A day-night rhythm in the heart including the sinoatrial node: an intrinsic mechanism and neurohumoral regulation

Physiology 2023 (Harrogate, UK) (2023) Proc Physiol Soc 54, SA01

Research Symposium: A day-night rhythm in the heart including the sinoatrial node: an intrinsic mechanism and neurohumoral regulation

Mark Boyett1, Sunil Jit Logantha1, Cali Anderson1, Claire Wilson1, Sana Yaar1, Yanwen Wang1, Munir Hussain1, Henggui Zhang1, George Hart1, Morten Bækgaard

1University of Bradford Bradford United Kingdom, 2University of Liverpool Liverpool United Kingdom, 3University of Manchester Manchester United Kingdom, 4University of Manchester Manchester United Kingdom, 5University of Manchester Manchester United Kingdom, 6University of Copenhagen Copenhagen Denmark, 7National Institute of Environmental Health Sciences Research Triangle Park, North Carolina United States, 8National Institute of Environmental Health Sciences Research Triangle Park, North Carolina United States,

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In mammals, there is well known to be a day-night rhythm in the electrical activity of the heart (in heart rate, PR interval, QRS duration and QT interval) and arrhythmogenesis1. This has previously been attributed to short-term regulation of ionic conductances in the heart by the autonomic nervous system, but this explanation has been challenged1. Instead, recent studies of the mouse have provided an alternative explanation.

 

In the sinoatrial node, we have shown that there is an intrinsic mechanism that can explain or at least contribute to the day-night rhythm in heart rate: there is a day-night rhythm in ion channels, including the pacemaker channel HCN4, and block of HCN4 abolishes the day-night rhythm in heart rate in vivo and in vitro2. We have shown that there is a functioning circadian clock in the sinoatrial node that could be driving the day-night rhythm in ion channel gene transcription: in the case of HCN4 at least, knockout of the clock gene Bmal1 abolishes the day-night rhythm in Hcn42. However, data are emerging for a system of transcriptional ‘combinatorial regulation’ in which a specific combination of transcription factors is obligatory for gene transcription: there is a day-night rhythm in the sympathetic nervous system and chronic b-adrenergic receptor blockade also abolishes the day-night rhythm in ion channel transcripts (including Hcn4)3. For the atrioventricular node, a similar picture is emerging: there is day-night rhythm in ion channel transcripts and a functional circadian clock4 and genetic knockout of Bmal1 blunts the day-night rhythm in the PR interval (unpublished data). Again the picture is similar for the ventricles with a day-night rhythm in ion channel transcripts and a functional circadian clock3; the day-night rhythm in ion channel transcripts is suggested to be responsible for the well-known vulnerability to ventricular tachyarrhythmias at the start of the awake period. Once again there is evidence of combinatorial regulation: genetic knockout of Bmal1 abolishes the vulnerability to ventricular tachyarrhythmias at the start of the awake period5; chronic b-adrenergic receptor blockade abolishes the day-night rhythm in ion channel transcripts3; and RU486 (an antagonist to the glucocorticoid receptor, Nr3c1; of interest because there is a day-night rhythm in plasma corticosteroid) again abolishes the day-night rhythm in ion channel transcripts as well as the vulnerability to ventricular tachyarrhythmias at the start of the awake period (unpublished data). ATAC-seq has shown a day-night rhythm in accessibility to certain genes (chromatin has to be made accessible for transcription to take place) and in many cases of genes showing a day-night rhythm in accessibility there is a consensus binding site for Nr3c1 (a transcription factor as well as a receptor) (unpublished data). Genetic knockout of Nr3c1 also abolishes the vulnerability to ventricular tachyarrhythmias at the start of the awake period (unpublished data). In summary, a new explanation of the day-night rhythm in the heart is beginning to emerge involving a summation of inputs from an intrinsic cardiac circadian clock and neurohumoral factors.



Where applicable, experiments conform with Society ethical requirements.

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