Altered Na+ Currents in Atrial Fibrillation: Effects of Ranolazine on Arrhythmias and Contractility in Human Atrial Myocardium

Objectives estigated changes in Na+ currents (INa) in permanent (or chronic) atrial fibrillation (AF) and the effects of INa inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. ound ical remodeling during AF is typically associated with alterations in Ca2+ and K+ currents. It remains unclear whether INa is also altered. s atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied. s clamp experiments in isolated atrial myocytes showed significantly reduced peak INa density (∼16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late INa was significantly increased in myocytes from AF atria by ∼26%. Ran (10 μmol/l) decreased late INa by ∼60% (p < 0.05) in myocytes from patients with AF but only by ∼18% (p < 0.05) in myocytes from SR atria. Proarrhythmic activity was elicited in atrial trabeculae exposed to high [Ca2+]o or isoprenaline, which was significantly reversed by Ran (by 83% and 100%, respectively). Increasing pacing rates from 0.5 to 3.0 Hz led to an increase in diastolic tension that could be significantly decreased by Ran in atria from SR and AF patients. sions annels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of INa with Ran had antiarrhythmic effects and improved diastolic function. Thus, inhibition of late INa may be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction.