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The severity of many diseases varies across the day and night. For example, adverse cardiovascular incidents peak in the morning, asthma is often worse at night and temporal lobe epileptic seizures are most prevalent in the afternoon. These patterns may be due to the day/night rhythm in environment and behavior, and/or endogenous circadian rhythms in physiology. Furthermore, chronic misalignment between the endogenous circadian timing system and the behavioral cycles could be a cause of increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the magnitude, relevance and potential biological basis of such daily changes in disease severity and of circadian/behavioral misalignment, and present how these insights may help in the development of appropriate chronotherapy.
The severity of many diseases varies across the 24-hour period. For example, myocardial infarction occurs most frequently in the morning a few hours after waking up, epileptic seizures of the brain's temporal lobe usually occur in the late afternoon or early evening, and asthma is generally worse at night (Figure 1). There are also differences across the 24-hour period in cancer development and on chemotherapeutic effectiveness. In addition, 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, and this misalignment could be a cause of the increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the existence and magnitude of such daily changes in disease severity. We also describe what is known regarding the mechanisms underlying these time-variant changes in disease severity, in particular in terms of whether or not these changes are caused by the circadian pacemaker or due to behaviors that occur on a regular daily basis, including the sleep/wake cycle. Understanding the biological basis of these changes across the day and night can lead to better therapy e.g. appropriately timed medication to target specific phases of the body clock or to coincide with specific behaviors that cause vulnerability, while avoiding higher doses at other times when deleterious side effects could outweigh the benefits. Thus, current and future chronotherapeutic practices and targets are presented where appropriate.
Cardiovascular disease is the leading cause of death in the US. Myocardial ischemia (insufficient supply of oxygenated blood relative to the demand of the cardiac muscle) can be caused by rupture of an atherosclerotic plaque and subsequent thrombosis affecting the coronary circulation, by hypoxia, or by coronary vasospasm. In extreme cases `sudden cardiac death' can result from an ischemic event in association with severe myocardial infarction and/or ventricular tachycardia/fibrillation. There exists robust epidemiological evidence that the peak incidence of cardiac ischemic events, including angina, acute myocardial infarction and sudden cardiac death occurs around 9-11 AM1-6, The reasons for this day/night pattern are not yet known, although triggering behaviors occurring at specific times of day have been suggested as a cause. It is equally possible that endogenous circadian rhythms in an array of hemodynamic, hemostatic, endothelial and autonomic variables could cause a day/night pattern in adverse events6.
Ventricular tachyarrhythmias are the most common cause of sudden cardiac death. Studies of patients undergoing 24-h electrocardiographic monitoring have revealed a robust and prominent peak in ventricular tachyarrhythmias during the morning and a trough at night7-16. For example, Mallavarapu et al.13 analyzed the electrocardiograms from 390 implantable cardioverter-defibrillator recipients who sustained a total of 2692 episodes of ventricular tachycardia or ventricular fibrillation. The peak incidence of the arrhythmias occurred between 10 and 11 AM, with a nadir between 2 and 3 AM. This day/night pattern persisted regardless of age, gender, ejection fraction, or ventricular tachycardia cycle length. Further evidence of the morning increase in susceptibility to serious arrhythmias comes from defibrillation thresholds in patients with implantable cardioverter-defibrillators: Venditti et al.17 found that the defibrillation threshold was higher when implantation occurred in the morning than when implanted at other times of day (thus greater energy is required for termination of morning tachyarrhythmias), and in ambulant patients they found a significant peak in failed first shocks in the morning compared with other times.
Arterial blood pressure (BP) generally falls during sleep and rises during activity, contributing to a day/night pattern in BP in most normotensive people as well as those with uncomplicated essential hypertension. However, a `non-dipping' hypertensive phenotype exists without much of a decline during sleep, and this presents an independent predictor of cardiovascular morbidity and mortality18. Mechanisms for this phenotype could include enhanced sodium sensitivity19-22, underlying circadian rhythmicity, and theoretically the presence of sleep disorders, such as insomnia and obstructive sleep apnea, and more sleep during the daytime which would blunt the day/night pattern.
Sympathetic nervous activity is modulated in most circumstances as a protective homeostatic response. However, in some individuals with underlying pathophysiology or susceptibility, sympathetic activation can provoke adverse cardiovascular events, for instance by increasing blood pressure and arterial wall sheer forces that could potentially rupture vulnerable atherosclerotic plaques in coronary arteries. Thus, a day/night pattern in the activity of the sympathetic nervous system might underlie the day/night pattern of adverse events in vulnerable individuals. The day/night pattern could occur simply from a day/night pattern of behaviors, such as a surge of sympathetic activity upon standing up and becoming active in the morning or during REM sleep23-25,26, 27,28. Indeed, Deedwania et al. found that the morning increase in heart rate (HR) and blood pressure (BP) may cause a 40% increase in cardiac oxygen demand29. Andrews et al. found that about 80% of ambulatory ischemic events are accompanied by tachycardia30. Tachycardia, while normally promoting blood supply to peripheral tissues, actually decreases blood supply to the myocardium due to a relative reduction in diastole (when coronary arterioles receive most flow) vs. systole. In addition, platelets are a cornerstone of the hemostatic system and facilitate thrombus formation, which could impede coronary blood flow. Several in vivo and in vitro studies have found day/night variation in a number of functional platelet factors, with peaks in both activation and adhesiveness between 6 and 9 AM31-35. The increased morning platelet activation possibly could be caused by increased circulating catecholamines36, 37 or decreasing plasma melatonin38.
