BACKGROUND:Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low.METHODS:Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography.RESULTS:The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up.CONCLUSIONS:Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Objective: Clinical studies have demonstrated the efficacy of oral and intravenous amiodarone therapy to prevent postoperative atrial fibrillation. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. This study addressed the hypothesis that atrium-specific drug delivery through an amiodarone-eluting epicardial patch reduces vulnerability to atrial tachyarrhythmias, whereas ventricular and plasma drug concentrations are minimized.Methods: Right atrial epicardiums of goats were fitted with electrodes and a bilayered patch (poly[ethylene glycol]-based matrix and poly[lactide-co-caprolactone] backing layer) loaded with amiodarone (10 mg per patch, n=10) or without drug (n=6). Electrophysiologic parameters (atrial effective refractory period, conduction time, and rapid atrial response to burst pacing) and amiodarone levels in plasma and tissue were measured during 1 month's follow-up.Results: Epicardial application of amiodarone-eluting patches produced persistently higher drug concentrations in the right atrium than in the left atrium, ventricles, and extracardiac tissues by 2 to 4 orders of magnitude. Atrial effective refractory period and conduction time increased, whereas rapid atrial response inducibility decreased significantly (P<.05) during the 1-month follow-up compared with that seen in animals treated with drug-free patches. Amiodarone concentrations in plasma remained undetectably low (<10 ng/mL).Conclusions: Atrium-specific drug delivery through an amiodarone-eluting patch produces therapeutic atrial drug concentrations, whereas ventricular and systemic drug levels are minimized. This study demonstrates that sustained targeted drug delivery to a specific heart chamber is feasible and might reduce the risk for ventricular and extracardiac adverse effects. Epicardial application of amiodarone-eluting patches is a promising strategy to prevent postoperative atrial fibrillation. (J Thorac Cardiovasc Surg 2010; 140: 904-10)

Objective: Autologous platelet clots serve as slow-release delivery systems for platelet-derived growth factors and cytokines. Their application to the pericardial sac might facilitate salvage and repair of ischemically injured myocardium. However, little is known about platelet clot stability in the pericardial sac. We investigated the stability of platelet clots in vitro and after administration to the pericardial sac in pigs and patients.Methods: In 5 Yorkshire-Landrace pigs and 10 patients, in vitro manufactured autologous platelet gel (Medtronic Magellan Platelet Separator) and platelet- rich fibrin (Vivolution Vivostat System) were administered to the pericardial sac for 30 minutes. Two antifibrinolytics (tranexamic acid and aprotinin) were tested for their capacity to stabilize autologous platelet gel. In vitro clots, incubated at 37 degrees C for 48 hours, served as controls. Clot weight was measured before and after administration.Results: In vitro, autologous platelet gel clots of either formula liquefied almost entirely within 60 minutes whereas platelet- rich fibrin clots remained intact. In the pig, platelet clot weight decreased to 16.7% +/- 7.8% (P < .05) and 66.4% +/- 3.2% (P < .05) of initial clot weight for autologous platelet gel and platelet- rich fibrin, respectively. Addition of antifibrinolytics to autologous platelet gel did not reduce clot degradation significantly. In patients, autologous platelet gel and platelet- rich fibrin clot weight remained 9.0% +/- 1.5% (P < .05) and 73.7% +/- 2.6% (P < .05) of initial clot weight, respectively.Conclusions: Autologous platelet gel is unstable both in vitro and in vivo, whereas platelet- rich fibrin remains intact in vitro and, compared with autologous platelet gel, is less subject to degradation in pigs and in patients.

Dronedarone, a noniodinated benzofuran derivative of amiodarone, is believed to have a better side effect profile, and is currently undergoing phase III clinical trials. A novel method was developed for the determination of dronedarone and its principal metabolite debutyldronedarone in both plasma and myocardial tissue by high-performance liquid chromatography (HPLC) coupled with UV-detection. The assay was also validated for determination of amiodarone and desethylamiodarone. Samples were obtained from healthy humans (plasma) and goats (plasma and myocardium). Sample preparation included deproteinization with acetonitrile and extraction with a mixture of heptane and dichloromethane (50/50, v/v). Chromatographic separation was performed on a Pathfinder PS polymeric C18 column (50 mm × 4.6 mm, 2.5 μm) with a mobile phase of acetonitrile, isopropanol, water and ammonia (80/10/10/0.025, v/v/v/v) at a flow-rate of 1 ml/min. Calibration curves of all analytes were linear in the range of 0.01–5 μg/ml for plasma samples, with a lower limit of quantification (LLOQ) of 0.04 μg/ml. For myocardial tissue samples, linear curves of all analytes were observed in the range of 0.02–500 μg/g, with a LLOQ of 0.08 μg/g. Within- and between-day precision was <18%, and within- and between-day accuracy ranged from 97.5 to 109.7%, with a recovery of 67.6–79.9%. The present method enables sensitive and specific detection of dronedarone, amiodarone and principal metabolites in plasma as well as myocardial tissue.

Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg·kg−1·h−1. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (−74% ± 20% and −66% ± 30%, respectively) compared with IV delivery (−11% ± 17% and −17% ± 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (−70% ± 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.

Amiodarone (AM) is one of the most effective anti-arrhythmic drugs to prevent postoperative atrial fibrillation (AF). However, due to systemic side effects, prophylactic AM therapy is only appropriate for patients at high risk for postoperative AF. This study addressed the hypothesis that local epicardial delivery of AM produces therapeutic myocardial drug concentrations, while systemic levels remain low. Goats (n=14) were instrumented with right atrial epicardial patch electrodes, and a PEG-based hydrogel with AM (1 mg/kg bw) (n=9) or without drug (n=5) was applied to the right atrial epicardium. AF inducibility was assessed up to 28 days in awake goats by applying burst stimuli. Myocardial and plasma AM concentrations were analysed by HPLC. AM-hydrogel produced higher subepicardial than subendocardial drug concentrations, which both remained therapeutic up to 21 days after hydrogel application (fig. 1a ). In this period, AF inducibility was significantly lower in the AM-hydrogel group compared to hydrogel alone (fig. 1b ; p<0.05). Plasma AM and metabolite levels were below detection limits (<30 ng/L) during the 28-day follow-up. Epicardial AM-releasing hydrogel produces sufficient myocardial drug concentrations to reduce AF inducibility up to 3 weeks, whereas plasma drug levels remain undetectably low. This study demonstrates that local delivery of anti-arrhythmic drugs is a feasible approach to obtain therapeutically effective myocardial drug concentrations, while minimizing risk for systemic side effects. Locally applied AM-releasing hydrogel may be a novel strategy to prevent postoperative AF. Figure 1a. Amiodarone Distribution in Right Atrium (n=5) Figure 1b. AF Inducibility After Hydrogel Application (mean + SD)

Background: Amiodarone causes less ventricular transmural dispersion of repolarization (TDR) and proarrhythmia than sotalol. Effects of both drugs on atrial TDR, however, have not yet been well defined. We applied intrapericardial (IPC) drug delivery to produce in vivo transmural concentration gradients. We assessed the hypotheses that IPC amiodarone causes less atrial TDR than IPC sotalol and that IPC amiodarone is more effective than IPC sotalol in lowering atrial fibrillation (AF) inducibility. Methods: Goats (n = 25) were randomised into 5 groups receiving either IPC dextrose, amiodarone (IV or IPC) or d,l-sotalol (IV or IPC). Drugs were infused for 3 hours at a constant rate of 2 mg/kg per hour. Quadripolar catheters were placed on the epi- and endocardial surfaces of the right atrium. Atrial effective refractory period (AERP) and AF inducibility were measured by single premature stimuli at 4 times the diastolic threshold. Atria were freeze-microtomed parallel to the epicardial surface and analysed by HPLC. Results: IPC drug delivery produced high epicardial concentrations (fig.1a ) with significantly decreased epicardial AF inducibility. A similar decrease in endocardial AF inducibility was only observed in the IPC amiodarone group (fig.1b ). TDR (defined as endo-minus epicardial AERP) became negative after IPC sotalol (from 13.0 ± 3.2 to -30.7 ± 7.3 ms, p < 0.05). In the other groups TDR did not change significantly and remained positive. Conclusions: IPC delivery boosts epicardial drug concentration and efficacy. For amiodarone, this also increases endocardial efficacy. IPC sotalol, however, inverts TDR, which may explain its inferior endocardial efficacy. Figure 1a. Concentrations in right atrium (mean + SD) Figure 1b. Chang in AF inducibility (mean + SD)