Trends in Endocrinology & Metabolism
ReviewImpact of Circadian Disruption on Cardiovascular Function and Disease
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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