Most of the evidence demonstrating the existence of a 24-hour pattern in adverse cardiovascular events is epidemiological, which cannot attribute the underlying behavioral or circadian causes. Laboratory studies clearly show marked systematic changes in most hemodynamic and hemostatic variables with changes in behavior, such as exercise. Usually people sleep at the same phase of the circadian cycle so the relative contribution of behavioral and circadian influences on cardiovascular vulnerability cannot be determined. Such separation can be examined when keeping people awake and in the same conditions across at least 24 h or by shifting the time-relationship between the endogenous circadian clock and the behaviors (as occurs with shift work and during jet lag, which can be simulated in the laboratory) and examining the changes in relevant variables. A few laboratory studies have examined the existence of endogenous circadian influences on cardiovascular variables, principally be employing a `constant routine' protocol in which subjects remain in the same posture and awake for over 24 hours in dim light and with regular small snacks rather than larger irregular meals39-41. For example, Burgess et al.40 studied 16 subjects during a 26-hour constant routine protocol (to reveal underlying circadian rhythmicity) and a similar study in which sleep was permitted (to assess the additional effect of sleep beyond underlying circadian rhythmicity). They found that sympathetic activity was reduced during sleep (estimated from cardiac isvolumetric contraction time), whereas parasympathetic nervous system activity (estimated from heart rate variability) increased during the circadian `night' with little additional effect of sleep itself. Kerkhof et al.41, were unable to find a circadian fluctuation in BP in 12 healthy normotensive adults, but found significant circadian variation in HR (7 beats/min range, peak around 11 AM). Hu et al.42 found in healthy humans, the scale invariance of HR fluctuations changes toward an `unhealthy' state at a circadian phase corresponding to the peak in adverse events in other studies and populations. Experiments on rats discovered that circadian fluctuations in HR as well as the scale invariance of HR fluctuations were abolished upon lesioning of suprachiasmatic nucleus (SCN)43, 44. To quantify both circadian and behavioral effects as well as any interactions, Scheer et al. performed a forced desynchrony protocol that scheduled all behaviors evenly across all phases of the circadian cycle. They found robust circadian-related increases in HR and plasma epinephrine throughout the circadian `morning', with maxima occurring later than the time when cardiovascular risk is highest (~9 AM), raising the untested hypothesis that the rate of change of some sympathetic markers may be more relevant than the absolute level for the timing of adverse cardiovascular events45. These same authors found that certain behavioral stressors (mental stress, postural tilt or exercise) resulted in similar autonomic, hemostatic or hemodynamic effects when these stressors were presented at different phases of the circadian cycle. This result suggests that there is little functional interaction between the behavioral stressors and the circadian system, suggesting that these factors are additive in terms of affecting vulnerability to an adverse cardiovascular event46.
Although pharmacology for cardiovascular disease is a rapidly moving field, the current standard of care often includes utilization of a number of medications depending on each individual's disease[s] (e.g., coronary artery disease, congestive heart failure, arrhythmias, and/or hypertension), disease severity, and presence of co-morbidities (e.g., diabetes mellitus, renal insufficiency). The main classes of medications include: (a) Beta-adrenoreceptor antagonists (beta-blockers), which block the effects of endogenous catecholamines to decrease cardiac output and heart rate, and prolong diastole leading to improved myocardial blood supply; (b) Nitrates, which increase coronary artery diameter and blood flow to alleviate angina; (c) Calcium channel blockers (CCB), which are strong arterial vasodilators, and/or may have negative inotropic effects (decreasing the force of myocardial contractions) and negative chronotropic effects (decreasing heart rate); (d) Anti-hemostatic drugs that reduce platelet aggregation and thrombus formation, such as aspirin; (e) Angiotensin converting enzyme inhibitors and angiotensin receptor blockers, used primarily for reducing blood pressure; (f) Cholesterol lowering medications (e.g. statins) to reduce circulating low density lipoprotein, and thereby reduce the risk of atheroma formation on arterial walls; and (g) Experimental drugs, such as use of melatonin in hypertension.
Chronotherapy refers to the appropriately timed medication to achieve the most efficacious therapeutic levels in the body at the most needed times, while avoiding higher doses at other times when side effects could outweigh the benefits. For instance, rather than perpetually giving patients the maximum tolerated dose of beta-blocker, it may be better to time the beta blockade to coincide with the periods of greatest sympatho-excitation. This strategy may improve exercise tolerance in those with chronotropic incompetence (inadequate heart rate response) by allowing periods of reduced beta blockade during lower risk periods. Similarly, anti-platelet agents in cardiovascular disease could specifically target the periods of greatest platelet aggregability to reduce thrombotic complications, while minimizing hemorrhagic complications during periods of reduced platelet aggregation. Furthermore, by determining if certain behaviors alter disease severity (e.g., exercise-induced angina), timed medication can be planned to coincide with those behaviors, or such triggering behaviors could be scheduled outside periods of greater vulnerability.
CCBs are commonly used in hypertension, Prinz-Metal angina, supraventricular tachyarrhythmias (e.g. atrial fibrillation) and `non-Q wave' myocardial infarction. For example, Verapamil has potent negative inotropic and negative chronotropic effects and has a relatively weak arterial vasodilatory effect compared to Nifedipine. Chronotherapy with CCBs has been designed to achieve the highest plasma concentration during the most vulnerable time period while maintaining an adequate therapeutic dose throughout the remainder of the 24 hour period and has been marketed in the US since 1996. A variety of CCB delivery formulations (e.g., with controlled-onset and/or extended release) have been approved by the FDA47, 48, 49, and may be beneficially prescribed to lower BP, HR and rate-pressure product between 6:00 AM and noon depending on the time of administartion50, 51, 52. Another study demonstrated an improvement in the duration of exercise with evening doses of this Diltiazem preparation vs. morning dosing53.
