Adaptive Medicine 3(2): 85-90, 2011 DOI: 10.4247/AM.2011.

ABB006

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Review

Maladaptation in the Circadian System

Robert Joseph Thomas
Division of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA

Circadian rhythms are pervasive processes through a range of body functions. While the earlier focus was on effect on sleep and performance, significant current interest is turning to the effects of circadian factors in metabolic and cardiovascular regulation. This review will address clinical and experimental data demonstrating metabolic and cardiovascular effects of circadian maladaptation. This maladaptation likely occurs as circadian stressors are extremely new on the evolutionary pressure/time scale environmental light control, shift work and jet-lag effects did not previously exist. Key Words: circadian, maladaptation, metabolic, cardiovascular

evidence supports that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease (25, 63). Shift workers often maintain a state of chronic circadian misalignment. Forced desynchrony studies in normal healthy subjects lead to altered cardiometabolic function (52). Misalignment between the circadian system and behavioral cycles, as occurs in DSPS and other circadian stress conditions such as shift-work and so-called social jet-lag, therefore, could result in increased cardiometabolic risk.

Circadian Misalignment and Metabolic Dysregulation

Perturbations of the internal clock system and sleep constitute risk factors for disorders including obesity, diabetes mellitus, and metabolic syndrome (32). Peripheral clocks including those in the liver contributes to glucose homeostasis (21) and can be entrained by restricted feeding (62). There is crosstalk between circadian and metabolic regulatory pathways (4, 5, 32), utilizing pathways that involve the peroxisome proliferator-activated receptor-gamma coactivator-1 transcriptional coactivators (23) and Rev-erb- (71). In a rat model for shift-work, based on daily 8-h activity schedules during the resting phase, the major abnormalities induced (internal desynchrony, flattened glucose and locomotor rhythms, abdominal obesity) were observed when food intake occurred during the rest phase (51). Alternatively, shifting food intake to the normal activity phase prevented body weight increase and reverted metabolic and rhythmic disturbances of the shift work animals to control values. Several circadian mutants show abnormal metabolic regulation including the metabolic syndrome: the CLOCK mutant (66) and the BMAL1 knockout mouse (49). Clock genes expression in human adipose tissue is associated with metabolic

Introduction
Life forms have developed adaptive responses to a variety of environmental stressors. These include responses to gravity, temperature, hypoxia, hypercarbia, sodium load, and nutrient/caloric restriction. These stressors have been pervasive through evolution. The Earths 24-h light/dark cycle has had a profound effect on innate biological rhythms. However, this cycle has been invariant and thus not provided real challenges to adaptation. Circadian rhythm disorders have been so far characterized primarily as sleep disorders, resulting in sleep loss, circadian mismatch, and clinical symptoms of sleepiness, fatigue, dysphoric mood, and attentional difficulty. Delayed sleep phase syndrome (DSPS) is the most common circadian rhythm disorder in the sleep clinic, and has been associated with depression and attention deficit hyperactivity disorder. It is unknown if this disorder is associated with pathological effects in other systems known to be regulated by circadian mechanisms. The severity of many diseases follows circadian variation. For example, asthma is often worse at night and there is an increased incidence of cardiovascular events in the morning. Epidemiological

Corresponding author: Robert Joseph Thomas, M.D., Assistant Professor of Medicine, Division of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: +1-617-667-5864, Fax: +1-617-667-4849, E-mail: rthomas1@bidmc.harvard.edu Received: May 5, 2011; Accepted: June 21, 2011. 2011 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X. http://www.sast.org.tw

