title: Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation.
abstract: BACKGROUND
  Electrical, structural, and Ca2+ -handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca2+ -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca2+ -release events in paroxysmal AF (pAF) are unknown.
  
  
  RESULTS
  Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10-20 days preoperatively) were analyzed with simultaneous measurements of [Ca2+]i (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca2+ current, and Na+ /Ca2+ -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca2+ leak and incidence of delayed after-depolarizations in pAF. Ca2+ -transient amplitude and sarcoplasmic reticulum Ca2+ load (caffeine-induced Ca2+ -transient amplitude, integrated Na+/Ca2+ -exchange current) were larger in pAF. Ca2+ -transient decay was faster in pAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca2+ leak and sarcoplasmic reticulum Ca2+ -release events, causing delayed after-depolarizations/triggered activity in pAF.
  
  
  CONCLUSIONS
  Increased diastolic sarcoplasmic reticulum Ca2+ leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca2+ load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms.
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.|Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, USA.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal and Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.|Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
mesh_terms: D000368:Aged; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D020517:Atrial Appendage / Q000473:pathology / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003198:Computer Simulation; D005260:Female; D006325:Heart Atria / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000502:physiology; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban
keywords: atrial fibrillation; calcium; computational biology; electrophysiology; sarcoplasmic reticulum