Beta-adrenoreceptor blockers are associated with an overall decrease in adverse cardiovascular events as well as the abolition of the day/night pattern of adverse coronary events54-56. Andrews et al. also found that beta-blockers decrease the incidence of coronary events associated with tachycardia, but not with a normal heart rate, suggesting that this effect of beta blockers is mediated via decreased myocardial demand (reduced tachycardia) and/or improved myocardial blood supply (prolonged diastole).30 An evening dose of propranolol extended release results in peak levels that are sustained throughout the most vulnerable time for ischemic events. Such propranolol chronotherapy was approved by the FDA in 2003 for treating systemic hypertension, although this also seems to possess optimal pharmacokinetics properties for treating ischemic heart disease57. A potential setback for beta-blocker chronotherapy is that it can suppress nighttime melatonin production and could disrupt normal circadian rhythms58
Short acting nitrates control angina most effectively when administered in the morning59. In contrast, long acting nitrates are designed for once per day dosing and should normally be administered at bedtime to maintain a therapeutic concentration in the plasma throughout the night and the subsequent vulnerable morning hours60.
Aspirin inhibits cyclooxygenase in platelets, which normally induces thromboxane B to promote platelet aggregation and thrombus formation. Aspirin has reduced the incidence of myocardial infarction in males by 59% during morning hours and only 34% during the rest of the 24 hour cycle61. However, low dose aspirin in females decreased risk for ischemic stroke but not myocardial infarction62, and the mechanisms for this gender difference are currently unknown. Although the effect of aspirin on platelets is irreversible (lasting throughout the thrombocyte's lifespan, ~12 days), some data shows that the effect of aspirin has marked diurnal variation with a peak during morning63, possibly due to day/night variation in pharmacodynamics, bioavailability and rate of elimination63-65.
So far there is no solid evidence for the benefit of chronotherapy with ACE inhibitors in patients with hypertension or coronary artery disease was found66-68. For example, Kohno et al67 found no significant difference in BP decrease between morning and evening doses of imidaprol in either “dipping” and “non-dipping” hypertensive patients. Similarly, to the best of our knowledge there is no evidence for the benefit of chronotherapy with cholesterol lowering medication.
Generally used therapeutic strategies for sub-optimally controlled arterial hypertension include increasing the dose of current medications, or switching to or adding another medication with a different mechanism of action. A recent review69 indicates that most hypertensive patients take their medications once a day in the morning, which would likely prove sufficient for patients with a normal nighttime fall in BP. However, this strategy may be inadequate for the `non-dipper' phenotype as effective medication levels are still needed across the night. Thus, sustained release preparations, or twice a day dosing may be better suited for `non-dipping' hypertensive patients who are at higher risk for cardiovascular complications70. One paper found that `non-dippers' have impaired nocturnal melatonin secretion71. Moreover, a randomized placebo controlled crossover trial in men with uncontrolled essential hypertension found that melatonin administration for 3 weeks (2.5 mg orally 1 hour before sleep) decreased nighttime systolic and diastolic blood pressure by 6 and 4 mmHg, respectively72. These results have recently been extended to females, in whom 3 weeks of melatonin significantly decreased nocturnal systolic and diastolic blood pressure73. Thus, the approach of supplementing the traditional management of hypertension with melatonin therapy appears promising, but requires more investigation into both the mechanism and the clinical use.
A hallmark of bronchial asthma's natural course is that it is rarely stable. The highest frequency of asthmatic events occurs during the night74. More severe asthma is associated with more nocturnal symptoms75. Patients with nocturnal asthma demonstrate increased morbidity and mortality relative to patients without noticeable worsening of asthma at night76. There are three defining components of asthma; chronic inflammation, airway hyper-responsiveness and reversible airway obstruction77. Each of these parameters exhibit 24-hour fluctuations with worsening around 4 AM compared to 4 PM78, 79,80, 81,82-84. Such changes could be caused by the physiological consequences of sleep (e.g., increased vagal tone, decreased sympathetic activity, decreased temperature), the supine posture (e.g., causing reduced functional residual capacity of the lungs affecting the lower airway caliber), the environment (e.g., allergies to dust mites in the bedding) or factors related to the endogenous circadian system (e.g., increased pulmonary vagal bronchoconstrictive tone during the biological night). The relative contributions of these varied factors is not firmly established and these potentially change from patient-to patient and even within a patient from one day to the next, although some general findings may be applicable. For example, Hetzel et al. studied airway obstruction as indicated by peak expiratory flow (PEF) in 221 healthy and asthmatic subjects and found that even though the timing of the 24 hour rhythm in PEF was similar between these two groups, with more obstruction during the night, the amplitude of the fluctuation was 51% larger in asthma patients81. In patients with nocturnal worsening of asthma, airway-provoking agents (e.g., histamine, methacholine, house dust) had a greater effect on indices of airway obstruction during the night than during the day. For instance, Bonnet et al. found 24 hour oscillations in the pulmonary sensitivity to histamine and methacholine, with at least doubling concentrations required for the same effect at certain times of day82. There is day/night variability in sympathetic activity, related to sleep and/or circadian rhythms85-89. The lowest plasma epinephrine concentration generally occurs at ~4 AM corresponding to the nadir of PEF, suggesting that these may be linked86, 90. Patients with symptoms and signs of `nocturnal asthma' (i.e., disturbed sleep, nocturnal wheeze, overnight decreases in pulmonary function), exhibit significantly higher concentrations of inflammatory markers in the distal airways (e.g., leukocyte, neutrophil and eosinophil counts) at 4 AM compared to 4 PM79. The increase in neutrophils and eosinophils correlates with the overnight change in PEF79, 91. There is some evidence suggesting that patients with nocturnal asthma have abnormal functioning of hypothalamo-pituitary adrenal axis (HPA) and/or impaired cortisol binding and steroid responsiveness92, 93.