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syndrome parameters: hPer2 expression level in visceral fat is inversely correlated to waist circumference, while BMAL1, Per2 and Cry1 are all negatively correlated with total cholesterol and LDL cholesterol (12). Direct evidence of the effect of circadian misalignment on metabolism is available in humans from experimental, epidemiologic, and genetic studies. In a 10-day laboratory-based protocol in 10 subjects, hourly plasma leptin, insulin, glucose, and cortisol, every 2 h urinary catecholamines, blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, core body temperature, and daily polysomnographic sleep were measured (52). Circadian misalignmentwhen subjects ate and slept approximately 12 h out of phase from their habitual timessystematically decreased leptin (-17%), increased glucose (+6%) despite increased insulin (+22%), completely reversed the daily cortisol rhythm, increased mean arterial pressure (+3%), and reduced sleep efficiency (-20%). Simulated and real shift workers show relatively impaired glucose and lipid tolerance with feeding during the biological night vs. day (2, 13, 34, 46). Many studies demonstrate an increased risk of metabolic syndrome in shiftworkers. In a prospective study of night-shift nurses, initially free from components of metabolic syndrome, followed over four years and compared to a control group of day-shift nurses, the relative risk of developing metabolic syndrome was five times higher in the night workers (44). In a retrospective study of females working rotating shifts, there was an increased risk of progression to metabolic syndrome (24). Shift work is associated with higher body mass index, waist to hip ration, excess weight gain, obesity, and markers of insulin resistance (including hyperglycemia, increased triglycerides, and low HDL cholesterol) (15, 16, 37, 39). Impaired glucose tolerance also occurs in adolescent circadian rhythm disorders (65). A genetic variant of the melatonin receptor is associated with the risk of type 2 diabetes (7, 48). At a population level, individuals with strong morning or evening circadian preferences could be at increased risk for chronic and variable circadian cardiac, vascular and metabolic misalignment. While this may be less extreme than shift-workers with variable work schedules, these individuals also frequently suffer from chronic sleep debt and daytime fatigue. The proposed study will assess effects of circadian misalignment in subjects with delayed circadian phase on sympathetic regulation, glucose and insulin homeostasis, postprandial metabolism, and endothelial function, using this disorder as a potential model of body-wide circadian effects.

Inflammatory mediators are likely under circadian regulation and thus misalignment in the circadian system may result in increased systemic inflammation, a possible contributor to increased cardiometabolic risk. A diurnal rhythm in plasma concentration in many components involved in the systemic inflammatory response (such as cytokines and hormones) has been observed. These rhythms may be entrained by the central clock in the suprachiasmatic nucleus (54). In mice however, spleen, lymph nodes, and peritoneal macrophages are under autonomous regulation of intrinsic circadian clocks that coordinate circadian rhythms in innate immune function (18). Endotoxin stimulation of isolated spleen cells at different circadian times showed a circadian pattern to tumor necrosis factor-alpha (TNF-) and interleukin-6 (IL-6) secretion, controlled by a circadian clock localized to splenic macrophages (18). In humans, increased inflammation has been proposed as a potential mechanism of the increased cardiometabolic risk profiles seen in shift workers. In a large cross sectional European study comparing 877 day workers with 474 rotating shift workers, shift workers not only had higher BMI, waist circumference, diastolic blood pressure and Homeostasis Model Assessment index (HOMA), but were also found to have increased leukocyte counts, independent of age and smoking (58).

Circadian Misalignment and Endothelial Function

The circadian clock also influences vascular cell signaling and function. In a prospective study in humans evaluating a possible circadian pattern to vascular dysfunction, brachial flow mediated dilation was found to be blunted in early as compared to late morning (post-waking) hours and independently predictive of adverse cardiovascular risk in healthy subjects (14). Rodent studies offer further support for specific circadian roles in vascular regulation and dysfunction. Endothelial cells, smooth muscle cells and fibroblasts follow circadian rhythms (50). Mouse Bmal-1 knockout and Clock mutants have abnormal nitric oxide signaling and endothelial function (3) and the Bmal-1 knockout mouse demonstrates evidence of chronic vascular impairment with altered angiogenesis, vascular remodeling, and vascular stiffness (3).

Circadian Misalignment and Cardiovascular Function

There are known circadian patterns to cardiovascular risk. Epidemiological evidence shows the peak incidence of cardiovascular events (angina, myocardial

