Altered Na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium.
OBJECTIVE
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 Ca(2+) 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 ( approximately 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 approximately 26%. Ran (10 mumol/l) decreased late I(Na) by approximately 60% (p < 0.05) in myocytes from patients with AF but only by approximately 18% (p < 0.05) in myocytes from SR atria. Proarrhythmic activity was elicited in atrial trabeculae exposed to high [Ca(2+)](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.
Sossalla
Samuel
S
Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
Kallmeyer
Birte
B
Wagner
Stefan
S
Mazur
Marek
M
Maurer
Ulrike
U
Toischer
Karl
K
Schmitto
Jan D
JD
Seipelt
Ralf
R
Schöndube
Friedrich A
FA
Hasenfuss
Gerd
G
Belardinelli
Luiz
L
Maier
Lars S
LS
D000083:Acetanilides / Q000494:pharmacology*; D000368:Aged; D000704:Analysis of Variance; D020517:Atrial Appendage / Q000187:drug effects / Q000378:metabolism; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling; D006348:Cardiac Surgical Procedures / Q000379:methods; D017115:Catheter Ablation / Q000379:methods; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology*; D011336:Probability; D000069458:Ranolazine; D012016:Reference Values; D012494:Sampling Studies; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
D000083:Acetanilides; D015220:Calcium Channels; D010879:Piperazines; D015222:Sodium Channels; D000069458:Ranolazine