Many studies of nocturnal asthma have relied on making assessments when awake at 4 PM and comparing these measurements when subjects are awoken to make assessments at 4 AM. There are obvious limitations with such approaches - such as measurements at two time points likely underestimates the underlying peaks and troughs in a rhythmic signal, and the fact that the arousal provoked by waking someone to make measurements can presumably affect pulmonary function. Furthermore, there may be a carry-over effect from the differences in posture, state and environmental conditions preceding the measurements at 4 AM versus 4 PM on the subsequent assessments of pulmonary function. The separate contributions of behavioral and circadian influences on asthma severity can be examined by keeping people awake and in the same conditions for at least 24 hours or by shifting the time-relationship between the endogenous circadian clock and the behaviors, as occurs relatively uncontrolled with shift work. While such designs are well-suited to assess the separate circadian influence on pulmonary function and asthma severity assessed during wakefulness, assessments of asthma during sleep within these protocols is difficult because most indices of asthma severity (e.g., from forced spirometry or bronchoalveolar lavage) can only be performed when awake. To specifically assess the contribution of the endogenous circadian system to the day/night pattern of pulmonary function, Spengler et al. studied 10 healthy subjects during continuous wakefulness throughout a `constant routine' protocol performed in the same posture for 40 hours in dim light, with small evenly distributed meals, and with pulmonary function measured every two hours. There was a significant circadian variation in forced expired volume in 1 second (FEV1), with a trough during the biological night at the time when sleep would normally occur94. To further explore this in patients with asthma, Shea et al. examined endogenous circadian variations in pulmonary function throughout a `forced desynchrony' protocol conducted over 10 days in the laboratory, during which the behavioral sleep/wake cycles were adjusted systematically to occur across all phases of the endogenous circadian cycle, enabling analytical separation of the circadian and behavioral cycle effects on pulmonary function. PEF and airway resistance exhibited circadian rhythms, with worsening asthma during the biologic night, and an additional worsening caused by sleep itself (independent of the phase of the circadian cycle)95. The same authors found an endogenous circadian rhythm in rescue inhaler use in asthma, peaking during the biological night96. Although most people usually sleep at night, many people occasionally or even systematically stay awake throughout the biological night due to the high prevalence of jet lag, sleep disorders and shift work in today's society. So it is important to determine the extent to which the severity of asthma is affected by being awake and active across the night (as well as the effect on asthma of sleep during the day). Assuming that the behavioral and circadian cycle effects summate, these data suggest that when sleep occurs at night, asthma severity will be highest in some individuals due to a combined effect of sleep and the circadian system. Moreover, the severity of bronchoconstriction across the night can be masked by sleep due to lack or awakenings, reduced sensations upon awakening (e.g., due to `sleep inertia' upon awakening), and/or reduced ventilatory demands at night.
Despite substantial advances in our knowledge of the pathogenesis of bronchial asthma, as well as in the development of therapeutic measures, morbidity and mortality related to asthma remains high97. Asthma is usually classified based on severity of symptoms and pulmonary function97. Thus, mild intermittent asthma (daytime symptoms less than once a week and nocturnal less than twice a month) does not require daily medication, while short acting beta-2 agonist inhalers are used as sporadic `rescue' medication. Mild persistent asthma (daytime symptoms on 1-6 days/week, with nocturnal symptoms >twice/month) is commonly treated with low dose inhaled corticosteroids. Prior to the wide availability of inhaled corticosteroids, oral Theophylline was a mainstream therapy for moderate asthma. Nowadays, moderate persistent asthma requires higher doses of inhaled corticosteroids with or without sporadic `rescue' use inhaled beta2 adrenoreceptor agonists. In severe asthma (daily and frequent nocturnal symptoms) and for asthma exacerbations, systemic corticosteroids might be indicated. To counter the daily variation in asthma severity, chronotherapy has been attempted. Theophylline was prescribed as a chronotherapy for asthma as early as 198098. The recommended daily pattern of dosing is either a single evening dose, or one-third of the daily dose in the morning and two-thirds in the evening. Several studies have shown that the bioavailability of Theophylline is greater if administered in the evening than in the morning, and that such chronotherapy is more effective in preventing the nighttime dip in FEV1 than the conventional Theophylline administration (equally divided daily dose between morning and evening administration)99-101, although this effect may be concentration dependent102. Kraft et al. have also shown that administration of Theophylline to subjects with asthma in the evening improved the inflammatory profile of the distal airways, and this was correlated with improved nocturnal FEV1103.
A series of investigations has revealed that: (1) administration of corticosteroids in the mid afternoon (3 PM) is the most effective in preventing a nocturnal drop of FEV1 and improving the respiratory inflammatory profile in patients with nocturnal asthma104, 105; (2) glucocorticoids given in the morning or late at night did not prevent the drop of FEV1 during the nighttime105, 106; and (3) systemic glucocorticoids in healthy subjects during the daytime (8 AM - 3 PM) minimized suppression of the hypothalamo-pituitary-adrenal axis (HPA) activity104, 107. Thus, by administering systemic corticosteroids around 3 PM one might achieve the best therapeutic effect across the night while avoiding HPA suppression. Similar results were obtained for inhaled corticosteroids108-110. For example, Pincus et al.109 studied the effects in asthma of inhaled Triamcinolone given four times per 24-hour (QID), once at 8 AM, or once at 5 PM. There were clear improvements in FEV1, PEF, use of beta2-agonists rescue medication, nocturnal awakenings, and quality of life score in the QID group and the 5 PM group, but not in the 8 AM group.
