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Poster Abstract PresentationsSession Title: Poster Session 3

Abstract 430: Circadian Control of Heart Rate

Alicia D’souza, Sven Wegner, Anne Berit Johnsen, Eleanor Gill, Charlotte Cox, Halina Dobrzynski, Ulrik Wisløff, George Hart, Hugh D Piggins, Mark R Boyett
Circulation Research. 2015;117:A430
Alicia D’souza
Univ of Manchester, Manchester, United Kingdom
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Sven Wegner
Univ of Manchester, Manchester, United Kingdom
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Anne Berit Johnsen
Norwegian Univ of Science and Technology, Trondheim, Norway
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Eleanor Gill
Univ of Manchester, Manchester, United Kingdom
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Charlotte Cox
Univ of Manchester, Manchester, United Kingdom
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Halina Dobrzynski
Univ of Manchester, Manchester, United Kingdom
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Ulrik Wisløff
Norwegian Univ of Science and Technology, Trondheim, Norway
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George Hart
Univ of Manchester, Manchester, United Kingdom
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Hugh D Piggins
Univ of Manchester, Manchester, United Kingdom
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Mark R Boyett
Univ of Manchester, Manchester, United Kingdom
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Abstract

Background: Bradyarrhythmias occur more frequently at night. On the basis of heart rate variability this is attributed to high vagal tone. Here we tested the alternative hypothesis that an intrinsic circadian clock-driven remodelling of pacemaking ion channels underlies fluctuations in heart rate (HR).

Methods and results: The occurrence of a circadian rhythm in HR was tested by placing nocturnal C57BL6/J mice under a strict 12/12h light-dark cycle and telemetry-based ECG intervals measured every 2 h for 48 h. Under these conditions, the R-R interval was rhythmic (n=10). To test whether this is caused by circadian rhythms in the expression of ion channels controlling HR, sinus node (SAN) biopsies were collected at time points corresponding to the minima (ZT0, subjective day) and maxima (ZT12, subjective night) of HR, as determined by ECG recordings. Real-time PCR normalised to 28s demonstrated an elevated expression of the key pacemaking ion channel HCN4 that carries the pacemaker current If and genes encoding the Ca2+-handling proteins SERCA2a and RYR2 at ZT12 (P<0.05, n=10). Presence of clock machinery (essential transcription factors involved in setting intrinsic circadian rhythms) as potential regulators of ion channel oscillation were investigated in the SAN of mPer1Luc mice which carry the 5’ upstream region of the mPer1 gene (a key core clock component) fused to a luciferase gene. mPer1-luc bioluminescence was recorded in the isolated SAN using a light-tight photomultiplier tube assembly to reveal a circadian rhythm with a periodicity of 24 h (n=3). Disruption of the molecular clock by global knockout of core clock components Cry1 and Cry2 abrogated the circadian cycling of mPer1-luc in the SN of Cry1-/-/Cry2-/-double knockout mice (n=3). Examination of 10[[Unable to Display Character: &#8201;]]kb of the Hcn4 promoter revealed a conserved consensus binding site for CLOCK and its heterodimer BMAL1, other essential transcription factors involved in setting intrinsic circadian rhythms.

Conclusions: This is the first demonstration of a peripheral circadian clock in the cardiac pacemaker and circadian oscillations in key pacemaker mechanisms. Data reveal a novel regulator of SN function and the occurrence of bradyarrythmias at night.

  • Bradyarrythmias
  • Pacemaking ion channels
  • Circadian rhythm
  • Author Disclosures: A. D’souza: None. S. Wegner: None. A. Johnsen: None. E. Gill: None. C. Cox: None. H. Dobrzynski: None. U. Wisløff: None. G. Hart: None. H.D. Piggins: None. M.R. Boyett: None.

  • © 2015 by American Heart Association, Inc.
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Circulation Research
July 17, 2015, Volume 117, Issue Suppl 1
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    Abstract 430: Circadian Control of Heart Rate
    Alicia D’souza, Sven Wegner, Anne Berit Johnsen, Eleanor Gill, Charlotte Cox, Halina Dobrzynski, Ulrik Wisløff, George Hart, Hugh D Piggins and Mark R Boyett
    Circulation Research. 2015;117:A430, originally published October 21, 2015

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    Abstract 430: Circadian Control of Heart Rate
    Alicia D’souza, Sven Wegner, Anne Berit Johnsen, Eleanor Gill, Charlotte Cox, Halina Dobrzynski, Ulrik Wisløff, George Hart, Hugh D Piggins and Mark R Boyett
    Circulation Research. 2015;117:A430, originally published October 21, 2015
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