Yonsei Med J.  2011 Mar;52(2):211-219. 10.3349/ymj.2011.52.2.211.

The Role of the Calcium and the Voltage Clocks in Sinoatrial Node Dysfunction

• Joung B
• Chen PS
• Lin SF

• KMID: 1779654
• DOI: http://doi.org/10.3349/ymj.2011.52.2.211

Abstract

Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release) jointly regulate sinoatrial node (SAN) automaticity. However, the relative importance of the voltage clock and Ca2+ clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Cai) 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 Cai elevation (LDCAE) during beta-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca2+ release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca2+ clock of SAN was unresponsiveness to beta-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 Ca2+ clock and the voltage clock are important in sick sinus syndrome.

Keyword

Calcium; sinoatrial node; sarcoplasmic reticulum; sick sinus syndrome

MeSH Terms

Animals
Arrhythmia, Sinus/physiopathology
Atrial Fibrillation/physiopathology
Bradycardia/physiopathology
Calcium/*physiology
Calcium Channels/*physiology
Dogs
Humans
Sick Sinus Syndrome/physiopathology
Sinoatrial Node/physiology/*physiopathology

Figure

• 

  Fig. 1 Activation pattern of SAN and surrounding RA during isoproterenol infusion of 0.3 µmol/L. (A) Isochronal map of Vm. The number on the each isochronal line indicates time (ms). White shaded area is the SAN. (B) The Vm (blue) and Cai (red) recordings from the superior (a), middle (b), inferior (c) SANs and RA (d) presented in A. (C) Magnified view of Cai and Vm tracings of superior SAN. Note the robust LDCAE (solid arrow) before phase 0 of action potential (0 ms), which in turn was much earlier than onset of p wave on ECG. (D) The Vm and Cai ratio maps at times from - 60 ms before to 180 ms after phase 0 action potential of C. The LDCAE (broken arrows in frame - 40 and - 20 ms) was followed by the Cai sinkhole during early diastole (solid arrow in frame 180 ms). This figure was reproduced with permission from Joung, et al.23 SAN, sinoatrial node; RA, right atrium; LDCAE, late diastolic Cai elevation.

• 

  Fig. 2 Co-localization of LDCAE and the leading pacemaker site. (A) Upward shift of the leading pacemaker site with LDCAE during isoproterenol infusion. (a) Cai ratio maps of SAN at each sinus rate. (b) Corresponding Cai tracings from superior (1, 2), middle (3, 4) and inferior (5, 6) SAN. At 95 bpm, the sites 4 and 5 had most prominent LDCAEs (asterisks). As sinus rate gradually increased, the sites of Cai elevation progressively moved upward. At the maximum sinus rate of 173 bpm, the site 2 had the most apparent LDCAE. (B) Differential responses of different SAN sites to isoproterenol. (a) The Cai and Vm tracings from inferior, middle, and superior SAN sites at different sinus rates. (b) The LDCAE and DD slopes of superior SAN at different sinus rates. This figure was reproduced with permission from Joung, et al.23 SAN, sinoatrial node; LDCAE, late diastolic Cai elevation; DD, diastolic depolarization.

• 

  Fig. 3 Complete absence of LDCAE in AF dogs during isoproterenol infusion. (A) Isoproterenol response of normal dogs. In normal dogs, isoproterenol increased the heart rate and shifted the leading pacemaker site to the superior SAN with robust LDCAE (arrows). (B) Isoproterenol response of AF dogs. The LDCAE was complete absent in AF dogs during isoproterenol infusion. (a) RA Vm isochronal map. (b) Cai tracings from superior (S), mid (M), and inferior (I) SANs. (c) SAN LDCAE isochronal map. The unit of numbers on RA Vm isochronal map is ms. The earliest activation of RA was considered as 0 ms. This figure was reproduced with permission from Joung, et al.32,33 SAN, sinoatrial node; AF, atrial fibrillation; RA, right atrium; LDCAE, late diastolic Cai elevation.

• 

  Fig. 4 Tachybradycardia produced by prolonged isoproterenol and ZD 7288 infusion. The figure shows pseudo ECG from canine isolated RA. Upper panel, eight episodes of tachybradycardia. Lower panel, expanded view of a section marked by asterisk (*) showing 4.0 s and 3.5 s pauses. This figure was reproduced with permission from Joung, et al.39 RA, right atrium.

• 

  Fig. 5 The effect of prolonged low dose isoproterenol infusion (n = 8). (A) Heart rate trends after prolonged (> 1 hr) isoproterenol infusion of 0.01 µmol/L. Heart rate was increased maximum at 5 min, and decreased after 10 min. ZD 7288 infusion of 3 µmol/L decrease the heart rate again almost to the baseline level. B through E show Vm isochronal map of SAN and surrounding RA (upper panels), and Cai (red) and Vm (blue) tracings from superior (a and b), middle (c and d) and lower (e and f) SAN. (B) Baseline. Note the diastolic depolarization (asterisks) in SAN. C, Isoproterenol infusion for 5 min. Note the LDCAE (asterisks) from superior SAN. (D) Isoproterenol infusion for 1 hr. Note the disappearance of LDCAE with shifting of the leading pacemaker site to inferior SAN (site e). (E) ZD 7288 infusion for 30 min. The pacemaker site shifted to the more inferior SAN (site f). The unit of numbers on Vm isochronal map is ms. This figure was reproduced with permission from Joung, et al.39 SAN, sinoatrial node; LDCAE, late diastolic Cai elevation.

• 

  Fig. 6 The intermittent pattern of subthreshold DADs. These tracings were obtained during isoproterenol infusion (0.03 µmol/L) in the first RA preparation. (A) Optical signals of Cai (red) and Vm (blue) from superior (a and b), middle (c and d), and inferior (e and f) SAN, and RA (g). There were 3 consecutive activations in this figure. Among them, the first 1) and third beats show LDCAE (arrows) followed by the initiation of sinus beats from the same sites. In contrast, the second beat 2) showed both LDCAE on Cai tracings and subthreshold DADs on Vm tracings (asterisks). The downslope of the subthreshold DADs were observed because they failed to trigger an action potential. (B) Vm isochronal maps of the first (1) and second (2) beats. The white shaded area is the SAN. The first beat 1) was from SAN. Because subsequent LDCAE in the SAN (asterisks in Panel A) failed to trigger a sinus beat, an ectopic pacemaker was able to take over and activate the mapped region 2). This figure was reproduced with permission from Joung, et al.51 RAA, right atrial appendage; SVC, superior vena cava; A, anterior; P, posterior; S, superior; I, inferior, DAD, delayed afterdepolarization; SAN, sinoatrial node; RA, right atrium; LDCAE, late diastolic Cai elevation.

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