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

ObjectivesWe investigated changes in Na+currents (INa) in permanent (or chronic) atrial fibrillation (AF) and the effects of INainhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium.BackgroundElectrical remodeling during AF is typically associated with alterations in Ca2+and K+currents. It remains unclear whether INais also altered.MethodsRight atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied.ResultsPatch-clamp experiments in isolated atrial myocytes showed significantly reduced peak INadensity (∼16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late INawas significantly increased in myocytes from AF atria by ∼26%. Ran (10 μmol/l) decreased late INaby ∼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+]oor 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.ConclusionsNa+channels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of INawith Ran had antiarrhythmic effects and improved diastolic function. Thus, inhibition of late INamay be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction.