Chapter 19 - The impact of the circadian timing system on cardiovascular and metabolic function

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Abstract

Epidemiological studies show that adverse cardiovascular events peak in the morning (i.e., between 6 AM and noon) and that shift work is associated with cardiovascular disease, obesity, and diabetes. The endogenous circadian timing system modulates certain cardiovascular risk markers to be highest (e.g., cortisol, nonlinear dynamic heart rate control, and platelet activation) or to respond most unfavorably to stressors such as exercise (e.g., epinephrine, norepinephrine, and vagal cardiac modulation) at an internal body time corresponding to the time of day when adverse cardiovascular events most likely occur. This indicates that the circadian timing system and its interaction with external cardiovascular stressors (e.g., physical activity) could contribute to the morning peak in adverse cardiovascular events. Moreover, circadian misalignment and simulated night work have adverse effects on cardiovascular and metabolic function. This suggests that misalignment between the behavioral cycle and the circadian timing system in shift workers contributes to that population's increased risk for cardiometabolic disease.

Introduction

Western societies are rife with cardiovascular disease, diabetes, and obesity. In the United States, it is estimated that 83 million adults have cardiovascular disease (Roger et al., 2011), 26 million have diabetes (Centers for Disease Control and Prevention, 2011), and 80 million are obese (Flegal et al., 2010). The influence of behaviors (e.g., poor diet and physical inactivity) as underlying causes for these diseases has been researched for decades. However, more recently, evidence has been accumulating for a contributing role of the endogenous circadian timing system and its disruption in cardiovascular and metabolic disorders. In this review, we discuss—with a focus on mammals and particularly humans—the impact of the circadian timing system, its interaction with behaviors (e.g., exercise), and its disturbance on cardiovascular and metabolic function.

Section snippets

The circadian timing system

Most life on earth—ranging from single cellular organisms, plants, flies, rats, to humans—contains an endogenous timing system that optimally synchronizes physiology and behavior (e.g., rest/activity and fasting/feedings cycles) with the solar day. The system is known as the circadian (“circa,” around; “dies,” day) timing system and has two core characteristics: (1) endogenous rhythmicity that cycles approximately every 24 h, even in the absence of cyclic changes in external factors such as

The internal clock and the timing of adverse cardiovascular events

Epidemiological data demonstrate a 24-h rhythm in the frequency of adverse cardiovascular events such as angina, myocardial infarction, stroke, arrhythmias, cardiac arrest, and sudden cardiac death (Fig. 1), with the highest incidence occurring between approximately 6 AM and noon (Cannon et al., 1997, Cohen et al., 1997, D'Avila et al., 1995, Elliott, 1998, Goldberg et al., 1990, Levine et al., 1992, Marler et al., 1989, Muller et al., 1985, Muller et al., 1987, Twidale et al., 1989, Willich et

Circadian disruption and cardiovascular function

In the previous section, we provided recent evidence for the impact of the circadian timing system on cardiovascular risk markers that—if confirmed in vulnerable populations—may contribute to the morning peak in adverse cardiovascular events. However, in healthy individuals, the circadian timing system has been proposed to optimally regulate many physiological processes to prepare for the varying demands across the sleep/wake cycle. If this would be the case, it would be expected that circadian

Circadian disruption and metabolic function

Human endogenous circadian rhythms have been observed in many factors related to metabolism. For example, glucose, insulin, cortisol, epinephrine, norepinephrine, and leptin display endogenous circadian variation (Morgan et al., 1998, Scheer et al., 2009, Scheer et al., 2010, Shea et al., 2005, Van Cauter et al., 1994, Wehr et al., 2001). Recent research demonstrates that amino acid plasma concentrations are under endogenous circadian control, through Krüppel-like factor 15-control of the

Summary

The circadian timing system orchestrates cyclic variations in numerous cardiovascular and metabolic functions independent of external influences such as darkness/light, sleep/wakefulness, rest/activity, and fasting/eating. At rest, the circadian timing system causes some factors to peak during the biological morning (e.g., cortisol, platelet expression of activated GPIIb-IIIa, P-selectin, and GP1b), which could potentiate the onset of adverse cardiovascular events at that time. This suggests

Acknowledgments

C. J. M. was supported by the National Space Biomedical Research Institute through NASA NCC 9-58. F. A. J. L. S. was supported by National Institute of Health Grants P30-HL101299 and R01 HL094806.

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