title: Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common cardiac arrhythmia, however the mechanism(s) causing AF remain poorly understood and therapy is suboptimal. The ryanodine receptor (RyR2) is the major calcium (Ca2+) release channel on the sarcoplasmic reticulum (SR) required for excitation-contraction coupling in cardiac muscle.
  
  
  OBJECTIVE
  In the present study, we sought to determine whether intracellular diastolic SR Ca2+ leak via RyR2 plays a role in triggering AF and whether inhibiting this leak can prevent AF.
  
  
  RESULTS
  We generated 3 knock-in mice with mutations introduced into RyR2 that result in leaky channels and cause exercise induced polymorphic ventricular tachycardia in humans [catecholaminergic polymorphic ventricular tachycardia (CPVT)]. We examined AF susceptibility in these three CPVT mouse models harboring RyR2 mutations to explore the role of diastolic SR Ca2+ leak in AF. AF was stimulated with an intra-esophageal burst pacing protocol in the 3 CPVT mouse models (RyR2-R2474S+/-, 70%; RyR2-N2386I+/-, 60%; RyR2-L433P+/-, 35.71%) but not in wild-type (WT) mice (P<0.05). Consistent with these in vivo results, there was a significant diastolic SR Ca2+ leak in atrial myocytes isolated from the CPVT mouse models. Calstabin2 (FKBP12.6) is an RyR2 subunit that stabilizes the closed state of RyR2 and prevents a Ca2+ leak through the channel. Atrial RyR2 from RyR2-R2474S+/- mice were oxidized, and the RyR2 macromolecular complex was depleted of calstabin2. The Rycal drug S107 stabilizes the closed state of RyR2 by inhibiting the oxidation/phosphorylation induced dissociation of calstabin2 from the channel. S107 reduced the diastolic SR Ca2+ leak in atrial myocytes and decreased burst pacing-induced AF in vivo. S107 did not reduce the increased prevalence of burst pacing-induced AF in calstabin2-deficient mice, confirming that calstabin2 is required for the mechanism of action of the drug.
  
  
  CONCLUSIONS
  The present study demonstrates that RyR2-mediated diastolic SR Ca2+ leak in atrial myocytes is associated with AF in CPVT mice. Moreover, the Rycal S107 inhibited diastolic SR Ca2+ leak through RyR2 and pacing-induced AF associated with CPVT mutations.
authors: Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. arm42@columbia.edu
authors: Jian
authors: J
authors: Shan
authors: Wenjun
authors: W
authors: Xie
authors: Matthew
authors: M
authors: Betzenhauser
authors: Steven
authors: S
authors: Reiken
authors: Bi-Xing
authors: BX
authors: Chen
authors: Anetta
authors: A
authors: Wronska
authors: Andrew R
authors: AR
authors: Marks
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002110:Caffeine; D002118:Calcium; D004837:Epinephrine; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D013841:Thiazepines; C509259:FKBP1B protein, mouse; C540746:S-107 compound