Several studies have investigated the benefits of chronotherapy of beta2-agonist medication in the management of nocturnal asthma. Gaultier et al. measured total lung resistance in 6 children with asthma at 7:30 AM, 11:30 AM, 4:30 PM and 10:30 PM, each before and 10 min after 2 mg Orciprenaline (beta-adrenoreceptor agonist) aerosol. Inhaled Orciprenaline was mainly effective around 7:30 AM and to a lesser extent around 10:30 AM, whereas there was no detectable effect at the other times111. The effect of time of 20 mg oral Bambuterol (a long acting beta adrenoreceptor agonist) was assessed in a double blind cross-over design study in 30 adult patients with asthma, and a trend toward higher FEV1 throughout 24 hr period was found when Bambuterol was administered in the evening compared with the morning112. In a double blind randomized cross-over designed study, Salmeterol aerosol 100 mg inhaled at night is as effective as 50 mg inhaled twice a day in improving PEF and FEV1113. Montelukast-leukotriene inhibitors, which are widely used as add-on therapy for treating asthma particularly in patients with a prominent allergic component to asthma and co-morbid allergic rhinitis, improve FEV1 more effectively when dosed in the evening compared with the morning114, 115. These studies demonstrate that varied modes of chronotherapy remain potentially useful in some patients with nocturnal worsening of asthma. While the role of Theophylline has decreased over the last few decades, it still is an add-on therapy or used for patients who are unable to tolerate inhaled corticosteroids. Some data suggest positive effects of Theophylline on diaphragmatic function as well as mucociliary clearance116, 117, which may be of particular importance in asthma patients suffering from respiratory muscle fatigue and excessive mucus. The emergence of a new generation of inhaled corticosteroids was recently heralded by the appearance of Ciclesonide (approved by the FDA in 2008 for maintenance treatment and prophylactic therapy of bronchial asthma in adults). The most remarkable feature of Ciclesonide is that it becomes activated by intracellular esterases located in the lower airways, therefore the side effects in the upper airways (such as oropharyngeal candidiasis and hoarseness) may potentially be less prominent compared with other inhaled corticosteroids. Anticholinergic agents represent another class of agents that theoretically may be useful in the management of nocturnal asthma, as these cause bronchodilation by opposing the effects of the parasympathetic nervous system, and such vagal effects are greatest at night (including during sleep).
Existing epidemiological data indicate a link between various physiologic parameters having well-established day/night rhythms and carcinogenesis. For example, Rafnsson et al. found a higher rate of breast cancer in shift working and flight attendant females118. Severely disrupted rest/activity cycles in patients with metastatic colorectal cancer is accompanied by decreased survival compared with patients with a well-preserved rest/activity pattern119. There are a number of biomolecular and genetic factors that might be responsible for the relationship between the circadian system and carcinogenesis. First, circadian clock proteins play an important role in regulating cell apoptosis, proliferation and differentiation, DNA repair and the cell cycle, by influencing the expression of numerous genes. For example, c-Myc is a proto-oncogen that regulates cell differentiation and proliferation, has a day/night rhythm120, and is over-expressed in cells of many human cancers. mPER2 and CLOCK knock-out mice have over-expressed c-Myc, are cancer prone and more susceptible to gamma radiation with reduced survival when compared to their wild-type counterparts121, 122. PER2 has a tumor suppressor effect, depletion of PER2 protein was observed in varied types of cancer cells in humans123, 124, and induction of PER2 expression in cancer cells inhibits growth, arrests the cell cycle and reduces apoptosis (at least partially through inhibiting c-Myc gene transcription). Such effects of PER2 induction do not occur in normal human cell lines125. Some data suggests that CCAAT/enhancer binding protein (C/EBP) alfa, a transcription factor that is ubiquitous in human tissues and plays a role in regulation of cell growth and differentiation, mediates part of its influence through up-regulation of PER2 protein expression123. Gery et al., induced expression of C/EBP alfa genes in chronic myeloid leukemia, Burkitt's lymphoma and murine fibroblast cell lines. Using microarray analysis these authors showed that induction of the C/EBP alfa gene increased expression of the PER2 gene, which may explain C/EBP's inhibitory effect on c-Myc expression in cancer cells126. Circadian clock proteins, such as PER1, also participate in cell apoptosis via modulation of the `checkpoint' proteins: ataxia telangiectasia mutated (ATM), kinase-1 and kinase-2124. Clock proteins modulate the cell cycle by affecting the expression of cell-cycle related genes cyclin B1, cyclin D1 and WEE1 transcription127. The c-Myc oncogene participates in G0/G1 cell phase transition in normal and tumor cells128, 129, such that circadian clock proteins may influence the cell cycle through expression of the c-Myc gene as well. Thus, each aspect of a cell's life cycle, including proliferation, differentiation, cell cycle phase shifting and apoptosis, is affected by circadian clock genes, providing the theoretical basis for cancer chronotherapy. It is becoming more recognized that chemotherapy for different types of malignancy at specific points of the molecular clock cycle and cell cycle can minimize adverse effects, increase tolerable doses, and help achieve better therapeutic responses and survival130. In addition, gene therapy is now being used in some field, including oncology131. Thus, in the future, modulating the expression of certain clock genes could be a therapeutic target in treating and/or preventing certain types of cancer132, 133 both in the general population as well as populations at risk, such as night shift workers. Finally, there is need for future studies on the potential therapeutic value of melatonin as anti-oncogenic therapy134
Epilepsy is another disorder that often exhibits a day/night variation in clinical presentation. Pavlova et al.135, found that temporal lobe epileptic seizures occur more frequently between 3 PM and 7 PM, whereas the peak incidence for extra temporal lobe epileptic seizures occurs between 7 PM and 11 PM. Among those seizures that occurred during sleep, the majority originated in the temporal lobe135. Similarly, analysis of 131 adults with localized epilepsy revealed that the day/night distribution of epileptiform activity depended on brain area involved: most frontal and parietal seizures occurred between 4-7 AM whereas temporal lobe seizures had two peaks (4-7 PM and 7-10 AM). Seizures of occipital origin occurred mostly between 4-7 PM.136 Whether these patterns are caused by the behavioral sleep/wake cycle and/or by a circadian rhythm in vulnerability is unknown. Some preliminary data indicate an endogenous circadian rhythm in epileptiform inter-ictal discharges while awake in some subjects with generalized epilepsy, with a peak in the beginning of habitual sleep period (11 PM - 3 AM)137. However considering all inter-ictal discharges - regardless of sleep/wake state - the distribution appeared random137. Sleep is well known to activate some seizures, including benign Rolandic epilepsy of childhood and autosomal dominant nocturnal frontal lobe epilepsy, but the mechanism of interaction between sleep physiology and cryptogenic and localization-related epilepsy is yet to be clarified138.
