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) 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.
Joung
Boyoung
B
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Lin
Shien-Fong
SF
Chen
Zhenhui
Z
Antoun
Patrick S
PS
Maruyama
Mitsunori
M
Han
Seongwook
S
Piccirillo
Gianfranco
G
Stucky
Marcelle
M
Zipes
Douglas P
DP
Chen
Peng-Sheng
PS
Das
Mithilesh Kumar
MK
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*
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