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  1. 1. Adaptive Medicine 3(2): 85-90, 2011 85DOI: 10.4247/AM.2011.ABB006ReviewMaladaptation in the Circadian SystemRobert Joseph ThomasDivision of Pulmonary, Critical Care and Sleep, Beth Israel Deaconess Medical Center and Harvard Medical School,330 Brookline Avenue, Boston, MA 02215, USACircadian rhythms are pervasive processes through a evidence supports that shift work is associated withrange of body functions. While the earlier focus was on increased risk for obesity, diabetes, and cardiovasculareffect on sleep and performance, significant current disease (25, 63). Shift workers often maintain a stateinterest is turning to the effects of circadian factors in of chronic circadian misalignment. Forced desyn-metabolic and cardiovascular regulation. This review chrony studies in normal healthy subjects lead towill address clinical and experimental data demonstrat- altered cardiometabolic function (52). Misalignmenting metabolic and cardiovascular effects of circadianmaladaptation. This maladaptation likely occurs as between the circadian system and behavioral cycles,circadian stressors are extremely new on the evolutionary as occurs in DSPS and other circadian stress condi-pressure/time scale – environmental light control, shift tions such as shift-work and so-called social jet-lag,work and jet-lag effects did not previously exist. therefore, could result in increased cardiometabolic risk.Key Words: circadian, maladaptation, metabolic, car- diovascular Circadian Misalignment and Metabolic DysregulationIntroduction Perturbations of the internal clock system and sleepLife forms have developed adaptive responses to constitute risk factors for disorders including obe-a variety of environmental stressors. These include sity, diabetes mellitus, and metabolic syndrome (32).responses to gravity, temperature, hypoxia, hyper- Peripheral clocks including those in the liver con-carbia, sodium load, and nutrient/caloric restriction. tributes to glucose homeostasis (21) and can beThese stressors have been pervasive through evolution. entrained by restricted feeding (62). There is cross-The Earth’s 24-h light/dark cycle has had a profound talk between circadian and metabolic regulatoryeffect on innate biological rhythms. However, this pathways (4, 5, 32), utilizing pathways that involvecycle has been invariant and thus not provided real the peroxisome proliferator-activated receptor-gammachallenges to adaptation. coactivator-1 transcriptional coactivators (23) and Circadian rhythm disorders have been so far Rev-erb-α (71). In a rat model for “shift-work”,characterized primarily as sleep disorders, resulting based on daily 8-h activity schedules during the restingin sleep loss, circadian mismatch, and clinical symp- phase, the major abnormalities induced (internal de-toms of sleepiness, fatigue, dysphoric mood, and at- synchrony, flattened glucose and locomotor rhythms,tentional difficulty. Delayed sleep phase syndrome abdominal obesity) were observed when food intake(DSPS) is the most common circadian rhythm disorder occurred during the rest phase (51). Alternatively,in the sleep clinic, and has been associated with de- shifting food intake to the normal activity phasepression and attention deficit hyperactivity disorder. prevented body weight increase and reverted metabolicIt is unknown if this disorder is associated with and rhythmic disturbances of the shift work animalspathological effects in other systems known to be to control values.regulated by circadian mechanisms. Several circadian mutants show abnormal The severity of many diseases follows circadian metabolic regulation including the metabolicvariation. For example, asthma is often worse at syndrome: the CLOCK mutant (66) and the BMAL1night and there is an increased incidence of car- knockout mouse (49). Clock genes’ expression indiovascular events in the morning. Epidemiological human adipose tissue is associated with metabolicCorresponding author: Robert Joseph Thomas, M.D., Assistant Professor of Medicine, Division of Pulmonary, Critical Care and Sleep, BethIsrael 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.eduReceived: May 5, 2011; Accepted: June 21, 2011.2011 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X.
  2. 2. 86 Thomassyndrome parameters: hPer2 expression level in Inflammatory mediators are likely under circadianvisceral fat is inversely correlated to waist circum- regulation and thus misalignment in the circadianference, while BMAL1, Per2 and Cry1 are all nega- system may result in increased systemic inflammation,tively correlated with total cholesterol and LDL a possible contributor to increased cardiometaboliccholesterol (12). risk. A diurnal rhythm in plasma concentration in Direct evidence of the effect of circadian many components involved in the systemic inflam-misalignment on metabolism is available in humans matory response (such as cytokines and hormones)from experimental, epidemiologic, and genetic studies. has been observed. These rhythms may be entrainedIn a 10-day laboratory-based protocol in 10 subjects, by the central clock in the suprachiasmatic nucleushourly plasma leptin, insulin, glucose, and cortisol, (54). In mice however, spleen, lymph nodes, andevery 2 h urinary catecholamines, blood pressure, peritoneal macrophages are under autonomousheart rate, cardiac vagal modulation, oxygen consump- regulation of intrinsic circadian clocks that coordinatetion, respiratory exchange ratio, core body tempera- circadian rhythms in innate immune function (18).ture, and daily polysomnographic sleep were measured Endotoxin stimulation of isolated spleen cells at(52). Circadian misalignment—when subjects ate different circadian times showed a circadian patternand slept approximately 12 h out of phase from their to tumor necrosis factor-alpha (TNF-α) and inter-habitual times—systematically decreased leptin leukin-6 (IL-6) secretion, controlled by a circadian(-17%), increased glucose (+6%) despite increased clock localized to splenic macrophages (18).insulin (+22%), completely reversed the daily cortisol In humans, increased inflammation has beenrhythm, increased mean arterial pressure (+3%), and proposed as a potential mechanism of the increasedreduced sleep efficiency (-20%). Simulated and real cardiometabolic risk profiles seen in shift workers. Inshift workers show relatively impaired glucose and a large cross sectional European study comparinglipid tolerance with feeding during the biological 877 day workers with 474 rotating shift workers, shiftnight vs. day (2, 13, 34, 46). Many studies demonstrate workers not only had higher BMI, waist circumference,an increased risk of metabolic syndrome in shift- diastolic blood pressure and Homeostasis Modelworkers. In a prospective study of night-shift nurses, Assessment index (HOMA), but were also found toinitially free from components of metabolic syndrome, have increased leukocyte counts, independent of agefollowed over four years and compared to a control and smoking (58).group of day-shift nurses, the relative risk of devel-oping metabolic syndrome was five times higher in Circadian Misalignment andthe night workers (44). In a retrospective study of Endothelial Functionfemales working rotating shifts, there was an increasedrisk of progression to metabolic syndrome (24). Shift The circadian clock also influences vascular cellwork is associated with higher body mass index, signaling and function. In a prospective study inwaist to hip ration, excess weight gain, obesity, and humans evaluating a possible circadian pattern tomarkers of insulin resistance (including hyperglyce- vascular dysfunction, brachial flow mediated dilationmia, increased triglycerides, and low HDL cholesterol) was found to be blunted in early as compared to late(15, 16, 37, 39). Impaired glucose tolerance also morning (post-waking) hours and independentlyoccurs in adolescent circadian rhythm disorders (65). predictive of adverse cardiovascular risk in healthyA genetic variant of the melatonin receptor is as- subjects (14). Rodent studies offer further support forsociated with the risk of type 2 diabetes (7, 48). specific circadian roles in vascular regulation and At a population level, individuals with strong dysfunction. Endothelial cells, smooth muscle cellsmorning or evening circadian preferences could be at and fibroblasts follow circadian rhythms (50). Mouseincreased risk for chronic and variable circadian Bmal-1 knockout and Clock mutants have abnormalcardiac, vascular and metabolic misalignment. While nitric oxide signaling and endothelial function (3)this may be less extreme than shift-workers with and the Bmal-1 knockout mouse demonstratesvariable work schedules, these individuals also evidence of chronic vascular impairment with alteredfrequently suffer from chronic sleep debt and daytime angiogenesis, vascular remodeling, and vascularfatigue. The proposed study will assess effects of stiffness (3).circadian misalignment in subjects with delayedcircadian phase on sympathetic regulation, glucose Circadian Misalignment andand insulin homeostasis, postprandial metabolism, Cardiovascular Functionand endothelial function, using this disorder as apotential model of body-wide circadian effects. There are known circadian patterns to cardiovascular risk. Epidemiological evidence shows the peak in-Circadian Misalignment and Inflammation cidence of cardiovascular events (angina, myocardial