Circadian Misalignment and Inflammation

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infarction, stroke, and sudden cardiac death) occurs during morning hours (8, 29, 33, 35, 47, 69). The physiologic pattern of blood pressure dipping during sleep is considered cardio-protective, while the absence of blood pressure dipping is an independent cardiovascular risk factor (61). The cardiomyocyte exhibits a robust circadian time-keeping system; 1015% of all myocardial genes oscillate in a time-ofday dependent manner (10). This clock is important for normal myocardial metabolism and contractile function (6, 9, 11, 56). Cardiac gene oscillations take 5-8 days to re-entrain after a 12-h shift of the lightdark cycle (9). Circadian desynchrony leads to impaired cardiac function and phenotypes. Circadian misalignments augment pressure overload induced myocardial dysfunction (31). Under conditions of circadian misalignment, the heterozygous tau mutant hamster develops heart failure (30). In experimental ischemia-reperfusion, clock genes show decreased amplitude of oscillations in the ischemic tissue (20). Mice with genetic ablation of the BMAL1 display premature aging and a prothrombotic phenotype (57). Circulating von Willebrand Factor, fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are significantly elevated in BMAL1 (-/-) mice. CLOCK and Bmal-1 directly regulate the activity of vWF promoter, and the lack of Bmal-1 results in upregulation of vWF both at mRNA and protein level. Evidence suggests that abnormal circadian function contributes to essential hypertension. Patients with hypertension demonstrate decreased daytimenighttime rhythms of sympathovagal balance (38) while those with coronary artery disease show an abnormal pattern of endothelial-dependant vasodilatation with loss of diurnal variation seen in controls (55). A small randomized double-blind placebocontrolled crossover study in 16 males with untreated hypertension (essential) found that daily melatonin over three weeks lowered systolic and diastolic blood pressure during sleep and increased the amplitude of the diurnal blood pressure rhythm (53). Shift-work has been associated with adverse cardiovascular outcomes (1, 45). Mechanisms implicated include stress, sleep deprivation, depression, and circadian misalignment. Derangements in the biological time-keeping mechanisms which are active in the cardiovascular system may contribute to the notable increase in cardiovascular pathology in this population. A simulated shift work forced desynchrony study in healthy humans found a 3% increase in mean arterial blood pressure and complete reversal of the cortisol rhythm during circadian misalignmentwhen subjects ate and slept 12 h out of phase from their habitual times (52).

In addition to cardiovascular and metabolic risks, circadian misalignment has been associated with malignancy, gastrointestinal disorders and early aging effects. Vinogradova et al., using a rat model of various light and dark regimens from age 25 days until natural death, found that the rats exposed to both natural light and constant light routines (as opposed to a standard 12:12 h light dark cycle) developed metabolic syndrome, spontaneous tumors, and a reduced life-span (68).

Sleep Quality, Quantity, and Cardiometabolic Risk

Insufficient sleep quantity and inadequate quality have been linked to cardiometabolic dysfunction. Studies suggest that poor sleep increases cardiovascular risk (26, 27). Two independent studies of 24-h total sleep deprivation in humans demonstrated increased diastolic blood pressure and decreased sympathetic activity (MSNA) (17, 41), suggesting that either a peripheral mechanism contributing to altered vascular tone, or a central component resulting in resetting of the baroreflex, explain the change in diastolic blood pressure. Sleep deprivation studies demonstrate changes in sympathetic activation, cortisol, thyrotropin, inflammatory mediators, leptin levels, and insulin sensitivity in normal, healthy subjects (19, 36, 59, 67). Studies of selective sleep stage suppression and partial sleep restriction also resulted in cardiometabolic effects. Increased diabetes risk and sympathetic activation were demonstrated in a selective sleep stage restriction study. Using the Minimal Model analysis (42) of the frequently sampled IV glucose tolerance test, Tasali et al. demonstrated reduced insulin sensitivity and reduced disposition index (D I ) [the product of insulin sensitivity index (SI) and the acute insulin response to glucose (AIRg)] after 3 nights of selective slow wave sleep (SWS) suppression compared to baseline sleep (7.5 h, 11pm7:30 am) (64). DI is a validated marker of diabetes risk (28, 43, 70). Also seen was an increase in the normalized LF/HF ratio (low frequency to high frequency ratio, a marker of sympathovagal balance) after selective SWS suppression upon assessment of heart rate variability of daytime electrocardiogram recordings (64) suggesting that sympathetic activation is increased after selective SWS suppression. Further, a moderate length study (6 nights) of limited sleep time (4-h/night) followed by recovery sleep showed a statistically significant decrease in oral glucose tolerance in the sleep debt condition compared to post-exposure recovery (59). Epidemiologic studies suggest that insomnia may be a risk factor for diabetes and cardiovascular disease (40, 71) . Normotensive subjects with chronic

Circadian Misalignment and General Health

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primary insomnia were found to have higher nighttime systolic blood pressure and blunted blood pressure dipping response compared to sex and age-matched good sleepers (22). In an effort to adapt to societally driven schedules of work, school and family/social commitments, patients with delayed circadian phase frequently suffer from insomnia and maintain a state of chronic sleep debt, similar to shift workers. Thus, the potential for pathological interactions between sleep duration, quality and timing, to amplify cardiometabolic dysfunction, is evident.

Summary
The circadian system was not ever under evolutionary pressure to adapt to rapid shifts in day/night cues. Thus circadian stress induces maladaptive responses in multiple organ system. The consequences of circadian stress to humans needs better study, as the 24-h society markedly alters light/dark cues in ways that have never occurred in the history of life.

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