Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation

Boyoung Joung, Shien-Fong Lin, Zhenhui Chen, Patrick S. Antoun, Mitsunori Maruyama, Seongwook Han, Gianfranco Piccirillo, Marcelle Stucky, Douglas P. Zipes, Peng Sheng Chen, Mithilesh Kumar Das*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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) Ca2+ release (Ca2+ 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 (Cai) 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 μmol/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 Cai 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). Conclusion: SAN dysfunction in AF is associated with Ca2+ clock malfunction, characterized by unresponsiveness to isoproterenol and caffeine and down-regulation of RyR2 in SAN.

Original languageEnglish
Pages (from-to)88-95
Number of pages8
JournalHeart Rhythm
Issue number1
StatePublished - Jan 2010


  • Atrial fibrillation
  • Calcium
  • Sarcoplasmic reticulum
  • Sinoatrial node dysfunction

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