Ranolazine Causes Atrial-Selective Electrophysiological Effects and Suppresses the Induction of Atrial Fibrillation in a Canine Model of Heart Failure

Abstract

Background Heart failure (HF) and atrial fibrillation (AF) frequently coexist. There is a critical need for safer and more effective pharmacologic treatment of AF in the setting of HF. The atrial-selective electrophysiologic (EP) effects as well as anti-AF efficacy of ranolazine (RAN) have been demonstrated in healthy canine atria. In the current study, we investigated the EP and anti-AF effects of a clinically relevant concentration of RAN (5 μM) in coronary-perfused right atrial (RA) and left ventricular (LV) preparations isolated from the hearts of HF dogs. Methods HF was induced by ventricular tachypacing (2–6 weeks at 200–240 bpm; n=17 dogs). Transmembrane action potentials were recorded using standard microelectrode techniques. Results A single premature beat reproducibly induced AF in 10/17 atria lasting up to 20 minutes. RAN (5 μM) suppressed induction of AF in 7/10 atria. In the remaining 3 atria, ranolazine slowed AF frequency and reduced the duration. In RA, RAN caused little change in action potential duration (APD 70 : from 105 ± 12 to 114 ± 15 ms, P = NS) but significantly prolonged effective refractory period ([ERP] from 127 ± 21 to 176 ± 25 ms, P max ) decreased (229 ± 55 vs 189 ± 50 V/s), diastolic threshold of excitation (DTE) increased (0.24 ± 0.05 vs 0.42 ± 0.16 mA), and P-wave duration (atrial conduction time) prolonged in response to 5 μM RAN (31.6 ± 7.6 vs 36.5 ± 6.5 ms, P 90 , ERP, DTE, V max , and QRS duration (n = 5–6). Conclusions Our results demonstrate the effect of a relatively low concentration of RAN to suppress induction of AF much more effectively (70%) in an HF model of AF than previously described in vagal models of AF. In both models, depression of peak sodium channel current-dependent parameters is atrial selective. In view of the clinical safety of RAN (MERLIN-TIMI 36), our results suggest a need for studies specifically designed to evaluate the clinical utility of RAN for rhythm control of AF in patients with HF.