Review
Impact of Circadian Disruption on Cardiovascular Function and Disease

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Highlights

  • Adverse CV events, including myocardial infarction, arrhythmias, and stroke, show time-of-day variations. Underlying factors may include circadian system control over a plethora of markers associated with CV function.

  • Our modern lifestyle, which includes shiftwork, jet lag, and disturbed sleep, has been associated with increased CV risk.

  • Misalignment of the endogenous circadian timing system and behavioral/environmental cycles can adversely impact on CV function in both animal models and human studies. These mechanistic insights may help to explain why some aspects of our modern lifestyle can increase CV risk.

  • Circadian disruption may play a role in the onset and development of CV disease, and treatments aimed at mitigating circadian disruption may diminish CV risk.

The circadian system, that is ubiquitous across species, generates ∼24 h rhythms in virtually all biological processes, and allows them to anticipate and adapt to the 24 h day/night cycle, thus ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular (CV) events, and controlled laboratory studies demonstrate a circadian influence on key markers of CV function and risk. Furthermore, circadian misalignment, that is typically experienced by shift workers as well as by individuals who experience late eating, (social) jet lag, or circadian rhythm sleep–wake disturbances, increases CV risk factors. Therefore, understanding the mechanisms by which the circadian system regulates CV function, and which of these are affected by circadian disruption, may help to develop intervention strategies to mitigate CV risk.

Section snippets

Why Is Time of Day Important for CV Risk?

Adverse CV events, including myocardial infarction, stroke, and ventricular arrhythmias, are worldwide leading causes of death [1]. Epidemiological evidence supports a heightened risk of these adverse CV events during the ‘vulnerable morning hours’ (6:00 am–12:00 pm) 2, 3. Importantly, these time-of-day variations are not fully explained by daily rhythms in behavioral triggers such as physical activity [4], fasting/feeding, and sleep schedules. They may instead be due to the influence of the

Circadian Rhythms in CV Risk

In humans, there are day/night rhythms in key aspects of CV function, including blood pressure (BP; higher levels during the day and lower levels at night [25]), and platelet aggregability (higher levels in the morning 26, 27). Epidemiologic studies report a morning peak in adverse CV events 2, 28. However, such data collected during regular sleep/wake cycles cannot determine whether this temporal pattern is caused by the circadian system or by behavioral and environmental factors. Circadian

Impact of Circadian Misalignment on CV Risk

If circadian rhythms contribute to CV health [42], then circadian disruption/misalignment may influence CV risk. Circadian misalignment effects on circadian factors and CV risk factors in humans (Figure 3) can be determined using controlled in-laboratory studies, including FD and simulated shiftwork protocols [43]. In a FD protocol, where participants lived for seven 28 h ‘days’ under dim light [20], waketime BP was higher during circadian misalignment. These misalignment-induced effects on BP

Molecular Mechanisms of Circadian Misalignment Effects on CV Risk

Animal experimental paradigms to test how circadian disruption adversely affects CV function include models of light/dark (LD) cycle manipulation, meal timing schedules, genetic mutations with a circadian period phenotype (changing circadian cycle length of the whole animal or a specific tissue), circadian rhythm ablation mutations (complete molecular knockout of the clock in a whole animal or tissue), and SCN lesion studies [50]. In a LD cycle manipulation model, mice were randomized to

Clinical Implications of Circadian Misalignment for CV Disease

Human physiological mechanistic work provides translational evidence for the involvement of the circadian system in daily rhythms in adverse CV events 21, 33, 34, 35, 36, 37, 38, 39, as well as the contribution of circadian disruption (e.g., misalignment) to increasing CV risk factors 20, 22, 23, 24. Mechanistic insights from preclinical experimental work have shed light on the existence of circadian clocks throughout the CV system, and that circadian clocks in myocardial tissue become altered

Concluding Remarks and Future Perspectives

Time-of-day patterns in the risk of acute myocardial infarction were first described in 1963 [69]. Since then, numerous studies have reported time-of-day variations of system-level markers of CV function, and in molecular and gene control in the heart, vasculature, and kidneys, which may play a role in the onset and development of CV diseases. Central to these time-of-day fluctuations is the modulatory role of the circadian timing system, as well as its interaction with behavioral/environmental

Acknowledgments

S.L.C was supported by National Institutes of Health (NIH) grant R01HL118601. N.V was supported by NIH grant R01 DK099512. J.S.W. was supported by NIH grants R01HL127146, R01HL136567, R01HL141406, P01AG009975, R56HL114765, and R01HL144779. F.A.J.L.S. was supported by NIH grants R01HL094806, R01HL118601, R01DK099512, R01DK102696, R01DK105072, and R01HL140574.

Disclaimer Statement

F.A.J.L.S. has received lecture fees from Bayer HealthCare, Sentara HealthCare, Philips, Vanda Pharmaceuticals, and Pfizer Pharmaceuticals. S.L.C, N.V., and J.S.W. report no conflicts of interest.

Glossary

Circadian disruption
disruption of endogenous circadian rhythms. This can occur from the level of the molecular clock mutations to misalignment between the circadian system with behavioral and/or environmental cycles.
Circadian misalignment
misalignment between the endogenous circadian timing system and behavioral/environmental cycles (i.e., sleep/wake, light/dark, fasting/feeding), or between components of the circadian system.
Circadian rhythm
a biological process with an endogenous, entrainable

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