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Circadian rhythms and the molecular clock in cardiovascular biology and disease

Abstract

The Earth turns on its axis every 24 h; almost all life on the planet has a mechanism — circadian rhythmicity — to anticipate the daily changes caused by this rotation. The molecular clocks that control circadian rhythms are being revealed as important regulators of physiology and disease. In humans, circadian rhythms have been studied extensively in the cardiovascular system. Many cardiovascular functions, such as endothelial function, thrombus formation, blood pressure and heart rate, are now known to be regulated by the circadian clock. Additionally, the onset of acute myocardial infarction, stroke, arrhythmias and other adverse cardiovascular events show circadian rhythmicity. In this Review, we summarize the role of the circadian clock in all major cardiovascular cell types and organs. Second, we discuss the role of circadian rhythms in cardiovascular physiology and disease. Finally, we postulate how circadian rhythms can serve as a therapeutic target by exploiting or altering molecular time to improve existing therapies and develop novel ones.

Key points

  • Molecular clocks are found in all cardiovascular cell types.

  • Various cardiovascular functions, including endothelial function, thrombus formation, blood pressure and heart rate, are regulated by the circadian clock.

  • Disruption of 24-h rhythms leads to cardiovascular disease, including heart failure, myocardial infarction and arrhythmias.

  • 24-h rhythms are present in the development, risk factors, incidence and outcome of cardiovascular disease.

  • Cardiovascular disease leads to disrupted circadian rhythm and sleep problems.

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Fig. 1: Overview of the core molecular clockwork within the cardiovascular system.

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Acknowledgements

The authors acknowledge support from Innovation and the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Science. S.C. receives support from the Jacob Jongbloed Talent Society Grant (Circulatory Health, University Medical Centre Utrecht). J.P.G.S. receives support from Horizon2020 ERC-2016-COG EVICARE (725229).

Reviewer information

Nature Reviews Cardiology thanks G. Cornelissen, R. Manfredini and K. Otsuka for their contribution to the peer review of this work.

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Correspondence to Linda W. Van Laake.

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Glossary

Circadian rhythms

Endogenous biorhythms with a period of approximately 24 h; self-sustainable but can be entrained.

Period

Duration of one circadian cycle.

Central or primary clock

Group of neurons in the suprachiasmatic nucleus (part of the hypothalamus) of the brain, which orchestrates rhythmicity within the body.

Peripheral clocks

Molecular mechanism within individual cells that regulates circadian rhythm.

Synchronizer

External or environmental cue (such as light, food intake or exercise) that synchronizes or entrains circadian rhythms; also known as Zeitgeber (‘time giver’).

24-h rhythms

Patterns re-occurring every 24 h.

Chronotherapy

Scheduling of treatment in relation to 24-h rhythms to increase effectiveness of the therapy and/or reduce adverse effects.

Clock-controlled genes

Genes whose transcription is controlled by the molecular circadian clock.

Core clock genes

Genes that form a basis for generation and regulation of circadian rhythms by encoding BMAL1, CLOCK, CRY and PER proteins.

Amplitude

Difference between mesor and peak of the sinusoidal-shaped circadian rhythm.

Mesor

Mean value of a (circadian) cycle or rhythm.

Serum shock

Acute exposure to a high concentration of serum (50% fetal bovine serum for 2 h) to align desynchronized circadian phases in a multicellular system.

Chronotypes

Propensity to be active, inactive or asleep at a specific time during a 24-h cycle.

Acrophase

Time at which the peak of the rhythm occurs.

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Crnko, S., Du Pré, B.C., Sluijter, J.P.G. et al. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol 16, 437–447 (2019). https://doi.org/10.1038/s41569-019-0167-4

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