Yegnaranayan et al. randomized 103 epileptic subjects who were receiving subtherapeutic plasma levels of anti-epileptic medications (Phenytoin/Carbamazepin) to two treatment groups: one was allowed to increase the dose but not the timing of medication, the second group maintained the same dose but potentially altered the time of administration to 8 PM (regardless of when it was previously scheduled). This latter `chronotherapy' was better as it achieved more therapeutic levels of plasma medication and improved clinical outcomes (no seizures within 1 year), whereas symptoms of toxicity were more often observed in the conventional dose scheduling group (p<0.05)139. Thus, while data on chronotherapy for epilepsy is quite limited, there may be clinical utility in investigating this more.
Gastroesophageal reflux disease that occurs during wakefulness is usually postprandial and rapidly cleared. Nocturnal gastroesophageal reflux events occur less frequently than during the daytime but are associated with longer acid clearance time140 due to sleep and/or circadian-related decreases in swallowing141, saliva production (saliva contains mucous and bicarbonates that neutralize any acid from the stomach)142, peristalis143 and reduced symptoms of heartburn such that protective mechanisms are not as quickly initiated144. These all may potentially be paired with decreased gastric emptying during NREM sleep. While sleep and the supine posture can promote some of these deleterious effects, currently there are no studies that have determined whether the endogenous circadian system also contributes to any of these effects, and no consistent data on chronotherapy for gastroesophageal reflux disease.
Alzheimer disease (AD) affects about 15 million people worldwide, and is most commonly seen after age of 50, with progressive cognitive decline, circadian rhythm disturbances and sleep disturbances, including insomnia. It is tragic for the patient, causes major physical and emotional burden for primary caregivers, and represents a large economic burden for society. Altered sleep/wake regulation is the most common reason for institutionalizing patients with AD due to increased locomotor activity and need for care during the night145. “Sundowning” is a feature of AD, characterized by a late afternoon/evening predominance of activity146, which some authors attribute to insufficient melatonin production147. A pathoanathomical sign of AD is the deposition of beta-amyloid in certain areas of the brain, including the SCN148. Beta-amyloid is a potent generator of free radicals, which may cause neuronal damage and cell loss in the SCN and other brain structures, mediating circadian rhythm disruption149 and cognitive deficits in AD150. There is a significant decrease in vasoactive intestinal peptide (VIP) expressing neurons within the SCN of patients with AD151, 152. VIP plays an important role in the synchronization of clock gene expression across the SCN153. Lack of VIP or its receptors eliminates diurnal fluctuations of corticosteroids secretion in rats154. Disruption of the SCN neuronal output and/or the lack of a 24-hour fluctuation in beta1 adrenoreceptor expression in the pineal gland155, 156 are thought underlie the observed decrease in melatonin secretion in AD. Moreover, melatonin deficiency might also be implicated in the pathogenesis of AD as melatonin is a potent anti-oxidant that may protect neural tissue from the effects of reactive oxygen species157. A series of studies also support the notion that melatonin may decrease beta-amyloid related neurotoxicity158-160. The peak of melatonin serum concentration at night is decreased with age.161 Some data suggest that exogenous melatonin administration may improve sleep, decrease sundowning and slow the progression of cognitive deficit in AD patients162, 163. The anti-inflammatory effect of melatonin164, 165 as well as its protective effect on the cholinergic system demonstrated in rats166, 167 may have a therapeutic effect on some aspects of AD pathogenesis in humans. In a recent, double-blind, placebo-controlled trial on the effects of light and melatonin (Latin square) in 189 elderly subjects, it was shown that increased daytime environmental light exposure resulted in decreased cognitive deterioration, improved depressive symptoms, and attenuated the increase in functional limitations168. In this same study, melatonin supplementation shortened sleep onset latency and increased total sleep time. However, melatonin also decreased affect ratings and increased withdrawn behavior which was counteracted by light. Combined treatment reduced aggressive behavior, increased sleep efficiency and improved nocturnal restlessness.
