A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate

Alicia D’Souza, Yanwen Wang, Cali Anderson, Annalisa Bucchi, Mirko Baruscotti, Servé Olieslagers, Pietro Mesirca, Anne Berit Johnsen, Svetlana Mastitskaya, Haibo Ni, Yu Zhang, Nicholas Black, Charlotte Cox, Sven Wegner, Beatriz Bano-Otalora, Cheryl Petit, Eleanor Gill, Sunil Jit R.J. Logantha, Halina Dobrzynski, Nick AshtonGeorge Hart, Rai Zhang, Henggui Zhang, Elizabeth J. Cartwright, Ulrik Wisloff, Matteo E. Mangoni, Paula A. da Costa Martins, Hugh D. Piggins, Dario DiFrancesco, Mark R. Boyett

Research output: Contribution to journalArticlepeer-review


Background: Heart rate follows a diurnal variation and slow heart rhythms occur primarily at night.
Objective: The lower heart rate during sleep is assumed to be neural in origin but here we tested whether a day-night difference in intrinsic pacemaking is involved.
Methods: In vivo and in vitro ECG recordings, vagotomy, transgenics, quantitative polymerase chain reaction, western blotting, immunohistochemistry, patch clamp, reporter bioluminescence recordings and chromatin immunoprecipitation were used.
Results: The day-night difference in the average heart rate of mice was independent of fluctuations in average locomotor activity and persisted under pharmacological, surgical and transgenic interruption of autonomic input to the heart. Spontaneous beating rate of isolated (i.e. denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic mRNA expression of ion channels including HCN4. In vitro studies demonstrated 24 h rhythms in the human HCN4 promoter and the corresponding funny current. The day-night heart rate difference in mice was abolished by HCN block both in vivo and in the isolated SN. Rhythmic expression of canonical circadian clock factors, e.g. Bmal1 and Cry, were identified in the SN and disruption of the local clock (by cardiac-specific knockout of Bmal1) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local clock with intrinsic rate control.
Conclusion: The circadian variation in heart rate involves SN local clock-dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.
Original languageEnglish
Pages (from-to)801-810
Number of pages10
JournalHeart Rhythm
Issue number5
Early online date3 Dec 2020
Publication statusPublished - 1 May 2021


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