Abstract 2355: Targeting of Ischemic/reperfused Myocardium by Liposomal Amiodarone Reduced Ventricular Fibillilation in Rats
Background: Liposomes are nanoparticles that can deliver various agents to target tissues and delay degradation of these agents. Recently, we reported that liposomes could accumulate in and selectively deliver drugs to ischemic/reperfused myocardium. Although amiodarone has strong anti-arrhythimic effects, it causes significant adverse effects, e.g. interstinal pnumoniae, hypothyroidism. We hypothesized that amiodarone in liposomes specifically accumulate in ischemic/reperfused (I/R) myocardium, leading to augmented anti-arrhythimic effects.
Methods and Results: We prepared liposomal amiodarone (mean diameter: 113±8nm) by the thin film method and investigated acute effects of liposomal amiodarone on lethal arrhythmia after myocardial infarction (MI) in rats. Left coronary artery was occluded for 5 minutes followed by reperfusion. First, we examined whether liposomes could accumulate in ischemic/reperfused myocardium in such a brief duration of ischemia. Using ex vivo bioluminescence imaging, it could be observed that fluorescent-labeled liposomes accumulated in I/R myocardium without necrosis evaluated by triphenyltetrazolium chloride staining. Next a bolus intravenous infusion of liposomal amiodarone (3 mg/kg) before ischemia significantly reduced the incidence of ventricular fibllilation (VF) (0 %) and a duration of VF or ventricular tachycardia (18±9 sec) compared with an infusion of saline (VF: 67%, and 195±42 sec, p<0.05) and free amiodarone (VF: 33%, and 141±43 sec). The mortality of rats received saline and free amiodarone was 67% and 33%, respectively. Suprisingly, the mortality of rats received liposomal amiodarone was 0%. Furthermore, at the smaller dose of 1mg/kg, the duration of VF was significantly reduced in the liposomal amiodarone group. The mortality of rats administered free amiodarone and liposomal amiodarone were 33% and 0%, respectively.
Conclusions: Targeting delivery of liposomal amiodarone into I/R myocardium exerted stronger anti-arrhythmic effects in acute phase of MI. Nano-size liposomes would be a promising drug delivery system to treat lethal arrhythmia with augmenting drug effects and reducing adverse side effects of them.