There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/ feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h ''day.'' Subjects ate 4 isocaloric meals each 28-h ''day.'' For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling Ϸ1,000 assays/ subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept Ϸ12 h out of phase from their habitual times, systematically decreased leptin (؊17%, P < 0.001), increased glucose (؉6%, P < 0.001) despite increased insulin (؉22%, P ‫؍‬ 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (؉3%, P ‫؍‬ 0.001), and reduced sleep efficiency (؊20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work. autonomic nervous system ͉ diabetes ͉ glucose metabolism ͉ leptin ͉ obesity A pproximately 8.6 million Americans perform shift work (1), which is associated with increased risk of obesity, diabetes, and cardiovascular disease (2-6). The endogenous circadian timing system, including the suprachiasmatic nucleus (SCN) in the hypothalamus and peripheral oscillators in vital organs, optimally regulates much of our physiology and behavior across the 24-h day when it is properly aligned with the sleep/wake cycle. However, shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/ feeding cycles (7,8). Shift workers often experience symptoms akin to jet lag, with gastrointestinal complaints, fatigue, and sleepiness during the scheduled wake periods, and poor sleep during the daytime sleep attempts (9). Moreover, chronic circadian misalignment has been proposed to be the underlying cause for the adverse metabolic and cardiovascular health effects of shift work (10, 11). The SCN regulates circadian rhythms in leptin, plasma glucose, glucose tolerance, corticosteroids, and ...

The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.

We investigate if known extrinsic and intrinsic factors fully account for the complex features observed in recordings of human activity as measured from forearm motion in subjects undergoing their regular daily routine. We demonstrate that the apparently random forearm motion possesses dynamic patterns characterized by robust scale-invariant and nonlinear features. These patterns remain stable from one subject to another and are unaffected by changes in the average activity level that occur within individual subjects throughout the day and on different days of the week, since they persist during daily routine and when the same subjects undergo time-isolation laboratory experiments designed to account for the circadian phase and to control the known extrinsic factors. Further, by modeling the scheduled events imposed throughout the laboratory protocols, we demonstrate that they cannot account for the observed scaling patterns in activity fluctuations. We attribute these patterns to a previously unrecognized intrinsic nonlinear multi-scale control mechanism of human activity that is independent of known extrinsic factors such as random and scheduled events, as well as the known intrinsic factors which possess a single characteristic time scale such as circadian and ultradian rhythms.

Leptin and adiponectin play important physiological roles in regulating appetite, food intake, and energy balance and have pathophysiological roles in obesity and anorexia nervosa. To assess the relative contributions of day/night patterns in behaviors (sleep/wake cycle and food intake) and of the endogenous circadian pacemaker on observed day/night patterns of adipokines, in six healthy subjects we measured circulating leptin, soluble leptin receptor, adiponectin, glucose, and insulin levels throughout a constant routine protocol (38 h of wakefulness with constant posture, temperature, and dim light, as well as identical snacks every 2 h) and throughout sleep and fasting periods before and after the constant routine. There were significant endogenous circadian rhythms in leptin, glucose, and insulin, with peaks around the usual time of awakening. Sleep/fasting resulted in additional systematic decreases in leptin, glucose, and insulin, whereas wakefulness/food intake resulted in a systematic increase in leptin. Thus, the day/night pattern in leptin is likely caused by combined effects from the endogenous circadian pacemaker and day/night patterns in behaviors. Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening, which, by influencing food intake and energy balance, could be implicated in the increased prevalence of obesity in the shift work population.

