investigate its short-term, antiarrhythmic properties, Dron was given aft er almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of expe riments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAV E dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LVAPD, 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms ) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. A lmokalant-induced TdP was characterized by an increased repolarization dura tion, Delta APD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LVAPD, 505 +/- 110 to 45 5 +/- 80 ms, and Delta APD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dro n increased the PP interval, CL-IVR, and QT((c)) time. Tn contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, result ing in suppression of EAD-dependent acquired TdP. The increased VERP/QT rat io after Dron i.v. may indicate an important second antiarrhythmic property .