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

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:55

Article

Sossalla, Samuel¹  Kallmeyer, Birte¹  Wagner, Stefan¹  Mazur, Marek¹  Maurer, Ulrike¹  Toischer, Karl¹  Schmitto, Jan D.²  Seipelt, Ralf²  Schoendube, Friedrich A.²  Hasenfuss, Gerd¹  Belardinelli, Luiz³  Maier, Lars S.¹ 

[1] Univ Gottingen, Dept Cardiol & Pneumol, Ctr Heart, D-37075 Gottingen, Germany

[2] Univ Gottingen, Dept Thorac & Cardiovasc Surg, D-37075 Gottingen, Germany

[3] Gilead Sci Inc, Palo Alto, CA USA

关键词: antiarrhythmia agents;    atrial fibrillation;    diastolic function;    sodium channels;   

DOI  :  10.1016/j.jacc.2009.12.055

来源: Elsevier

【 摘 要 】

Objectives We investigated changes in Na+ currents (I-Na) in permanent (or chronic) atrial fibrillation (AF) and the effects of I-Na inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. Background Electrical remodeling during AF is typically associated with alterations in Ca2+ and K+ currents. It remains unclear whether I-Na is also altered. Methods Right atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied. Results Patch-clamp experiments in isolated atrial myocytes showed significantly reduced peak I-Na density (similar to 16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late I-Na was significantly increased in myocytes from AF atria by similar to 26%. Ran (10 mu mol/l) decreased late I-Na by similar to 60% (p < 0.05) in myocytes from patients with AF but only by similar to 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. Conclusions Na+ channels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of I-Na with Ran had antiarrhythmic effects and improved diastolic function. Thus, inhibition of late I-Na may be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction. (J Am Coll Cardiol 2010;55:2330-42) (C) 2010 by the American College of Cardiology Foundation

【 授权许可】

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