Rationale Blood pressure (BP) usually decreases during nocturnal sleep and increases during daytime activities. Whether the endogenous circadian control system contributes to this daily BP variation has not been determined under appropriately controlled conditions. Objective To determine if there exists an endogenous circadian rhythm of BP in humans. Methods and Results In 28 normotensive adults (16 men), we assessed BP across three complementary, multi-day, in-laboratory protocols performed in dim light, throughout which behavioral and environmental influences were controlled and/or uniformly distributed across the circadian cycle via: (1) a 38-h ‘constant routine’, including continuous wakefulness; (2) a 196-h ‘forced desynchrony’ with seven recurring 28-h sleep/wake cycles; and (3) a 240-h ‘forced desynchrony’ with twelve recurring 20-h sleep/wake cycles. Circadian phases were derived from core body temperature. Each protocol revealed significant circadian rhythms in systolic and diastolic BP, with almost identical rhythm profiles among protocols. The peak-to-trough amplitudes were 3–6 mmHg for systolic BP and 2–3 mmHg for diastolic BP (always P<0.05). All six peaks (systolic and diastolic BP in three protocols) occurred at a circadian phase corresponding to ~9 PM. Based on substantial phase differences among circadian rhythms of BP and other variables, the rhythm in BP appeared to be unrelated to circadian rhythms in cortisol, catecholamines, cardiac vagal tone, heart rate, or urine flow. Conclusions There exists a robust endogenous circadian rhythm in BP. The highest BP occurred at the circadian time corresponding to ~9 PM, suggesting that the endogenous BP rhythm is unlikely to underlie the well-documented morning peak in adverse cardiovascular events.

High psychological distress is pervasive across all employee subtypes and remains largely untreated. Risk factors identified will guide the targeting of mental health promotion, prevention and screening programs.

Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0°). Data were segregated according to: (1) circadian phase (60° bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300°, ~2300–0300 h in these subjects) than during the biological day (bin 180°, ~1500–1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.

There exists a robust day͞night pattern in the incidence of adverse cardiac events with a peak at Ϸ10 a.m. This peak traditionally has been attributed to day͞night patterns in behaviors affecting cardiac function in vulnerable individuals. However, influences from the endogenous circadian pacemaker independent from behaviors may also affect cardiac control. Heartbeat dynamics under healthy conditions exhibit robust complex fluctuations characterized by self-similar temporal structures, which break down under pathologic conditions. We hypothesize that these dynamical features of the healthy human heartbeat have an endogenous circadian rhythm that brings the features closer to those observed under pathologic conditions at the endogenous circadian phase corresponding to Ϸ10 a.m. We investigate heartbeat dynamics in healthy subjects recorded throughout a 10-day protocol wherein the sleep͞wake and behavior cycles are desynchronized from the endogenous circadian cycle, enabling assessment of circadian factors while controlling for behavior-related factors. We demonstrate that the scaling exponent characterizing temporal correlations in heartbeat dynamics does exhibit a significant circadian rhythm (with a sharp peak at the circadian phase corresponding to Ϸ10 a.m.), which is independent from scheduled behaviors and mean heart rate. Cardiac dynamics under pathologic conditions such as congestive heart failure also are associated with a larger value of the scaling exponent of the interbeat interval. Thus, the sharp peak in the scaling exponent at the circadian phase coinciding with the period of highest cardiac vulnerability observed in epidemiological studies suggests that endogenous circadian-mediated influences on cardiac control may be involved in the day͞night pattern of adverse cardiac events in vulnerable individuals.detrended fluctuation analysis ͉ forced desynchrony protocol ͉ heartbeat dynamics ͉ correlations ͉ scaling A dverse cardiac events are the leading cause of mortality in the United States (1). These events do not occur randomly during the day. Epidemiological studies demonstrate that myocardial infarction (2-6), stroke (7,8), angina (9), ventricular arrhythmias (10), and sudden cardiac death (11, 12) have a 24-h day͞night pattern with a primary occurrence peak around 10 a.m. This 24-h pattern of cardiac risk is widely assumed to be caused by day͞night patterns in behaviors that affect cardiovascular variables such as autonomic balance, blood pressure, and platelet aggregability in vulnerable individuals. The suprachiasmatic nuclei of the anterior hypothalamus contain the principal endogenous circadian pacemaker, which is normally synchronized with the light͞dark cycle and the sleep͞wake cycle but also has independent effects on the sympathovagal balance of the autonomic nervous system (13, 14). These last effects raise the possibility that the circadian pacemaker contributes to the 24-h pattern of adverse cardiac events in vulnerable individuals.Recent studies based on approaches derived from statisti...