About 10 percent of the US labor force works rotating, irregular or permanent night shifts. 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. Thus, such people may be attempting to sleep during the daytime at a circadian phase better `designed' for optimal activity, and conversely, attempting to remain awake during the night at a circadian phase better designed for sleep and fasting. The effect of Jet lag is similar but results from rapid travel across a number of time zones, and is characterized by insomnia or hypersomnolence, fatigue, behavioral symptoms, headaches, and gastrointestinal disturbances. Symptoms of jet lag syndrome usually last not more than a week, but with shift work there can be chronic circadian misalignment together with increased risk of diabetes, obesity, cardiovascular disease, gastrointestinal disorders and certain cancers. These adverse consequences of working night shifts could be mediated by direct effects of the misalignment between the endogenous circadian cycle and behavioral cycles (i.e., sleep/wake, feed/fast and rest/activity schedule), or secondary effects of such misalignment including altered family and society schedules, leading to generalized stress and the potential development of mood disorders, such as depression and anxiety, as well as chronic partial sleep deprivation, which can cause a number of adverse cardiovascular, endocrine and neurocognitive outcomes169-171. For instance, some surveys suggest that night shift workers sleep 10 fewer hours per week than those who work day shifts172. Gander et al. found that during long haul flights crew operators were sleep deprived with only 6.5 hours sleep over a 24 hour period173. Mittler et al. found that truck drivers had on average 3.8 hours sleep over a 24 hour period174. Similar data have emerged for other professions that require night shifts, including police officers and medical residents. The direct effects of misalignment are presented below.
From a study of 79,109 female nurses, the relative risk (RR) for development of coronary heart disease in women working night shifts >6 years was 1.51 (95% Confidence Interval: 1.12-2.03) compared with those who had never worked night shifts.175 The risk persisted after adjustment for smoking, alcohol intake, history of hypertension, diabetes mellitus, hypercholesterolemia, postmenopausal status, hormone replacement therapy, aspirin use and family history of myocardial infarction. From a study of 2,354 shift workers and 3,088 day workers, shift workers demonstrated increased mortality from coronary heart disease after adjusting for age, lifestyle, blood pressure and lipid profile (Odds ratio 1.83; 1.01-3.32)176. However, Boggild et al. found no increased risk for ischemic heart disease with night shifts in a prospective study with a 22-year follow-up period (RR=1.0; CI 95%=0.9-1.2; n=5,249 Danish males), whether or not adjusting for age and social class177. The authors discuss the potential of “healthy worker effect” and “survival bias” leading to a relatively healthy population among these middle-aged shift workers as a potential explanation for the lack of an effect. There were several cross-sectional and longitudinal prospective studies confirming the higher prevalence of cardiovascular disorders in people working rotating or night shifts178-181. There are a number of autonomic consequences of circadian misalignment that could be implicated in the adverse cardiovascular effects, such as increased cortisol, increased catecholamine output, increased cardiac sympathetic predominance and reduced parasympathetic activity182. For instance, there is less of a drop in blood pressure during the sleep periods of shift workers183, 184.
A cross-sectional study found that among 6,676 workers, night shift work was associated with a higher body mass index and higher waist-to-hip ratio185. A longitudinal study found that weight gains that exceeded 7 kg were more frequent among nurses on night work than on daytime work186. In a study of 27,485 individuals, obesity was more prevalent in shift workers than in day workers even after adjustment for age and socio-economic status (Odds ratio 1.41; 1.25-1.59).187 Obesity is a risk factor for insulin resistance and diabetes mellitus, and it was found that markers associated with insulin resistance, including hyperglycemia, increased triglyceride concentrations, low HDL cholesterol and hypertension, were more prevalent among night shifter workers than among day workers188. In the study of female nurses noted above, the risk of developing diabetes also rose with increasing duration of night shift work.175 In a study by Mikuni et al., the prevalence of diabetes in rotating shift workers was 2.1% versus 0.9% in day shift workers189. Night shift work increases the likelihood of developing insulin resistance190. These adverse metabolic effects of night shift work could be mediated via deleterious effects on glucose regulation or indirectly via increased appetite, leading to weight gain and obesity, a major risk factor for insulin resistance and type 2 diabetes191. Leptin is secreted by adipocytes and inhibits appetite and food intake to produce energy balance in normal weight individuals. Low leptin levels have been associated with chronic short habitual sleep duration in epidemiological studies192, 193, following acute sleep deprivation in laboratory studies (e.g., two nights of 4 hours sleep/night)194 and following reduced sleep for one week195. Reduced leptin signals a negative energy balance, leading to increased appetite. Leptin resistance eventually appears in obesity and has been implicated in sympathetic activation196 and insulin resistance197, 198. There is a significant circadian rhythm in leptin secretion, and circadian misalignment was predicted to alter the day/night range in circulating leptin, which could increase appetite199. Other hormones that are secreted by adipose tissue and exhibit day/night patterns that could be affected by shift work include adiponectin which is positively correlated with insulin sensitivity (adiponectin concentrations are high during the day and low at night200), and resistin which causes insulin resistance in rodents201 (concentrations are high during the dark/feeding phase in nocturnal rodents). Furthermore, ghrelin, an appetite-stimulating hormone primarily secreted from the gastric fundic mucosa202, is associated with type 2 diabetes203, may have a direct effect on the SCN204, and is increased by sleep loss193. Complementary epidemiologic evidence links short sleep with reduced leptin and increased ghrelin levels with increased body mass index205. Since these hormones are affected by day/night, food intake/fasting and in some cases circadian rhythms, misalignment of these factors due to shift work may cause prominent metabolic affects. Indeed, circadian misalignment leads to a suppression of leptin levels, which may play a role in explaining the increased risk for obesity in shift workers206.