  3. 3. Circadian Maladaptation 87infarction, stroke, and sudden cardiac death) occurs In addition to cardiovascular and metabolic risks,during morning hours (8, 29, 33, 35, 47, 69). The circadian misalignment has been associated withphysiologic pattern of blood pressure dipping during malignancy, gastrointestinal disorders and early agingsleep is considered cardio-protective, while the effects. Vinogradova et al., using a rat model of vari-absence of blood pressure dipping is an independent ous light and dark regimens from age 25 days untilcardiovascular risk factor (61). The cardiomyocyte natural death, found that the rats exposed to bothexhibits a robust circadian time-keeping system; 10- natural light and constant light routines (as opposed15% of all myocardial genes oscillate in a time-of- to a standard 12:12 h light dark cycle) developedday dependent manner (10). This clock is important metabolic syndrome, spontaneous tumors, and afor normal myocardial metabolism and contractile reduced life-span (68).function (6, 9, 11, 56). Cardiac gene oscillations take5-8 days to re-entrain after a 12-h shift of the light- Sleep Quality, Quantity, and Cardiometabolicdark cycle (9). Circadian desynchrony leads to Riskimpaired cardiac function and phenotypes. Circadianmisalignments augment pressure overload induced Insufficient sleep quantity and inadequate qualitymyocardial dysfunction (31). Under conditions of have been linked to cardiometabolic dysfunction.circadian misalignment, the heterozygous tau mutant Studies suggest that poor sleep increases cardiovas-hamster develops heart failure (30). In experimental cular risk (26, 27). Two independent studies of 24-hischemia-reperfusion, clock genes show decreased total sleep deprivation in humans demonstratedamplitude of oscillations in the ischemic tissue (20). increased diastolic blood pressure and decreasedMice with genetic ablation of the BMAL1 display sympathetic activity (MSNA) (17, 41), suggestingpremature aging and a prothrombotic phenotype (57). that either a peripheral mechanism contributing toCirculating von Willebrand Factor, fibrinogen and altered vascular tone, or a central component resultingplasminogen activator inhibitor-1 (PAI-1) are sig- in resetting of the baroreflex, explain the change innificantly elevated in BMAL1 (-/-) mice. CLOCK diastolic blood pressure. Sleep deprivation studiesand Bmal-1 directly regulate the activity of vWF demonstrate changes in sympathetic activation,promoter, and the lack of Bmal-1 results in up- cortisol, thyrotropin, inflammatory mediators, leptinregulation of vWF both at mRNA and protein level. levels, and insulin sensitivity in normal, healthyEvidence suggests that abnormal circadian function subjects (19, 36, 59, 67). Studies of selective sleepcontributes to essential hypertension. Patients with stage suppression and partial sleep restriction alsohypertension demonstrate decreased daytime- resulted in cardiometabolic effects. Increased diabetesnighttime rhythms of sympathovagal balance (38) risk and sympathetic activation were demonstrated inwhile those with coronary artery disease show an a selective sleep stage restriction study. Using theabnormal pattern of endothelial-dependant vasodila- Minimal Model analysis (42) of the frequently sampledtation with loss of diurnal variation seen in controls IV glucose tolerance test, Tasali et al. demonstrated(55). A small randomized double-blind placebo- reduced insulin sensitivity and reduced dispositioncontrolled crossover study in 16 males with untreated index (D I ) [the product of insulin sensitivity indexhypertension (essential) found that daily melatonin (SI) and the acute insulin response to glucose (AIRg)]over three weeks lowered systolic and diastolic blood after 3 nights of selective slow wave sleep (SWS)pressure during sleep and increased the amplitude suppression compared to baseline sleep (7.5 h, 11pm-of the diurnal blood pressure rhythm (53). 7:30 am) (64). DI is a validated marker of diabetes Shift-work has been associated with adverse risk (28, 43, 70). Also seen was an increase in thecardiovascular outcomes (1, 45). Mechanisms im- normalized LF/HF ratio (low frequency to high fre-plicated include stress, sleep deprivation, depression, quency ratio, a marker of sympathovagal balance)and circadian misalignment. Derangements in the after selective SWS suppression upon assessment ofbiological time-keeping mechanisms which are active heart rate variability of daytime electrocardiogramin the cardiovascular system may contribute to the recordings (64) suggesting that sympathetic activationnotable increase in cardiovascular pathology in this is increased after selective SWS suppression. Further,population. A simulated shift work forced desyn- a moderate length study (6 nights) of limited sleepchrony study in healthy humans found a 3% increase time (4-h/night) followed by recovery sleep showedin mean arterial blood pressure and complete reversal a statistically significant decrease in oral glucoseof the cortisol rhythm during circadian misalignment- tolerance in the sleep debt condition compared towhen subjects ate and slept 12 h out of phase from post-exposure recovery (59).their habitual times (52). Epidemiologic studies suggest that insomnia may be a risk factor for diabetes and cardiovascularCircadian Misalignment and General Health disease (40, 71) . Normotensive subjects with chronic
  4. 4. 88 Thomasprimary insomnia were found to have higher nighttime 10. Durgan, D.J. and Young, M.E. The cardiomyocyte circadiansystolic blood pressure and blunted blood pressure clock: emerging roles in health and disease. Circ. Res. 106: 647- 658, 2010.dipping response compared to sex and age-matched 11. Durgan, D.J. and Young, M.E. Linking the cardiomyocyte cir-good sleepers (22). In an effort to adapt to “societally cadian clock to myocardial metabolism. Cardiovasc. Drugs Ther.driven” schedules of work, school and family/social 22: 115-124, 2008.commitments, patients with delayed circadian phase 12. Gomez-Abellan, P., Hernandez-Morante, J.J., Lujan, J.A., Madrid,frequently suffer from insomnia and maintain a state J.A. and Garaulet, M. Clock genes are implicated in the human metabolic syndrome. Int. J. Obes. (Lond) 32: 121-128, 2008.of chronic sleep debt, similar to shift workers. Thus, 13. 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