title: Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
abstract: BACKGROUND
  The mechanism of sinoatrial node (SAN) dysfunction in atrial fibrillation (AF) is unclear.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that defective spontaneous sarcoplasmic reticulum (SR) Ca(2+) release (Ca(2+) clock) is in part responsible for SAN dysfunction in AF.
  
  
  METHODS
  Arrhythmic events and SAN function were evaluated in pacing-induced AF dogs (n = 7) and in normal dogs (n = 19) with simultaneous intracellular calcium (Ca(i)) and membrane potential recording.
  
  
  RESULTS
  AF dogs had frequent sinus pauses during Holter monitoring. Isolated right atrium (RA) from AF dogs showed slower heart rate (P = .001), longer SAN recovery time (P = .001), and longer sinoatrial conduction time (P = .003) than normal. In normal RAs, isoproterenol 0.3 and 1 mumol/L increased heart rate by 96% and 105%, respectively. In contrast, in RAs from AF dogs, isoproterenol increased heart rate by only 60% and 72%, respectively. Isoproterenol induced late diastolic Ca(i) elevation (LDCAE) at superior SAN in all 19 normal RAs but in only 3 of 7 AF RAs (P = .002). In AF RAs without LDCAE (n = 4), heart rate increased by the acceleration of ectopic foci. Caffeine (20 mmol/L) injection increased heart rate with LDCAE in all 6 normal RAs but did not result in LDCAE in any of the 5 AF RAs (P = .002). Type 2 ryanodine receptor (RyR2) in the superior SAN of AF dogs was decreased to 33% of normal (P = .02).
  
  
  CONCLUSIONS
  SAN dysfunction in AF is associated with Ca(2+) clock malfunction, characterized by unresponsiveness to isoproterenol and caffeine and down-regulation of RyR2 in SAN.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Antoun
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Seongwook
authors.initials: S
authors.lastname: Han
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Piccirillo
authors.forename: Marcelle
authors.initials: M
authors.lastname: Stucky
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Zipes
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Mithilesh Kumar
authors.initials: MK
authors.lastname: Das
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000145:classification / Q000209:etiology / Q000503:physiopathology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012849:Sinoatrial Node / Q000503:physiopathology*
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000697:Central Nervous System Stimulants; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D007545:Isoproterenol; D002118:Calcium