Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Edward A Hayter; Sophie M T Wehrens; Hans P A Van Dongen; Alessandra Stangherlin; Shobhan Gaddameedhi; Elena Crooks; Nichola J Barron; Luigi A Venetucci; John S O' Neill; Timothy M Brown; Debra J Skene; Andrew W Trafford; David A Bechtold

doi:10.1038/s41467-021-22788-8

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Edward A Hayter, Sophie M T Wehrens, Hans P A Van Dongen, Alessandra Stangherlin, Shobhan Gaddameedhi, Elena Crooks, Nichola J Barron, Luigi A Venetucci, John S O' Neill, Timothy M Brown, Debra J Skene, Andrew W Trafford, David A Bechtold

Research output: Contribution to journal › Article › peer-review

Abstract

Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.

Original language	English
Article number	2472
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22788-8
Publication status	Published - 30 Apr 2021

Keywords

ARNTL Transcription Factors/genetics
Adult
Animals
Arrhythmias, Cardiac/genetics
Atrioventricular Node/metabolism
Autonomic Nervous System/physiology
Circadian Clocks/physiology
Circadian Rhythm/physiology
Electrocardiography
Female
Gene Expression Regulation/genetics
Heart Rate/physiology
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Myocytes, Cardiac/metabolism
Sinoatrial Node/metabolism
Sleep/physiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-22788-8

https://www.nature.com/articles/s41467-021-22788-8.pdf

1 Finished
1 Not started

Centre for Biological Timing
Lucas, R. (PI), Bechtold, D. (PI), Fustin, J.-M. (PI), Ashe, H. (PI), Brown, T. (PI), Blaikley, J. (PI), Brass, A. (PI), Chandola, T. (PI), Durrington, H. (PI), Else, K. (PI), Hepworth, M. (PI), Hunter, L. (PI), Kadler, K. (PI), Kitchen, G. (PI), Loudon, A. (PI), Macdonald, A. (PI), Mcbeth, J. (PI), Milosavljevic, N. (PI), Rattray, M. (PI), Rutter, M. (PI), Sharrocks, A. (PI), Spiller, D. (PI), Storchi, R. (PI), Belle, M. (PI), Meng, Q.-J. (PI), Allen, A. (PI), Dixon, W. (PI), Gibbs, J. (PI), Hazel, A. (PI), Papalopulu, N. (PI), Ray, D. (PI), White, M. (PI) & Chang, J. (PI)
Project: Research
Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology
Bechtold, D. (PI), Brown, T. (CoI) & Trafford, A. (CoI)
1/06/21 → 31/05/24
Project: Research

Cite this

Hayter, E. A., Wehrens, S. M. T., Van Dongen, H. P. A., Stangherlin, A., Gaddameedhi, S., Crooks, E., Barron, N. J., Venetucci, L. A., Neill, J. S. O., Brown, T. M., Skene, D. J., Trafford, A. W., & Bechtold, D. A. (2021). Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia. Nature Communications, 12(1), Article 2472. https://doi.org/10.1038/s41467-021-22788-8

@article{fa7b53c592304e93b8b3371b76b24f7f,

title = "Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia",

abstract = "Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.",

keywords = "ARNTL Transcription Factors/genetics, Adult, Animals, Arrhythmias, Cardiac/genetics, Atrioventricular Node/metabolism, Autonomic Nervous System/physiology, Circadian Clocks/physiology, Circadian Rhythm/physiology, Electrocardiography, Female, Gene Expression Regulation/genetics, Heart Rate/physiology, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Myocytes, Cardiac/metabolism, Sinoatrial Node/metabolism, Sleep/physiology",

author = "Hayter, {Edward A} and Wehrens, {Sophie M T} and {Van Dongen}, {Hans P A} and Alessandra Stangherlin and Shobhan Gaddameedhi and Elena Crooks and Barron, {Nichola J} and Venetucci, {Luigi A} and Neill, {John S O'} and Brown, {Timothy M} and Skene, {Debra J} and Trafford, {Andrew W} and Bechtold, {David A}",

