title: The role of the calcium and the voltage clocks in sinoatrial node dysfunction.
abstract: Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release) jointly regulate sinoatrial node (SAN) automaticity. However, the relative importance of the voltage clock and Ca(2+) clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Ca(i)) and membrane potentials of the normal intact SAN simultaneously using optical mapping in Langendorff-perfused canine right atrium. We demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with robust late diastolic Ca(i) elevation (LDCAE) during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca(2+) release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca(2+) clock of SAN was unresponsiveness to β-adrenergic stimulation and caffeine. Ryanodine receptor 2 (RyR2) in SAN was down-regulated. Using the prolonged low dose isoproterenol together with funny current block, we produced a tachybradycardia model. In this model, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the right atrium, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Finally, if the LDCAE was too small to trigger an action potential, then it induced only delayed afterdepolarization (DAD)-like diastolic depolarization (DD). The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca(2+) clock and the voltage clock are important in sick sinus syndrome.
authors.affiliation: Division of Cardiology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
mesh_terms: D000818:Animals; D001146:Arrhythmia, Sinus / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000503:physiopathology; D001919:Bradycardia / Q000503:physiopathology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D004285:Dogs; D006801:Humans; D012804:Sick Sinus Syndrome / Q000503:physiopathology; D012849:Sinoatrial Node / Q000502:physiology / Q000503:physiopathology*
chemical_list: D015220:Calcium Channels; D002118:Calcium