title: Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model.
abstract: BACKGROUND
  The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca(2+) leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca(2+) release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms.
  
  
  RESULTS
  CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca(2+) release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca(2+)/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca(2+) release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca(2+)-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice.
  
  
  CONCLUSIONS
  RyR2-mediated SR Ca(2+) leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca(2+) release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.|TBMM program, Baylor College of Medicine, Houston, TX.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: Department of Cardiology, The Methodist Hospital, Houston, TX.
authors.forename: Sufen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.|Division of Experimental Cardiology, Heidelberg University, Mannheim, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Respress
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Sameer
authors.initials: S
authors.lastname: Ather
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Jordan
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Horrigan
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Germany.
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.affiliation: Division of Experimental Cardiology, Heidelberg University, Mannheim, Germany.
authors.forename: Miguel
authors.initials: M
authors.lastname: Valderrabano
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, Quebec, 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, Heidelberg University, Mannheim, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.|Department of Medicine.Cardiology), Baylor College of Medicine, Houston, TX.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
mesh_terms: D000367:Age Factors; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: atrial fibrillation; calcium; mice; ryanodine receptor calcium release channel