An early study by Taylor and Pocock found higher cancer-attributed mortality in night shift workers compared with day shift ones207. A series of more recent investigations have confirmed and extended these findings, showing a higher risk for breast cancer in females whose job involves shift and/or night work, such as flight attendants118, nurses208, radio operators and telegraph operators209. In a study of 7,565 women with breast cancer, past employment requiring work at night for >6 months was associated with higher risk of development of breast cancer compared with a daytime working schedule (Odds ratio 1.5; CI 1.3-1.7), after adjusting for age, social class, age at birth of last child and number of children210. In a prospective, 10 year longitudinal study of 78,586 women, working at least 3 nights per month for >15 years increased risk of developing colon cancer compared to those who never worked rotating night shifts (RR 1.35; 1.03-1.77)211. A higher risk for prostate cancer was reported among those whose profession requires working rotating night shifts at least at some point in time, including police officers, firefighters, physicians and pilots212, 213. The International Agency for Research of Cancer (IARC), a unit of World Health Organization (WHO) recently announced that night shift work is probably carcinogenic. The underlying pathological mechanism could include exposure to light during the biological night which suppresses melatonin secretion by pineal gland. This is because melatonin has growth inhibitory and oncostatic properties. For example, melatonin: (i) inhibited breast cancer cells proliferation in vitro by 60-78%214; (ii) inhibited invasive and metastatic properties of breast cancer cells in vitro by decreasing attachment to basal membrane and counteracting the stimulatory effect of estradiol on cell adhesiveness215; (iii) enhanced apoptosis of breast cancer cells216; (iv) increased expression of p53 and p21WAF1 genes (tumor suppression genes) in breast cells culture217; (v) reversed the mammary tumor promoting effects of pinealectomy in rats218; and (vi) had an anti-tumor effect on prostate cancer in vitro. Interestingly, Zhu et al. found that a polymorphism in PER3 might be linked to breast cancer219; several animal experiments demonstrate the modulating effect of light exposure on PER2 gene expression in the SCN220, 221 which may affect its neurohumoral output, leading to alteration in clock genes expression in peripheral tissues. Finally, alteration in PER2 affects the DNA damage response and tumor suppression in mice and may play a role in apoptosis of cancerous cells121. Thus, it is plausible that light exposure during night shift work may affect clock gene expression and alter the regulatory effects of clock genes on cell proliferation, differentiation, apoptosis and DNA damage responses.
In a study of 11,657 employees, there were significant increases in both gastric and duodenal ulcers in shift workers compared to day workers222. Many gastrointestinal variables exhibit robust day/night fluctuations that may be affected by shift work. For example: (i) in rats there are day/night fluctuations in gastrin receptor expression223, acid, bicarbonate secretion, gastric mucus efflux and gastric mucosa blood flow during fasting224, 225; and prostacyclin activity in gastric tissue during fasting226; (ii) in humans there are day/night rhythms in gastric mucosa vulnerability for aspirin and ethanol related injury227, 228, gastric emptying (longer at 8 PM vs. 8 AM)229; gastrointestinal motor propagation speed (slower during the night)230; and basal gastric secretion (highest from 9 PM until midnight)231. Studies on rats indicated that the peak of gastric acid secretion in rats is out of phase with that of bicarbonate secretion by about 7 hours232, creating a period of gastric mucosa vulnerability to injury. Thus, it is reasonable to speculate that an imbalance between acid secretion and protective factors as well as alterations in the inflammatory profile and activation of stress responses due to circadian and rest/activity and fasting/feeding rhythm misalignment might cause gastrointestinal morbidity in night shift workers compared to day workers.
It is also noteworthy that there have been a number of reports of increased reproductive function abnormalities in those who work night or rotating shifts, including irregular menstruation, increased risk of miscarriage, premature birth, and low birth weight233, 234.
We have reviewed: (i) how interactions between the circadian and behavioral systems affect disease severity, notably, the day/night pattern of adverse cardiovascular events, seizures and asthma exacerbations; (ii) how a disease can affect circadian rhythmicity, notably the circadian disruption of Alzheimer's disease; and (iii) the adverse health consequences of circadian misalignment, typical of chronic shift work. In each case, chronotherapeutic considerations are presented. With a few notable exceptions described above, chronotherapy is probably currently underused in most fields of medicine considering the very prominent day/night variation in disease severity. This reticence may be due to a need for improved physician education, availability of suitable medications with appropriate pharmacodynamics, and greater understanding of whether the vulnerable periods are produced by specific behaviors and/or the circadian phase. This last point is important when determining the therapeutic target, which becomes particularly relevant to consider when circadian rhythms and behaviors become differently aligned, as with sleep deprivation, shift work, jet lag and certain sleep disorders. While there are numerous options to improve neurocognitive function and sleep in conditions of circadian misalignment, less is known about the therapeutic countermeasures to the many physiological changes that accompany circadian misalignment that might underlie the increased hypertension, cardiovascular disease, diabetes, obesity, cancer, gastroesophageal and reproductive problems in shift workers. However, there is growing recognition of these problems. In addition, researchers are now beginning to study how functional circadian clocks exist in many peripheral tissues (e.g., heart, liver, lung, circulating blood) which potentially can become desynchronized from the central circadian pacemaker in the SCN. The consequences of peripheral-central desynchronization are not well understood, but may have implications for physiological function, metabolism, sleep, neurocognitive function and health. The molecular and genetic underpinnings of this rhythmicity are currently being studied in numerous animal models, laying the groundwork for future translational research to the bedside. The practical implementation of chronotherapy for many disorders warrants further exploration. Finally, determination of useful biomarkers or genetic analyses that can be reliably used to identify individuals at particular risk for adverse circadian disease-related effects, or adverse consequences of circadian misalignment would have numerous far-reaching consequences.
This work was supported by Grant K24 HL76446 from the National Institutes of Health to SA Shea, by Grant R21 AT002713 from the National Institutes of Health to FAJL Scheer and by grant 43-PA-08 from the American Sleep Medicine Foundation (a foundation of the American Academy of Sleep Medicine) to M Litinski.