Ranolazine and Dofetilide Effectively Suppress Acute Atrial Fibrillation in Isolated Sheep Hearts

Background Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity and mortality, yet pharmacologic treatments remain suboptimal. Methods Electrophysiologic effects of ranolazine, alone or in combination with dofetilide, were determined in optically mapped atria of isolated sheep hearts perfused with the voltage-sensitive dye di-4-ANEPPS. The objective was to determine the efficacy of drugs for suppression of acute AF initiated by tachypacing in the presence of continuous isoproterenol (100 nM) perfusion for up to 48 minutes. Results After 15 minutes of isoproterenol-maintained AF, the dominant frequency (DF) of activations were 11.5 ± 0.9 and 15.2 ± 0.8 Hz in right atrial (RA) and left atrial (LA) free walls, respectively (N = 8). In 4 of 8 hearts, DF decreased to 7.3 ± 0.7 Hz and 7.6 ± 0.8 Hz in the RA and LA, respectively ( P P P P P = .06) in hearts that converted to SR. The combination of ranolazine plus dofetilide decreased the number of SP before converting to SR in 6 hearts (5.10 ± 1.5 to 1.51 ± 0.62 per frame, P Conclusion Ranolazine and dofetilide reduce both DF and SP during isoproterenol-maintained AF. Ranolazine alone converted AF to SR in 50% (4/8) vs 86% (6/7) of trials when combined with dofetilide. Our results show an enhanced efficacy of ranolazine when combined with I Kr inhibition for suppressing acute AF.