Accelerated conversion of atrial fibrillation to normal sinus rhythm by pulmonary delivery of flecainide acetate in a porcine model

• Published in: Heart rhythm Vol. 15; no. 12; pp. 1882 - 1888
• Main Authors: Verrier, Richard L., Bortolotto, Alexandre L., Silva, Bruna A., Marum, Alexandre A., Stocco, Fernando G., Evaristo, Ederson, de Antonio, Victor Z., Silva, Anderson C., Belardinelli, Luiz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2018
• Subjects: Atrial depolarization duration; Atrial fibrillation; Flecainide; Intratracheal instillation; Pulmonary delivery; Intratracheal instillation; Flecainide; Atrial fibrillation; Atrial depolarization duration; Pulmonary delivery
• ISSN: 1547-5271; 1556-3871
• DOI: 10.1016/j.hrthm.2018.06.036

Pulmonary delivery of antiarrhythmic agents has the potential to increase rapidly targeted drug concentrations in pulmonary veins and left atrium to terminate atrial fibrillation (AF). We evaluated the efficacy of flecainide administered via intratracheal instillation in terminating AF in a reliable preclinical model. In 11 closed-chest anesthetized Yorkshire pigs, AF was induced by intrapericardial administration of acetylcholine (1 mL of 102.5 mM solution) followed by burst pacing and allowed to continue for 2 minutes before intratracheal flecainide (0.4 or 0.75 mg/kg) administration. Both the 0.4- and 0.75-mg/kg doses of intratracheal flecainide significantly reduced AF duration by 35% (P = .02) and 54% (P = .001), respectively, compared to no-drug baseline. There was a strong inverse correlation (r2 = 0.87; P = .03) between the duration of AF and the change in atrial depolarization duration in response to intratracheal flecainide. Induction of AF resulted in a marked increase in ventricular rate and corresponding reduction in mean arterial pressure, which returned to baseline levels within 5 minutes after conversion. Intratracheal flecainide instillation is effective in rapidly converting AF to normal sinus rhythm and restoring mean arterial pressure and heart rate to baseline values. The basis for this efficacy is likely rapid absorption of the drug through the lungs and delivery as a first-pass bolus to the left atrial and ventricular chambers and then to the coronary arterial circulation. The anti-AF effect of flecainide is inversely correlated with the drug’s prolongation of atrial depolarization, implicating slowing of intra-atrial conduction as an important mechanism underlying conversion of AF to normal sinus rhythm.