Ca2+ clock malfunction in a canine model of pacing-induced heart failure

Tetsuji Shinohara, Hyung Wook Park, Seongwook Han, Mark J. Shen, Mitsunori Maruyama, Daehyeok Kim, Peng Sheng Chen, Shien-Fong Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca2+ release (Ca2+ clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg -1·min-1) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca2+ and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal (n = 7) and failing hearts (n = 6). Iso increased sinus rate, enhanced late diastolic Ca2+ elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current (I f) blocker. We conclude that HF results in the suppression of Ca 2+ clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the If at the latent pacemaking sites in lower crista terminalis.

Original languageEnglish
Pages (from-to)H1805–H1811
Number of pages7
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number6
StatePublished - 1 Dec 2010


  • Calcium
  • Sarcoplasmic reticulum
  • Sympathetic nerve activity

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