Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation
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.
Keywords: Atrial fibrillation, Calcium, Sarcoplasmic reticulum, Sinoatrial node dysfunction
Abbreviations: AF, atrial fibrillation, APD, action potential duration, cSNRT, corrected sinoatrial node recovery time, LDCAE, late diastolic Cai elevation, RA, right atrium, RyR2, type 2 ryanodine receptor, SACT, sinoatrial node conduction time, SAN, sinoatrial node, SERCA2a, sarcoplasmic reticulum Ca2+-ATPase 2a, SNRT, sinoatrial node recovery time, SR, sarcoplasmic reticulum
This manuscript was processed by a guest editor. This study was supported in part by National Institutes of Health Grants P01 HL78931, R01 HL78932, and 71140; a Korean Ministry of Information and Communication and Institute for Information Technology Advancement through research and develop support project to Dr. Joung; an AHA Established Investigator Award to Dr. Lin; a Nihon Kohden/St. Jude Medical Electrophysiology fellowship to Dr. Maruyama; Medtronic-Zipes Endowments to Dr. Chen; and a VA Young Investigator Grant and St. Jude Medical, Inc., research grant to Dr. Das. Dr. Zipes and Chen are consultants to Medtronic, Inc. Dr. Das receives research grants from St. Jude Medical. Medtronic provided equipment used in this study.
PII: S1547-5271(09)01030-3
doi:10.1016/j.hrthm.2009.09.018
Published by Elsevier Inc.
