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Current guidelines recommend vernakalant for pharmacologic cardioversion of recent-onset atrial fibrillation. However, this drug is not established as chronic therapy.In total, 15 rabbit hearts were Langendorff-perfused. A burst pacing protocol-induced atrial fibrillation in 7 of 15 hearts at baseline (10 episodes). Subsequently, a combination of acetylcholine and isoproterenol (ACH/ISO) has been administered to increase occurrence of atrial fibrillation resulting in a reduction of atrial action potential duration (−25 ms, P < 0.05) as well as atrial effective refractory period (aERP; −36 ms, P < 0.05). Then, atrial fibrillation occurred in all 15 hearts (124 episodes). Additional treatment with vernakalant (10 μmol/l) induced a significant reduction of atrial fibrillation (6 of 15 hearts, 63 episodes). Infusion of vernakalant did not significantly alter atrial action potential duration (+8 ms) but increased aERP (+16 ms, P < 0.05 as compared with ACH/ISO).Results were compared to 12 further rabbit hearts treated with ranolazine. Late sodium current inhibition by ranolazine also induced a significant increase of aERP. Here, atrial fibrillation was inducible after ranolazine infusion in 6 of 12 hearts (46 episodes). Of note, 10 of 12 hearts presented atrial fibrillation during sole treatment with ACH/ISO (174 episodes).Vernakalant and ranolazine demonstrated a comparable antiarrhythmic efficacy. Therefore, vernakalant treatment may represent a potential therapeutic option to reduce atrial fibrillation recurrence.