note = "Funding Information: We would like to thank the Biological Services Units at the University of Manchester and Laboratory of Molecular Biology for their excellent support of the animal work. We also thank our funders for their generous support: UK Biotechnology and Biological Sciences Research Council (BBSRC) grants to D.A.B. (BB/J017744/1; BB/I018654/1); AstraZeneca Blue Skies Initiative and the Medical Research Council (MC_UP_1201/4) to J.S.O.; Human study one was supported by an EU Marie Curie Research Training Network grant (CT-2004-512362) to D.J.S., 6th Framework project EUCLOCK (018741) to D.J.S. and Stockgrand Ltd (University of Surrey) to S.M.T.W. and D.J.S. Human study two was supported by start-up funds from the College of Pharmacy and Pharmaceutical Sciences at Washington State University to S.G. and by Congressionally Directed Medical Research Program and U.S. Army Medical Research and Development Command awards W81XWH-16-1-0319, W81XWH-18-1-0100 and W81XWH-20-1-0442 to H.P. A.V.D.; National Institutes of Health Grants R01ES030113 and R21CA227381 to S.G.; BBSRC Grant BB/I019405/1 to D.J.S.; and EU FP7-HEALTH-2011 EuRhythDia Grant 278397 to D.J.S. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = apr,

day = "30",

doi = "10.1038/s41467-021-22788-8",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

AU - Hayter, Edward A

AU - Wehrens, Sophie M T

AU - Van Dongen, Hans P A

AU - Stangherlin, Alessandra

AU - Gaddameedhi, Shobhan

AU - Crooks, Elena

AU - Barron, Nichola J

AU - Venetucci, Luigi A

AU - Neill, John S O'

AU - Brown, Timothy M

AU - Skene, Debra J

AU - Trafford, Andrew W

AU - Bechtold, David A

N1 - Funding Information: We would like to thank the Biological Services Units at the University of Manchester and Laboratory of Molecular Biology for their excellent support of the animal work. We also thank our funders for their generous support: UK Biotechnology and Biological Sciences Research Council (BBSRC) grants to D.A.B. (BB/J017744/1; BB/I018654/1); AstraZeneca Blue Skies Initiative and the Medical Research Council (MC_UP_1201/4) to J.S.O.; Human study one was supported by an EU Marie Curie Research Training Network grant (CT-2004-512362) to D.J.S., 6th Framework project EUCLOCK (018741) to D.J.S. and Stockgrand Ltd (University of Surrey) to S.M.T.W. and D.J.S. Human study two was supported by start-up funds from the College of Pharmacy and Pharmaceutical Sciences at Washington State University to S.G. and by Congressionally Directed Medical Research Program and U.S. Army Medical Research and Development Command awards W81XWH-16-1-0319, W81XWH-18-1-0100 and W81XWH-20-1-0442 to H.P. A.V.D.; National Institutes of Health Grants R01ES030113 and R21CA227381 to S.G.; BBSRC Grant BB/I019405/1 to D.J.S.; and EU FP7-HEALTH-2011 EuRhythDia Grant 278397 to D.J.S. Publisher Copyright: © 2021, The Author(s).

PY - 2021/4/30

Y1 - 2021/4/30

N2 - Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.

AB - Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.

KW - ARNTL Transcription Factors/genetics

KW - Adult

KW - Animals

KW - Arrhythmias, Cardiac/genetics

KW - Atrioventricular Node/metabolism

KW - Autonomic Nervous System/physiology

KW - Circadian Clocks/physiology

KW - Circadian Rhythm/physiology

KW - Electrocardiography

KW - Female

KW - Gene Expression Regulation/genetics

KW - Heart Rate/physiology

KW - Humans

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Middle Aged

KW - Myocytes, Cardiac/metabolism

KW - Sinoatrial Node/metabolism

KW - Sleep/physiology

U2 - 10.1038/s41467-021-22788-8

DO - 10.1038/s41467-021-22788-8

M3 - Article

C2 - 33931651

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2472

ER -

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Projects

Centre for Biological Timing

Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology

Cite this