Author + information
- Received July 28, 2009
- Revision received November 16, 2009
- Accepted December 7, 2009
- Published online May 25, 2010.
- Samuel Sossalla, MD⁎,
- Birte Kallmeyer, MS⁎,
- Stefan Wagner, MD⁎,
- Marek Mazur, MS⁎,
- Ulrike Maurer, MS⁎,
- Karl Toischer, MD⁎,
- Jan D. Schmitto, MD†,
- Ralf Seipelt, MD†,
- Friedrich A. Schöndube, MD†,
- Gerd Hasenfuss, MD⁎,
- Luiz Belardinelli, MD‡ and
- Lars S. Maier, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Lars S. Maier, Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
Objectives We 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.
Background Electrical remodeling during AF is typically associated with alterations in Ca2+and K+currents. It remains unclear whether INais 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 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.
Conclusions Na+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.
This work was funded by the DFGthrough a Heisenberg grant (MA1982/4-1), the Klinische Forschergruppe(MA1982/2-2), and CV Therapeutics. Drs. Maier and Hasenfuss have a collaboration/grant with CV Therapeutics. Dr. Belardinelli is an employee of CV Therapeutics (now Gilead Sciences).
- Received July 28, 2009.
- Revision received November 16, 2009.
- Accepted December 7, 2009.
- American College of Cardiology Foundation