title: Altered Na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium.
abstract: 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.
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Birte
authors.initials: B
authors.lastname: Kallmeyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Marek
authors.initials: M
authors.lastname: Mazur
authors.forename: Ulrike
authors.initials: U
authors.lastname: Maurer
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: Ralf
authors.initials: R
authors.lastname: Seipelt
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
mesh_terms: 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
chemical_list: D000083:Acetanilides; D015220:Calcium Channels; D010879:Piperazines; D015222:Sodium Channels; D000069458:Ranolazine